# projects

application_id: 6833966
project_number: 5R01DK054774-07
project_title: DHEA:PPAR-Dependent and Independent Mechanisms of Action
administering_ic: NIDDK
award_notice_date: 2004-12-09
application_type: 5
activity_code: R01
ic: DK
serial_number: 054774
program_official: MARGOLIS, RONALD N
project_start_date: 1999-03-15
project_end_date: 2006-12-31
study_section: Alcohol and Toxicology Subcommittee 1[ALTX-1]
contact_pi_person_id: 1886009
contact_pi: PROUGH, RUSSELL ALLEN
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-01-01
project_abstract:
EXCEED THE SPACE PROVIDED. We hypothesize that the protective action of DHEA in part involves the modulation of the expression ofl cytochrome P450 monooxygenase(s) and/or other detoxification enzymes required for the bioactivation and disposition of chemicals through both Peroxisome Proliferator Activated Receptor Alpha dependent and independent pathways. Several studies have demonstrated that DHEA ameliorates environmental diseases at dosages lower than those required for DHEA-dependent peroxisome proliferation. 1. The goal of Specific Aim 1 is to establish whether metabolites of DHEA serve as proximal activators of PPAR or other nuclear receptors using cell-based reporter assays. We will test the ability of DHEA metabolites to activate PPARa PXR CAR LXR and FXR/BAR using reporter assays. 2. The goal of Specific Aim 2 is to test the hypothesis that 7a-hydroxy-DHEA and 7-oxo-DHEA are formed from DHEA in the hippocampus of rats and to characterize the gene regulation of these enzymes. The effect of DHEA treatment on levels of 7a-hydroxy- and 7-oxo-DHEA in the dentate gyrus region of hippocampus in rats will be determined. 3. The goal of Specific Aim 3 is to test the hypothesis that DHEA treatment activates PPAR by altering PPAR phosphorylation. Therefore we will test the hypothesis that DHEA activates PPAR by affecting its phosphorylation status in rat hepatocytes and increases its action in transcription. 4. The goal of Specific Aim 4 is to test the hypothesis that the induction of Cyp3all in mouse liver by DI-IEA treatment is a PXR-dependent process. We will use PPARa and PXR-null mice to test the hypothesis that induction ofCyp3al 1 and other target genes by DHEA is PXR-dependent. 5. The goal of Specific Aim 5 is to test the hypothesis that DHEA induces gene expression through processes other than those mediated by PPARa and PXR. We will test changes in gene expression after DHEA treatment of wild-type PPAR -null and PXR-null mice using a mouse gene array to assess common pathways of regulation of these genes through PPAR PXR or unknown signaling pathways. PERFORMANCE SITE ========================================Section End===========================================


application_id: 6832870
project_number: 5R01HL063442-04
project_title: Mixed HSC Chimerism in Sensitized Recipients
administering_ic: NHLBI
award_notice_date: 2004-12-07
application_type: 5
activity_code: R01
ic: HL
serial_number: 063442
program_official: DI FRONZO, NANCY L
project_start_date: 2001-12-01
project_end_date: 2006-11-30
study_section: Hematology Subcommittee 1[HEM-1]
contact_pi_person_id: 1878929
contact_pi: ILDSTAD, SUZANNE T
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2004-12-01
project_abstract:
DESCRIPTION (provided by applicant): Mixed chimerism induces donor-specific         tolerance. However graft-versus-host disease (GVHD) and failure of engraftment     have limited the clinical application of this approach. Depletion of marrow         T-cells or transplantation of highly purified hematopoietic stem cells (HSC)       into allogeneic recipients avoids GVHD but the risk of graft failure is            substantially increased. Non-HSC bone marrow populations increase engraftment.      Bone marrow T cells eliminate alloreactive host cells and thus increase HSC         engraftment in partially conditioned recipients. However T-cell alloreactivity     may also result in the death of the host through graft-versus-host disease          (GVHD). We have discovered and two independent labs have confirmed a novel        CD8+TCR- cell in bone marrow that facilitates engraftment of highly purified        HSC in allogeneic recipients. A novel receptor consisting of the TCRbeta chain     CD3epsilon and an FC-specific "p33-FC" protein was recently discovered and         hypothesized to mediate direct HSC recognition by FC. Our preliminary               gene-array analyses of CD8+TCR- FC revealed transcripts in common between FC        and T cells but only FC had message for TNFalpha. Moreover our recent data        indicate that FC from TNFalpha-/- mice are not functional. Our central              hypothesis is that CD8+TCR- FC. unlike T cells maintain long-term renewal of       HSC through a TNFalpha-dependent mechanism and that FC are derived from a          common lymphoid progenitor (CLP) and as such share functional molecules with        conventional T or NK cells but are distinct from them. To test our hypothesis      we will evaluate the role of FC and bone-marrow gamma and alphabeta+T-cells        and CD8alpha and CD8beta molecules in the maintenance of HSC long-term renewal      in allogeneic engraftment. Moreover we will determine the role of TNFalpha in      FC-mediated engraftment and HSC survival through the use of mice deleted for        TNFalpha and its receptors as a source of FC HSC or as recipients in               allogeneic transplantation. We will directly test the role of the FC in             survival of HSC by 1) providing HSC with a transgenic-BCL2 survival molecule to     determine if they become independent of FC in allogeneic transplantation and       2) examining the cobblestone-area-forming capacity (CAFC) of HSC in marrow from     mice we determine to be defective in FC function. Finally we will use mice         mutant for CD3epsilon CD3delta and CD3zeta in combination with lineage            tracking of transplanted GFP-transgenic tagged HSC and lymphoid-progenitor          cells to investigate the ontogeny of the FC and the biologic role of the CD3        complex in facilitation.

project_terms:
B lymphocyte;T cell receptor;antibody receptor;biological models;cell population study;cyclophosphamide;cytotoxic T lymphocyte;genetically modified animals;graft versus host disease;helper T lymphocyte;hematopoietic stem cells;hematopoietic tissue transplantation;homologous transplantation;immunoglobulin structure;kidney transplantation;laboratory mouse;model design /development;protein structure function;radiation dosage;stem cell transplantation;tissue mosaicism;transplantation immunology;tumor necrosis factor alpha


application_id: 6832198
project_number: 5F32CA097760-03
project_title: Expressive Writing with Cancer Patients
administering_ic: NCI
award_notice_date: 2005-01-19
opportunity_number: PA-00-104
application_type: 5
activity_code: F32
ic: CA
serial_number: 097760
program_official: LOHREY, NANCY
project_start_date: 2003-02-20
project_end_date: 2005-04-30
study_section: Special Emphasis Panel[ZRG1-RPHB-3(01)S]
contact_pi_person_id: 6440507
contact_pi: GRAVES, KRISTI DOVE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The aim of this project is to enhance the quality of life andsurvivorship experiences of cancer patients through evaluation of an expressive writing intervention within a randomized trail. Strong support for the efficacy of expressive writing interventions with both healthy and medically ill populations suggests its utility for application within an oncology setting.Expressive writing is a very brief cost-effective treatment approach that can serve as an attractive alternative for patients not interested in attending lengthy group programs. A randomized clinical trail with 165 cancer patients will be conducted. Participants will be recruited from Hollings Cancer Center and randomized to one of three conditions: expressive writing intervention social cognitive intervention or standard care. Randomization will occur after stratification of demographic characteristics including disease type age and gender. Study outcomes of psychological and selfreported physical functioning will be assessed at enrollment treatment completion and 2 and 6 months following intervention completion. Outcomes include: quality of life health functioning emotional processing and expression benefit-finding and mood. The effect of treatment on quality of life and health functioning will be determined by analysis of co-variance controlling for pre-test scores as well as relevant demographic characteristics. If expressive writing improves psychological and/or physical functioning it can serve as a cost-effective brief psychological treatment that improves cancer patients' quality of life.


application_id: 6831681
project_number: 5R01HL067284-04
project_title: Regulation of Vascular Smooth Muscle Contracting
administering_ic: NHLBI
award_notice_date: 2004-12-10
application_type: 5
activity_code: R01
ic: HL
serial_number: 067284
program_official: LIN, MICHAEL
project_start_date: 2002-01-01
project_end_date: 2006-12-31
study_section: Experimental Cardiovascular Sciences Study Section[ECS]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-01-01
project_abstract:
DESCRIPTION (provided by the applicant): The overall aim of this research is to     elucidate the cellular mechanisms that mediate agonist-stimulated vascular          smooth muscle contraction and relaxation. To achieve these goals we must           identify the specific signaling molecules and decipher their role in signal         transduction pathways that lead to smooth muscle contraction and relaxation.        Major objectives of the current proposal are to elucidate the molecular             mechanisms and physiological significance of arachidonic acid (AA)-induced          Ca2+-sensitization in regulation of vascular smooth muscle contraction.             Ca2+-sensitization describes a mechanism through which an excitatory agonist        induces significant smooth muscle contraction under constant free Ca2+. Much        evidence indicates that AA released by various Ca2+-sensitizing agonists may      contribute to this G-protein mediated Ca2+-sensitization. However the              phospholipase A2 (PLA2) responsible for AA release the G protein that              regulates AA release and the molecular mechanism through which AA induces          Ca2+-sensitization remain unclear. We propose to test the hypothesis that AA       released by ras-mediated activation of Ca2+-independent iPLA2 contributes to       the agonist-induced Ca2+-sensitization by acting at multiple sites: rho-kinase      (ROK). protein kinase C (PKC) and myosin phosphatase (MLCP). Specific aims are            (1) To test the hypothesis that iPLA2 mediates the GTPgammaS-induced               Ca2+-independent AA release and Ca2+-sensitization in vascular smooth muscle.       (2) To test the hypothesis that ras mediates agonist-induced activation of          iPLA2 and Ca2+-independent AA release in regulation of Ca2+-sensitization of        smooth muscle contraction. (3) To test the hypothesis that in vascular smooth       muscle tissue AA inhibits myosin phosphatase by acting at multiple sites: ROK     PKC and MLCP. a-toxin or beta-escin-permeabilized rabbit femoral arteries or        portal veins will be used to determine the effects of selective activation and      inhibition of AA pathway on agonist- and GTPgammaS-induced activation of ras       ROK PKC inhibition of myosin phosphatase and Ca2+-sensitization of force and      MLC20 phosphorylation. AA pathway will be selectively activated by adding free      AA or overexpressing iPLA2 and selectively inhibited by using a selective          iPLA2 inhibitor (BEL) or antisense oligonucleotide.                                                                                                                     Understanding the cellular signal transduction pathways in vascular smooth          muscle will help to identify the cause(s) of cardiovascular diseases. This          information may lead to strategic drug design and/or molecular biological           approaches targeted at messenger molecules that provide new treatments for          cardiovascular diseases.

project_terms:
arachidonate;biological signal transduction;calcium flux;enzyme inhibitors;guanine nucleotide binding protein;laboratory rabbit;myosins;phospholipase A2;phosphoprotein phosphatase;vascular smooth muscle;vasomotion


application_id: 6830179
project_number: 5R01AI051533-03
project_title: Vector Population Modification Using Wolbachia Symbionts
administering_ic: NIAID
award_notice_date: 2004-12-27
application_type: 5
activity_code: R01
ic: AI
serial_number: 051533
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2002-12-01
project_end_date: 2006-11-30
study_section: Special Emphasis Panel[ZRG1-TMP(01)]
contact_pi_person_id: 7876895
contact_pi: DOBSON, STEPHEN LEONARD
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: UNIVERSITY-WIDE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2004-12-01
project_abstract:
EXCEED THE SPACE PROVIDED Intracellular Wolbachia bacteria infect a diverse range of invertebrate hosts including medically important disease vectors. Many Wolbachia infections cause cytoplasmic incompatibility which effectively sterilizes matings between host individuals that harbor differing infection types. We have recently developed a model that defines the relationship between the Wolbachia infection frequency and host population size. Model simulations predict a novel strategy for suppressing insect populations. This strategy is based upon artificially prolonging an unstable coexistence that occurs when two or more incompatible Wolbachia types infect a host population resulting in host population suppression. As Wolbachia occurs naturally within a broad range of invertebrates this strategy is potentially applicable to a variety of medically and economically important systems. In addition to population suppression strategies population replacement strategies propose to employ Wolbachia as a vehicle for spreading desired genotypes (e.g. refractoriness to disease transmission) into vector populations. In the outlined research we will develop test and evaluate population suppression and replacement strategies predicted by model simulations in populations of the vector mosquito Culex pipiens. Cx. pipiens has been selected as the initial target due to its importance as a disease vector and the availability of multiple incompatible Wolbachia infections in naturally-occurring Culex populations. Additional experiments will examine strategies for retarding arresting or reversing Wolbachia-based population replacement. The latter strategies represent an appropriate safeguard that may prove necessary if unexpected negative consequences become associated with population replacement. To improve strategy design implementation and evaluation aims will include better defining the infection dynamics of the Culex/Wolbachia symbiosis (e.g. maternal transmission rates and Wolbachia effects on host fitness) simplifying discrimination between Culex infection types and improving methods for field cage evaluation of Wolbachia control strategies. PERFORMANCE SITE ========================================Section End===========================================


application_id: 6828262
project_number: 5R01AI047864-04
project_title: Allograft Tolerance with Fas/FasL-Mediated Apoptosis
administering_ic: NIAID
award_notice_date: 2004-12-06
application_type: 5
activity_code: R01
ic: AI
serial_number: 047864
program_official: KEHN, PATRICIA J
project_start_date: 2001-12-15
project_end_date: 2007-11-30
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2004-12-01
project_abstract:
Transplantation of vascularized allografts is an effective therapeutic alternative for patients with end-stage organ failure.  Transplantation of organs between genetically different individuals however is limited by our ability to control the immunological rejection of the graft by the recipient.  Immunosuppressive drugs may reduce the severity of rejection but fail to create a state of permanent specific tolerance to the graft. We herein propose an immunomodulatory approach using a modified form of FasL with potent apoptotic activity to eliminate alloreactive T cells for the prevention of cardiac allograft rejection and induction of tolerance.  FasL-induced apoptosis is the main mechanism of activation-induced cell death that is responsible for immune homeostasis and self-tolerance.  The use of wild type (wt)FasL to prevent allograft rejection has been controversial.  FasL is initially synthesized as a membranous molecule that induces apoptosis when prevention the cell surface. wtFasL is also shed from the cell surface by metalloproteinases within minutes of expression and the soluble form is antiapoptotic and chemotactic for neutrophils.  We hypothesize that FasL can be used as an immunomodulatory molecule if its apoptotic activity is separated from anti-apoptotic and chemotactic functions.  We generated modified forms of FasL with potent apoptotic activity and developed a novel approach to express FasL at the protein level on the surface of antigen- presenting cells (APCs) and vascular endothelium within 1 hour. In preliminary experiments we demonstrated that delivery of FasL on donor APCs blocked alloreactive responses in naive and presensitized animals and prevented islet allograft rejection. Expression of FasL protein on vascular endothelium under conditions adapted from clinical settings prolonged survival of cardiac allografts. In this proposal rats and mice will be immunized with allogeneic APCs expressing FasL at various times pre-and post- transplantation.  FasL will also be expressed on the surface of heart endothelium for immune evasion and prevention of rejection. Several mutant and transgenic animals will be used to test whether apoptosis induced by FasL is the main mechanism of the observed immune nonresponsiveness.  This protein-based approach may be readily applied to the clinic and may provide a significant advantage because of its safety and simplicity as compared with immunomodulatory approaches using DNA-based expression.

project_terms:
T cell receptor;antigen presenting cell;apoptosis;chimeric proteins;cytotoxic T lymphocyte;disease /disorder prevention /control;enzyme linked immunosorbent assay;flow cytometry;gene induction /repression;genetically modified animals;heart function;heart transplantation;helper T lymphocyte;homeostasis;homologous transplantation;immune tolerance /unresponsiveness;immunocytochemistry;immunoprecipitation;isoantigen;laboratory mouse;laboratory rat;membrane proteins;nucleic acid sequence;transplant rejection;vascular endothelium;western blottings


application_id: 6826804
project_number: 5R01NS042862-04
project_title: Gene Therapy Neural Grafts & Parkinson's Disease
administering_ic: NINDS
award_notice_date: 2004-11-26
application_type: 5
activity_code: R01
ic: NS
serial_number: 042862
program_official: SUTHERLAND, MARGARET L
project_start_date: 2001-12-15
project_end_date: 2007-11-30
study_section: Special Emphasis Panel[ZRG1-BDCN-1(01)]
contact_pi_person_id: 7875446
contact_pi: YUREK, DAVID M
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2004-12-01
project_abstract:
Clinical trials have provided encouraging evidence that grafts of fetal dopamine neurons are an effective therapeutic approach toward counteracting the symptoms of Parkinson's disease. Modest therapeutic benefits are observed in grafted patients despite clinical and experimental evidence that survival of grafted cells is low and graft reinnervation is incomplete. The poor survival and limited fiber outgrowth may be a consequence of neural grafts placed ectopically into an environment where the grafted neurons do not receive the proper signals for successful growth and integration into the neural circuitry of the host brain. Gene therapy may be a viable technique to introduce factors [neurotrophic factors] into brain tissue that can potentiate the survival and functional outgrowth of neural grafts and thus improve the therapeutic value of the graft. In the proposed studies regulated viral vectors will be injected into the lesioned nigrostriatal pathway of rodents with experimental Parkinson's disease in order to induce transgene expression of several neurotrophic factors that have a history of providing potent neurotrophic support for dopamine neurons. Subsequently neural grafts will be implanted into lesioned/transduced brain sites and the survival reinnervation and function of the grafts will be assessed. Because Parkinson's disease has a higher incidence in the elderly than in the younger population and recent experimental evidence suggests that the expression of endogenous neurotrophic factors are diminished in the aged striatum following a neurodegenerative lesion experiments will be performed in young middle-age or old rats with experimental Parkinson's disease and the results will be compared within and between each age group. The studies are designed to determine the optimal temporal expression of neurotrophic factors [GDNF BDNF FGF-2] that improve graft development and function using regulated viral neurotrophic factors [GDNF BDNF FGF-2] that improve graft development and function using regulated viral vectors in young and aged animals with experimental Parkinsonism. These studies will also determine if combinations of viral vectors expressing different neurotrophic factors can be used to improve the therapeutic effects of dopamine grafts.

project_terms:
Parkinson&apos;s disease;age difference;behavioral /social science research tag;cell sorting;cell transplantation;corpus striatum;dopamine;enzyme linked immunosorbent assay;functional ability;gene therapy;glia;immunocytochemistry;juvenile animal;laboratory rat;mature animal;nervous system disorder therapy;nervous system transplantation;neurons;neurotrophic factors;nonhuman therapy evaluation;statistics /biometry;stereotaxic techniques;substantia nigra;transfection /expression vector


application_id: 6824030
project_number: 5R01HL059878-08
project_title: Physiology of Respiratory Muscle Cells
administering_ic: NHLBI
award_notice_date: 2004-11-24
application_type: 5
activity_code: R01
ic: HL
serial_number: 059878
program_official: SMITH, ROBERT A
project_start_date: 1998-04-10
project_end_date: 2006-11-30
study_section: Special Emphasis Panel[ZRG1-SSS-3(03)M]
contact_pi_person_id: 1869134
contact_pi: REID, MICHAEL B
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2004-12-01
project_abstract:
DESCRIPTION (provided by applicant): Tumor necrosis factor-alpha (TNF-alpha) is     suggested to promote atrophy and weakness of respiratory and limb skeletal          muscles in diseases that range from chronic obstructive pulmonary disease to        cancer from congestive heart failure to AIDS. Despite its putative                 pathophysiological significance surprisingly little is known about the             mechanisms of TNF-alpha action in skeletal muscle. The long-term goal of this       project is to determine the redox mechanisms by which TNF-alpha compromises         muscle performance. Thus far we have established that clinically-relevant          levels of TNF-alpha act directly on skeletal muscle cells to stimulate loss of      muscle protein without inducing apoptotic or necrotic cell death. Early             signaling events in this catabolic response include activation of nuclear           factor-kB (NFkB). Over several days TNF-alpha/NFkB signaling accelerates           degradation of muscle protein causing a net protein loss. The current project      extends our work on this pathway to address the underlying signaling events in      greater depth and to evaluate the mechanism of accelerated protein degradation.     We have three Specific Aims: 1.) To define receptor-mediated signaling events       by which TNF-alpha activates NFkB in skeletal muscle. 2.) To evaluate               regulation of ubiquitin conjugating activity by TNF-alpha. 3.) To evaluate the      ubiquitin conjugating enzyme UbcH2 as an essential element of                       TNF-alpha/NFkB-regulated catabolism. These aims will be addressed using an          integrative approach that incorporates muscle preparations ranging from             cultured myotubes to TNF-alpha treated animals. Cause/effect relationships will     be evaluated using a panel of pharmacologic immunologic and genetic               interventions. Results of the proposed studies will help establish molecular        mechanisms whereby TNFalpha stimulates catabolism of respiratory and limb           skeletal muscle.

project_terms:
acid aminoacid ligase;atrophy;cachexia;enzyme induction /repression;fluorescent dye /probe;free radical oxygen;genetic regulation;genetically modified animals;intermolecular interaction;laboratory mouse;molecular pathology;muscle cells;muscle disorders;nuclear factor kappa beta;oxidation reduction reaction;protein degradation;protein structure function;receptor coupling;respiratory muscles;tissue /cell culture;tumor necrosis factor alpha;ubiquitin


application_id: 6819992
project_number: 5R01HL067321-04
project_title: Dissecting the Molecular Pathology of LAM Disease
administering_ic: NHLBI
award_notice_date: 2004-11-19
application_type: 5
activity_code: R01
ic: HL
serial_number: 067321
program_official: PEAVY, HANNAH H
project_start_date: 2001-12-05
project_end_date: 2006-11-30
study_section: Lung Biology and Pathology Study Section[LBPA]
contact_pi_person_id: 1858513
contact_pi: NOONAN, DANIEL J
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2004-12-01
project_abstract:
DESCRIPTION (provided by applicant): Lymphangioleiomyomatosis (LAM) is a rarelung disease limited principally to women of child bearing age and ischaracterized by an abnormal proliferation of smooth muscle cells in thepulmonary interstitium. The only viable treatment for the disease is lungtransplantation. The limited available information on LAM demonstratescorrelations with 2 metabolic phenomena one being fluctuations in the femalesex steroid hormone estrogen and the other being the genetic disease tuberoussclerosis. Recent work in our laboratory and preliminary data presented inthis proposal for the first time offer a direct link between the activities ofthe gene mapping to the genetic locus for tuberous sclerosis (TSC2) withtranscription events mediated by estrogen activation of its intracellularreceptor (ER) and the intracellular signaling switch calmodulin (CaM). Ourcurrent working hypothesis is that LAM is an aberration in intracellularsignaling that leads to inappropriate gene regulation of specific cell cyclecontrol components. To establish the potential biological relevance of thishypothesis to the pathogenesis of LAM the following specific aims will attemptto dissect the relationships between TSC CaM and in the ER modulation oftranscription and cell proliferation events. 1) Characterization ofCaM-specific regulatory sequences in the TSC2 gene. 2) Characterization ofCa++/CaM signaling in TSC2/ER-mediated events. 3) Characterization of the roleof calcium regulated phosphorylation events might play in TSC2-modulatedsteroid receptor-mediated transcription. 4) Characterization of TSC1?s role inthe TSC2/calmodulin signaling pathway. 5) Characterization of links betweenTSC/CaM signaling and cell cycle control. The preliminary data presented inthis grant provide a strong foundation for dissecting the molecular eventsassociated with normal function of the TSC2 genes. The intriguing link amongTSC2 ER and CaM for the first time offers a potential mechanism for cellproliferation events as observed with the loss of heterozygosity or deletion ofthe TSC genes. With this knowledge also comes potential avenues for drugdevelopment and interventions into this heretofore vaguely understood diseasecondition. It is truly believed that the results of these studies will providecritical insight into the pathology of LAM (and most likely tuberous sclerosis)as well as avenues for intervention into that pathology.

project_terms:
calcium flux;calmodulin;cell growth regulation;cell proliferation;disease /disorder etiology;estrogen receptors;flow cytometry;gene mutation;genetic mapping;genetic regulation;genetic transcription;green fluorescent proteins;lymphangioleiomyomatosis;molecular pathology;phosphorylation;protein localization;tissue /cell culture;transfection;tuberous sclerosis


application_id: 6819978
project_number: 5R21NS045282-03
project_title: Role of Complement C9 in Ischemic Cerebral Injury
administering_ic: NINDS
award_notice_date: 2004-12-07
opportunity_number: PA-02-045
application_type: 5
activity_code: R21
ic: NS
serial_number: 045282
program_official: UTZ, URSULA
project_start_date: 2002-12-01
project_end_date: 2006-05-31
study_section: Special Emphasis Panel[ZRG1-BDCN-4(01)]
contact_pi_person_id: 2061110
contact_pi: FELDHOFF, PAMELA W
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
EXCEED THE SPACE  PROVIDED. Our goal is to define the role of complement in ischemic stroke. C9 is the major cytolytic component ot complement but the role of C9 in post-ischemic cerebral injury is not known. Recent experiments revealed that administration of human C9 to developmentally C9-deficlent neonatal rats increased ischemic cerebral in_rct volume by 85% (P < 0.05). Therefore we will test the Hypotheses stated in three Specific Aims: 1) in post-ischemic cerebra plasma C9 crosses a compromised blood brain barrier is activated and is incorporated into complement membrane attack complexes (MAC) assembled on neurons and oligodendrocytes. Unilateral ischemic cerebral infarction will be induced in adult and neonatal rats. Assays will be performed using computer-based planimetry (cerebral infarct volume) post-ischemic cerebral measurement of Evans blue accumulation cerebral quan_ of C9 by ELISA and Westem blot and confocal double label fluorescence immunohistochemistry using antibodies specific for activated C9 incorporated in MAC. 2) Following cerebral ischemla C9 deposition augments a) loss of the complement regulatory protein CD59 from neurons and b) synthesis of C9 by neurons microglia and astr(mytes. ELISA Western blot dbonuclease protection assay in situ hybridization and double label mmunofluorescence will be employed to test this hypothesis in the post-ischemic cerebra of neonatal rats  njected ipwith human C9. 3) Incorporation of C9 into MAC on oligodendrocytes and neurons induces a) ylolysls or b) apoptosis. Oligodendrocytes and neurons will be cultured from neonatal and embryonic rat forebrain. The effect of C9 on cytolysis and apoptosis will be assessed by immunofluorescence microscopy (oligodendrocytes) lactic acid dehydrogenase release (neurons) measurement of three different markers of apoptosis (annexin V labeling cytochrome c release detection of single stranded DNA) and electron microscopy in each specific aim the neuroprotective effect of four different agents that inhibit C9 activity will be assessed. These studies will reveal an unrecognized C9-medlated mechanism of ischemic cerebral injury and a novel strategy to reduce the injury by inhibiUng C9-mediated neumtoxicity. PERFORMANCE SITE ========================================Section End===========================================


application_id: 6819270
project_number: 5R01AI053101-03
project_title: Borrelia burgdorferi LuxS-mediated quorum sensing
administering_ic: NIAID
award_notice_date: 2004-12-06
application_type: 5
activity_code: R01
ic: AI
serial_number: 053101
program_official: BAKER, PHILLIP J
project_start_date: 2003-06-15
project_end_date: 2007-11-30
study_section: Special Emphasis Panel[ZRG1-BM-1(01)Q]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2004-12-01
project_abstract:
EXCEED THE SPACE PROVIDED. The spirochete Borrelia burgdorferi the causative agent of Lyme disease is transmitted to humans and other warm blooded animals through the bite of infected Ixodes spp. ticks. The establishment of B. burgdorferi infection involves numerous interactions between the bacteria and a variety of vertebrate host and arthropod vector tissues. Different bacterial proteins are required at specific points of this infectious cycle and precise regulation of the synthesis of such proteins is essential for successful infection to occur. We have discovered that these spirochetes utilize a regulatory mechanism to control protein expression patterns that involves a chemical signal known as autoinducer-2 (AI-2). This molecule is produced by the B. burgdorferi LuxS protein which we have demonstrated to be a functional enzyme. Our preliminary studies suggest that B. burgdorferi can regulate LuxS synthesis. Addition of AI-2 to cultured B. burgdorferi dramatically alters the expression of more than 50 different proteins increasing expression levels of some proteins while decreasing expression of others. Through this mechanism a population of Lyme disease spirochetes may synchronize production of proteins needed for infection processes. We hypothesize that B. burgdorferi uses AI-2 as an important signaling molecule to control expression of proteins during the natural infectious cycle of the Lyme disease spirochetes. The proposed studies will characterize the expression of LuxS during bacterial infection the mechanisms by which B. burgdorferi controls synthesis of AI-2 and functions of AI-2-regulated proteins. Results from these studies will enhance our understanding of the complex interactions between B. burgdorferi and its hosts as well as identifying potential bacterial targets for improved therapies to prevent and treat Lyme disease. PERFORMANCE SITE ========================================Section End===========================================


application_id: 6818771
project_number: 5R01HL068698-05
project_title: WNT13 & WNT13-signaling in Endothelial Cell Survival
administering_ic: NHLBI
award_notice_date: 2004-11-15
application_type: 5
activity_code: R01
ic: HL
serial_number: 068698
program_official: GOLDMAN, STEPHEN
project_start_date: 2001-12-03
project_end_date: 2008-08-28
study_section: Pathology A Study Section[PTHA]
contact_pi_person_id: 7876874
contact_pi: MAO, CATHERINE D
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2004-12-01
project_abstract:
Endothelial cells (EC) play a key role in the development and progression of vascular diseases involving vascular injury and chronic inflammation such as atherosclerosis. The identification of all the factors controlling EC behavior is crucial to design appropriate therapy.  Recent evidence suggest that Wnt proteins and Wnt-signaling components may represent a novel class of factors controlling EC behavior.  We and others have shown that the expression of antagonists of the Wnt- signaling pathway members of the FRP family is increased during vascular injury in association with vascular cell apoptosis.  We have shown that lithium an agonist of Wnt signaling pathway induces a cell cycle arrest and a senescent-like phenotype in EC and activates the tumor suppressor p53-dependent pathway.  These findings implicate lithium in the activation of a survival pathway in EC.  Moreover we recently showed that the Wnt13 gene is expressed in EC and up-regulated by inhibitors of EC proliferation (TNFalpha lithium).  Our goal is to investigate the role of an autocrine Wnt13 pathway in the control of EC survival and its underlying mechanisms of action.  In aim 1 we will investigate the functional role of Wnt13 protein in the control of EC survival.  This will be addressed by manipulating Wnt13 expression levels in EC by over- and under-expression and by following the resulting i) changes in EC survival in the absence or presence of apoptotic stimuli and ii) changes in EC gene expression profile by cDNA array and by iii) testing whether Wnt13 mediates the effects of lithium on EC survival.  In aim 2 we will identify downstream effectors of the Wnt13 signaling pathway in EC.  The activation of a novel Ca2+- dependent Wnt-signaling pathway will be tested by measuring changes i) in intracellular Ca2+ concentration ii) in the activity of the Ca2+-dependent kinase PYK2 and iii) in Wnt13- target gene expression in response to Wnt13 in the presence of known inhibitors or dominant-negative isoform of effectors of Ca2+-dependent pathways.  This will be followed by the identification and characterization iv) of novel transcription factors involved in the Wnt13-signaling pathway.  In aim 3 we will investigate the regulation of Wnt13 gene expression by survival signals.  This will be achieved i) by quantification of Wnt13 mRNA levels in EC in response to lithium and other EC survival or apoptosis inducers ii) by characterizing Wnt13 gene promoter/enhancer sequences and iii) by identifying the responsive sequence(s) and transcription factor(s) mediating lithium-dependent regulation of Wnt13 gene expression.

project_terms:
angiogenesis;apoptosis;autocrine;calcium flux;cell cycle;cell growth regulation;confocal scanning microscopy;cytokine;developmental genetics;flow cytometry;gene induction /repression;genetic regulation;genetic regulatory element;intermolecular interaction;lithium;microarray technology;northern blottings;phosphorylation;protein localization;protein structure function;protein tyrosine kinase;protooncogene;tissue /cell culture;transcription factor;vascular endothelium;western blottings


application_id: 6744178
project_number: 5R01MH062654-04
project_title: Reduced Interneuronal Space in Schizophrenic Brains
administering_ic: NIMH
award_notice_date: 2005-07-26
application_type: 5
activity_code: R01
ic: MH
serial_number: 062654
program_official: MEINECKE, DOUGLAS L
project_start_date: 2002-06-04
project_end_date: 2007-05-31
study_section: Special Emphasis Panel[ZRG1-BDCN-6(01)]
contact_pi_person_id: 1905047
contact_pi: CASANOVA, MANUEL F
other_pis: Not Applicable
congressional_district: 03
department: PSYCHIATRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-06-01
project_abstract:
DESCRIPTION: (provided by applicant) It has been postulated that the prefrontal     cortices of schizophrenic patients have less interneuronal space than controls     specifically in areas 9 and 46. This is thought to reflect an alteration in the     neuronal circuitry of these areas that according to Selemon et al. (1995) is a      possible component of the pathology of schizophrenia. This study and those         that followed were based on measures of neuronal density. Our goal is              two-fold: one is to examine this finding based on the cortical minicolumn and      secondly to elucidate the distribution of interneuronal space in regards to        the morphology of the cell column. Our preliminary study used a small               population of normal controls (n = 16) and schizophrenic patients (n = 9)          diagnosed according to DSM ffl-R criteria. Our test revealed smaller values for     all spacing distances and neuropil space in area 9 of schizophrenic brains. The     greatest reduction occurred in the minicolumn compartment where the majority of     apical dendrite bundles thalamocortical and cortico-cortical fibers are           found. This study will examine columnar differences in 40 schizophrenic (DSM IV     diagnosis) and 52 controls derived from the Runwell ifi collection. Specimens       will be derived from areas 9 46 17 and 4 (Brodmann). Magnified images (lOOx)     of Nissi-stained cell columns in layers III-VI will be analyzed by powerful         computer imaging hardware and software enabling researchers to precisely            quantify details of cell column morphology. Stereological techniques will be        used to estimate neuronal density. If our preliminary findings are                  corroborated the smaller than normal minicolumns will demonstrate a                reorganization of brain circuitry most probably defined during development.

project_terms:
brain morphology;clinical research;human tissue;intercellular connection;neuropathology;postmortem;prefrontal lobe /cortex;schizophrenia;stereotaxic techniques


application_id: 100190
project_number: 90PD0297-01
administering_ic: ACF
program_official: MEYER, ALETA
project_start_date: 2016-09-29
project_end_date: 2018-09-28
contact_pi: KELLER, PEGGY
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: COLLEGE OF ARTS AND SCIENCE
organization_zip: 405260001
organization_country: UNITED STATES
budget_start_date: 2016-09-29
budget_end_date: 2017-09-28
assistance_listing_number: 93.647
project_title:
PARENTAL EMPATHY PSYCHOLOGICAL CONTROL AND CHILD MALADJUSTMENT: AN EVALUATION OF THE NEST PARENT EDUCATION AND SUPPORT PROGRAM

project_abstract:
This project partners with The Nest Center for Women Children and Families (referred to as "The Nest" below) to (1) provide a preliminary evaluation of their implementation of the Nurturing Parenting Program (NPP) and (2) improve understanding of the role of parental empathy in physically and psychologically aggressive parenting. Scientific estimates of the association between empathy and aggression are mixed creating a need for additional research. The proposed study addresses this need by employing multiple measures of empathy in relation to multiple outcomes. Specific aims are to: (1) Estimate relations between parental empathy and parental physical aggression and psychological aggression in a sample of high risk low income parents prior to (typically court-mandated) NPP; (2) Determine whether parental empathy increases following NPP administered by The Nest; (3) Evaluate mediated associations between parental empathy and child adjustment; it is expected that greater parental empathy will be associated with less aggressive parenting which will be related to fewer adjustment problems in children.

project_terms:
adjustment problems;child maladjustment;family strengthening;intervention;parental empathy;parenting;psychological control


application_id: 11139393
project_number: 5I01BX006408-02
administering_ic: VA
award_notice_date: 2025-08-22
opportunity_number: BX-23-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 006408
project_start_date: 2024-07-01
project_end_date: 2028-06-30
study_section: ZRD1-SURG-P(01)
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-07-01
budget_end_date: 2026-06-30
project_title:
Mechanism of the adrenal stress response protection against therapy-induced lethal immune activation

project_abstract:
Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapyfor hematologic malignancies and other diseases in which the donor's stem cells areused to replace the recipient's damaged or destroyed cells. The Veterans HealthAdministration has been offering allo-HCT services since 1982 which have savedthousands of veterans' lives. However this life-saving therapy comes at a cost - lethalimmune activation caused by cytokine release syndrome (CRS). Currentlyglucocorticoids (GC) and IL-6 antagonists are used for CRS treatment but somepatients do not respond well to treatment. A limitation is that CRS may causeirreversible organ injury before treatment is initiated as the indicator of treatment isCRS itself. Therefore there is an urgent need to identify patients at high risk of CRSand provide preventive therapy. We recently reported that the adrenal stress response defined by a 6-foldincrease in induced GC (iGC) production is an essential host response against therapy-induced lethal immune activation. We identified scavenger receptor BI (SR-BI) an HDLreceptor as a key regulator for iGC production. Using SR-BI null mice as an adrenalstress response deficiency model we demonstrated that the adrenal stress responseprotects against therapy-induced death by controlling CRS. Conversely relative adrenalinsufficiency (RAI) - the absence of adrenal stress response - is a risk factor for CRS.Our study provides proof-of-concept that diagnosing RAI may help identify patients atrisk of CRS and selective GC therapy for patients with RAI prior to the onset of CRSmay reduce mortality from therapy-induced lethal immune activation. The goal of thisapplication is to delineate the mechanisms of the adrenal stress response protectionagainst CRS in allo-HCT-induced lethal immune activation and to translate themechanistic findings into a precision medicine approach to prevent CRS in allo-HCT-induced lethal immune activation.

project_terms:
Adrenal Glands;Adrenal gland hypofunction;Allogenic;Antigen-Presenting Cells;CD3 Antigens;Carcinogens;Cells;Cessation of life;Data;Diagnosis;Disease;Dose;Exposure to;Glucocorticoids;Goals;HDL receptor;Hematologic Neoplasms;Hematopoietic Neoplasms;Hematopoietic Stem Cell Transplantation;Immune response;Immunologic Stimulation;Immunosuppression;Individual;Inflammatory;Injections;Interleukin-6;Knockout Mice;Life;Malignant Neoplasms;Modeling;Mus;Pathogenesis;Patients;Positioning Attribute;Predisposition;Prevention;Preventive therapy;Preventive treatment;Production;Publishing;Regulation;Reporting;Risk;Risk Factors;SR-BI receptor;Services;Signal Transduction;Stress;T-Lymphocyte;Testing;Time;Translating;Transplant Recipients;Veterans;Veterans Health Administration;Work;agent orange;antagonist;biological adaptation to stress;clinical translation;cost;curative treatments;cytokine;cytokine release syndrome;donor stem cell;high risk;immune activation;improved;military service;mortality;multidisciplinary;organ injury;precision medicine;preclinical study;prevent;side effect;success;systemic inflammatory response;transplantation therapy

public_health_relevance:
The US Veterans are at risk to develop blood cancers due to exposure to carcinogens such as AgentOrange during their active military service. Many of these cancers are treated with allogeneichematopoietic cell transplantation (allo-HCT). While allo-HCT is a life-saving therapy for hematologicmalignancies this life-saving therapy has life-threatening side effects - lethal immune activationcaused by cytokine release syndrome (CRS). This proposal aims to understand the mechanism ofCRS regulation identify risk for CRS and develop preventive treatment for CRS in allo-HCT therapywhich may save the lives of both the public and veterans.


application_id: 11129665
project_number: 5I01BX003405-08
project_title: Targeting mitostasis via activation of mitochondrial biogenesis after TBI
administering_ic: VA
award_notice_date: 2025-08-21
opportunity_number: BX-21-003
application_type: 5
activity_code: I01
ic: BX
serial_number: 003405
project_start_date: 2017-01-01
project_end_date: 2027-06-30
study_section: ZRD1-NURC-H(01)
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-07-01
project_abstract:
Experience in contemporary military operations suggests that traumatic brain injury (TBI) is the signature injuryof modern wars making our troops a high-risk population for TBI. Among the 327388 OEF/OIF veterans usingVA services in 2009 6.7% were diagnosed with TBI of which 73% of those were diagnosed with posttraumaticstress disorder (PTSD). However to date there is no approved treatment for TBI in part due to an incompleteunderstanding of the pathobiology underlying TBI. Compelling experimental data demonstrate that mitochondrialdysfunction is a pivotal link in the neuropathological sequelae of brain injury. This premise comes from ourpublished work (and that of others) demonstrating that loss of mitochondrial homeostasis and increasedmitochondrial reactive oxygen species (ROS) production occurs following TBI. Protecting or restoringmitochondrial function by therapeutically targeting mitochondrial impairment improves neuronal function afterTBI. Here we propose a novel approach of activating mitochondrial biogenesis (MB) a necessary process inmitochondrial dynamics after TBI using pharmacological intervention. Through MB dysfunctional mitochondriaare replaced via signaling networks involving peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1) as a master regulator. Activation of MB can be an important intervention to modulatemitochondrial dynamics and prevent metabolic disruption after TBI. Recently two drugs formoterol andlasmiditan have been screened by us and our collaborators and found to induce PGC-1 via activation of twoindependent receptors 2-adrenoreceptor (2AR) and 5-hydroxytryptamine1F (5-HT1F) respectively. Wehypothesize that MB activation at the optimized drug dosage will improve mitochondrial functionmitigate pathology and restore cognitive function following TBI. To test this hypothesis in Specific Aim1 we will examine the temporal and spatial aspects of MB after TBI in the injured cortex and hippocampus byanalyzing molecular markers of MB. We will also refine and establish the dose-response and therapeuticwindow of intervention for formoterol and lasmiditan treatment to optimize MB after TBI. In this Aim we will alsotest the hypothesis that treatment with MB activators promotes cognitive recovery following TBI at the optimaltherapeutic regime. In Specific Aim 2 we will assess cell- and tissue-specific changes in energy homeostasisfollowing TBI and MB activation therapy using bioenergetic and metabolomic approaches and a novelapproach to isolate synaptic mitochondria. We will also examine the underlying metabolic mechanisms of TBIand MB activation using in vivo and ex vivo 13C-labeled tracing followed by advanced stable isotope-resolvedmetabolomic analysis. Lastly in Specific Aim 3 we will assess the specificity of MB activators on induction ofMB after TBI. Using 5-HT1F/2AR KO mice we hypothesize that functional benefit is dependent on thespecific receptor signaling leading to activation of MB. Overall we hypothesize that optimizing the therapeuticwindow and dose response of these MB activators after TBI will lead to improved bioenergetic homeostasisand neurocognitive performance after TBI.

project_terms:
Adult;Animals;Award;Behavioral;Bioenergetics;Biogenesis;Biological Assay;Brain;Brain Injuries;Cell Count;Cell Physiology;Cells;Clinical;Coupled;Data;Diagnosis;Diet;Dose;Energy Metabolism;FDA approved;Female;Glucose;Grant;Hippocampus;Histologic;Histology;Homeostasis;Impaired cognition;Impairment;Injury;Intervention;Intervention Strategies;Ipsilateral;Knockout Mice;Label;Link;Liquid substance;Magnetism;Mass Spectrum Analysis;Measures;Mediating;Metabolic;Metabolism;Methods;Military Personnel;Mitochondria;Mitochondrial DNA;Modernization;Molecular;Mus;Neurocognition;Neurocognitive;Neurons;Outcome Measure;PPAR gamma;Pathogenesis;Pathology;Pathway interactions;Performance;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Pharmacotherapy;Pioglitazone;Post-Traumatic Stress Disorders;Process;Production;Proto-Oncogene Proteins c-akt;Publishing;Pyruvate;Reactive Oxygen Species;Receptor Signaling;Regimen;Resolution;Sampling;Services;Signal Transduction;Specificity;Synapses;TBI treatment;Techniques;Technology;Testing;Therapeutic;Therapeutic Intervention;Tissues;Transgenic Mice;Traumatic Brain Injury;Treatment Efficacy;Treatment Protocols;Veterans;War;Work;brain dysfunction;central nervous system injury;cognitive function;cognitive recovery;cohort;controlled cortical impact;dosage;experience;formoterol;high risk population;improved;in vivo;injured;mRNA Expression;male;metabolomics;military operation;mitochondrial dysfunction;mitochondrial metabolism;mitochondrial therapeutics;molecular marker;morris water maze;neurobehavioral;neurogenesis;neuropathology;novel;novel strategies;object recognition;prevent;primary outcome;prophylactic;protein expression;receptor;response;spatiotemporal;stable isotope;therapeutic target;therapeutically effective;treatment optimization;white matter

public_health_relevance:
Clinical evidence coupled with experience in contemporary military arenas clearly indicates that traumatic braininjury (TBI) is becoming a signature injury of war which makes our troops a high-risk population. In fact 6.7% ofOEF/OIF veterans in 2009 were diagnosed with TBI and 73% of those were diagnosed with posttraumatic stressdisorder (PTSD). At present there is no approved treatment for TBI due to an incomplete understanding of theunderlying pathobiology. This proposal examines the potential of targeting mitochondrial biogenesis and pushforward the repurposing of the FDA approved drugs formoterol and lasmiditan to limit the brain damage anddysfunction resulting from TBI.


application_id: 11105829
project_number: 5I01BX005254-04
project_title: RA synovial fibroblast exosomes(RA-EXo) mediated bone erosion via AhR/TRAF2pathway
administering_ic: VA
award_notice_date: 2025-04-04
opportunity_number: BX-21-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 005254
project_start_date: 2022-04-01
project_end_date: 2026-03-31
study_section: ZRD1-IMMA-G(01)1
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-04-01
project_abstract:
Rheumatoid Arthritis (RA) is more prevalent among veterans than nonveterans. Women comprise anincreasing proportion of military personnel and have a higher prevalence of arthritis than men. Thus RA is a highlyrelevant problem for the Veterans Administration (VA). In RA synovium rheumatoid arthritis synovial fibroblasts(RASFs) are hyper proliferated the leading cell type in the terminal layer of the hyperplastic synovial tissue thatinvades and degrades adjacent cartilage and bone. TRAF2 mediated activation of NF-B and JNK leads tohyperproliferation of RASFs chronic inflammation and the erosive arthritis which is the hallmark of RA. How NF-B and JNK is activated in rheumatoid synovial fibroblast remains elusive though studies have demonstrated thatthe blockade of TNF mediated activation of NF-B and JNK attenuates the RA progression. However a largepopulation of RA patients are non-response to anti-TNF therapy. Research from our group and others has shownthat exosomes released from rheumatoid synovial fibroblasts (RA-Exo) contribute to RA pathogenicity andinflammation in several different animal models of joint disease including RA. Exosomes are small cell derivedvesicles that are 30-100 nm in size and of endocytic origin. Exosomes released by exocytosis into the extracellularspace where they are considered important drivers of intercellular communication. Exosomes in synovial fluid ofRA patients can lead to inflammation degeneration of cartilage and destruction of joints. However exosomes insynovial fluid could be released by different types of cells including RASFs in the synovium. Which cell typesrelease exosomes that contribute to joint inflammation and degeneration of cartilage is not well studied.Of particular relevance to this proposal we have demonstrated that RASF exosomes (RA-Exo) activate the TNF-receptor-associated factor 2 (TRAF2) mediated activation of the NF-B and JNK pathways is promoted bystabilization of TRAF2. More importantly our preliminary data clearly demonstrate that aryl hydrocarbon receptor(AhR) expression is significantly elevated in synovium from patients with RA. Expression positively correlates withbone erosion and is localized with TRAF2 strongly supporting the relevance of this pathway in the pathogenesisof RA in humans. Mechanistically AhR is enriched in the RA-Exo and RA-Exo AhR is required for stabilizingTRAF2. Our OVERALL HYPOTHESIS is that targeting AhR centered networks in RA-Exo leads to TRAF2degradation and the prevention of TRAF2 mediated activation of the NF-B and JNK pathways in RASFs.Therefore disruption of the AhR network in RA exosomes will eliminate/attenuate bone erosion and inflammationby affecting RA-Exo mediated pathways contributing to the development of bone erosion in synovium of RApatients.Our plan to accomplish this objective are outlined in these three specific aims: 1. Identify the RA-Exo AhR network that results in the development of arthritis in the mouse models. 2. Determine whether RA-Exo AhR-associated kinase activity mediates dissociation of TRAF2AF from the TRAF2 complex. 3. Determine whether blocking the recruitment of VCIP135 to RA-Exo AhR results in preventing the development of erosive arthritis in the huRASF/SCID mouse model.The positive outcome of this study for future products would provide a basis for developing mechanism-driven noveldrugs for RA therapy. Moreover it is of high value for predicting biomarkers from RA-Exo of non-responsiveindividuals prior to commencing anti-TNF or personalized drug therapy.

project_terms:
ARA9 protein;Affect;Animal Model;Arthritis;Aryl Hydrocarbon Receptor;Attenuated;Autoimmune Diseases;Biological;Biological Markers;Biological Response Modifiers;Biotin;Biotinylation;Bone Development;CRISPR/Cas technology;Cartilage;Cells;Chondrocytes;Chronic;Complex;Cytosol;Data;Development;Diagnosis;Dissociation;Endothelial Cells;Exocytosis;Extracellular Space;Fibroblasts;Future;Guidelines;Health Status;Heat-Shock Proteins 90;High Prevalence;Human;Hyperplasia;Immune;Immunocompetent;Implant;Individual;Inflammation;Invaded;Knock-out;Knowledge;Label;Ligase;MAPK8 gene;Mediating;Mediator;Military Personnel;Modeling;Molecular Target;Mus;Mutate;NF-kappa B;Osteitis;Outcome;Outcome Study;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Pharmacotherapy;Phosphorylation;Phosphotransferases;Play;Population;Predictive Value;Prevention;Process;Proliferating;Proteins;Publishing;Receptor Activation;Research;Rheumatoid Arthritis;Role;SCID Mice;Severities;Site;Sorting;Synovial Cell;Synovial Fluid;Synovial Membrane;System;TNF Receptor-Associated Factors;TNF gene;TNF receptor-associated factor 2;Testing;Therapeutic;Tissues;United States Department of Veterans Affairs;Vesicle;Veterans;Virulence Factors;Woman;arthritis therapy;arthropathies;bone;bone erosion;cartilage degradation;cell type;disability;exosome;experimental study;extracellular;improved;in vivo;intercellular communication;joint destruction;joint inflammation;joint injury;member;men;mouse model;novel therapeutics;patient population;personalized medicine;precision drugs;predictive marker;prevent;protein protein interaction;receptor expression;recruit;valosin-containing protein

public_health_relevance:
Rheumatoid arthritis (RA) is a common cause of disability in Veterans. Although TNF blockers have been usedfor treatment unresponsiveness to treatment is high in Veteran RA patients; the mechanism(s) underlying theunresponsiveness is/are unknown. RA commonly involves multiple cell types. It is well-known that exosomesmediate intercellular crosstalk among immune cells synovial cells endothelial cells and chondrocytes therebyinfluencing various processes in RA pathogenesis. However the precise function of exosomes in patients withRA is not fully understood. The results generated from this study will also provide a guideline for administeringpersonalized medicine which would selectively prevent RA pathogenic factor(s) from sorting into RA synovialfibroblast (RASF) exosomes which in turn contribute to RA pathogenesis. In addition we can identify RASFdependent exosome signatures that may serve as promising biomarkers for diagnosing or assessing RA activityand thus improving the health status of members of the VA patient population.


application_id: 11063280
project_number: 5IK6BX006563-02
project_title: BLRD Merit Review Research Career Scientist Award
administering_ic: VA
award_notice_date: 2025-02-20
opportunity_number: BX-23-022
application_type: 5
activity_code: IK6
ic: BX
serial_number: 006563
project_start_date: 2024-04-01
project_end_date: 2029-03-31
study_section: ZRD1-RCSR-N(01)
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-04-01
project_abstract:
My research work largely explores the underlying physiologic questions regarding tiny vesicles called exosomes.These exosomes are released from many different types of cells or food-derived exosome-like nanoparticles andI am investigating in VA patients the promising role of exosomes as therapeutic vehicles in delivering treatmentfor a diverse but specific group of medical conditions i.e. inflammation related diseases including widespreadbrain inflammation related diseases obesity rheumatoid arthritis nonalcoholic fatty liver disease (NASH) andcancer. The accumulation of inflammatory cells that release proinflammatory cytokines and chemokines not onlypromote brain disease progression such as Gulf War Syndrome but also rheumatoid arthritis obesity and/orcancer. These diseases pose special burdens on veterans who depend on the VA for healthcare.Since receiving my initial Research Career Scientist award my research group has published more than 60manuscripts on this subject. Collectively our findings support continued funding of my team to investigate thefollowing aims: (1). Develop a therapeutic strategy to target delivery of therapeutic agents to microglia fortreatment of brain inflammation related diseases such as Gulf War Syndrome. Microglia cells respond vigorouslyto both chronic disease and acute insults affecting brain function. Targeted delivery of therapeutic agents tomicroglia is needed but highly challenging. The results published from my group (Theranostics 20221220-1246Cell Host Microbe 2022 944-960 and Small 2022 2105385) provide emerging evidence for the developmentof edible exosome-like nanoparticles as a safe delivery system for targeting different tissues including brainmicroglial cells either by systemic or oral administration. (2). Investigate the role of tumor exosomes inimmunosuppression through induction of myeloid-derived suppressor cells inhibition of dendritic celldifferentiation and inhibition of activation of NK cell immunotherapy. This approach is supported based on ourpublished results (Nature Communications. 2017 Feb 17;8:14448 Nature communications. 2015;6:6956). (3).Exosomes are released from non-tumor cells and we will determine their role in: (a) exosome accumulation inadipose tissue (Diabetes. 2009 Nov;58(11):2498-505 Hepatology 2013 57(3):1250-61) we will investigate therole of adipose tissue exosome-like vesicles in activation of macrophage-induced insulin resistance and inductionof liver NKT cell anergy; and (b) investigate exosomes released from rheumatoid synovial fibroblasts and inhibitregulatory T cell development. Their role in contributing to damaging joint cartilage will be further investigated.(4). Based on the results we published as listed below we will further develop customized exosome-likenanoparticles from edible plants as therapeutic vehicles to treat/prevent specific disease. (a) Ginger exosome-like nanoparticles (GELNs) are preferentially taken up by Lactobacillaceae in a GELN lipid-dependent mannerand contain microRNAs that target various genes in Lactobacillus rhamnosus (LGG) to prevent DSS inducedmouse colitis (Cell Host Microbe 2018 p637-652). Oral administration of oat nanoparticles inhibits braininflammation and improves brain memory function of mice fed alcohol by targeting microglial cells (Small 20222105385). We have shown that targeted drug/therapeutic miRNAs (Nature Communications. 2013;4:1867) aredelivered to intestinal macrophages brain microglia cells (Molecular therapy: 2015 Volume 24 Issue 1 p96105) inflammatory tumor sites (Cancer Research 2015;75:2520-9) by edible and health plant derived ELN.Broccoli-derived nanoparticle inhibits mouse colitis by induction of tolerogenic gut associated dendritic cells(Molecular Therapy. 2017) and grape exosome-like nanoparticles induce intestinal stem cells (MolecularTherapy. 2013 Jul;21(7):1345-57). Collectively our findings will not only open up a new avenue for investigatingELNs as a means to protect against the development of inflammation related diseases such as alcohol inducedliver and gut damage brain and joint inflammation related diseases but sheds light on studying the cellular andmolecular mechanisms underlying inter-species communication via edible plant-derived nanoparticles.

project_terms:
Acute;Address;Adipose tissue;Affect;Alcohols;Antibodies;Antiinflammatory Effect;Avena sativa;Award;Binding;Biology;Brain;Brain Diseases;Brain Neoplasms;Broccoli - dietary;Cartilage;Cell Communication;Cell Differentiation process;Cells;Chronic;Chronic Disease;Colitis;Colon Carcinoma;Colonic Neoplasms;Communication;Complex;Curcumin;DNA;Data;Dendritic Cells;Development;Diabetes Mellitus;Diet;Disease;Disease Progression;Drug Targeting;Edible Plants;Encephalitis;Equilibrium;Fibroblasts;Folic Acid;Food;Funding;Future;Garlic;Gene Expression;Genes;Ginger;Goals;Grapefruit;Grapes;Growth;Health;Health Care;Health Status;Hepatology;High Fat Diet;Homeostasis;Homing;Immune system;Immunity;Immunosuppression;Impaired cognition;Inflammation;Inflammatory;Insulin Resistance;Intestines;Lactobacillaceae;Lactobacillus casei rhamnosus;Lipids;Liver;Macrophage;Macrophage Activation;Malignant Neoplasms;Manuscripts;Mediating;Mediator;Medical;Memory;Metabolic;Methods;MicroRNAs;Microbe;Microglia;Modeling;Molecular;Mus;Myeloid-derived suppressor cells;NK Cell Activation;NK cell therapy;Natural Killer T cell;Nature;Nerve Degeneration;Neuroimmune;Obese Mice;Obesity;Oncoproteins;Oral Administration;Outcome Study;Pathway interactions;Patients;Persian Gulf Syndrome;Pharmaceutical Preparations;Physiological;Plants;Post-Traumatic Stress Disorders;Prevention strategy;Probiotics;Promoter Regions;Publishing;RNA;Regulatory T-Lymphocyte;Research;Rheumatoid Arthritis;Role;S100A8 gene;Scientist;Shapes;Signal Pathway;Signal Transduction;Site;Small Interfering RNA;Sodium Dextran Sulfate;Sorting;Specificity;Surface;System;T-Cell Activation;T-Cell Development;TP53 gene;Therapeutic;Therapeutic Agents;Tissues;Tumor Suppressor Proteins;Vesicle;Veterans;Work;aged;anergy;anti-cancer research;antimicrobial;c-myc Genes;cancer prevention;career;cell type;chemokine;chemokine receptor;cytokine;dectin 1;dextran sulfate sodium induced colitis;disease diagnosis;exosome;expression vector;gut bacteria;gut microbiome;gut microbiota;improved;in vivo;insight;interleukin-22;interspecies communication;intestinal stem cells;joint inflammation;joint injury;lipid nanoparticle;liver inflammation;member;military veteran;mouse model;murine colitis;nanoparticle;nanovector;neoplastic cell;new therapeutic target;non-alcoholic fatty liver disease;novel strategies;novel therapeutic intervention;patient population;pressure;prevent;recruit;side effect;small molecule;targeted delivery;theranostics;therapeutic development;therapeutic miRNA;tissue repair;translational study;treatment strategy;tumor;tumor progression

public_health_relevance:
The most frequently diagnosed diseases among VA patients are inflammation related diseases including braininflammation related diseases obesity rheumatoid arthritis and colon cancer. Determining the precisemechanism(s) by which inflammation contributes to the development of these diseases is essential for thedevelopment of therapeutic strategies against these diseases. The focus of my career research is to characterizethese mechanisms and then to determine whether targeting of these mechanisms effectively prevents/treatsthese diseases. Specifically I will focus on the molecular mechanism(s) underlying how exosome-likenanoparticles from healthy edible plants contribute to the inhibition of microphage-mediated inflammation. Apositive outcome for this study would be significant for the development of future products that provide a basisfor developing mechanism-driven novel strategies for the prevention of chronic inflammation via non-invasiveoral administration of treatments and thus improve the health status of members of the VA patient population.


application_id: 10925141
project_number: 5I21RX003766-03
project_title: Developing Novel Models for Assessing Fundamental Mechanisms of Neuroma
administering_ic: VA
award_notice_date: 2023-12-20
opportunity_number: RX-20-009
application_type: 5
activity_code: I21
ic: RX
serial_number: 003766
project_start_date: 2021-10-01
project_end_date: 2023-12-31
study_section: Rehabilitation Research and Development SPiRE Program[RRDS]
contact_pi_person_id: 9011081
contact_pi: PETRUSKA, JEFFREY C
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-10-01
project_abstract:
Neuromas are painful tumors of nerve tissue that result from amputation or other nerve injury. Peripheral nerveinjury is the most-impactful comorbidity associated with the most common types of battlefield trauma andmany of these cases eventually result in formation of a painful neuroma. This condition often requiresadditional invasive surgery for our Veterans including resectioning of the injured nerve to remove theneuroma which may form again. Diabetes a chronic health problem that is a priority for VAMCs across thecountry is another common cause of amputation. Neuroma pain (or nerve pain as it is commonly called inthe amputee community) is also one of the major reasons patients reduce/stop use of assistive devicesincluding prosthetics. Further presence of neuroma can be a disqualifying factor for some prosthetics andnerve interfaces. Although treatments are available there is currently no clinical Standard of Care forprevention or treatment of neuroma because the available approaches are not sufficiently effective. Althoughessentially all unrepaired nerve injuries result in a neuroma not all neuromas are painful. Unfortunately thereis no safe window for neuromas  pain can begin at any point after the nerve injury which induced theneuroma. Neuromas continue to grow and their structure evolves over time likely introducing interactions thatwould not occur in normal tissue and developing emergent properties. These etiological factors suggest thatalthough sensory neurons are necessary for neuroma pain it is the neuroma structure itself that may establishthe physical relationships which lead to pain. Therefore understanding what factors control formation ofneuroma structure is necessary to develop approaches to prevent neuroma formation. Our plan to be pursued in subsequent MERIT applications will tests the hypothesis that it is regeneration ofinjured axons which controls neuroma formation and that subsequent aberrant coupling of sympathetic ormotor axons and/or immune cells with sensory axons is the major factor driving neuroma pain. To this end thisSPiRE proposal is designed to validate genetic models and experimental designs to enable us and the field toaddress fundamental questions which remain unanswered. This project will test the utility of a set of cell type-specific knockout and reporter mice for neuroma research. The premise for the proposed mouse lines is thatneuroma formation is apparently completely prevented by global knockout of a gene required for axonalregeneration. The premise for the new experimental design is that no existing animal models reflect the clinicalreality of the repeated nerve injury that occurs with neuroma resection and recurrence despite the fact that thecondition of repeated injury induces changes that differ from that of single injuries. This SPiRE project willprovide the animal lines visualization methods and preliminary data vital for MERIT projects to determinemechanisms and test treatments.

project_terms:
Address;Afferent Neurons;Amputation;Amputees;Animal Model;Animals;Automobile Driving;Axon;Basic Science;Biological;Biological Factors;Biological Models;Breeding;Cell Proliferation;Cells;Chronic;Clinical;Communities;Country;Coupling;Data;Dependence;Development;Devices;Diabetes Mellitus;Disease;Etiology;Excision;Experimental Designs;Future;Genes;Genetic Models;Goals;Growth;Health;Image;Immune;Injury;Investigation;Knock-out;Knockout Mice;Local Anesthetics;Methods;Modeling;Motor;Mus;Natural regeneration;Nerve;Nerve Pain;Nerve Tissue;Neuroma;Neurons;Normal tissue morphology;Operative Surgical Procedures;Pain;Patients;Peripheral;Peripheral nerve injury;Pharmacogenetics;Physical Rehabilitation;Physical therapy;Population;Prevention;Preventive therapy;Property;Prosthesis;Proteins;Quality of life;Recurrence;Rehabilitation therapy;Reporter;Research;Resources;Schwann Cells;Self-Help Devices;Sensory;Signal Transduction;Structure;Study models;Testing;Therapeutic;Time;Transgenic Mice;Trauma;Validation;Veterans;Visualization;Work;activating transcription factor 3;axon injury;axon regeneration;cell type;comorbidity;design;experimental study;improved;improved outcome;innovation;knockout gene;loss of function;model design;motor axon regeneration;nerve injury;novel;optogenetics;prevent;recruit;regenerative;response;standard of care;therapy design;therapy development;three dimensional structure;tool;translational approach;tumor

public_health_relevance:
The project aims to validate new genetic models for studying the mechanisms underlying painful neuromawhich occurs after nerve injury and seriously impacts Veterans quality of life engagement with rehabilitationand use of prosthetics. The causes of painful neuroma are not known which hinder development of treatmentsand preventions. The proposed work will take a basic science approach to enable new types of experiments toanswer some of the fundamental questions which will directly influence the design of translational strategies.


application_id: 10923182
project_number: 1I01BX006646-01
project_title: Spinal targets to treat persistent bladder pain
administering_ic: VA
award_notice_date: 2024-10-04
opportunity_number: BX-23-035
application_type: 1
activity_code: I01
ic: BX
serial_number: 006646
project_start_date: 2024-10-01
project_end_date: 2028-09-30
study_section: Special Emphasis Panel[ZRD1 NURP-N (01)]
contact_pi_person_id: 8093598
contact_pi: VERA, PEDRO L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-10-01
project_abstract:
Interstitial cystitis/Bladder pain syndrome (IC/BPS) is a painful condition of unknownetiology. IC/BPS often results in poor quality of life and affects approximately 1.08% and 0.66%in female and male veterans and corresponding to 22134 female veterans and 109183 maleveterans respectively. are affected by IC/BPS. Bladder pain is the characteristic symptom ofinterstitial cystitis/bladder pain syndrome (IC/BPS) where 90% patients do not show anyevidence of underlying bladder infection pathology or injury. Our long-term goal is to discover novel therapeutic targets for persistent bladder pain.We plan to accomplish this by identifying novel spinal targets capable of modulating persistentbladder pain using a rodent model that is comparable to non-Hunner type IC/BPS: persistentbladder hyperalgesia (BHA) after repeated activation of intravesical protease-activatedreceptors-4 (PAR4) receptors with minor or no inflammatory changes in the bladder. Our centralhypothesis is spinal proteomic changes mediated by activation of specific macrophagemigration inhibitory factor (MIF) or high mobility group box 1 (HMGB1) receptors in thelumbosacral spinal cord mediate persistent bladder hyperalgesia without overt bladder injury.We plan to test our central hypothesis by pursuing the following specific aims: 1. Investigate novel MIF-modulated spinal protein targets associated with persistentBHA. We propose to validate a set of lumbosacral proteins that are associated with persistentBHA and that are also modulated by spinal MIF antagonism. In addition we will examine thefunctional roles of these proteins in persistent BHA. 2. Determine spinal protein changes mediated by specific receptors in persistent BHA.We propose to investigate the roles of specific spinal MIF or HMGB1 receptors in mediatingpersistent BHA. Based on our preliminary data our working hypothesis is that targets identified byunbiased proteomic analysis will show functional roles and that spinal MIF or HMGB1 receptorsmediate persistent BHA and are novel targets to modulate persistent BHA. We will apply ourestablished rodent (mouse) model of persistent bladder pain biochemical and histologicalapproaches for these preclinical studies. Successful completion of these studies is expected toidentify new components of the mechanism and to lead to discover novel spinal targets fortherapeutic interventions in bladder pain.

project_terms:
Affect;Biochemical;Bladder;Bladder Injury;Characteristics;Chronic;Data;Disease;Etiology;Female;Goals;HMGB1 gene;Health Care Costs;Health Care Systems;Histologic;Hyperalgesia;Individual;Infective cystitis;Inflammatory;Injury;Interstitial Cystitis;Knowledge;Mediating;Migration Inhibitory Factor;Minor;Modeling;Mus;Outcome;Pain;Pathology;Patients;Pelvis;Prevalence;Probability;Proteins;Proteomics;Publishing;Quality of life;Reporting;Research;Rodent;Rodent Model;Role;Spinal;Spinal Cord;Symptoms;Testing;Therapeutic Intervention;Translating;Urination;Veterans;antagonist;bladder pain;cost;cost comparison;interstitial;intravesical;male;new therapeutic target;novel;preclinical study;pressure;protease-activated receptor 4;receptor;statistics;targeted treatment;therapeutic target

public_health_relevance:
The proposed studies will contribute fundamental knowledge about the spinalmechanisms that mediate persistent bladder pain and identify novel potential therapeutictargets to treat persistent bladder pain that may ultimately benefit veterans with InterstitialCystitis/Bladder Pain Syndrome.


application_id: 10911147
project_number: 5I01BX003405-07
project_title: Targeting mitostasis via activation of mitochondrial biogenesis after TBI
administering_ic: VA
award_notice_date: 2024-07-01
opportunity_number: BX-21-003
application_type: 5
activity_code: I01
ic: BX
serial_number: 003405
project_start_date: 2017-01-01
project_end_date: 2027-06-30
study_section: ZRD1-NURC-H(01)
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-07-01
project_abstract:
Experience in contemporary military operations suggests that traumatic brain injury (TBI) is the signature injuryof modern wars making our troops a high-risk population for TBI. Among the 327388 OEF/OIF veterans usingVA services in 2009 6.7% were diagnosed with TBI of which 73% of those were diagnosed with posttraumaticstress disorder (PTSD). However to date there is no approved treatment for TBI in part due to an incompleteunderstanding of the pathobiology underlying TBI. Compelling experimental data demonstrate that mitochondrialdysfunction is a pivotal link in the neuropathological sequelae of brain injury. This premise comes from ourpublished work (and that of others) demonstrating that loss of mitochondrial homeostasis and increasedmitochondrial reactive oxygen species (ROS) production occurs following TBI. Protecting or restoringmitochondrial function by therapeutically targeting mitochondrial impairment improves neuronal function afterTBI. Here we propose a novel approach of activating mitochondrial biogenesis (MB) a necessary process inmitochondrial dynamics after TBI using pharmacological intervention. Through MB dysfunctional mitochondriaare replaced via signaling networks involving peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1) as a master regulator. Activation of MB can be an important intervention to modulatemitochondrial dynamics and prevent metabolic disruption after TBI. Recently two drugs formoterol andlasmiditan have been screened by us and our collaborators and found to induce PGC-1 via activation of twoindependent receptors 2-adrenoreceptor (2AR) and 5-hydroxytryptamine1F (5-HT1F) respectively. Wehypothesize that MB activation at the optimized drug dosage will improve mitochondrial functionmitigate pathology and restore cognitive function following TBI. To test this hypothesis in Specific Aim1 we will examine the temporal and spatial aspects of MB after TBI in the injured cortex and hippocampus byanalyzing molecular markers of MB. We will also refine and establish the dose-response and therapeuticwindow of intervention for formoterol and lasmiditan treatment to optimize MB after TBI. In this Aim we will alsotest the hypothesis that treatment with MB activators promotes cognitive recovery following TBI at the optimaltherapeutic regime. In Specific Aim 2 we will assess cell- and tissue-specific changes in energy homeostasisfollowing TBI and MB activation therapy using bioenergetic and metabolomic approaches and a novelapproach to isolate synaptic mitochondria. We will also examine the underlying metabolic mechanisms of TBIand MB activation using in vivo and ex vivo 13C-labeled tracing followed by advanced stable isotope-resolvedmetabolomic analysis. Lastly in Specific Aim 3 we will assess the specificity of MB activators on induction ofMB after TBI. Using 5-HT1F/2AR KO mice we hypothesize that functional benefit is dependent on thespecific receptor signaling leading to activation of MB. Overall we hypothesize that optimizing the therapeuticwindow and dose response of these MB activators after TBI will lead to improved bioenergetic homeostasisand neurocognitive performance after TBI.

project_terms:
Adult;Animals;Award;Behavioral;Bioenergetics;Biogenesis;Biological Assay;Brain;Brain Injuries;Cell Count;Cell Physiology;Cells;Clinical;Coupled;Data;Diagnosis;Diet;Dose;Energy Metabolism;FDA approved;Female;Glucose;Grant;Hippocampus;Histologic;Histology;Homeostasis;Impaired cognition;Impairment;Injury;Intervention;Ipsilateral;Knockout Mice;Label;Link;Liquid substance;Magnetism;Mass Spectrum Analysis;Measures;Mediating;Metabolic;Metabolism;Methods;Military Personnel;Mitochondria;Mitochondrial DNA;Modernization;Molecular;Mus;Neurocognition;Neurocognitive;Neurons;Outcome Measure;PPAR gamma;Pathogenesis;Pathology;Pathway interactions;Performance;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Pioglitazone;Post-Traumatic Stress Disorders;Process;Production;Proto-Oncogene Proteins c-akt;Publishing;Pyruvate;Reactive Oxygen Species;Receptor Signaling;Regimen;Resolution;Sampling;Services;Signal Transduction;Specificity;Synapses;TBI treatment;Techniques;Technology;Testing;Therapeutic;Therapeutic Intervention;Tissues;Transgenic Mice;Traumatic Brain Injury;Treatment Efficacy;Treatment Protocols;Veterans;War;Work;brain dysfunction;central nervous system injury;cognitive function;cognitive recovery;cohort;controlled cortical impact;dosage;experience;formoterol;high risk population;improved;in vivo;injured;mRNA Expression;male;metabolomics;military operation;mitochondrial dysfunction;mitochondrial metabolism;mitochondrial therapeutics;molecular marker;morris water maze;neurobehavioral;neurogenesis;neuropathology;novel;novel strategies;object recognition;pharmacologic;prevent;primary outcome;prophylactic;protein expression;receptor;response;stable isotope;therapeutic target;therapeutically effective;treatment optimization;white matter

public_health_relevance:
Clinical evidence coupled with experience in contemporary military arenas clearly indicates that traumatic braininjury (TBI) is becoming a signature injury of war which makes our troops a high-risk population. In fact 6.7% ofOEF/OIF veterans in 2009 were diagnosed with TBI and 73% of those were diagnosed with posttraumatic stressdisorder (PTSD). At present there is no approved treatment for TBI due to an incomplete understanding of theunderlying pathobiology. This proposal examines the potential of targeting mitochondrial biogenesis and pushforward the repurposing of the FDA approved drugs formoterol and lasmiditan to limit the brain damage anddysfunction resulting from TBI.


application_id: 10908265
project_number: 5IK2BX004883-05
administering_ic: VA
award_notice_date: 2024-05-21
opportunity_number: BX-19-008
application_type: 5
activity_code: IK2
ic: BX
serial_number: 004883
project_start_date: 2020-04-01
project_end_date: 2025-03-31
study_section: ZRD1-NURE-E(01)
contact_pi_person_id: 11890992
contact_pi: YAMASAKI, TRITIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-04-01
budget_end_date: 2025-03-31
project_title:
Enhancing diagnosis of Parkinson's disease and multiple system atrophy via detection of alpha-synuclein seeding activity

project_abstract:
Synucleinopathies such as Parkinson's disease (PD) and multiple systems atrophy (MSA) involve abnormalaccumulation of the protein alpha-synuclein (-syn). Although it has been nearly two centuries since PD wasfirst described a dearth of biomarkers has greatly impeded progress toward development of disease-modifyingtreatments and accurate and early diagnosis. This proposal is based on the hypothesis that pathology in thesediseases propagates through the brain via a mechanism in which transcellular movement of misfolded -synprotein aggregates or seeds occurs. There is also evidence that pathogenic -syn has diverse structures indiseases such as PD or MSA that may underlie the clinical and pathologic differences seen in thesesynucleinopathies. This proposal utilizes a novel cell-based assay that has been shown to detect and quantifyabnormal -syn seeding activity that differs both biochemically and structurally in brain extracts from patientswith PD and MSA. In this project we propose to (1) optimize the ability to detect aggregated forms of -synutilizing genetic manipulation of a cell-based sensor (2) utilize cutting edge molecular and imaging techniquesto parse out differences between -syn in the synucleinopathies MSA and PD and (3) determine whether -synseeding activity in blood components of patient samples can serve as a marker for clinical disease progression.The implications of this work include facilitation of diagnosis and therapeutics for patients with PD and MSA.The applicant is an Assistant Professor in the Department of Neurology at University of Kentucky who is firmlycommitted to an academic career as an independent translational scientist in the area of neurodegenerativedisease. The proposed training will take advantage of the rich and collaborative environment at the VA theexcellent clinical documentation and records system and the very relevant patient population affected by thesediseases and followed in clinic at the VA: all are factors that are integral and crucial to the success of thisproposal. Training will be conducted under the direction of an experienced mentor team. Dr. John Slevin will bethe primary mentor and has over 40 years of expertise in clinical research in Movement Disorders and holds aMerit Award at the VA in basic science research. Dr. Sidney Whiteheart and Dr. Haining Zhu will serve as co-mentors. They are experts in platelet biochemistry and abnormal protein aggregation respectively hold MeritAwards in their fields and are also faculty in the Department of Molecular and Cellular Biochemistry at Universityof Kentucky. These mentors have been specially selected to advance the candidates knowledge of moleculartechniques for investigating aggregated proteins in peripheral fluids of patients with movement disorders.Training during this proposal includes advanced genetic molecular and imaging-based techniques for proteinamplification and detection and techniques for isolation and analysis of exosomal and platelet fractions fromwhole blood. These components will be essential to completing the applicants immediate goal of developing abiomarker that can detect and differentiate between synucleinopathies in peripheral samples by utilizingdifferences in -syn seeding activity. The comprehensive training program will position the applicant to conductindependent research in the study of novel biomarkers in PD and related neurodegenerative disease.

project_terms:
Acceleration;Affect;Aging;Antibodies;Area;Award;Basic Science;Binding;Biochemical;Biochemistry;Biological Assay;Biological Markers;Biosensor;Blood;Blood Platelets;Blood specimen;Braak's hypothesis;Brain;C-terminal;Cell-Free System;Cells;Central Nervous System;Characteristics;Clinic;Clinical;Clinical Research;Consent;DNA Sequence Alteration;Deep Brain Stimulation;Detection;Development;Diagnosis;Diagnostic;Disease;Disease Progression;Documentation;Early Diagnosis;Elderly;Engineering;Epitopes;Erythrocytes;Evaluation;Expenditure;Exposure to;FDA approved;Faculty;Fluorescence Resonance Energy Transfer;Gender;Genetic;Goals;Healthcare;Image;Imaging Techniques;In Vitro;Kentucky;Knowledge;Ligands;Liquid substance;Mentors;Methods;Modality;Molecular;Molecular Conformation;Motor;Movement;Movement Disorders;Multiple System Atrophy;Nerve Degeneration;Neurodegenerative Disorders;Neurology;Parkinson Disease;Pathogenicity;Pathologic;Pathology;Patients;Peripheral;Persons;Plasma;Population;Positioning Attribute;Process;Prognosis;Property;Proteins;Publishing;Records;Research;Sampling;Solubility;Structure;System;Techniques;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;Toxin;Training;Training Programs;Universities;Veterans;Whole Blood;Work;accurate diagnosis;alpha synuclein;amplification detection;career;cerebral atrophy;collaborative environment;disorder risk;effective therapy;exosome;experience;genetic manipulation;imaging modality;insight;liquid biopsy;male;novel;novel marker;patient population;prion-like;professor;prognostic;protein aggregation;rare condition;sensor;success;synuclein;synucleinopathy;translational scientist;transmission process

public_health_relevance:
Parkinsons disease is the most common neurodegenerative movement disorder of the elderly affecting overfour million people worldwide and is responsible for significant health care dollar expenditures annually. Thisdisease afflicts a disproportionately large number of US Veterans based on factors such as advancing age malegender and exposure to certain toxins all of which are associated with increased risk for the disease. Progresstoward effective treatment has been hindered by the lack of a biomarker that can diagnose and distinguishParkinsons disease from related neurodegenerative conditions. The proposed research will detect pathogenicforms of the protein alpha-synuclein in the blood of patients with Parkinsons and related diseases with theultimate goal of expanding diagnostic prognostic and therapeutic options for affected US Veterans.


application_id: 10897357
project_number: 1IK6BX006563-01
project_title: BLRD Merit Review Research Career Scientist Award
administering_ic: VA
award_notice_date: 2024-03-28
opportunity_number: BX-23-022
application_type: 1
activity_code: IK6
ic: BX
serial_number: 006563
project_start_date: 2024-04-01
project_end_date: 2029-03-31
study_section: Special Emphasis Panel[ZRD1 RCSR-N (01)]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-04-01
project_abstract:
My research work largely explores the underlying physiologic questions regarding tiny vesicles called exosomes.These exosomes are released from many different types of cells or food-derived exosome-like nanoparticles andI am investigating in VA patients the promising role of exosomes as therapeutic vehicles in delivering treatmentfor a diverse but specific group of medical conditions i.e. inflammation related diseases including widespreadbrain inflammation related diseases obesity rheumatoid arthritis nonalcoholic fatty liver disease (NASH) andcancer. The accumulation of inflammatory cells that release proinflammatory cytokines and chemokines not onlypromote brain disease progression such as Gulf War Syndrome but also rheumatoid arthritis obesity and/orcancer. These diseases pose special burdens on veterans who depend on the VA for healthcare.Since receiving my initial Research Career Scientist award my research group has published more than 60manuscripts on this subject. Collectively our findings support continued funding of my team to investigate thefollowing aims: (1). Develop a therapeutic strategy to target delivery of therapeutic agents to microglia fortreatment of brain inflammation related diseases such as Gulf War Syndrome. Microglia cells respond vigorouslyto both chronic disease and acute insults affecting brain function. Targeted delivery of therapeutic agents tomicroglia is needed but highly challenging. The results published from my group (Theranostics 20221220-1246Cell Host Microbe 2022 944-960 and Small 2022 2105385) provide emerging evidence for the developmentof edible exosome-like nanoparticles as a safe delivery system for targeting different tissues including brainmicroglial cells either by systemic or oral administration. (2). Investigate the role of tumor exosomes inimmunosuppression through induction of myeloid-derived suppressor cells inhibition of dendritic celldifferentiation and inhibition of activation of NK cell immunotherapy. This approach is supported based on ourpublished results (Nature Communications. 2017 Feb 17;8:14448 Nature communications. 2015;6:6956). (3).Exosomes are released from non-tumor cells and we will determine their role in: (a) exosome accumulation inadipose tissue (Diabetes. 2009 Nov;58(11):2498-505 Hepatology 2013 57(3):1250-61) we will investigate therole of adipose tissue exosome-like vesicles in activation of macrophage-induced insulin resistance and inductionof liver NKT cell anergy; and (b) investigate exosomes released from rheumatoid synovial fibroblasts and inhibitregulatory T cell development. Their role in contributing to damaging joint cartilage will be further investigated.(4). Based on the results we published as listed below we will further develop customized exosome-likenanoparticles from edible plants as therapeutic vehicles to treat/prevent specific disease. (a) Ginger exosome-like nanoparticles (GELNs) are preferentially taken up by Lactobacillaceae in a GELN lipid-dependent mannerand contain microRNAs that target various genes in Lactobacillus rhamnosus (LGG) to prevent DSS inducedmouse colitis (Cell Host Microbe 2018 p637-652). Oral administration of oat nanoparticles inhibits braininflammation and improves brain memory function of mice fed alcohol by targeting microglial cells (Small 20222105385). We have shown that targeted drug/therapeutic miRNAs (Nature Communications. 2013;4:1867) aredelivered to intestinal macrophages brain microglia cells (Molecular therapy: 2015 Volume 24 Issue 1 p96105) inflammatory tumor sites (Cancer Research 2015;75:2520-9) by edible and health plant derived ELN.Broccoli-derived nanoparticle inhibits mouse colitis by induction of tolerogenic gut associated dendritic cells(Molecular Therapy. 2017) and grape exosome-like nanoparticles induce intestinal stem cells (MolecularTherapy. 2013 Jul;21(7):1345-57). Collectively our findings will not only open up a new avenue for investigatingELNs as a means to protect against the development of inflammation related diseases such as alcohol inducedliver and gut damage brain and joint inflammation related diseases but sheds light on studying the cellular andmolecular mechanisms underlying inter-species communication via edible plant-derived nanoparticles.

project_terms:
Acute;Address;Adipose tissue;Affect;Alcohols;Antibodies;Antiinflammatory Effect;Avena sativa;Award;Binding;Biology;Brain;Brain Diseases;Brain Neoplasms;Broccoli - dietary;Cartilage;Cell Communication;Cell Differentiation process;Cells;Chronic;Chronic Disease;Colitis;Colon Carcinoma;Colonic Neoplasms;Communication;Complex;Curcumin;DNA;Data;Dendritic Cells;Development;Diabetes Mellitus;Diet;Disease;Disease Progression;Drug Targeting;Edible Plants;Encephalitis;Equilibrium;Fibroblasts;Folic Acid;Food;Funding;Future;Garlic;Gene Expression;Genes;Ginger;Goals;Grapefruit;Grapes;Growth;Health;Health Status;Healthcare;Hepatology;High Fat Diet;Homeostasis;Homing;Immune system;Immunity;Immunosuppression;Impaired cognition;Inflammation;Inflammatory;Insulin Resistance;Intestines;Lactobacillaceae;Lactobacillus casei rhamnosus;Lipids;Liver;Macrophage;Macrophage Activation;Malignant Neoplasms;Manuscripts;Mediating;Mediator;Medical;Memory;Metabolic;Methods;MicroRNAs;Microbe;Microglia;Modeling;Molecular;Mus;Myeloid-derived suppressor cells;NK Cell Activation;Natural Killer Cell Immunotherapy;Nature;Nerve Degeneration;Neuroimmune;Obese Mice;Obesity;Oncoproteins;Oral Administration;Outcome Study;Pathway interactions;Patients;Persian Gulf Syndrome;Pharmaceutical Preparations;Physiological;Plants;Post-Traumatic Stress Disorders;Prevention strategy;Probiotics;Promoter Regions;Publishing;RNA;Regulatory T-Lymphocyte;Research;Rheumatoid Arthritis;Role;S100A8 gene;Scientist;Shapes;Signal Pathway;Signal Transduction;Site;Small Interfering RNA;Sodium Dextran Sulfate;Sorting;Specificity;Surface;System;T-Cell Activation;T-Cell Development;TP53 gene;Therapeutic;Therapeutic Agents;Tissues;Tumor Suppressor Proteins;Vesicle;Veterans;Work;aged;alcohol prevention;anergy;anti-cancer research;antimicrobial;c-myc Genes;cancer prevention;career;cell type;chemokine;chemokine receptor;cytokine;dectin 1;dextran sulfate sodium induced colitis;disease diagnosis;exosome;expression vector;gut bacteria;gut microbiome;gut microbiota;improved;in vivo;insight;interleukin-22;interspecies communication;joint inflammation;joint injury;lipid nanoparticle;liver inflammation;member;military veteran;mouse model;murine colitis;nanoparticle;nanovector;neoplastic cell;new therapeutic target;non-alcoholic fatty liver disease;novel strategies;novel therapeutic intervention;patient population;pressure;prevent;recruit;side effect;small molecule;stem cells;targeted delivery;theranostics;therapeutic development;therapeutic miRNA;tissue repair;translational study;treatment strategy;tumor;tumor progression

public_health_relevance:
The most frequently diagnosed diseases among VA patients are inflammation related diseases including braininflammation related diseases obesity rheumatoid arthritis and colon cancer. Determining the precisemechanism(s) by which inflammation contributes to the development of these diseases is essential for thedevelopment of therapeutic strategies against these diseases. The focus of my career research is to characterizethese mechanisms and then to determine whether targeting of these mechanisms effectively prevents/treatsthese diseases. Specifically I will focus on the molecular mechanism(s) underlying how exosome-likenanoparticles from healthy edible plants contribute to the inhibition of microphage-mediated inflammation. Apositive outcome for this study would be significant for the development of future products that provide a basisfor developing mechanism-driven novel strategies for the prevention of chronic inflammation via non-invasiveoral administration of treatments and thus improve the health status of members of the VA patient population.


application_id: 10862575
project_number: 5I01CX002219-06
project_title: Inflammation Resolving Lipid Mediators: Novel Therapy for Alcohol AssociatedLiver Disease
administering_ic: VA
award_notice_date: 2024-07-04
opportunity_number: CX-22-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 002219
project_start_date: 2023-07-01
project_end_date: 2027-06-30
study_section: ZRD1-GAST-L(01)1
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-07-01
project_abstract:
Alcohol-associated liver disease (ALD) is a major health problem in the US (especially in the Veteranpopulation) and alcohol abuse/ALD has increased dramatically during the COVID pandemic. In spite of themagnitude of this problem there is no FDA-approved therapy for any stage of ALD. In addition the mechanismsand regulators of disease progression and severity are incompletely understood. Dietary fats play an importantinteractive role with alcohol consumption in ALD pathogenesis however the role of specific n3 polyunsaturatedfatty acids (PUFAs) in ALD are not well defined. Our central hypothesis is that n3 PUFAs are beneficial inALD in part via n3-PUFA-derived pro-resolving mediators which facilitate inflammation resolutionimprovement in the gut-liver axis and subsequent attenuation of liver injury. We propose that n3 PUFA-derived resolvin D1 (RvD1) is a potential therapeutic agent in ALD acting via RvD1-FPR2-NEAT1 signaling tosuppress pro-inflammatory cytokines and to promote repair of hepatocellular damage in part via enhancementof pro-restorative macrophages. We postulate that compromised inflammation resolution due to impaired RvD1production/signaling is a critical nutritional factor contributing to the progression and severity of ALD/alcohol-associated hepatitis (AH) in humans. The Specific Aims of the proposal are: Aim 1: determine the role andmolecular mechanism(s) underlying n3 PUFA and RvD1 beneficial effects in EtOH-induced liver injury andresolution of inflammation associated with ALD. We will determine whether beneficial effects occur through anincrease in n3-PUFA-derived specialized pro-resolving mediators (SPMs) and RvD1-FPR2 and Neat1-mediatedsuppression of pro-inflammatory cytokine signaling and reprogramming pro-inflammatory macrophages to a pro-restorative phenotype. Wild Type (WT) Fpr2-/- Neat1-/- and transgenic fat-1 mice (which are able toendogenously convert n6 to n3 PUFAs) will be used in this Aim. Aim 2: examine the role n3-PUFAs and RvD1in maintaining gut barrier integrity and in the resolution of intestinal inflammation in experimental ALD. We will:i) test in vivo in animal models and in vitro in intestinal organoid culture whether n3 PUFAs or RvD1 improveintestinal barrier damage by attenuating intestinal immune dysregulation; ii) test in vivo whether disruption of theRvD1-FPR2 axis exacerbates while blocking Neat1 signaling attenuates intestinal inflammation and alterationsin the gut barrier integrity; and iii) determine the contribution of the gut microbiota to the beneficial effects of n3PUFAs and RvD1 in experimental ALD. Aim 3: translate and extend our findings in animal models to humanALD. Utilizing human samples obtained from Veteran AH patients we will: i) examine plasma SPM levels andcorrelate plasma SPM levels with markers of liver injury systemic inflammation and intestinal permeability; ii)evaluate basal and LPS-inducible SPM production in whole blood (ex-vivo system) and blood monocytes; andiii) test whether RvD1 improves the phagocytosis/efferocytosis capacity of blood monocytes and determine ifdisruption of the RvD1-FPR2 axis will enhance while silencing of NEAT1 will decrease pro-inflammatorycytokine expression in human monocytes. These three aims will define both untested novel mechanisms for ALDinitiation/progression as well as potential novel therapy that could be rapidly initiated for Veterans with ALD.

project_terms:
Alcohol abuse;Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Arachidonate 15-Lipoxygenase;Attenuated;Biological Response Modifiers;Breast;COVID-19 pandemic;Cessation of life;Chronic;Cirrhosis;Clinical;Colon;Cytokine Signaling;Data;Diet;Dietary Fats;Dietary Intervention;Disease;Disease Progression;Down-Regulation;Epidemic;Ethanol;Experimental Animal Model;FAT gene;FDA approved;FPR2 gene;Future;GPR32 gene;Health;Health Care Costs;Hepatic;Hepatitis;Hepatitis C;Hepatocellular Damage;Homeostasis;Host Defense;Human;Immune;Immune response;Immunity;Impairment;In Vitro;Individual;Inflammation;Inflammatory;Intestinal permeability;Intestines;Linoleic Acids;Liver diseases;Macrophage;Mediating;Mediator;Modeling;Molecular;Mus;Nuclear;Nutritional;Organoids;PTGS2 gene;Pathogenesis;Pathway interactions;Patients;Phagocytosis;Phenotype;Plasma;Play;Polyunsaturated Fatty Acids;Production;Prognosis;Prostate;Research;Resolution;Rodent;Role;Sampling;Severities;Severity of illness;Signal Transduction;Survivors;System;Testing;Therapeutic Agents;Time;Tissues;Transcript;Transgenic Organisms;Translating;United States Department of Veterans Affairs;Untranslated RNA;Veterans;Whole Blood;attenuation;cancer type;cyclooxygenase 1;cytokine;gut inflammation;gut microbiota;gut-liver axis;improved;in vivo evaluation;intestinal barrier;intestinal injury;lipid mediator;liver inflammation;liver injury;military veteran;monocyte;mortality;new therapeutic target;novel;novel therapeutics;preclinical study;receptor;repaired;systemic inflammatory response;tissue repair

public_health_relevance:
Alcohol abuse exacts a major toll on health and health costs in Veterans. Even though there has been anepidemic of hepatitis C in the U.S. and the Veterans Administration alcohol-related liver injury remains ahigher cause of mortality. Studies from the Veterans Administration showed that patients with cirrhosis andsuperimposed alcoholic hepatitis had > 60% mortality over a four-year period of time with most of thosedeaths occurring in the first few months. Thus the prognosis for this stage of ALD is worse than many commontypes of cancer such as breast prostate and colon. Unfortunately there is no FDA-approved therapy for anystage of ALD and this makes the need for this proposed research even more compelling. The proposedstudies will help to better understand the molecular mechanisms of alcohol-induced liver and intestinal injuryincluding alcohol-diet interactions which may lead to identification of new therapeutic targets and potentialdietary interventions for treating ALD as well as help to explain why only some heavy drinkers developclinically important ALD.


application_id: 10847383
project_number: 5I21RX003173-04
project_title: Tuning Up Memory-related Brain Potentials using Real-time Neurofeedback in Older Veterans"
administering_ic: VA
award_notice_date: 2023-08-23
opportunity_number: RX-19-003
application_type: 5
activity_code: I21
ic: RX
serial_number: 003173
project_start_date: 2020-10-01
project_end_date: 2023-09-30
study_section: Rehabilitation Research and Development SPiRE Program[RRDS]
contact_pi_person_id: 7875188
contact_pi: JIANG, YANG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-04-01
project_abstract:
Military deployment is associated with increased risk of mild cognitive impairment (MCI).Combat stress related memory deficits has been well documented. Mild cognitive impairmentsuch as memory deficits are the most common and earliest symptoms of Alzheimers diseaseand related dementia (ADRD). The complaints about declined memory are common in healthyand cognitively intact civilian older adults but less understood in aging combat veterans. Braintraining strategies to enhance cognitive skills and especially memory processes are unmetneeds in aging combat veterans who are at additional risk for MCI induced by ADRD. Sincecurrently there is no effective drug treatment to stop cognitive decline noninvasive brain trainingto boost memory functions in older veterans is an increasingly attractive option to attenuatingdecline in memory. The proposed project is poised to investigate state-of-art neurofeedback (NF;biofeedback of brain activity) training for self-modulation of neural plasticity to boost memoryperformance in veterans. The recent advance of NF with Brian-Computer Interface (BCI) hasprovided a novel way to examine brain functions and plasticity. Thus far there has been limitedapplication in developing effective experimental and clinical paradigms for rehabilitation inveterans. Historically brainwave patterns during memory task performance have beenanalyzed offline a methodology which does not allow real-time NF modulation and training.The proposed project is poised to investigate state-of-art neurofeedback (NF; biofeedback ofbrain activity) training for self-modulation of neural plasticity to boost memory performance inveterans. The central hypothesis guiding this research is that optimal memory-related brainwavepatterns of a veteran can be trained. The online NF allows maximization of brainwave patternsassociated with healthier memory states. The development of efficient NF paradigms to augment memory performance is animportant first step for the application of this nonpharmacologic intervention to improve combatveterans memory functions and potential for treating MCI due to mild TBI or pain. We will usestate-of-the-art wearable wireless brain-computer interface headset which is affordable and canbe easily set up in VAMCs and eventually in remote assessment settings. This innovativecognitive neuroscience based nonpharmacologic intervention serves to revolutionize thediagnosis and treatment of combat veterans who are at risk for degenerative dementia.

project_terms:
Age;Aging;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease related dementia;Alzheimer's disease risk;Biofeedback;Biological Markers;Brain;Classification;Clinical;Cognitive;Computer Interface;Crossover Design;Dementia;Deposition;Development;Diagnosis;Elderly;Electrophysiology (science);Etiology;Functional disorder;Goals;Human;Impaired cognition;Individual;Intervention;Link;Measures;Memory;Memory Loss;Memory impairment;Mental disorders;Methodology;Methods;Military Personnel;Modeling;Neurocognitive;Neuronal Plasticity;Pain;Pattern;Performance;Persons;Pharmacotherapy;Physical Performance;Pilot Projects;Protocols documentation;Reaction Time;Rehabilitation therapy;Research;Research Design;Rest;Rewards;Risk;Sensory;Short-Term Memory;Signal Transduction;Stress;Symptoms;Synapses;Task Performances;Testing;Time;Training;Veterans;brain computer interface;cognitive enhancement;cognitive function;cognitive neuroscience;cognitive performance;cognitive rehabilitation;cognitive skill;cognitive testing;cognitive training;combat;combat veteran;community setting;effectiveness testing;high risk;improved;innovation;memory process;memory retrieval;mild cognitive impairment;mild traumatic brain injury;military veteran;neurofeedback;neuroregulation;novel;processing speed;rapid growth;rehabilitation paradigm;remote assessment;support network;tau Proteins;tau aggregation;wireless

public_health_relevance:
Military deployment is associated with increased risk of mild cognitive impairment such ascombat stress related memory deficits. The complaints about declined memory are common inhealthy and cognitively intact civilian older adults but less understood in aging combat veterans.The recent advances of wireless brain-computer interface and biofeedback of brain activity haveprovided novel ways to examine brain functions and plasticity. The proposed innovativecognitive neuroscience based non-pharmacologic intervention serves to revolutionize thediagnosis and treatment of combat veterans who are at risk for cognitive impairment anddementia.


application_id: 10832480
project_number: 5I01BX005889-02
project_title: Sex differences in ASK1-mediated pulmonary fibrosis
administering_ic: VA
award_notice_date: 2024-06-06
opportunity_number: BX-22-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 005889
project_start_date: 2023-04-01
project_end_date: 2027-03-31
study_section: ZRD1-PULM-N(01)1
contact_pi_person_id: 1860187
contact_pi: WATERS, CHRISTOPHER M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-04-01
project_abstract:
Idiopathic pulmonary fibrosis (IPF) is a devastating illness with a poor prognosis andboth the incidence and prevalence of IPF among U.S. Veterans has increased during the last 10years. In addition the occurrence of pulmonary fibrosis developing following acute lung injuryhas been prominent in survivors of COVID-19. The pathogenic mechanisms underlying thedevelopment of fibrosis are not completely understood. The fundamental processes developdue to genetic abnormalities and/or environmental factors that lead to repetitive injury to thealveolar epithelium dysregulated epithelial repair mechanisms and an increase in fibroblastsand (apoptosis-resistant) myofibroblasts that produce excessive extracellular matrix. IPF ismore prevalent in men than in women but the reasons for the differences are not wellunderstood. Apoptosis signal regulating kinase 1 (ASK1) is a mitogen activated protein kinasekinase kinase (MAP3K5) that is activated by oxidative stress and causes stimulation of MAPKpathways but the downstream signaling pathways are highly tissue dependent and have notbeen investigated in the context of pulmonary fibrosis. The overall objective of this applicationis to establish that ASK1 is a central mediator of the development of pulmonary fibrosis. Thecentral hypothesis of this proposal is that ASK1 promotes pulmonary fibrosis by p38-mediatedinflammation and stimulation of ERK1/2-mediated pathways and that these pathways areregulated in part by sex hormones. The rationale for the proposed research is that theidentification of ASK1 as a central regulator in the development of fibrosis will advance ourfundamental understanding and lead to new therapeutic options for the treatment of IPFpatients. These mechanisms will be investigated using both ASK1-deficient mice and an ASK1inhibitor in a bleomycin-induced fibrosis mouse model. In addition primary cultures of alveolartype II epithelial cell and fibroblasts as well as cell lines with knockdown of ASK1 and other keymediators will be used to define specific ASK1-dependent pathways. Aim 1 will test thehypothesis that fibrosis is exacerbated by repetitive oxidative stress that activates p38 signalingvia ASK1 and that these pathways are regulated by sex hormones. Aim 2 will test thehypothesis that sex-dependent differences in ASK1 and ERK1/2 activation stimulate pro-fibroticpathways. These studies will advance our fundamental understanding of fibrosis and sexdifferences and establish ASK1 as a potential therapeutic target to reduce the progression ofIPF.

project_terms:
Acute Lung Injury;Aging;Alveolar;Apoptosis;Bleomycin;COVID-19 survivors;Cell Culture Techniques;Cell Line;Cessation of life;Chronic Disease;Data;Death Rate;Development;Diagnosis;Disease;Disease Progression;Environmental Risk Factor;Epithelial Cells;Epithelium;Estrogen Receptors;Exposure to;Extracellular Matrix;Extracellular Signal Regulated Kinases;Female;Fibroblasts;Fibrosis;Gases;Goals;Gonadal Steroid Hormones;Hyperoxia;Incidence;Inflammation;Injury;JUN gene;Knowledge;Life Expectancy;Lipopolysaccharides;MAP Kinase Gene;MAP Kinase Kinase Kinase;MAP3K5 gene;MAPK3 gene;MAPK8 gene;Macrophage;Mechanical ventilation;Mediating;Mediator;Mesenchymal;Modeling;Molecular Abnormality;Morbidity - disease rate;Mus;Myofibroblast;NADPH Oxidase;Oxidative Stress;Oxygen;Pathogenicity;Pathway interactions;Patients;Phosphothreonine;Pirfenidone;Prevalence;Process;Prognosis;Proteins;Pulmonary Fibrosis;Regulation;Reporting;Research;Resistance;Role;Sex Differences;Signal Pathway;Signal Transduction;Survivors;TXN gene;Testing;Therapeutic Intervention;Tissues;Transforming Growth Factor beta;Veterans;Woman;alveolar epithelium;epithelial injury;epithelial repair;fibrotic lung;idiopathic pulmonary fibrosis;improved;inhibitor;knock-down;lung injury;male;men;mortality;mouse model;new therapeutic target;nintedanib;novel;novel therapeutic intervention;novel therapeutics;p38 Mitogen Activated Protein Kinase;response;severe COVID-19;sex;targeted treatment;therapeutic target

public_health_relevance:
Pulmonary fibrosis is a devastating illness that involves progressive remodeling and scarring of lungtissue that can eventually lead to poor gas exchange. The incidence of idiopathic pulmonary fibrosis isincreasing worldwide including among Veterans mortality rates are high and the average life expectancy is 3to 5 years after diagnosis. This proposed study will investigate a previously unrecognized mechanisticpathway that contributes to the development of pulmonary fibrosis and will identify potential targets fortherapeutic intervention to reduce fibrosis.


application_id: 10816390
project_number: 5I01BX003274-06
project_title: The Vagus Nerve in Lung Disease
administering_ic: VA
award_notice_date: 2023-07-04
opportunity_number: BX-17-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 003274
project_start_date: 2018-04-01
project_end_date: 2024-03-31
study_section: Respiration[PULM]
contact_pi_person_id: 2084836
contact_pi: YU, JERRY (JUN)
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-04-01
project_abstract:
Pulmonary neuroendocrine (PNECs) cells are widely distributed throughout theairway mucosa. These cells can be solitary or aggregated to form neuroepithelialbodies (NEBs) which are richly innervated by the vagus nerve. PNECs/NEBs areimportant for early phases of lung development and also associated with stem cellniches in the airways. They are airway sensors. Airway sensory receptors arebiosensors that detect lung inflammation and injury through various mediators andcytokines. This information is transmitted through vagal afferents to the brain andproduces a host of responses that regulate the pathophysiological process.Increasing evidence suggests that the vagus nerve plays an important role in avariety of pulmonary diseases from asthma COPD ARDS to lung cancer.Pulmonary fibrosis (PF) can result from a variety of insults to the lung. Lung repairfollowing an insult-induced injury is a complex process involving both resident cellsand recruited cells. The progression of PF results from a network of interactionsamong mediators cytokines and growth factors derived from inflammatoryendothelial and epithelial cells which leads to lung remodeling deposition ofcollagen limitation of gas exchange and dyspnea. The vagus nerve is closelyrelated to each component of this network thus its function may influence theoutcome of PF. Since lung injury is a major component in the development of PFand harmful insults to the lung may stimulate the NEB-Vagal System (NVS) a novelhypothesis that activation of the NVS promotes lung fibrosis will be tested. [If thishypothesis is correct suppression of the NVS should attenuate fibrosis whereasstimulation of the NVS should promote fibrosis. By examining lung fibrosis inbleomycin treated mice in which the NVS is either stimulated or suppressed(vagotomy medication gene manipulation or cell adoptive transfer) and byassessing well-established cellular and molecular pathways that lead to PF withdifferent techniques (histology physiology cytology and biochemistry) theunderlying neural mechanisms will be delineated.] Successful completion of thestudies will establish a novel neural mechanism in the pathogenesis of PF. [Thispotentially may lead to a new pharmacological approach to treat or to limit chronicfibrotic diseases in the Veteran population.]

project_terms:
Acetylcholine;Acute Respiratory Distress Syndrome;Adoptive Cell Transfers;Agonist;Asthma;Attenuated;Biochemical;Biochemistry;Biological;Biosensor;Brain;Bronchoalveolar Lavage;Cell Count;Cells;Central Nervous System;Cessation of life;Chronic;Chronic Obstructive Pulmonary Disease;Cicatrix;Collagen;Complex;Cytology;Data;Deposition;Development;Disease;Dyspnea;Endothelial Cells;Epithelial Cells;Fibroblasts;Fibrosis;Gases;Gene Expression;Growth Factor;Histology;Hospitals;Immune response;Inflammatory;Injury;Lung;Lung diseases;Malignant neoplasm of lung;Mammals;Mediating;Mediator;Molecular;Mus;Myofibroblast;Nerve;Nerve Block;Neural Pathways;Neuroendocrine Cell;Neuroepithelial Bodies;Neuroimmune;Neurosecretory Systems;Outcome;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Physiology;Plasma;Play;Process;Pulmonary Fibrosis;Pulmonary Inflammation;Research;Respiratory Mucosa;Role;Sensory Receptors;Severities;System;Techniques;Testing;Transforming Growth Factor beta;Vagotomy;Vagus nerve structure;antagonist;chemical release;cytokine;effective therapy;fibrogenesis;fibrotic lung disease;genetic manipulation;improved;indium-bleomycin;lung development;lung injury;lung repair;military veteran;mouse model;neuromechanism;novel;novel strategies;patient population;pharmacologic;protein expression;receptor;recruit;sensor;stem cell niche;transmission process;vagus nerve stimulation

public_health_relevance:
Lung diseases are a major cause of illness and death in the Veteran population. Many of thediseases are related to lung fibrosis (LF) which is due to increased collagen and has no effectivetreatment. In the lung there are specialized neuroendocrine cells connected to nerves forming aneuroendocrine system (NS). The NS is essential for lung repair and influences progression ofpulmonary diseases. We hypothesize that the NS promotes LF. We examined biochemistryphysiology and histology of both lungs in a mouse model for LF with one lung denervated andcompared severity of the LP. Indeed we found that a chemical released from the NS can promoteLF. In this application we will investigate the mechanism. Since pulmonary diseases related to LFform a major pulmonary patient population at VA hospitals successful completion of the studies willestablish a novel neural mechanism in the lung disease and may improve VA patient management.


application_id: 10812319
project_number: 5I01CX001353-07
project_title: Modulation of mitochondrial respiration to treat colitis
administering_ic: VA
award_notice_date: 2024-02-27
opportunity_number: CX-21-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 001353
project_start_date: 2022-01-01
project_end_date: 2025-12-31
study_section: ZRD1-GAST-L(01)1
contact_pi_person_id: 1883566
contact_pi: BARRETT, TERRENCE A.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-01-01
project_abstract:
The importance of mucosal healing in inflammatory bowel disease (IBD) derives from clinical data thatdemonstrate it to be a predictor of remission. Unfortunately many IBD patients remain refractory or loseresponsiveness to therapies leading to persistent mucosal ulceration. Prospective pediatric studies show thatreduced mitochondrial gene expression predict unfavorable outcomes in ulcerative colitis (UC). Consistentlyincreased expression of mitochondrial respiratory chain genes has been shown to predict favorable Crohnsdisease (CD) outcomes. Based on these results and our own data we hypothesize that a critical driver of chroniculceration in IBD is the failure of intestinal epithelial cells (IEC) to increase mitochondrial respiration. In studiesleading up to this submission we found that mitochondrial deficiency caused poor ulcer healing due to inadequatecrypt fissioning occurring at ulcer edges (Progress Report). These findings led us to develop a novel gold (Au)-based drug based on the current safe and effective gold therapy for Rheumatoid arthritis (Auranofin). This newdrug AuPhos localizes to mitochondria where it increases mitochondrial respiration and mitochondrial reactiveoxygen species (mtROS) production. Induction of low levels of endogenous mtROS are known to promotehealthy adaptive responses in cells including anti-oxidant enzyme activities (Background). In preliminarystudies we found that oral AuPhos 1) enhances mucosal repair in DSS colitis 2) increases IEC mitochondrialoxygen consumption rate (OCR) and oxidative phosphorylation (OXPHOS) 3) mtROS and H2O2 production inIEC as well as 4) phosphoinositides-3 kinase (PI3K) and nuclear factor erythroid 2-related factor (Nrf2) signalingwith 5) improved expression of proteins that induce mitochondrial biogenesis [peroxisome proliferator activatedreceptor- coactivator 1 alpha (PGC1) and transcription factor A mitochondrial (TFAM). Studies proposed inAim 1 interrogate mitochondrial function under baseline conditions to allow assessment of AuPhos-inducedchanges in mitochondrial mass activity (mtROS) and OCR ATP turnover electron transport chain (ETC) activityinduction of adaptive responses [anti-oxidant catalase MnSOD (superoxide dismutase) and glutathione(reduced/oxidized)] as well as assess changes in tissue oxidant stress (4HNE protein carbonylationnitrotyrosine IHC). Aim 2 will build upon these studies by evaluating AuPhos effects in TNF-stimulated smallbowel (SB) and colonic organoids from veterans (normal and IBD). Studies in 3D organoids will allow formechanistic testing of AuPhos-induced crypt budding and IEC gene expression. Results of Aim 2 will instructstudies in Aim 3A that study therapeutic effects of AuPhos on IEC gene expression and crypt fissioning thatheal ulcers in DSS colitis. In Aim 3B scRNAseq analysis of human biopsies incubated with AuPhos will allowus to examine induction of mitochondrial gene expression in discrete IEC clusters. Proposed studies are drivenby a novel hypothesis that restoration of IEC mitochondrial respiration is a key step in mucosal healing. Togetherthese preclinical studies with a VA-sponsored new drug (AuPhos) have the potential of transitioning this agentto the therapy of IBD in veterans.

project_terms:
3-Dimensional;3-nitrotyrosine;Acceleration;Antioxidants;Auranofin;Bioenergetics;Biogenesis;Biopsy;Cell Survival;Cells;Childhood;Chronic;Clinical;Clinical Data;Colitis;Colon;Crohn's disease;Data;Disease;Disease Outcome;Disease remission;Distant;Electron Transport;Epithelial Cells;Event;Failure;Gene Expression;Genes;Glutathione;Goals;Gold;Gold Compounds;Healthcare Systems;Human;Hydrogen Peroxide;Immunosuppression;In Vitro;Incubated;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Intestines;Messenger RNA;Mitochondria;Modeling;Morbidity - disease rate;Mucositis;Mucous Membrane;Mus;Oral;Organ;Organoids;Outcome;Oxidative Phosphorylation;Oxidative Stress;Oxygen Consumption;PPAR gamma;Patients;Pharmaceutical Preparations;Phosphatidylinositols;Phosphotransferases;Production;Progress Reports;Proteins;Reactive Oxygen Species;Refractory;Research;Respiration;Respiratory Chain;Rheumatoid Arthritis;Risk;Role;SOD2 gene;Secondary to;Signal Induction;Signal Transduction;Small Intestines;Superoxide Dismutase;TNF gene;Testing;Therapeutic;Therapeutic Effect;Therapeutic Studies;Tissues;Toxicology;Ulcer;Ulcerative Colitis;Veterans;Work;antioxidant enzyme;catalase;chronic ulcer;cytokine;dextran sulfate sodium induced colitis;enzyme activity;healing;improved;in vivo;innovation;intestinal crypt;intestinal epithelium;mtTF1 transcription factor;murine colitis;novel;novel therapeutics;nuclear factor-erythroid 2;oxidant stress;preclinical study;prospective;protein expression;repaired;response;restoration;single-cell RNA sequencing;synergism;uptake

public_health_relevance:
The increase in inflammatory bowel disease (IBD) among veterans in recent years presents a significantclinical problem in the VA healthcare system. Major concerns for IBD veteran patients are the increaseddisease morbidity and risk of therapies. Further research is needed to develop safe and effective agents thatenhance mucosal repair and reduce immune-suppression. Previous work from our lab has indicates thatmitochondrial respiration promotes ulcer healing. This finding led us to postulate that increasing mitochondrialrespiration constitutes a novel therapeutic goal in IBD. To improve mitochondrial function in IBD we developedAuPhos an oral agent that enhances mitochondrial electron transport that potentiates mitochondrialbio-energetics and mitochondrial reactive oxygen species (mtROS) production. The current project willascertain the impact of this novel gold compound (AuPhos) on mitochondrial function and ulcer healing inmouse models of colitis as well as biopsy tissue explants from veterans with IBD.


application_id: 10767112
project_number: 5IK2BX004618-05
project_title: Psychological deficits after low level blast exposure: role of neurovascular disruption
administering_ic: VA
award_notice_date: 2024-05-30
opportunity_number: BX-19-008
application_type: 5
activity_code: IK2
ic: BX
serial_number: 004618
project_start_date: 2020-01-01
project_end_date: 2024-12-31
study_section: ZRD1-NURC-H(01)
contact_pi_person_id: 14823099
contact_pi: HUBBARD, WILLIAM BRAD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-01-01
project_abstract:
Many Veterans experience occupational exposure to low-level blast (LLB) during normal training operationsincluding but not limited to breaching activity. These Veterans are at increased risk for persistingneuropsychological impairment due to repeated LLB exposure over several deployments with limited time forrecovery between exposures. The extent of the long-term consequences after cumulative LLB exposure isunknown though reports show that deficits can be present late in life. Furthermore the resultant post-traumaticstress disorder (PTSD)-related behavioral deficits are more pronounced in soldiers and Veterans with a historyof chronic blast exposure. There is no clear understanding of which pathological mechanisms drive this chronicPTSD phenotype after LLB exposure. A few animal models have been established to address this incompleteunderstanding of the pathobiological mechanisms underlying LLB exposure. These models replicate thechronic depressive anxiogenic and PTSD-related traits observed in Veterans though there are manyknowledge gaps in what contributes to these chronic deficits. In general blast exposure causes acute blood-brain barrier (BBB) and neurovascular unit abnormalities that can persist over time. The overall objective of thisapplication is to determine the timing of acute neurovascular dysfunction after LLB and how repeating LLBcontributes to chronic neurovascular impairment and neuropsychological deficits. Our central hypothesis is thatLLB repeated at a time interval of maximal BBB impairment after the first LLB will result in persistent PTSD-like behavioral traits. Additionally these deficits will be associated with changes in the profile of serum-derivedexosomal miRNAs and platelet bioenergetics. These hypotheses were formulated based on current literatureand our own published and preliminary data demonstrating anxiety and amygdalar BBB disruption after blastexposure. By utilizing a multimodal blast simulator at the University of Kentucky these studies will be able toexamine the longitudinal behavioral profile coupled with pathologically relevant biomarkers. These hypotheseswill be tested in three specific aims: 1) examine acute neurovascular deficits after a single LLB exposure anddetermine their relationship to longitudinal behavioral traits 2) determine how repeating LLB at various timeintervals based on the acute neurovascular profile contributes to exacerbated or prolonged PTSD-likebehavioral traits and chronic neurovascular impairment 3) identify if modulating either acute or chronicneurovascular health using sildenafil will mitigate long-term PTSD-like behavioral traits. This research willdrastically improve our understanding of the effects of LLB as well as potentially identify novel clinically-relevant biomarkers. The proposed research is significant because it will establish a platform to understand thechronic effects of occupational blast exposure which affects many Veterans. In addition this line ofinvestigation can lead to better therapeutic targeting of neurovascular dysfunction to improve neurologicaloutcome in aging Veterans. In addition to the research products gained by this proposal the applicant willgreatly benefit from a mentoring team that has a variety of preclinical translational and clinical perspectiveswhich will contribute to a well-rounded career development plan. The training program will add additionaltechniques to Dr. Hubbards repertoire contributing not only to this proposal but to his VA research programmoving forward. With prior knowledge in blast injury modeling additional behavioral and biomarker assays willgreatly advance his research expertise. In the latter years of this proposal Dr. Hubbard will continue to expandgrant writing student mentoring collaborative research and presentation skills required of independentresearchers. Overall the proposed studies and diverse mentoring program will culminate in producing a highlysuccessful independent VA researcher.

project_terms:
3-Dimensional;Acute;Address;Affect;Aggressive behavior;Aging;Amygdaloid structure;Animal Model;Animals;Anxiety;Behavior;Behavior assessment;Behavioral;Bioenergetics;Biological Assay;Biological Markers;Blast Injuries;Blood - brain barrier anatomy;Blood Platelets;Blood Vessels;Brain;Brain region;Cerebrovascular Circulation;Chronic;Chronic Post Traumatic Stress Disorder;Clinical;Coupled;Data;Development;Development Plans;Euthanasia;Exposure to;Foundations;Functional disorder;Grant;Health;Image;Immunohistochemistry;Impairment;Investigation;Kentucky;Knowledge;Life;Literature;Matrix Metalloproteinases;Measures;Mentors;MicroRNAs;Military Personnel;Modeling;Nervous System Trauma;Neurocognitive;Neurologic Deficit;Neurologic Dysfunctions;Neurological outcome;Neurons;Neuropsychology;Occupational;Occupational Exposure;Outcome;Pathologic;Peripheral;Phenotype;Post-Traumatic Stress Disorders;Predisposition;Proteins;Publishing;Rattus;Recording of previous events;Recovery;Reporting;Research;Research Personnel;Risk;Rodent;Rodent Model;Role;Serum;Social Interaction;Soldier;Stains;Symptoms;Techniques;Testing;Therapeutic;Time;Tissues;Training;Training Programs;Universities;Vascular Diseases;Veterans;Writing;arterial spin labeling;behavior test;behavioral impairment;biomarker identification;blast exposure;blood-based biomarker;blood-brain barrier disruption;career development;cerebrovascular;cerebrovascular reactivity;clinically relevant;cohort;depressive symptoms;exosome;experience;improved;inhibitor;military veteran;multimodality;neuroimaging;neuropathology;neurovascular;neurovascular unit;novel;operation;phosphodiesterase V;pre-clinical;pressure;primary outcome;programs;psychologic;psychological outcomes;restoration;sildenafil;skills;stress related disorder;student mentoring;therapeutic target;time interval;trait

public_health_relevance:
Many Veterans experience low-level blast (LLB) exposure during tour of duty and training operations. Theextent of chronic post-traumatic stress disorder (PTSD) traits after cumulative LLB exposure is unknown.Additionally there is no clear understanding of which pathological mechanisms drive impairment after LLBexposure. The overall objective of this application is to determine the timing of acute neurovascular dysfunctionafter LLB and how repeating LLB contributes to chronic neurovascular impairment and neuropsychologicaldeficits. We will examine the behavioral profile and neurovascular outcomes after LLB coupled withpathologically relevant biomarkers. This research will improve our understanding of the effects of LLB andidentify biomarkers for neurological injury. The proposed mentored research plan will increase understandingof the chronic effects of occupational blast exposure to identify therapies which will improve Veteran healthwhile providing a foundation for the applicants independent VA research program.


application_id: 10745327
project_number: 5I21RX003872-02
administering_ic: VA
award_notice_date: 2024-03-15
opportunity_number: RX-22-011
application_type: 5
activity_code: I21
ic: RX
serial_number: 003872
project_start_date: 2022-12-01
project_end_date: 2024-11-30
study_section: Rehabilitation Research and Development SPiRE Program[RRDS]
contact_pi_person_id: 15804087
contact_pi: CLEMENS, SHEILA M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-12-01
budget_end_date: 2024-11-30
project_title:
Identifying the magnitude and impact of pelvic floor disorders in Veterans with lower limb amputation

project_abstract:
Pelvic floor disorders (PFDs) is the broad term used to describe a number of impairments that affect millions ofwomen and men in the U.S. Symptoms of PFDs resulting from over- or underactivity of pelvic musculaturemanifest in a variety of ways including urinary and fecal incontinence urinary frequency or urgency as wellsexual dysfunction and pelvic pain syndromes. Pelvic floor disorders are poorly understood in people withphysical disabilities and Veterans with lower limb amputation (LLA) are one such group of individuals. Pelvicfloor disorders are effectively managed with conservative non-pharmacological treatment but left undiagnosedcan adversely affect many facets of functioning and well-being. People with LLA frequently exhibit conditionsassociated with PFDs in the non-LLA population including low back pain and heightened fall risk yet thepresence of PFDs have not been systematically assessed in individuals with LLA. With over a million peopleliving with LLA in the U.S. this may pose a significant health burden that is currently not being addressed. Theoverall objective of this proposal is to better understand the magnitude and impact of PFDs on health-relatedquality of life in Veterans with LLA. We will explore the prevalence of PFDs amongst men and women with LLAand the physical and behavioral sequalae associated with the presence of symptoms of PFDs. We propose tocomprehensively address the gaps in knowledge by administering surveys including psychometrically soundoutcome measures to assess symptoms of PFDs to 200 study participants of both sexes (n  100 females). Allsurveys will be remotely administered to participants to optimize convenience and study enrollment. Ourproposed study has three aims:Specific Aim 1: To estimate the prevalence of PFDs in a cohort of male and female Veterans with LLA.This descriptive aim will provide seminal data on the magnitude of PFDs in Veterans with LLA and can serve asa proxy estimate for rates in the LLA population in general. Estimates will be provided based on sex and level ofLLA (trantibial transfemoral etc.) The primary measure of PFD symptoms will be the Pelvic Floor DistressInventory (PFDI-20) with secondary measures administered to explore other aspects related to PFDs in menand women. Furthermore this aim will assess the feasibility of collecting self-reported pelvic/urogenitalinformation and the acceptability by Veterans to PFD-related survey items.Specific Aim 2: To examine associations between PFDs and low back pain and prosthetic mobility inVeterans with LLA. This aim is designed to determine physical sequelae related to the presence of PFDs. Weexpect that (2A) there will be significant relationships between PFDs and scores on the Oswestry Disability Indexas a measure of low back pain and (2B) lower scores of prosthetic mobility as measured by the Prosthetic LimbUsers Survey of Mobility will be associated with PFDs.Specific Aim 3: To examine the extent to which PFDs contribute to fall risk and levels of activityparticipation in Veterans with LLA. This aim will examine the impact of reported PFDs relative to behaviorconstructs affecting health-related quality of life. We anticipate that (3A) there will be significant levels ofassociation between PFDs with reported fall occurrence and that (3B) the presence of PFDs will be associatedwith decreased activity participation both social and work related.Impact. Successful completion of this work will establish an evidence base regarding PFDs in male and femaleVeterans with LLA. This SPiRE presents an opportunity to shift the paradigm of LLA rehabilitation by elevatingthe consideration of often-ignored variables that could be contributing to increased rates of falls low back painand poorer quality of life in this population.

project_terms:
Address;Affect;Behavioral;Data;Disability scale;Distress;Enrollment;Equipment and supply inventories;Exhibits;Fecal Incontinence;Female;Femur;Genitourinary system;Health;Impairment;Increased frequency of micturition;Individual;Individuals with physical disabilities;Knowledge;Left;Limb Prosthesis;Low Back Pain;Lower Extremity;Measures;Nonpharmacologic Therapy;Outcome Measure;Participant;Patient Self-Report;Pelvic Floor Disorders;Pelvic Pain;Pelvic floor structure;Pelvis;Personal Satisfaction;Persons;Population;Prevalence;Prosthesis;Proxy;Psychometrics;Quality of life;Rehabilitation therapy;Reporting;Seminal;Sexual Dysfunction;Surveys;Symptoms;Syndrome;Urinary Incontinence;Veterans;Woman;Work;behavioral construct;cohort;design;evidence base;fall risk;falls;health related quality of life;limb amputation;male;men;micturition urgency;remote administration;sex;social;sound

public_health_relevance:
Pelvic floor disorders (PFDs) is the broad term used to describe a number of conditions that affect millions ofwomen and men in the U.S. Pelvic floor disorders resulting from over- or underactivity of pelvic muscles resultin a variety of symptoms including urinary and fecal incontinence urinary frequency or urgency as well sexualproblems and pelvic pain syndromes. Despite the common occurrence of PFDs there is no research examiningif PFDs are a problem for men and women with lower limb amputation (LLA). Common impairments of low backpain (LBP) falls and mobility deficits in people with LLA could be associated with coexisting undiagnosed PFDs.The overall purpose of this research is to better understand the extent at which PFDs occur in Veterans with LLAand any impact on lifestyle and functioning with their prosthesis. The clinical significance of the study will be inestablishing an evidence base of PFDs in people with LLA and providing a foundation for future research on theevaluation and treatment of PFDs in people with LLA.Project Narrative


application_id: 10661481
project_number: 5I21RX003300-03
administering_ic: VA
award_notice_date: 2022-07-07
opportunity_number: RX-19-003
application_type: 5
activity_code: I21
ic: RX
serial_number: 003300
project_start_date: 2020-06-01
project_end_date: 2022-12-18
study_section: Rehabilitation Research and Development SPiRE Program[RRDS]
contact_pi_person_id: 10388308
contact_pi: BAZRGARI, BABAK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-06-01
budget_end_date: 2022-12-18
project_title:
The assessment of lower back mechanical behavior and spinal loads in veterans with non-specific low back pain: a feasibility study

project_abstract:
Low back pain (LBP) is strongly associated with opioid consumption among veterans and improved clinicalmanagement of LBP is likely to reduce reliance on opioid among veterans. Up to 60% of patients with an acuteepisode of non-specific LBP experience either symptom persistence or symptom relapse within one year. Thisis likely an indication of a failure in addressing the underlying mechanisms of pain or initiation of a newetiology; both may stem from a mismatch between patients and treatments. The overall goal of our researchis to develop validate and implement measures that are relevant to known mechanisms of LBP which canthen be used to holistically gauge the health status of patients lower backs beyond self-reporting of symptoms.More accurate measurements will help better match of patients with existing treatments or development ofmore effective new treatments. The specific objective of this study is to generate evidence in support of thefeasibility of our methods for 1) the evaluation of relative contribution of lower back tissues to spinal loads and2) the investigation of the resultant spinal loads in veterans with non-specific LBP. We have developed apowerful set of tools for the comprehensive assessment of spinal loads and lower back mechanical behavior(MB) that will enable us to examine the existence or development of abnormalities in spinal loads and lowerback MB in [five] groups of veterans with different experiences with non-specific LBP. These groups willinclude [1) veterans with chronic non-specific LBP and high level of disability (n=10) 2) veterans with chronicnon-specific LBP and low level of disability (n=10)] 3) veterans with non-chronic non-specific LBP (n=10) 4)asymptomatic veterans with a recent history (i.e. during the past year) of non-specific LBP (n=10) and 5)asymptomatic veterans without a recent history of non-specific LBP (n=10; serving as control group).Successful completion of this feasibility project will pave the way for future studies (merit grant applications)that will verify the role of abnormalities in lower back MB and spinal loads in the clinical presentation of LBP.Such an understanding has the potential to help the affected veterans with disabling non-specific LBP.Specifically measures of lower back MB and spinal loads can be used not only to identify veterans withmechanical abnormalities in their lower back who are likely to experience LBP in the future but also to guidenovel integrated physical and psychological preventative treatments aimed at improved lower back mechanics.Ultimately the goal and resultant improvement in clinical outcomes of treatment for non-specific LBPis to diminish reliance on opioids for the symptom management of particularly veterans with chronicLBP.

project_terms:
Activities of Daily Living;Acute;Address;Affect;Applications Grants;Back;Behavior;Biomechanics;Characteristics;Chronic;Chronic low back pain;Clinic;Clinical;Clinical Management;Control Groups;Development;Elements;Etiology;Evaluation;Failure;Feasibility Studies;Financial compensation;Future;Gender;Goals;Health Status;Individual;Investigation;Life;Low Back Pain;Manuals;Measurement;Measures;Mechanics;Medical center;Methods;Muscle;Nature;Opioid;Outcome;Pain;Participant;Patient Self-Report;Patients;Pelvis;Physical Function;Plant Roots;Population;Preventive treatment;Questionnaires;Recording of previous events;Recurrence;Reflex action;Relapse;Relaxation;Reporting;Research;Research Personnel;Risk;Role;Screening procedure;Source;Spinal;Stress;Surveys;Symptoms;Testing;Tissues;Treatment outcome;Vertebral column;Veterans;Walking;design;disability;effective intervention;effective therapy;experience;high risk;human model;improved;innovation;mechanical behavior;mechanical properties;neuromuscular;neuromusculoskeletal;novel;opioid use;opioid user;pain relief;prescription pain reliever;psychologic;recruit;response;stem;symptom management;tool

public_health_relevance:
Low back pain is strongly associated with opioid consumption among veterans. This project will investigate thepresence of abnormalities in spinal loads and/or lower back mechanical behavior as potential contributingfactors to relapse or persistence of low back pain by examining five groups of veterans with differentexperiences of low back pain. Aiming at enhanced clinical management of low back pain our project has thepotential to help reduce reliance on opioid in veterans with disabling non-specific low back pain by enablingmore accurate assessment of lower back health status.


application_id: 10656408
project_number: 5I01BX003405-06
project_title: Targeting mitostasis via activation of mitochondrial biogenesis after TBI
administering_ic: VA
award_notice_date: 2023-08-21
opportunity_number: BX-21-003
application_type: 5
activity_code: I01
ic: BX
serial_number: 003405
project_start_date: 2017-01-01
project_end_date: 2026-06-30
study_section: ZRD1-NURC-H(01)
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-07-01
project_abstract:
Experience in contemporary military operations suggests that traumatic brain injury (TBI) is the signature injuryof modern wars making our troops a high-risk population for TBI. Among the 327388 OEF/OIF veterans usingVA services in 2009 6.7% were diagnosed with TBI of which 73% of those were diagnosed with posttraumaticstress disorder (PTSD). However to date there is no approved treatment for TBI in part due to an incompleteunderstanding of the pathobiology underlying TBI. Compelling experimental data demonstrate that mitochondrialdysfunction is a pivotal link in the neuropathological sequelae of brain injury. This premise comes from ourpublished work (and that of others) demonstrating that loss of mitochondrial homeostasis and increasedmitochondrial reactive oxygen species (ROS) production occurs following TBI. Protecting or restoringmitochondrial function by therapeutically targeting mitochondrial impairment improves neuronal function afterTBI. Here we propose a novel approach of activating mitochondrial biogenesis (MB) a necessary process inmitochondrial dynamics after TBI using pharmacological intervention. Through MB dysfunctional mitochondriaare replaced via signaling networks involving peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1) as a master regulator. Activation of MB can be an important intervention to modulatemitochondrial dynamics and prevent metabolic disruption after TBI. Recently two drugs formoterol andlasmiditan have been screened by us and our collaborators and found to induce PGC-1 via activation of twoindependent receptors 2-adrenoreceptor (2AR) and 5-hydroxytryptamine1F (5-HT1F) respectively. Wehypothesize that MB activation at the optimized drug dosage will improve mitochondrial functionmitigate pathology and restore cognitive function following TBI. To test this hypothesis in Specific Aim1 we will examine the temporal and spatial aspects of MB after TBI in the injured cortex and hippocampus byanalyzing molecular markers of MB. We will also refine and establish the dose-response and therapeuticwindow of intervention for formoterol and lasmiditan treatment to optimize MB after TBI. In this Aim we will alsotest the hypothesis that treatment with MB activators promotes cognitive recovery following TBI at the optimaltherapeutic regime. In Specific Aim 2 we will assess cell- and tissue-specific changes in energy homeostasisfollowing TBI and MB activation therapy using bioenergetic and metabolomic approaches and a novelapproach to isolate synaptic mitochondria. We will also examine the underlying metabolic mechanisms of TBIand MB activation using in vivo and ex vivo 13C-labeled tracing followed by advanced stable isotope-resolvedmetabolomic analysis. Lastly in Specific Aim 3 we will assess the specificity of MB activators on induction ofMB after TBI. Using 5-HT1F/2AR KO mice we hypothesize that functional benefit is dependent on thespecific receptor signaling leading to activation of MB. Overall we hypothesize that optimizing the therapeuticwindow and dose response of these MB activators after TBI will lead to improved bioenergetic homeostasisand neurocognitive performance after TBI.

project_terms:
Adult;Animals;Award;Behavioral;Bioenergetics;Biogenesis;Biological Assay;Brain;Brain Injuries;Cell Count;Cell physiology;Cells;Clinical;Coupled;Data;Diagnosis;Diet;Dose;Energy Metabolism;FDA approved;Female;Glucose;Grant;Hippocampus;Histologic;Histology;Homeostasis;Impaired cognition;Impairment;Injury;Intervention;Ipsilateral;Knockout Mice;Label;Link;Liquid substance;Magnetism;Mass Spectrum Analysis;Measures;Mediating;Metabolic;Metabolism;Methods;Military Personnel;Mitochondria;Mitochondrial DNA;Modernization;Molecular;Mus;Neurocognition;Neurocognitive;Neurons;Outcome Measure;PPAR gamma;Pathogenesis;Pathology;Pathway interactions;Performance;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Pioglitazone;Post-Traumatic Stress Disorders;Process;Production;Proto-Oncogene Proteins c-akt;Publishing;Pyruvate;Reactive Oxygen Species;Receptor Signaling;Regimen;Resolution;Sampling;Services;Signal Transduction;Specificity;Synapses;TBI treatment;Techniques;Technology;Testing;Therapeutic;Therapeutic Intervention;Tissues;Transgenic Mice;Traumatic Brain Injury;Treatment Efficacy;Treatment Protocols;Veterans;War;Work;brain dysfunction;central nervous system injury;cognitive function;cognitive recovery;cohort;controlled cortical impact;dosage;experience;formoterol;high risk population;improved;in vivo;injured;mRNA Expression;male;metabolomics;military operation;mitochondrial dysfunction;mitochondrial metabolism;molecular marker;morris water maze;neurobehavioral;neurogenesis;neuropathology;novel;novel strategies;object recognition;pharmacologic;prevent;primary outcome;prophylactic;protein expression;receptor;response;stable isotope;therapeutic target;therapeutically effective;treatment optimization;white matter

public_health_relevance:
Clinical evidence coupled with experience in contemporary military arenas clearly indicates that traumatic braininjury (TBI) is becoming a signature injury of war which makes our troops a high-risk population. In fact 6.7% ofOEF/OIF veterans in 2009 were diagnosed with TBI and 73% of those were diagnosed with posttraumatic stressdisorder (PTSD). At present there is no approved treatment for TBI due to an incomplete understanding of theunderlying pathobiology. This proposal examines the potential of targeting mitochondrial biogenesis and pushforward the repurposing of the FDA approved drugs formoterol and lasmiditan to limit the brain damage anddysfunction resulting from TBI.


application_id: 10608932
project_number: 5I01BX004252-05
project_title: CD47 as a therapeutic target for obesity
administering_ic: VA
award_notice_date: 2022-10-12
opportunity_number: BX-17-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 004252
project_start_date: 2018-10-01
project_end_date: 2023-09-30
study_section: Endocriniology A[ENDA]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-10-01
project_abstract:
Brown adipose tissue (BAT) dissipates energy through UCP1-mediated uncoupled respiration and its activationmay represent a therapeutic strategy to combat obesity. Preliminary studies identified a novel role of CD47in regulating BAT function and its contribution to energy homeostasis and the development of obesity.CD47 a ubiquitously expressed cell membrane receptor implicated in self-recognition and immune functionwas upregulated in adipose tissue from obese animals. Moreover CD47 deficiency protected mice from diet-induced obesity (DIO) through activation of BAT function (e.g. enhanced mitochondria uncoupling and heatproduction) and increased energy expenditure. These data suggest that CD47 is a negative regulator of BATactivity. Therefore inhibition of CD47 signaling might be a novel anti-obesity strategy which is furthersupported by a recent human genome-wide study showing the association of single-nucleotide polymorphismsin CD47 gene with body weight and BMI. In this proposal the mechanisms by which CD47 downregulatesbrown fat cell function will be determined in Aim 1. The contribution of brown adipocyte specific CD47deficiency on obesity development will be determined in Aim 2. Whether inhibition of CD47 signaling by CD47-antisense oligo (ASO) treatment activates BAT and prevents/ameliorates obesity development in animalmodels will be determined in Aim 3. These studies will not only provide novel information on the mechanismsby which CD47 down-regulates brown fat function and its contribution to energy homeostasis and thedevelopment of obesity but also test the anti-obesity potential of a CD47-ASO in obese mouse models.Therefore these studies have clinical significance.

project_terms:
Adipocytes;Adipose tissue;Animal Model;Animals;Antisense Oligonucleotides;Attenuated;Body Weight;Body fat;Body mass index;Brown Fat;CD47 gene;Carnitine Palmitoyltransferase I;Cell Line;Cell membrane;Cell physiology;Cells;Complex;Cyclic AMP;Cyclic GMP;Data;Development;Diet;Eating;Energy Intake;Energy Metabolism;Exhibits;Fatty acid glycerol esters;Functional disorder;Genes;Genotype;High Fat Diet;Homeostasis;Human Genome;In Vitro;Insulin Resistance;Investigation;Knockout Mice;Mediating;Membrane;Metabolic;Mitochondria;Modeling;Molecular;Mus;Nerve;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Obesity;Obesity Epidemic;Resistance;Respiration;Risk Factors;Rodent;Rodent Model;Role;Signal Pathway;Signal Transduction;Single Nucleotide Polymorphism;System;Testing;Therapeutic;Thermogenesis;Tissues;Wild Type Mouse;Work;adipocyte differentiation;blood glucose regulation;clinically significant;combat;comorbidity;diet-induced obesity;fatty liver disease;genome-wide analysis;human subject;immune function;improved;in vivo;knock-down;lipid biosynthesis;lipid metabolism;mouse model;novel;novel therapeutic intervention;obesity development;obesity genetics;obesity treatment;oxidation;prevent;receptor;therapeutic target;tool

public_health_relevance:
Obesity an imbalance of energy intake and energy expenditure is a major risk factor for the development ofinsulin resistance and type 2 diabetes. Preliminary studies identified that CD47 is a novel regulator of obesity-associated brown fat cell dysfunction. In this application while delineating mechanisms of CD47 to regulatebrown adipocyte function study will also focus on the development of novel therapeutic strategies in thetreatment of obesity and its associated metabolic complications.


application_id: 10597524
project_number: 5I01RX002316-06
project_title: Force Feedback Redistribution & Eccentric-Focused Rehab post-SCI
administering_ic: VA
award_notice_date: 2022-04-21
opportunity_number: RX-16-012
application_type: 5
activity_code: I01
ic: RX
serial_number: 002316
project_start_date: 2017-04-01
project_end_date: 2023-03-31
study_section: Spinal Cord Injury/Disorders & Neuropathic Pain[RRDA]
contact_pi_person_id: 1904515
contact_pi: HOWLAND, DENA R.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-04-01
project_abstract:
Extensor muscles of the leg are actively involved in weight support and walking activities. These muscles areextensively linked by inhibitory bidirectional force dependent pathways that contribute to the successfulexecution of a range of functional behaviors including locomotion. These reflex pathways are thought to arisefrom Golgi tendon organs and are believed to regulate limb stiffness and promote inter-joint coordination duringmovements. The relative magnitudes of these linkages in the two directions between any two muscles varyacross control decerebrate animals when quiescent but obey a predominantly proximal to distal gradientduring stepping on a treadmill. This finding indicates that the strength and distribution of these reflex pathwaysare subject to modulation in a task-dependent manner. Our preliminary data suggest that thoracic spinal cordlateral hemisection immediately and persistently alters the normal distribution and a dominant distal-to-proximal inhibitory gradient emerges. Animals with this lesion do not exhibit clasp-knife inhibition aphenomenon known to be mediated by receptors other than Golgi tendon organs and that results from bilateralinjury to the dorsal half of the spinal cord. The change in the strength and distribution of force feedback thatwe have observed is correlated with diminished limb stiffness and poor weight acceptance during locomotortasks  both of which are challenging problems seen in humans with spinal cord injuries. These findingsprovide new insight into potential mechanisms contributing to disruption of motor function following injury andidentify a new potential rehabilitation strategy. Our guiding hypothesis is that SCI-induced force-feedbackdysregulation results in strong inhibition directed toward proximal muscles contributes to inadequatelimb stiffness during weight support phases of movement and can be reversed using eccentric-focused training. The current application has evolved from collaborative work using a large animal modelacross two established laboratories bringing together expertise in spinal cord injury plasticity force feedbackand motor control. The proposed studies are divided into two sets of experiments. The first set will carefullycharacterize the impact of a low thoracic hemisection on gait kinematics during subphases where inhibitoryforce feedback is thought to be most active (Aim 1a). These phases typically are associated with coordinatedeccentric activity and/or weight acceptance/support. Pre- and post-SCI data across time will be compared. Inthe same animals a comprehensive picture of force-feedback organization following SCI will be developedduring terminal decerebrate studies at two chronic time points (Aim 1b). Both standing and walkingpreparations in combination with mechanographic approaches will be used to test task-specificity ofheterogenic force feedback responses in specific muscle combinations. In the second set of experiments thebasic experimental design is the same except that eccentric-focused training will be introduced at 2 wks post-SCI. This allows animals used in Aims 1a and 1b to serve as the controls for Aims 2a and 2b. Eccentrictraining will use different downslope gait tasks to more strongly activate force feedback circuitry. Gaitkinematics will be carefully assessed during select subphases to test for training effects during different flat anddownslope tasks (Aim 2a) and decerebrate mechanographic studies used to characterize training effects onforce dependent organization at the level of specific muscle combinations. Histology will be completed in allanimals to verify lesion characteristics. Data generated in the proposed work will be compared with an existinglaboratory database containing force feedback findings from control decerebrate preparations to reduce thenumber of animals used. Collectively these studies will provide important information for evidence-basedrehabilitation of motor skills by understanding the gait-associated impact of disrupting force feedback (Aim 1a)the extent of the disruption of this intralimb control system following SCI (Aim 1b) and the potential to alter thisdisruption at the voluntary gait (Aim 2a) and basic reflex levels (2b) using a physical training approach.

project_terms:
Address;Adult;Animal Model;Animals;Behavior;Bilateral;Characteristics;Chest;Chronic;Cicatrix;Data;Data Collection;Databases;Decerebrate State;Development;Disease;Distal;Dorsal;Experimental Designs;Extensor;Feedback;Felis catus;Gait;Goals;Golgi Tendon Organs;Health;Histology;Human;Injury;Joints;Knowledge;Laboratories;Lateral;Leg;Lesion;Limb structure;Link;Locomotion;Locomotor training;Maps;Mediating;Mission;Modeling;Motor;Motor Skills;Movement;Muscle;Normal Statistical Distribution;Pathway interactions;Performance;Phase;Physical Rehabilitation;Preparation;Procedures;Production;Productivity;Quality of life;Ramp;Recovery;Reflex action;Rehabilitation therapy;Research;Research Proposals;Specificity;Spinal;Spinal Cord;Spinal Cord Lesions;Spinal cord injury;Stains;System;Testing;Thoracic spinal cord structure;Time;Tissues;Training;Veterans;Walking;Weight;Work;base;care systems;design;evidence base;experimental study;force feedback;gait examination;gait rehabilitation;improved;injured;innovation;insight;kinematics;locomotor tasks;motor control;motor disorder;motor recovery;motor rehabilitation;nervous system disorder;novel;receptor;rehabilitation strategy;relating to nervous system;response;translational model;treadmill

public_health_relevance:
The mission of the Spinal Cord Injury & Disorders System of Care is to support promote andmaintain the health independence quality of life and productivity of veterans with SCIthroughout their lives. The current research proposal addresses these needs through basicanimal studies which assess the effects of SCI and a novel rehabilitation strategy. Coordinationof muscles in each leg and appropriate limb stiffness are critical for weight support and walking.Even though not directly damaged the basic system responsible lying partially in the musclebecomes dysfunctional post-SCI. This study will increase understanding of and test a newrehabilitation strategy designed to reverse these changes and improve weight support andwalking. The long term goal is enhanced recovery for those with SCIs. Knowledge gained alsomay be relevant for other neurological disorders with loss of connections and walking difficulty.


application_id: 10592236
project_number: 5I01BX003274-05
project_title: The Vagus Nerve in Lung Disease
administering_ic: VA
award_notice_date: 2022-05-10
opportunity_number: BX-17-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 003274
project_start_date: 2018-04-01
project_end_date: 2024-03-31
study_section: Respiration[PULM]
contact_pi_person_id: 2084836
contact_pi: YU, JERRY (JUN)
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-04-01
project_abstract:
Pulmonary neuroendocrine (PNECs) cells are widely distributed throughout theairway mucosa. These cells can be solitary or aggregated to form neuroepithelialbodies (NEBs) which are richly innervated by the vagus nerve. PNECs/NEBs areimportant for early phases of lung development and also associated with stem cellniches in the airways. They are airway sensors. Airway sensory receptors arebiosensors that detect lung inflammation and injury through various mediators andcytokines. This information is transmitted through vagal afferents to the brain andproduces a host of responses that regulate the pathophysiological process.Increasing evidence suggests that the vagus nerve plays an important role in avariety of pulmonary diseases from asthma COPD ARDS to lung cancer.Pulmonary fibrosis (PF) can result from a variety of insults to the lung. Lung repairfollowing an insult-induced injury is a complex process involving both resident cellsand recruited cells. The progression of PF results from a network of interactionsamong mediators cytokines and growth factors derived from inflammatoryendothelial and epithelial cells which leads to lung remodeling deposition ofcollagen limitation of gas exchange and dyspnea. The vagus nerve is closelyrelated to each component of this network thus its function may influence theoutcome of PF. Since lung injury is a major component in the development of PFand harmful insults to the lung may stimulate the NEB-Vagal System (NVS) a novelhypothesis that activation of the NVS promotes lung fibrosis will be tested. [If thishypothesis is correct suppression of the NVS should attenuate fibrosis whereasstimulation of the NVS should promote fibrosis. By examining lung fibrosis inbleomycin treated mice in which the NVS is either stimulated or suppressed(vagotomy medication gene manipulation or cell adoptive transfer) and byassessing well-established cellular and molecular pathways that lead to PF withdifferent techniques (histology physiology cytology and biochemistry) theunderlying neural mechanisms will be delineated.] Successful completion of thestudies will establish a novel neural mechanism in the pathogenesis of PF. [Thispotentially may lead to a new pharmacological approach to treat or to limit chronicfibrotic diseases in the Veteran population.]

project_terms:
Acetylcholine;Acute Respiratory Distress Syndrome;Address;Adoptive Cell Transfers;Agonist;Asthma;Attenuated;Biochemical;Biochemistry;Biological;Biosensor;Brain;Bronchoalveolar Lavage;Cell Count;Cells;Cessation of life;Chronic;Chronic Obstructive Pulmonary Disease;Cicatrix;Collagen;Complex;Cytology;Data;Deposition;Development;Disease;Dyspnea;Endothelial Cells;Epithelial Cells;Fibroblasts;Fibrosis;Gases;Gene Expression;Growth Factor;Histology;Hospitals;Immune response;Inflammatory;Injury;Lead;Lung;Lung diseases;Malignant neoplasm of lung;Mammals;Mediating;Mediator of activation protein;Molecular;Mus;Myofibroblast;Nerve;Nerve Block;Neural Pathways;Neuraxis;Neuroendocrine Cell;Neuroepithelial Bodies;Neuroimmune;Neurosecretory Systems;Outcome;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacology;Phase;Physiology;Plasma;Play;Process;Pulmonary Fibrosis;Pulmonary Inflammation;Research;Respiratory Mucosa;Role;Sensory Receptors;Severities;System;Techniques;Testing;Transforming Growth Factor beta;Vagotomy;Vagus nerve structure;antagonist;chemical release;cytokine;effective therapy;fibrogenesis;fibrotic lung disease;genetic manipulation;improved;indium-bleomycin;lung development;lung injury;lung repair;military veteran;mouse model;neuromechanism;novel;novel strategies;patient population;protein expression;receptor;recruit;sensor;stem cells;vagus nerve stimulation

public_health_relevance:
Lung diseases are a major cause of illness and death in the Veteran population. Many of thediseases are related to lung fibrosis (LF) which is due to increased collagen and has no effectivetreatment. In the lung there are specialized neuroendocrine cells connected to nerves forming aneuroendocrine system (NS). The NS is essential for lung repair and influences progression ofpulmonary diseases. We hypothesize that the NS promotes LF. We examined biochemistryphysiology and histology of both lungs in a mouse model for LF with one lung denervated andcompared severity of the LP. Indeed we found that a chemical released from the NS can promoteLF. In this application we will investigate the mechanism. Since pulmonary diseases related to LFform a major pulmonary patient population at VA hospitals successful completion of the studies willestablish a novel neural mechanism in the lung disease and may improve VA patient management.


application_id: 10586977
project_number: 1I21RX003872-01A1
administering_ic: VA
award_notice_date: 2022-11-21
opportunity_number: RX-22-011
application_type: 1
activity_code: I21
ic: RX
serial_number: 003872
suffix: A1
project_start_date: 2022-12-01
project_end_date: 2024-11-30
study_section: Rehabilitation Research and Development SPiRE Program[RRDS]
contact_pi_person_id: 15804087
contact_pi: CLEMENS, SHEILA M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-12-01
project_title:
Identifying the magnitude and impact of pelvic floor disorders in Veterans with lower limb amputation

project_abstract:
Pelvic floor disorders (PFDs) is the broad term used to describe a number of impairments that affect millions ofwomen and men in the U.S. Symptoms of PFDs resulting from over- or underactivity of pelvic musculaturemanifest in a variety of ways including urinary and fecal incontinence urinary frequency or urgency as wellsexual dysfunction and pelvic pain syndromes. Pelvic floor disorders are poorly understood in people withphysical disabilities and Veterans with lower limb amputation (LLA) are one such group of individuals. Pelvicfloor disorders are effectively managed with conservative non-pharmacological treatment but left undiagnosedcan adversely affect many facets of functioning and well-being. People with LLA frequently exhibit conditionsassociated with PFDs in the non-LLA population including low back pain and heightened fall risk yet thepresence of PFDs have not been systematically assessed in individuals with LLA. With over a million peopleliving with LLA in the U.S. this may pose a significant health burden that is currently not being addressed. Theoverall objective of this proposal is to better understand the magnitude and impact of PFDs on health-relatedquality of life in Veterans with LLA. We will explore the prevalence of PFDs amongst men and women with LLAand the physical and behavioral sequalae associated with the presence of symptoms of PFDs. We propose tocomprehensively address the gaps in knowledge by administering surveys including psychometrically soundoutcome measures to assess symptoms of PFDs to 200 study participants of both sexes (n  100 females). Allsurveys will be remotely administered to participants to optimize convenience and study enrollment. Ourproposed study has three aims:Specific Aim 1: To estimate the prevalence of PFDs in a cohort of male and female Veterans with LLA.This descriptive aim will provide seminal data on the magnitude of PFDs in Veterans with LLA and can serve asa proxy estimate for rates in the LLA population in general. Estimates will be provided based on sex and level ofLLA (trantibial transfemoral etc.) The primary measure of PFD symptoms will be the Pelvic Floor DistressInventory (PFDI-20) with secondary measures administered to explore other aspects related to PFDs in menand women. Furthermore this aim will assess the feasibility of collecting self-reported pelvic/urogenitalinformation and the acceptability by Veterans to PFD-related survey items.Specific Aim 2: To examine associations between PFDs and low back pain and prosthetic mobility inVeterans with LLA. This aim is designed to determine physical sequelae related to the presence of PFDs. Weexpect that (2A) there will be significant relationships between PFDs and scores on the Oswestry Disability Indexas a measure of low back pain and (2B) lower scores of prosthetic mobility as measured by the Prosthetic LimbUsers Survey of Mobility will be associated with PFDs.Specific Aim 3: To examine the extent to which PFDs contribute to fall risk and levels of activityparticipation in Veterans with LLA. This aim will examine the impact of reported PFDs relative to behaviorconstructs affecting health-related quality of life. We anticipate that (3A) there will be significant levels ofassociation between PFDs with reported fall occurrence and that (3B) the presence of PFDs will be associatedwith decreased activity participation both social and work related.Impact. Successful completion of this work will establish an evidence base regarding PFDs in male and femaleVeterans with LLA. This SPiRE presents an opportunity to shift the paradigm of LLA rehabilitation by elevatingthe consideration of often-ignored variables that could be contributing to increased rates of falls low back painand poorer quality of life in this population.

project_terms:
Address;Affect;Behavioral;Data;Distress;Enrollment;Equipment and supply inventories;Exhibits;Fecal Incontinence;Female;Femur;Genitourinary system;Health;Impairment;Increased frequency of micturition;Individual;Knowledge;Left;Limb Prosthesis;Low Back Pain;Lower Extremity;Measures;Outcome Measure;Participant;Patient Self-Report;Pelvic Floor Disorders;Pelvic Pain;Pelvic floor structure;Pelvis;Personal Satisfaction;Persons;Population;Prevalence;Prosthesis;Proxy;Psychometrics;Quality of life;Rehabilitation therapy;Reporting;Seminal;Sexual Dysfunction;Surveys;Symptoms;Syndrome;Urinary Incontinence;Veterans;Woman;Work;behavioral construct;cohort;design;disability;evidence base;fall risk;falls;health related quality of life;indexing;limb amputation;male;men;micturition urgency;physically handicapped;remote administration;sex;social;sound

public_health_relevance:
Pelvic floor disorders (PFDs) is the broad term used to describe a number of conditions that affect millions ofwomen and men in the U.S. Pelvic floor disorders resulting from over- or underactivity of pelvic muscles resultin a variety of symptoms including urinary and fecal incontinence urinary frequency or urgency as well sexualproblems and pelvic pain syndromes. Despite the common occurrence of PFDs there is no research examiningif PFDs are a problem for men and women with lower limb amputation (LLA). Common impairments of low backpain (LBP) falls and mobility deficits in people with LLA could be associated with coexisting undiagnosed PFDs.The overall purpose of this research is to better understand the extent at which PFDs occur in Veterans with LLAand any impact on lifestyle and functioning with their prosthesis. The clinical significance of the study will be inestablishing an evidence base of PFDs in people with LLA and providing a foundation for future research on theevaluation and treatment of PFDs in people with LLA.Project Narrative


application_id: 10582848
project_number: 1I01BX005889-01A1
project_title: Sex differences in ASK1-mediated pulmonary fibrosis
administering_ic: VA
award_notice_date: 2023-04-24
opportunity_number: BX-22-001
application_type: 1
activity_code: I01
ic: BX
serial_number: 005889
suffix: A1
project_start_date: 2023-04-01
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZRD1 PULM-N (01)]
contact_pi_person_id: 1860187
contact_pi: WATERS, CHRISTOPHER M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Idiopathic pulmonary fibrosis (IPF) is a devastating illness with a poor prognosis andboth the incidence and prevalence of IPF among U.S. Veterans has increased during the last 10years. In addition the occurrence of pulmonary fibrosis developing following acute lung injuryhas been prominent in survivors of COVID-19. The pathogenic mechanisms underlying thedevelopment of fibrosis are not completely understood. The fundamental processes developdue to genetic abnormalities and/or environmental factors that lead to repetitive injury to thealveolar epithelium dysregulated epithelial repair mechanisms and an increase in fibroblastsand (apoptosis-resistant) myofibroblasts that produce excessive extracellular matrix. IPF ismore prevalent in men than in women but the reasons for the differences are not wellunderstood. Apoptosis signal regulating kinase 1 (ASK1) is a mitogen activated protein kinasekinase kinase (MAP3K5) that is activated by oxidative stress and causes stimulation of MAPKpathways but the downstream signaling pathways are highly tissue dependent and have notbeen investigated in the context of pulmonary fibrosis. The overall objective of this applicationis to establish that ASK1 is a central mediator of the development of pulmonary fibrosis. Thecentral hypothesis of this proposal is that ASK1 promotes pulmonary fibrosis by p38-mediatedinflammation and stimulation of ERK1/2-mediated pathways and that these pathways areregulated in part by sex hormones. The rationale for the proposed research is that theidentification of ASK1 as a central regulator in the development of fibrosis will advance ourfundamental understanding and lead to new therapeutic options for the treatment of IPFpatients. These mechanisms will be investigated using both ASK1-deficient mice and an ASK1inhibitor in a bleomycin-induced fibrosis mouse model. In addition primary cultures of alveolartype II epithelial cell and fibroblasts as well as cell lines with knockdown of ASK1 and other keymediators will be used to define specific ASK1-dependent pathways. Aim 1 will test thehypothesis that fibrosis is exacerbated by repetitive oxidative stress that activates p38 signalingvia ASK1 and that these pathways are regulated by sex hormones. Aim 2 will test thehypothesis that sex-dependent differences in ASK1 and ERK1/2 activation stimulate pro-fibroticpathways. These studies will advance our fundamental understanding of fibrosis and sexdifferences and establish ASK1 as a potential therapeutic target to reduce the progression ofIPF.

project_terms:
Acute Lung Injury;Aging;Alveolar;Apoptosis;Bleomycin;COVID-19 survivors;Cell Culture Techniques;Cell Line;Cessation of life;Chronic Disease;Data;Development;Diagnosis;Disease;Disease Progression;Environmental Risk Factor;Epithelial Cells;Epithelium;Estrogen Receptors;Exposure to;Extracellular Matrix;Extracellular Signal Regulated Kinases;Female;Fibroblasts;Fibrosis;Gases;Goals;Gonadal Steroid Hormones;Hyperoxia;Incidence;Inflammation;Injury;JUN gene;Knowledge;Life Expectancy;Lipopolysaccharides;MAP Kinase Gene;MAP Kinase Kinase Kinase;MAP3K5 gene;MAPK3 gene;MAPK8 gene;Macrophage;Mechanical ventilation;Mediating;Mediator;Mesenchymal;Modeling;Molecular Abnormality;Morbidity - disease rate;Mus;Myofibroblast;NADPH Oxidase;Oxidative Stress;Oxygen;Pathogenicity;Pathway interactions;Patients;Phosphothreonine;Pirfenidone;Prevalence;Process;Prognosis;Proteins;Pulmonary Fibrosis;Regulation;Reporting;Research;Resistance;Role;Sex Differences;Signal Pathway;Signal Transduction;Survivors;TXN gene;Testing;Therapeutic Intervention;Tissues;Transforming Growth Factor beta;Veterans;Woman;alveolar epithelium;epithelial injury;epithelial repair;fibrotic lung;idiopathic pulmonary fibrosis;improved;inhibitor;knock-down;lung injury;male;men;mortality;mouse model;new therapeutic target;nintedanib;novel;novel therapeutic intervention;novel therapeutics;p38 Mitogen Activated Protein Kinase;response;severe COVID-19;sex;targeted treatment;therapeutic target

public_health_relevance:
Pulmonary fibrosis is a devastating illness that involves progressive remodeling and scarring of lungtissue that can eventually lead to poor gas exchange. The incidence of idiopathic pulmonary fibrosis isincreasing worldwide including among Veterans mortality rates are high and the average life expectancy is 3to 5 years after diagnosis. This proposed study will investigate a previously unrecognized mechanisticpathway that contributes to the development of pulmonary fibrosis and will identify potential targets fortherapeutic intervention to reduce fibrosis.


application_id: 10560494
project_number: 5I01CX001353-06
project_title: Modulation of mitochondrial respiration to treat colitis
administering_ic: VA
award_notice_date: 2023-03-20
opportunity_number: CX-21-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 001353
project_start_date: 2016-10-01
project_end_date: 2025-12-31
study_section: ZRD1-GAST-L(01)1
contact_pi_person_id: 1883566
contact_pi: BARRETT, TERRENCE A.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-01-01
project_abstract:
The importance of mucosal healing in inflammatory bowel disease (IBD) derives from clinical data thatdemonstrate it to be a predictor of remission. Unfortunately many IBD patients remain refractory or loseresponsiveness to therapies leading to persistent mucosal ulceration. Prospective pediatric studies show thatreduced mitochondrial gene expression predict unfavorable outcomes in ulcerative colitis (UC). Consistentlyincreased expression of mitochondrial respiratory chain genes has been shown to predict favorable Crohnsdisease (CD) outcomes. Based on these results and our own data we hypothesize that a critical driver of chroniculceration in IBD is the failure of intestinal epithelial cells (IEC) to increase mitochondrial respiration. In studiesleading up to this submission we found that mitochondrial deficiency caused poor ulcer healing due to inadequatecrypt fissioning occurring at ulcer edges (Progress Report). These findings led us to develop a novel gold (Au)-based drug based on the current safe and effective gold therapy for Rheumatoid arthritis (Auranofin). This newdrug AuPhos localizes to mitochondria where it increases mitochondrial respiration and mitochondrial reactiveoxygen species (mtROS) production. Induction of low levels of endogenous mtROS are known to promotehealthy adaptive responses in cells including anti-oxidant enzyme activities (Background). In preliminarystudies we found that oral AuPhos 1) enhances mucosal repair in DSS colitis 2) increases IEC mitochondrialoxygen consumption rate (OCR) and oxidative phosphorylation (OXPHOS) 3) mtROS and H2O2 production inIEC as well as 4) phosphoinositides-3 kinase (PI3K) and nuclear factor erythroid 2-related factor (Nrf2) signalingwith 5) improved expression of proteins that induce mitochondrial biogenesis [peroxisome proliferator activatedreceptor- coactivator 1 alpha (PGC1) and transcription factor A mitochondrial (TFAM). Studies proposed inAim 1 interrogate mitochondrial function under baseline conditions to allow assessment of AuPhos-inducedchanges in mitochondrial mass activity (mtROS) and OCR ATP turnover electron transport chain (ETC) activityinduction of adaptive responses [anti-oxidant catalase MnSOD (superoxide dismutase) and glutathione(reduced/oxidized)] as well as assess changes in tissue oxidant stress (4HNE protein carbonylationnitrotyrosine IHC). Aim 2 will build upon these studies by evaluating AuPhos effects in TNF-stimulated smallbowel (SB) and colonic organoids from veterans (normal and IBD). Studies in 3D organoids will allow formechanistic testing of AuPhos-induced crypt budding and IEC gene expression. Results of Aim 2 will instructstudies in Aim 3A that study therapeutic effects of AuPhos on IEC gene expression and crypt fissioning thatheal ulcers in DSS colitis. In Aim 3B scRNAseq analysis of human biopsies incubated with AuPhos will allowus to examine induction of mitochondrial gene expression in discrete IEC clusters. Proposed studies are drivenby a novel hypothesis that restoration of IEC mitochondrial respiration is a key step in mucosal healing. Togetherthese preclinical studies with a VA-sponsored new drug (AuPhos) have the potential of transitioning this agentto the therapy of IBD in veterans.

project_terms:
3-Dimensional;3-nitrotyrosine;Acceleration;Antioxidants;Auranofin;Bioenergetics;Biogenesis;Biopsy;Cell Survival;Cells;Childhood;Chronic;Clinical;Clinical Data;Colitis;Colon;Crohn's disease;Data;Disease;Disease Outcome;Disease remission;Distant;Electron Transport;Epithelial Cells;Event;Failure;Gene Expression;Genes;Glutathione;Goals;Gold;Gold Compounds;Healthcare Systems;Human;Hydrogen Peroxide;Immunosuppression;In Vitro;Incubated;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Intestines;Messenger RNA;Mitochondria;Modeling;Morbidity - disease rate;Mucositis;Mucous Membrane;Mus;Oral;Organ;Organoids;Outcome;Oxidative Phosphorylation;Oxidative Stress;Oxygen Consumption;PPAR gamma;Patients;Pharmaceutical Preparations;Phosphatidylinositols;Phosphotransferases;Production;Progress Reports;Proteins;Reactive Oxygen Species;Refractory;Research;Respiration;Respiratory Chain;Rheumatoid Arthritis;Risk;Role;SOD2 gene;Secondary to;Signal Induction;Signal Transduction;Small Intestines;Superoxide Dismutase;TNF gene;Testing;Therapeutic;Therapeutic Effect;Therapeutic Studies;Tissues;Toxicology;Ulcer;Ulcerative Colitis;Veterans;Work;antioxidant enzyme;catalase;chronic ulcer;cytokine;dextran sulfate sodium induced colitis;enzyme activity;healing;improved;in vivo;innovation;intestinal crypt;intestinal epithelium;mtTF1 transcription factor;murine colitis;novel;novel therapeutics;nuclear factor-erythroid 2;oxidant stress;preclinical study;prospective;protein expression;repaired;response;restoration;synergism;uptake

public_health_relevance:
The increase in inflammatory bowel disease (IBD) among veterans in recent years presents a significantclinical problem in the VA healthcare system. Major concerns for IBD veteran patients are the increaseddisease morbidity and risk of therapies. Further research is needed to develop safe and effective agents thatenhance mucosal repair and reduce immune-suppression. Previous work from our lab has indicates thatmitochondrial respiration promotes ulcer healing. This finding led us to postulate that increasing mitochondrialrespiration constitutes a novel therapeutic goal in IBD. To improve mitochondrial function in IBD we developedAuPhos an oral agent that enhances mitochondrial electron transport that potentiates mitochondrialbio-energetics and mitochondrial reactive oxygen species (mtROS) production. The current project willascertain the impact of this novel gold compound (AuPhos) on mitochondrial function and ulcer healing inmouse models of colitis as well as biopsy tissue explants from veterans with IBD.


application_id: 10552612
project_number: 5IK2BX004618-04
project_title: Psychological deficits after low level blast exposure: role of neurovascular disruption
administering_ic: VA
award_notice_date: 2023-01-20
opportunity_number: BX-19-008
application_type: 5
activity_code: IK2
ic: BX
serial_number: 004618
project_start_date: 2020-01-01
project_end_date: 2024-12-31
study_section: ZRD1-NURC-H(01)
contact_pi_person_id: 14823099
contact_pi: HUBBARD, WILLIAM BRAD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-01-01
project_abstract:
Many Veterans experience occupational exposure to low-level blast (LLB) during normal training operationsincluding but not limited to breaching activity. These Veterans are at increased risk for persistingneuropsychological impairment due to repeated LLB exposure over several deployments with limited time forrecovery between exposures. The extent of the long-term consequences after cumulative LLB exposure isunknown though reports show that deficits can be present late in life. Furthermore the resultant post-traumaticstress disorder (PTSD)-related behavioral deficits are more pronounced in soldiers and Veterans with a historyof chronic blast exposure. There is no clear understanding of which pathological mechanisms drive this chronicPTSD phenotype after LLB exposure. A few animal models have been established to address this incompleteunderstanding of the pathobiological mechanisms underlying LLB exposure. These models replicate thechronic depressive anxiogenic and PTSD-related traits observed in Veterans though there are manyknowledge gaps in what contributes to these chronic deficits. In general blast exposure causes acute blood-brain barrier (BBB) and neurovascular unit abnormalities that can persist over time. The overall objective of thisapplication is to determine the timing of acute neurovascular dysfunction after LLB and how repeating LLBcontributes to chronic neurovascular impairment and neuropsychological deficits. Our central hypothesis is thatLLB repeated at a time interval of maximal BBB impairment after the first LLB will result in persistent PTSD-like behavioral traits. Additionally these deficits will be associated with changes in the profile of serum-derivedexosomal miRNAs and platelet bioenergetics. These hypotheses were formulated based on current literatureand our own published and preliminary data demonstrating anxiety and amygdalar BBB disruption after blastexposure. By utilizing a multimodal blast simulator at the University of Kentucky these studies will be able toexamine the longitudinal behavioral profile coupled with pathologically relevant biomarkers. These hypotheseswill be tested in three specific aims: 1) examine acute neurovascular deficits after a single LLB exposure anddetermine their relationship to longitudinal behavioral traits 2) determine how repeating LLB at various timeintervals based on the acute neurovascular profile contributes to exacerbated or prolonged PTSD-likebehavioral traits and chronic neurovascular impairment 3) identify if modulating either acute or chronicneurovascular health using sildenafil will mitigate long-term PTSD-like behavioral traits. This research willdrastically improve our understanding of the effects of LLB as well as potentially identify novel clinically-relevant biomarkers. The proposed research is significant because it will establish a platform to understand thechronic effects of occupational blast exposure which affects many Veterans. In addition this line ofinvestigation can lead to better therapeutic targeting of neurovascular dysfunction to improve neurologicaloutcome in aging Veterans. In addition to the research products gained by this proposal the applicant willgreatly benefit from a mentoring team that has a variety of preclinical translational and clinical perspectiveswhich will contribute to a well-rounded career development plan. The training program will add additionaltechniques to Dr. Hubbards repertoire contributing not only to this proposal but to his VA research programmoving forward. With prior knowledge in blast injury modeling additional behavioral and biomarker assays willgreatly advance his research expertise. In the latter years of this proposal Dr. Hubbard will continue to expandgrant writing student mentoring collaborative research and presentation skills required of independentresearchers. Overall the proposed studies and diverse mentoring program will culminate in producing a highlysuccessful independent VA researcher.

project_terms:
3-Dimensional;Acute;Address;Affect;Aggressive behavior;Aging;Amygdaloid structure;Animal Model;Animals;Anxiety;Behavior;Behavior assessment;Behavioral;Bioenergetics;Biological Assay;Biological Markers;Blast Injuries;Blood - brain barrier anatomy;Blood Platelets;Blood Vessels;Brain;Brain region;Cerebrovascular Circulation;Chronic;Chronic Post Traumatic Stress Disorder;Clinical;Coupled;Data;Development;Development Plans;Euthanasia;Exposure to;Foundations;Functional disorder;Grant;Health;Image;Immunohistochemistry;Impairment;Investigation;Kentucky;Knowledge;Life;Literature;Matrix Metalloproteinases;Measures;Mentors;MicroRNAs;Military Personnel;Modeling;Nervous System Trauma;Neurocognitive;Neurologic Deficit;Neurologic Dysfunctions;Neurological outcome;Neurons;Neuropsychology;Occupational;Occupational Exposure;Outcome;Pathologic;Peripheral;Phenotype;Post-Traumatic Stress Disorders;Predisposition;Proteins;Publishing;Rattus;Recording of previous events;Recovery;Reporting;Research;Research Personnel;Risk;Rodent;Rodent Model;Role;Serum;Social Interaction;Soldier;Stains;Symptoms;Techniques;Testing;Therapeutic;Time;Tissues;Training;Training Programs;Universities;Vascular Diseases;Veterans;Writing;arterial spin labeling;behavior test;behavioral impairment;biomarker identification;blast exposure;blood-based biomarker;blood-brain barrier disruption;career development;cerebrovascular;clinically relevant;cohort;depressive symptoms;exosome;experience;improved;inhibitor;military veteran;multimodality;neuroimaging;neuropathology;neurovascular;neurovascular unit;novel;operation;phosphodiesterase V;pre-clinical;pressure;primary outcome;programs;psychologic;psychological outcomes;restoration;sildenafil;skills;stress related disorder;student mentoring;therapeutic target;time interval;trait

public_health_relevance:
Many Veterans experience low-level blast (LLB) exposure during tour of duty and training operations. Theextent of chronic post-traumatic stress disorder (PTSD) traits after cumulative LLB exposure is unknown.Additionally there is no clear understanding of which pathological mechanisms drive impairment after LLBexposure. The overall objective of this application is to determine the timing of acute neurovascular dysfunctionafter LLB and how repeating LLB contributes to chronic neurovascular impairment and neuropsychologicaldeficits. We will examine the behavioral profile and neurovascular outcomes after LLB coupled withpathologically relevant biomarkers. This research will improve our understanding of the effects of LLB andidentify biomarkers for neurological injury. The proposed mentored research plan will increase understandingof the chronic effects of occupational blast exposure to identify therapies which will improve Veteran healthwhile providing a foundation for the applicants independent VA research program.


application_id: 10516043
project_number: 5I01BX004639-04
project_title: HDL as a therapeutic target for sepsis
administering_ic: VA
award_notice_date: 2022-10-13
opportunity_number: BX-18-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 004639
project_start_date: 2019-10-01
project_end_date: 2024-06-30
study_section: ZRD1-SURG-P(01)
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-10-01
project_abstract:
Sepsis is a major health issues for public and for veterans. A recent study conducted in118 VA hospitals showed that 4.1% of patients undergoing surgery developedpostoperative sepsis. The mortality rate of sepsis is high exceeding 30% due to a lackof efficient therapy. A great barrier for sepsis therapy is that sepsis is a multi-factordisease involving endotoxin from bacteria dysregulated response in immune effectorcells all of which lead to cell damage and endothelial dysfunction resulting in organinjuries and septic death which may explain why extensive efforts (more than 100clinical trials) to block one or another component of the inflammatory or coagulationpathways have had little impact on patient survival. Here we propose that targeting anendogenous factor with multi-protective effects against sepsis may present a novelapproach for sepsis therapy and high density lipoprotein (HDL) is such a target. HDL isa major component of circulating blood with multi-protective properties in vascularendothelial cells and immune effector cells. However the levels of HDL decrease by 40-70% in septic patients which is associated with a poor prognosis. Using mice deficientin HDL we recently reported that mice lacking HDL are susceptible to cecal ligation andpuncture (CLP)-induced septic death and increase HDL levels protects CLP-inducedseptic death. These clinical and animal studies indicate that a decrease in HDL levels isa risk factor for sepsis and raising circulating HDL levels may provide an efficienttherapy for sepsis. Reconstituted or synthetic HDL (sHDL) is a new tool for promotingthe biological activity of HDL. In the preliminary study we generated a new type ofsHDL (YGZL3) and showed that the YGZL3 treatment significantly increases HDL levelsand protects mice from CLP- and bacterial-induced septic death indicating that sHDL(YGZL3) is a potential effective therapy for sepsis. Based on our preliminary data andexisting knowledge of HDL biology we hypothesize that sHDL therapy protects sepsisby restoring both HDL level and its multi-protective functions. The objectives of thisgrant are to understand the mechanism(s) underlying sHDL (YGZL3) protection againstsepsis to optimize the treatment regimen and to assess pharmacokinetics and toxicityof sHDL (YGZL3). Completion of this study will provide a body of mechanistic andpreclinical data for a novel sHDL-based therapy for sepsis and position it for futureInvestigational New Drug (IND) studies and rapid clinical translation which will improvethe health of public and veterans.

project_terms:
Animals;Bacteria;Biological;Biology;Blood;Cessation of life;Clinical;Clinical Data;Clinical Trials;Coagulation Process;Data;Disease;Dose;Drops;Drug Kinetics;Effector Cell;Endogenous Factors;Endothelial Cells;Endotoxins;Frequencies;Future;Generations;Grant;Health;High Density Lipoprotein therapy;High Density Lipoproteins;Hospitals;Immune;Immune response;Immunity;In Vitro;Infection;Inflammatory;Inflammatory Response;Investigational Drugs;Knockout Mice;Knowledge;Macrophage;Mediating;Modeling;Mus;Operative Surgical Procedures;Pathogenesis;Pathway interactions;Patients;Play;Positioning Attribute;Postoperative Period;Predisposition;Prognosis;Property;Public Health;Regimen;Reporting;Risk;Risk Factors;Role;Sepsis;Signal Transduction;Testing;Therapeutic;Toxic effect;Treatment Protocols;Vascular Endothelial Cell;Veterans;cecal ligation puncture;cell injury;clinical translation;drug development;effective therapy;endothelial dysfunction;experience;improved;in vivo;innovation;mortality;neutrophil;novel;novel strategies;organ injury;overexpression;pre-clinical;protective effect;reconstitution;response;septic;septic patients;success;targeted treatment;therapeutic target;tool;treatment optimization

public_health_relevance:
Sepsis is a major health issues for public and for veterans. The mortality rate of sepsis is highexceeding 30% due to a lack of efficient therapy. A great barrier for sepsis therapy is that sepsis is amulti-factor disease which may explain why extensive efforts (more than 100 clinical trials) to block asingle component in inflammatory or coagulation pathways have had little impact on patient survival.Here we propose a new approach for sepsis therapy - targeting multiple factors in sepsis with a newtype of synthetic high density lipoprotein (sHDL YDZL3). Our proposal is well-supported by clinicalfindings the existing knowledge of HDL and our preliminary studies. Completion of this study willprovide a body of mechanistic and preclinical data for a novel sHDL-based therapy for sepsis andposition it for future Investigational New Drug (IND) studies and rapid clinical translation which willimprove the health of public and veterans.


application_id: 10515674
project_number: 5I01BX003643-04
project_title: TBI-induced exosome release accelerates Alzheimer's disease pathology
administering_ic: VA
award_notice_date: 2022-10-13
opportunity_number: BX-18-004
application_type: 5
activity_code: I01
ic: BX
serial_number: 003643
project_start_date: 2019-10-01
project_end_date: 2023-09-30
study_section: ZRD1-NURD-C(01)1
contact_pi_person_id: 2275110
contact_pi: BIEBERICH, ERHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-10-01
project_abstract:
Alzheimer's disease (AD) is characterized by build-up of A peptides forming amyloid plaques and hyper-phosphorylation of tau protein forming neurofibrillary tangles a two-fold protein aggregation process leading toprogressive neurodegeneration and cognitive decline. Epidemiological studies show that the risk of developingAD is 4-fold higher in persons who have experienced head trauma or traumatic brain injury (TBI) which isprevalent in Veterans returning from active combat. Reasons for this increased risk are unclear and no strategyto prevent AD pathology exists. A critical barrier to progress is the lack of understanding of how amyloid andtau are rendered neurotoxic and how TBI may induce or accelerate this process. Our goal is to understandand prevent amyloid and tau neurotoxicity and delay the onset and reduce neurodegeneration in ADparticularly when induced or accelerated by TBI in Veterans. Our central hypothesis is that TBI-inducedshear force shakes and repeatedly bends cilia in astrocytes which leads to calcium influx reprogramming ofceramide metabolism and sustained secretion of ceramide-enriched exosomes termed astrosomes(immediate effect). A42 and tau associate with ceramide and turn astrosomes into neurotoxic betasomeseven years after TBI (delayed effect). Betasomes also contain prostate apoptosis response 4 (PAR-4) aprotein sensitizing neurons to ceramide-induced apoptosis. Betasomes are transported to mitochondria wherethey enhance A42 and tau-mediated mitochondrial dysfunction and neurotoxicity. Consistent with ourhypothesis betasomes are detectable in serum from AD patients and 5xFAD mice and induce mitochondrialdamage caspase activation and tau aggregation in N2a cells and primary cultured neurons. Our hypothesispredicts that astrosome secretion association with A42 and tau and neurotoxicity are prevented by blockingTBI-induced calcium influx and ceramide generation. Our expected outcomes include 1) determiningenzymes in upregulation of ceramide and specific calcium channels that are activated by shear force; 2)defining a ceramide composition in astrosomes that induces interaction with A42 tau aggregation andmito/neurotoxicity; 3) identifying ceramide-modulating drugs and calcium channel blockers that preventastrosome secretion betasome formation mitochondrial dysfunction and tau aggregation and neurotoxicity;and 4) quantifying astrosomes and betasomes in serum that indicate severity of TBI-induced AD (TBI-AD) andsuccess of therapeutic treatment. The impact of this project on protection of Veterans and public health willinclude knowledge needed for the development of new treatment strategies that could delay and/or prevent theonset of progressive neurodegeneration in AD in particular when induced by mild TBI in Veterans.

project_terms:
Acceleration;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease patient;Amyloid;Amyloid beta-42;Amyloid beta-Protein;Apoptosis;Astrocytes;Axon;Binding;Brain;Calcium;Calcium Channel;Calcium Channel Blockers;Caspase;Cell secretion;Cells;Ceramides;Cilia;Closed head injuries;Craniocerebral Trauma;Development;Drug Modulation;Enzymes;Generations;Goals;Impaired cognition;Impairment;Induction of Apoptosis;Interruption;Knowledge;Mediating;Metabolism;Mitochondria;Monitor;Mus;Nerve Degeneration;Neurofibrillary Tangles;Neurons;Outcome;Pathology;Patients;Peptides;Persons;Prevention;Process;Prostate;Proteins;Public Health;Research;Risk;Senile Plaques;Serum;Severities;Testing;Therapeutic;Traumatic Brain Injury;Up-Regulation;Vesicle;Veterans;Voltage-Dependent Anion Channel;amyloid peptide;axonal degeneration;cell motility;combat;cytochrome c;diagnostic biomarker;epidemiology study;exosome;experience;hyperphosphorylated tau;inhibitor;lipid metabolism;mild traumatic brain injury;mitochondrial dysfunction;mouse model;neuron loss;neurotoxic;neurotoxicity;novel diagnostics;novel therapeutic intervention;prevent;programs;progressive neurodegeneration;protein aggregation;protein folding;response;success;tau Proteins;tau aggregation;tau-1;uptake

public_health_relevance:
Traumatic brain injury (TBI) resulting from combat is a prevalent head injury among Veterans. TBI can increasethe risk of developing Alzheimer's disease (AD) by 4-fold. AD is characterized by build-up of amyloid peptidesforming plaques and hyper-phosphorylation of tau protein forming neurofibrillary tangles a two-fold proteinaggregation process leading to neurodegeneration and cognitive decline. It is not known how TBI increases therisk of developing AD and how to prevent TBI-induced AD. Our research showed that even mild TBI elicitsshear forces in the brain that make particular cells secrete vesicles called exosomes. These TBI-inducedexosomes bind to amyloid peptide and tau protein and enhance their neurotoxicity. Our goal is to interrupt TBI-induced exosome secretion to prevent or delay the onset of AD in Veterans.


application_id: 10486302
project_number: 2I01BX003405-05A1
project_title: Targeting mitostasis via activation of mitochondrial biogenesis after TBI
administering_ic: VA
award_notice_date: 2022-06-29
opportunity_number: BX-21-003
application_type: 2
activity_code: I01
ic: BX
serial_number: 003405
suffix: A1
project_start_date: 2017-01-01
project_end_date: 2026-06-30
study_section: Special Emphasis Panel[ZRD1 NURC-H (01)]
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adult;Animals;Award;Behavioral;Bioenergetics;Biogenesis;Biological Assay;Brain;Brain Injuries;Cell Count;Cell physiology;Cells;Clinical;Coupled;Data;Diagnosis;Diet;Dose;Energy Metabolism;FDA approved;Female;Glucose;Grant;Hippocampus (Brain);Histologic;Histology;Homeostasis;Impaired cognition;Impairment;Injury;Intervention;Ipsilateral;Knockout Mice;Label;Link;Liquid substance;Magnetism;Mass Spectrum Analysis;Measures;Mediating;Metabolic;Metabolism;Methods;Military Personnel;Mitochondria;Mitochondrial DNA;Modernization;Molecular;Molecular Analysis;Mus;Neurocognition;Neurocognitive;Neurons;Outcome Measure;PPAR gamma;Pathogenesis;Pathology;Pathway interactions;Performance;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Pharmacology;Pioglitazone;Post-Traumatic Stress Disorders;Process;Production;Proto-Oncogene Proteins c-akt;Publishing;Pyruvate;Reactive Oxygen Species;Receptor Signaling;Regimen;Resolution;Sampling;Services;Signal Transduction;Specificity;Synapses;TBI treatment;Techniques;Technology;Testing;Therapeutic;Therapeutic Intervention;Tissues;Transgenic Mice;Traumatic Brain Injury;Treatment Efficacy;Treatment Protocols;Veterans;War;Work;base;brain dysfunction;central nervous system injury;cognitive function;cognitive recovery;cohort;controlled cortical impact;dosage;experience;formoterol;high risk population;improved;in vivo;injured;mRNA Expression;male;metabolomics;military operation;mitochondrial dysfunction;mitochondrial metabolism;molecular marker;morris water maze;neurobehavioral;neurogenesis;neuropathology;novel;novel strategies;object recognition;prevent;primary outcome;prophylactic;protein expression;receptor;response;stable isotope;therapeutic target;therapeutically effective;treatment optimization;white matter


application_id: 10479207
project_number: 1I01BX005254-01A2
project_title: RA synovial fibroblast exosomes(RA-EXo) mediated bone erosion via AhR/TRAF2pathway
administering_ic: VA
award_notice_date: 2022-05-13
opportunity_number: BX-21-001
application_type: 1
activity_code: I01
ic: BX
serial_number: 005254
suffix: A2
project_start_date: 2022-04-01
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZRD1 IMMA-G (01)]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Animal Model;Anti-Tumor Necrosis Factor Therapy;Arthritis;Aryl Hydrocarbon Receptor;Attenuated;Autoimmune;Biological;Biological Availability;Biological Markers;Biological Response Modifiers;Biotin;Bone Development;CRISPR/Cas technology;Cartilage;Cells;Chondrocytes;Chronic;Complex;Cytosol;Data;Development;Diagnosis;Dissociation;Endothelial Cells;Exocytosis;Extracellular Space;Fibroblasts;Future;Guidelines;Health Status;Heat-Shock Proteins 90;High Prevalence;Human;Hyperplasia;Immune;Immunocompetent;Implant;Individual;Inflammation;Invaded;Knock-out;Knowledge;Label;Lead;Ligase;MAPK8 gene;Mediating;Mediator of activation protein;Military Personnel;Modeling;Molecular Target;Mus;Mutate;NF-kappa B;Osteitis;Outcome;Outcome Study;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Pharmacotherapy;Phosphotransferases;Play;Population;Predictive Value;Prevention;Process;Proliferating;Proteins;Publishing;Receptor Activation;Research;Rheumatoid Arthritis;Role;SCID Mice;Severities;Site;Sorting - Cell Movement;Synovial Cell;Synovial Fluid;Synovial Membrane;System;TNF Receptor-Associated Factors;TNF gene;TNF receptor-associated factor 2;TRAF2 gene;Testing;Therapeutic;Tissues;United States Department of Veterans Affairs;Vesicle;Veterans;Virulence Factors;Woman;arthropathies;base;bone;bone erosion;cartilage degradation;cell type;disability;exosome;experimental study;extracellular;improved;in vivo;intercellular communication;joint destruction;joint inflammation;joint injury;member;men;mouse model;novel therapeutics;patient population;personalized medicine;precision drugs;predictive marker;prevent;protein protein interaction;receptor expression;recruit;valosin-containing protein


application_id: 10477234
project_number: 5I01BX004275-04
project_title: Mechanisms linking obesity and abdominal aortic aneurysm
administering_ic: VA
award_notice_date: 2022-09-02
opportunity_number: BX-18-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 004275
project_start_date: 2019-07-01
project_end_date: 2023-06-30
study_section: ZRD1-CARB-R(01)1
contact_pi_person_id: 8777124
contact_pi: KAROUNOS, DENNIS G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-07-01
project_abstract:
Obesity has emerged as a risk factor for human and angiotensin II (AngII)-induced abdominal aorticaneurysms (AAA). Obesity is highly prevalent in Veterans; the Veteran population also has high prevalence ofother risk factors for AAAs (male sex smoking hypertension). To date no single therapy has proven effectiveto blunt progressive growth of AAAs likely due to diverse etiologies underlying AAAs in the human population.Thus therapies must be individualized to target the relevant risk factor(s) such as obesity and itsmechanisms to effectively ameliorate AAA initiation and progression. We previously reported that obesitypromotes AngII-induced AAAs in mice through inflammation in the perivascular adipose tissue. We now havepreliminary data demonstrating that whole body deficiency of serum amyloid A (SAA) profoundly reducesAngII-induced AAAs in the setting of obesity. Moreover our recently published data demonstrate that SAAstimulates macrophage secretion of IL-1 an inflammatory cytokine implicated in both human and AngII-induced AAAs. In obese subjects adipocytes become a predominate source of local and systemic SAA. Wepropose that AngII periaortic fat and SAA come together in the setting of obesity to create a pro-inflammatoryenvironment immediately adjacent to the abdominal aorta which leads to AAA initiation and expansion. Thecentral hypothesis of this proposal is in the setting of obesity adipocyte-derived SAA activates the NLRP3inflammasome in macrophages to promote AAA development in obesity. Aim 1 will test the hypothesis thatadipocyte-derived SAA is central in creating the pro-inflammatory environment that promotes AngII-inducedAAA formation in obesity. In Aim 2 we will test the hypothesis that adipocyte-derived SAA promotes obesity-induced AAA by activating the NLRP3 inflammasome in macrophages. We have unique mouse models of SAAdeficiency as well as transgenic mice with tissue-specific SAA-overexpression in which we can overexpressSAA only in liver or only in fat. We will employ translational therapeutic approaches to prevent the formationand progression of AngII-induced AAAs in obesity. The impact of these studies is that we will identify SAA andperiaortic fat burden as biomarkers and risk factors for AAA development and progression in the obesepopulation which may identify precision-targeted AAA therapeutics.

project_terms:
Abdominal Aortic Aneurysm;Acute;Adipocytes;Adipose tissue;Age;Angiotensin II;Angiotensins;Biological Markers;C57BL/6 Mouse;Cause of Death;Consumption;Data;Development;Etiology;Fatty acid glycerol esters;Gender;Goals;Growth;Health;High Fat Diet;High Prevalence;Human;Hyperlipidemia;Hypertension;Inflammasome;Inflammation;Inflammatory;Interleukin-1 beta;Link;Liver;Mediator of activation protein;Modeling;Mus;Obese Mice;Obesity;Overweight;Phase;Population;Production;Protein Isoforms;Proteins;Publishing;Reporting;Resistance;Risk Factors;Role;Ruptured Abdominal Aortic Aneurysm;Serum amyloid A protein;Signal Transduction;Smoking;Source;Stimulus;Testing;Therapeutic;Tissues;Transgenic Mice;United States;United States Department of Veterans Affairs;Veterans;abdominal aorta;age group;cytokine;high risk;human very old age (85+);hypercholesterolemia;inflammatory milieu;macrophage;male;military veteran;mouse model;novel;novel therapeutic intervention;obese person;overexpression;prevent;sex;tool;translational therapeutics;vascular inflammation

public_health_relevance:
This project focuses on obesity as a risk factor for the formation and progressive growth of abdominalaortic aneurysms (AAAs). We focus on serum amyloid A (SAA) since levels of this protein increase withobesity. Our approach should delineate why obesity is a risk factor for AAAs and identify new therapeuticapproaches.


application_id: 10454876
project_number: 5I01BX004542-04
project_title: Optogenetics: A tool to probe mechanism and an agent to block TBI-induced epileptogenesis.
administering_ic: VA
award_notice_date: 2022-05-09
opportunity_number: BX-18-003
application_type: 5
activity_code: I01
ic: BX
serial_number: 004542
project_start_date: 2019-04-01
project_end_date: 2023-03-31
study_section: ZRD1-NURB-H(01)
contact_pi_person_id: 9405862
contact_pi: SLEVIN, JOHN T.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-04-01
project_abstract:
Over two million people are treated medically each year in the United States after sustaining atraumatic brain injury (TBI). Posttraumatic epilepsy (PTE) develops in up to 39% of patients with moderate tosevere non-penetrating TBI. As with other acquired epilepsies spontaneous recurrent seizures associatedwith PTE develop with a latency (>1 week and up to many years) after the initial injury. This seizure-free periodafter TBI represents the period of epileptogenesis during which the brain undergoes physiological anatomicalcellular and molecular changes leading to a state of chronically increased seizure susceptibility. This delaybetween the TBI and development of PTE also represents a period during which strategies might be employedto inhibit the reactive plasticity in the brain that leads to PTE but the molecular mechanisms underlying theepileptogenic process leading to acquired epilepsy are largely unknown and no anti-epileptogenic therapieshave been successfully developed to date. Animal models of posttraumatic epileptogenesis (PTEgenesis) pointto reactive plasticity of hippocampal networks with alteration in the balance of excitation/inhibition as a driverof permanent brain changes and the epileptic state. However the prime molecular and electrophysiologicaltransformations remain murky. The hypothesis to be tested: Post-injury activity and network changes in the hippocampus induced inpart by alterations in the vesicular neurotransmitter release machinery are primary drivers of PTEgenesis. TheSpecific Aims are to: 1) Use channelrhodopsin-2 (ChR2) to optogenetically drive neural activity and theprocess of PTEgenesis by depolarizing specific primary neuronal populations in dentate gyrus (DG). 2) Usehalorhodopsin (NpHR) to retard PTEgenesis induced using a standard method by optogenetically inhibitingneural activity in DG. Proven techniques will be integrated into a new and unique model to detect network andmolecular drivers of PTE and PTEgenesis. Using the controlled cortical impact (CCI) model of TBI ourproposed studies combine 1) unique microelectrode array electrochemistry (MEA) to monitor real-timeglutamate release and oxygen change as a metric of epileptiform activity; 2) immunohistochemistry to definechanges in specific cell phenotypes; and 3) slice electrophysiology with custom Western blot quantitation ofneurotransmitter release machinery on a novel optogenetically-modified hippocampal platform. Aim 1: Studies will be accomplished by AAV2/5 viral transfection of a ChR2-promotor construct intohippocampal DG of rats utilizing optogenetic activation of DG neurons of free-roaming rats after CCI-inducedTBI to enhance PTEgenesis. Extra-cellular glutamate electrophysiological immunohistochemical andvesicular release biochemical measures will be made on animals at discrete behavioral stages during theprogression of epileptogenesis. Aim 2: Studies will be accomplished by AAV2/5 viral transfection of an NpHR-promoter construct into hippocampal DG of rats prior to CCI injury and optogenetic inhibition of DG circuitsafter CCI to inhibit PTEgenesis. MEA electrophysiological immunohistochemical and biochemical measureswill be made. As one component of these studies transient glutamate surges and changes in oxygen in DGdetected by MEAs will trigger real-time optogenetic inhibition as a potential means to abort PTEgenesis. Our approach should allow network neuronal and presynaptic release changes to be clearly tied tobiochemical anatomical electrophysiological and behavioral outcomes associated with epileptogenesis. Thestudies in this proposal will pave the way to development of comprehensive novel analyses of the progressionof PTE and will provide preliminary data to support studies identifying causative effects of activity-dependentsynaptogenesis in the development of PTE. In addition these studies will test a potentially novel therapy forPTEgenesis. Thus this research is directly relevant to the care of a large proportion of service men andwomen veterans and the general population.

project_terms:
Acute;Anatomy;Animal Model;Animals;Antiepileptogenic;Behavioral;Biochemical;Brain;Caring;Cells;Chronic;Chronic Disease;Clinical Trials;Custom;Data;Development;Electrochemistry;Electrophysiology (science);Epilepsy;Epileptogenesis;Equilibrium;Excision;General Population;Glutamates;Goals;Halorhodopsins;Hippocampus (Brain);Human;Immunohistochemistry;Individual;Injury;Life;Measures;Medical;Methods;Microelectrodes;Modeling;Molecular;Neurons;Neurosurgical Procedures;Oxygen;Patients;Persons;Phenotype;Physiological;Population;Post-Traumatic Epilepsy;Predisposition;Process;Protein Biochemistry;Rattus;Recurrence;Research;Seizures;Services;Slice;Techniques;Testing;Therapeutic;Time;Transfection;Translations;Traumatic Brain Injury;United States;Veterans;Viral;Western Blotting;Woman;acquired epilepsy;behavioral outcome;controlled cortical impact;critical period;dentate gyrus;economic cost;extracellular;high risk;instrumentation;men;neurotransmitter release;novel;novel therapeutics;optogenetics;presynaptic;prevent;promoter;real time monitoring;relating to nervous system;standard of care;synaptogenesis;tool;vesicular release

public_health_relevance:
Human posttraumatic epilepsy (PTE) is defined as repeated unprovoked seizures beginning more than oneweek but up to years after a traumatic brain injury (TBI). During the seizure-free interval between TBI andPTE the brain undergoes changes leading to a state of chronically increased seizure susceptibility. Themolecular mechanisms and network changes underlying this posttraumatic epileptogenesis (PTEgenesis) arelargely unknown and there are no therapeutic strategies to prevent it. Our approach using microelectrodearrays immunohistochemistry slice electrophysiology quantitative protein biochemistry and optogenetics toanalyze this latent period should allow us to correlate network neuronal and presynaptic release changes tomolecular anatomical electrophysiological and behavioral outcomes associated with PTEgenesis. In additionthese studies will test a potentially novel therapy to retard/halt PTEgenesis. Thus this research is directlyrelevant to the care of a large proportion of service men and women veterans and the general population.


application_id: 10454206
project_number: 5IK6BX004199-05
project_title: BLR&D Research Career Scientist Award application
administering_ic: VA
award_notice_date: 2022-05-05
opportunity_number: BX-17-022
application_type: 5
activity_code: IK6
ic: BX
serial_number: 004199
project_start_date: 2018-04-01
project_end_date: 2023-03-31
study_section: Research Career Scientist[RCSR]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-04-01
project_abstract:
My research work largely explores the underlying physiologic questions regarding tiny vesicles calledexosomes. These exosomes are released from many different types of cells or food-derived exosome-likenanoparticles and I am investigating in VA patients the promising role of exosomes as therapeutic vehicles indelivering treatment for a diverse but specific group of medical conditions i.e.obesity/diabetes Nonalcoholicfatty liver disease (NASH) and cancer. There is a substantial population of veterans who are obese and/orhave cancer. Obesity and cancer pose special burdens on veterans who depend on VA care. Obesitycontributes to over 300000 deaths per year and increases the risk of NASH type 2 diabetes and severalcancers including colon prostate and kidney. Since receiving my initial Research Career Scientist award myresearch group has published more than 50 manuscripts on this subject. Collectively our findings supportcontinued funding of my team to investigate the following 3 aims: (1) Tumor exosomes play a role in: (a)immunosuppression through induction of myeloid-derived suppressor cells inhibition of dendritic celldifferentiation and inhibition of activation of NK cell immunotherapy; (b) by sorting suppressor miRNAs fromtumor cells into exosomes based on the oncogenic major vault protein (MVP) tumors grow faster (NatureCommunications. 2017 Feb 17;8:14448 Nature communications. 2015;6:6956); and (c) more recently wediscovered a novel nanoparticle (Oncotarget. 2016 May 12). Unlike other EVs this extracellular nanovesicle(named HG-NV HG-NV stands for HomoGenous nanovesicle as well as for Huang-Ge- nanovesicle) releasedfrom both mouse and human breast tumor cells is enriched with RNAs. Tumor-derived HG-NVs are morepotent in promoting tumor progression than exosomes. Molecules predominantly present in breast tumor HG-NVs have been identified and characterized. This discovery may have implications in advancing bothmicrovesicle biology research and clinical management including potential useas a biomarker (2). Exosomesreleased from non-tumor cells play a role in: (a) adipose tissue exosome-like vesicles mediating activation ofmacrophage-induced insulin resistance (Diabetes. 2009 Nov;58(11):2498-505); (b) we also found thatintestinal mucus-derived exosomes mediate activation of Wnt/-catenin signaling and play a role in inductionof liver NKT cell anergy (Hepatology 2013 57(3):1250-61); and (c) intestinal mucusderived exosomes carryprostaglandin E2 and suppress activation of liver NKT cells (J Immunol 2013 190(7):3579-89); (3). Exosome-like nanoparticles from edible plants have an effect and therapeutic application on mammalian cells: (a) weused mouse models to show that interspecies communication between plant and mouse gut host cells throughedible plant derived exosomelike nanoparticles by inducing expression of genes for anti-inflammationcytokines antioxidation and activation of Wnt signaling which are crucial for maintaining intestinalhomeostasis. This finding not only opens up a new avenue for investigating ELNs as a means to protect againstthe development of liver related diseases such as alcohol induced liver damage but sheds light on studyingthe cellular and molecular mechanisms underlying inter-species communication in the liver via edible plant-derived nanoparticles; (b) targeted drug/therapeutic miRNAs (Nature Communications. 2013;4:1867) deliveryto intestinal macrophages brain microglia cells (Molecular therapy: 2015 Volume 24 Issue 1 p96105) andinflammatory tumor sites (Cancer Research 2015;75:2520-9) by grapefruit ELN is possible; (c) Broccoli-Derived Nanoparticle Inhibits Mouse Colitis by Activating Dendritic Cell AMP-Activated Protein Kinase(Molecular Therapy. 2017 in press); and (d) Grape exosome-like nanoparticles induce intestinal stem cellsand protect mice from DSS-induced colitis (Molecular Therapy. 2013 Jul;21(7):1345-57).

project_terms:
5'-AMP-activated protein kinase;Adipose tissue;Alcoholic liver damage;Antibodies;Award;Biological;Biological Markers;Biology;Brain;Brain Injuries;Brain Neoplasms;Breast Cancer Cell;Broccoli - dietary;Cancer Patient;Caring;Cell Communication;Cell Differentiation Inhibition;Cell Differentiation process;Cells;Cessation of life;Chronic;Clinical;Clinical Management;Colon;Colonic Neoplasms;Colorectal;Communication;Curcumin;Cutaneous Melanoma;DNA;Data;Dendritic Cells;Development;Diabetes Mellitus;Dinoprostone;Disease;Disease Progression;Drug Targeting;Edible Plants;Encephalitis;Explosion;Failure;Folic Acid;Food;Foundations;Funding;Gene Expression;Ginger;Goals;Grapefruit;Grapes;Health Status;Hepatocyte;Hepatology;High Fat Diet;Homeostasis;Homing;Human;Immunosuppression;Immunotherapy;Inflammation;Inflammatory;Insulin Resistance;International;Intestines;Journals;Kidney;Light;Link;Lipids;Liver;Long-Term Effects;Lung;Macrophage Activation;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mammalian Cell;Mammary Neoplasms;Manuscripts;Mediating;Medical;Methods;MicroRNAs;Microglia;Molecular;Mucous body substance;Mus;Myeloid-derived suppressor cells;NK Cell Activation;Names;Nature;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oncogenes;Oncogenic;Oncoproteins;Overweight;Patients;Pharmaceutical Preparations;Physiological;Plants;Play;Prostate;Publishing;RNA;Radiation therapy;Research;Resistance;Risk;Role;Scientist;Signal Transduction;Site;Small Interfering RNA;Sorting - Cell Movement;Specificity;T-Lymphocyte;Therapeutic;Therapeutic Agents;Tissues;Traumatic Brain Injury;Tumor Promotion;Tumor Suppressor Proteins;Tumor-Derived;Vesicle;Veterans;WNT Signaling Pathway;War;Work;alcohol prevention;anergy;anticancer research;base;beta catenin;cancer cell;cancer diagnosis;cancer immunotherapy;cancer prevention;cancer therapy;cancer type;career;cell type;chemokine;chemokine receptor;cytokine;delivery vehicle;dextran sulfate sodium induced colitis;exosome;expression vector;extracellular;folate-binding protein;improved;in vivo;interspecies communication;intestinal homeostasis;liver development;liver inflammation;liver injury;macrophage;major vault protein;member;microvesicles;mild traumatic brain injury;military veteran;mortality;mouse model;murine colitis;nanoparticle;nanovector;nanovesicle;neoplastic cell;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel strategies;novel therapeutic intervention;nuclear factor-erythroid 2;patient population;pressure;prevent;side effect;sound;stem cells;targeted delivery;therapeutic development;therapeutic miRNA;translational study;treatment strategy;tumor;tumor progression

public_health_relevance:
The VA estimates that 78 percent of Veterans are overweight or obese. Obesity has been linked to excess riskfor type 2 diabetes and many cancers. Determining the precise mechanism(s) by which obesity contributes tothe development of cancer is essential for the development of therapeutic strategies against cancer. The focusof my career research is to characterize these mechanisms and then to determine whether targeting of thesemechanisms effectively blocks the induction of vesicles that can be caused by a high-fat diet.These vesiclespromote exosome-mediated development of cancer and I am pursuing therapies to treat obesity/diabetes andcancer in VA patients. More importantly development of novel strategies to block/reverse high-fat diet inducedand tumor exosome mediated immunosuppression would also yield a new and practical therapeutic method fortreating chronic inflammatory related diseases and thus improve the health status of members of the VA patientpopulation.


application_id: 10454097
project_number: 5IK2BX004883-03
administering_ic: VA
award_notice_date: 2022-05-05
opportunity_number: BX-19-008
application_type: 5
activity_code: IK2
ic: BX
serial_number: 004883
project_start_date: 2020-04-01
project_end_date: 2025-03-31
study_section: ZRD1-NURE-E(01)
contact_pi_person_id: 11890992
contact_pi: YAMASAKI, TRITIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-04-01
budget_end_date: 2023-03-31
project_title:
Enhancing diagnosis of Parkinson's disease and multiple system atrophy via detection of alpha-synuclein seeding activity

project_abstract:
Synucleinopathies such as Parkinson's disease (PD) and multiple systems atrophy (MSA) involve abnormalaccumulation of the protein alpha-synuclein (-syn). Although it has been nearly two centuries since PD wasfirst described a dearth of biomarkers has greatly impeded progress toward development of disease-modifyingtreatments and accurate and early diagnosis. This proposal is based on the hypothesis that pathology in thesediseases propagates through the brain via a mechanism in which transcellular movement of misfolded -synprotein aggregates or seeds occurs. There is also evidence that pathogenic -syn has diverse structures indiseases such as PD or MSA that may underlie the clinical and pathologic differences seen in thesesynucleinopathies. This proposal utilizes a novel cell-based assay that has been shown to detect and quantifyabnormal -syn seeding activity that differs both biochemically and structurally in brain extracts from patientswith PD and MSA. In this project we propose to (1) optimize the ability to detect aggregated forms of -synutilizing genetic manipulation of a cell-based sensor (2) utilize cutting edge molecular and imaging techniquesto parse out differences between -syn in the synucleinopathies MSA and PD and (3) determine whether -synseeding activity in blood components of patient samples can serve as a marker for clinical disease progression.The implications of this work include facilitation of diagnosis and therapeutics for patients with PD and MSA.The applicant is an Assistant Professor in the Department of Neurology at University of Kentucky who is firmlycommitted to an academic career as an independent translational scientist in the area of neurodegenerativedisease. The proposed training will take advantage of the rich and collaborative environment at the VA theexcellent clinical documentation and records system and the very relevant patient population affected by thesediseases and followed in clinic at the VA: all are factors that are integral and crucial to the success of thisproposal. Training will be conducted under the direction of an experienced mentor team. Dr. John Slevin will bethe primary mentor and has over 40 years of expertise in clinical research in Movement Disorders and holds aMerit Award at the VA in basic science research. Dr. Sidney Whiteheart and Dr. Haining Zhu will serve as co-mentors. They are experts in platelet biochemistry and abnormal protein aggregation respectively hold MeritAwards in their fields and are also faculty in the Department of Molecular and Cellular Biochemistry at Universityof Kentucky. These mentors have been specially selected to advance the candidates knowledge of moleculartechniques for investigating aggregated proteins in peripheral fluids of patients with movement disorders.Training during this proposal includes advanced genetic molecular and imaging-based techniques for proteinamplification and detection and techniques for isolation and analysis of exosomal and platelet fractions fromwhole blood. These components will be essential to completing the applicants immediate goal of developing abiomarker that can detect and differentiate between synucleinopathies in peripheral samples by utilizingdifferences in -syn seeding activity. The comprehensive training program will position the applicant to conductindependent research in the study of novel biomarkers in PD and related neurodegenerative disease.

project_terms:
Affect;Aging;Antibodies;Area;Award;Basic Science;Binding;Biochemical;Biochemistry;Biological Assay;Biological Markers;Biosensor;Blood;Blood Platelets;Blood specimen;Braak's hypothesis;Brain;C-terminal;Cell-Free System;Cells;Characteristics;Clinic;Clinical;Clinical Research;Consent;DNA Sequence Alteration;Deep Brain Stimulation;Detection;Development;Diagnosis;Diagnostic;Disease;Disease Progression;Documentation;Early Diagnosis;Elderly;Engineering;Epitopes;Erythrocytes;Evaluation;Expenditure;Exposure to;FDA approved;Faculty;Fluorescence Resonance Energy Transfer;Gender;Genetic;Goals;Healthcare;Imaging Techniques;In Vitro;Investigative Techniques;Kentucky;Knowledge;Lead;Ligands;Liquid substance;Mentors;Methods;Modality;Molecular;Molecular Conformation;Motor;Movement;Movement Disorders;Multiple System Atrophy;Nerve Degeneration;Neuraxis;Neurodegenerative Disorders;Neurology;Parkinson Disease;Pathogenicity;Pathologic;Pathology;Patients;Peripheral;Persons;Plasma;Population;Positioning Attribute;Process;Prognosis;Property;Proteins;Publishing;Records;Research;Sampling;Seeds;Solubility;Structure;System;Techniques;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;Toxin;Training;Training Programs;Universities;Veterans;Whole Blood;Work;accurate diagnosis;alpha synuclein;amplification detection;base;career;cerebral atrophy;collaborative environment;detection method;disorder control;disorder risk;effective therapy;exosome;experience;genetic manipulation;imaging modality;insight;liquid biopsy;male;molecular imaging;novel;novel marker;patient population;prion-like;professor;prognostic;protein aggregation;rare condition;sensor;success;synuclein;synucleinopathy;translational scientist;transmission process

public_health_relevance:
Parkinsons disease is the most common neurodegenerative movement disorder of the elderly affecting overfour million people worldwide and is responsible for significant health care dollar expenditures annually. Thisdisease afflicts a disproportionately large number of US Veterans based on factors such as advancing age malegender and exposure to certain toxins all of which are associated with increased risk for the disease. Progresstoward effective treatment has been hindered by the lack of a biomarker that can diagnose and distinguishParkinsons disease from related neurodegenerative conditions. The proposed research will detect pathogenicforms of the protein alpha-synuclein in the blood of patients with Parkinsons and related diseases with theultimate goal of expanding diagnostic prognostic and therapeutic options for affected US Veterans.


application_id: 10415827
project_number: 5IK2BX004618-03
project_title: Psychological deficits after low level blast exposure: role of neurovascular disruption
administering_ic: VA
award_notice_date: 2022-01-19
opportunity_number: BX-19-008
application_type: 5
activity_code: IK2
ic: BX
serial_number: 004618
project_start_date: 2020-01-01
project_end_date: 2024-12-31
study_section: ZRD1-NURC-H(01)
contact_pi_person_id: 14823099
contact_pi: HUBBARD, WILLIAM BRAD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-01-01
project_abstract:
Many Veterans experience occupational exposure to low-level blast (LLB) during normal training operationsincluding but not limited to breaching activity. These Veterans are at increased risk for persistingneuropsychological impairment due to repeated LLB exposure over several deployments with limited time forrecovery between exposures. The extent of the long-term consequences after cumulative LLB exposure isunknown though reports show that deficits can be present late in life. Furthermore the resultant post-traumaticstress disorder (PTSD)-related behavioral deficits are more pronounced in soldiers and Veterans with a historyof chronic blast exposure. There is no clear understanding of which pathological mechanisms drive this chronicPTSD phenotype after LLB exposure. A few animal models have been established to address this incompleteunderstanding of the pathobiological mechanisms underlying LLB exposure. These models replicate thechronic depressive anxiogenic and PTSD-related traits observed in Veterans though there are manyknowledge gaps in what contributes to these chronic deficits. In general blast exposure causes acute blood-brain barrier (BBB) and neurovascular unit abnormalities that can persist over time. The overall objective of thisapplication is to determine the timing of acute neurovascular dysfunction after LLB and how repeating LLBcontributes to chronic neurovascular impairment and neuropsychological deficits. Our central hypothesis is thatLLB repeated at a time interval of maximal BBB impairment after the first LLB will result in persistent PTSD-like behavioral traits. Additionally these deficits will be associated with changes in the profile of serum-derivedexosomal miRNAs and platelet bioenergetics. These hypotheses were formulated based on current literatureand our own published and preliminary data demonstrating anxiety and amygdalar BBB disruption after blastexposure. By utilizing a multimodal blast simulator at the University of Kentucky these studies will be able toexamine the longitudinal behavioral profile coupled with pathologically relevant biomarkers. These hypotheseswill be tested in three specific aims: 1) examine acute neurovascular deficits after a single LLB exposure anddetermine their relationship to longitudinal behavioral traits 2) determine how repeating LLB at various timeintervals based on the acute neurovascular profile contributes to exacerbated or prolonged PTSD-likebehavioral traits and chronic neurovascular impairment 3) identify if modulating either acute or chronicneurovascular health using sildenafil will mitigate long-term PTSD-like behavioral traits. This research willdrastically improve our understanding of the effects of LLB as well as potentially identify novel clinically-relevant biomarkers. The proposed research is significant because it will establish a platform to understand thechronic effects of occupational blast exposure which affects many Veterans. In addition this line ofinvestigation can lead to better therapeutic targeting of neurovascular dysfunction to improve neurologicaloutcome in aging Veterans. In addition to the research products gained by this proposal the applicant willgreatly benefit from a mentoring team that has a variety of preclinical translational and clinical perspectiveswhich will contribute to a well-rounded career development plan. The training program will add additionaltechniques to Dr. Hubbards repertoire contributing not only to this proposal but to his VA research programmoving forward. With prior knowledge in blast injury modeling additional behavioral and biomarker assays willgreatly advance his research expertise. In the latter years of this proposal Dr. Hubbard will continue to expandgrant writing student mentoring collaborative research and presentation skills required of independentresearchers. Overall the proposed studies and diverse mentoring program will culminate in producing a highlysuccessful independent VA researcher.

project_terms:
3-Dimensional;Acute;Address;Affect;Aggressive behavior;Aging;Amygdaloid structure;Animal Model;Animals;Anxiety;Behavior;Behavior assessment;Behavioral;Bioenergetics;Biological Assay;Biological Markers;Blast Injuries;Blood - brain barrier anatomy;Blood Platelets;Blood Vessels;Brain;Brain region;Cerebrovascular Circulation;Chronic;Chronic Post Traumatic Stress Disorder;Clinical;Coupled;Data;Development;Development Plans;Exposure to;Foundations;Functional disorder;Grant;Health;Image;Immunohistochemistry;Impairment;Investigation;Kentucky;Knowledge;Lead;Life;Literature;Matrix Metalloproteinases;Measures;Mentors;MicroRNAs;Military Personnel;Modeling;Nervous System Trauma;Neurocognitive;Neurologic Deficit;Neurologic Dysfunctions;Neurological outcome;Neurons;Neuropsychology;Occupational;Occupational Exposure;Outcome;Pathologic;Peripheral;Phenotype;Post-Traumatic Stress Disorders;Predisposition;Proteins;Publishing;Rattus;Recording of previous events;Recovery;Reporting;Research;Research Personnel;Risk;Rodent;Rodent Model;Role;Serum;Social Interaction;Soldier;Stains;Symptoms;Techniques;Testing;Therapeutic;Time;Tissues;Training;Training Programs;Universities;Vascular Diseases;Veterans;Writing;arterial spin labeling;base;behavior test;behavioral impairment;blast exposure;blood-based biomarker;blood-brain barrier disruption;career development;cerebrovascular;clinically relevant;cohort;depressive symptoms;exosome;experience;improved;inhibitor;military veteran;multimodality;neuroimaging;neuropathology;neurovascular;neurovascular unit;novel;operation;phosphodiesterase V;pre-clinical;primary outcome;programs;psychologic;psychological outcomes;restoration;sildenafil;skills;stress related disorder;student mentoring;therapeutic target;time interval;trait

public_health_relevance:
Many Veterans experience low-level blast (LLB) exposure during tour of duty and training operations. Theextent of chronic post-traumatic stress disorder (PTSD) traits after cumulative LLB exposure is unknown.Additionally there is no clear understanding of which pathological mechanisms drive impairment after LLBexposure. The overall objective of this application is to determine the timing of acute neurovascular dysfunctionafter LLB and how repeating LLB contributes to chronic neurovascular impairment and neuropsychologicaldeficits. We will examine the behavioral profile and neurovascular outcomes after LLB coupled withpathologically relevant biomarkers. This research will improve our understanding of the effects of LLB andidentify biomarkers for neurological injury. The proposed mentored research plan will increase understandingof the chronic effects of occupational blast exposure to identify therapies which will improve Veteran healthwhile providing a foundation for the applicants independent VA research program.


application_id: 10412902
project_number: 5I01BX003643-03
project_title: TBI-induced exosome release accelerates Alzheimer's disease pathology
administering_ic: VA
award_notice_date: 2021-10-27
opportunity_number: BX-18-004
application_type: 5
activity_code: I01
ic: BX
serial_number: 003643
project_start_date: 2019-10-01
project_end_date: 2023-09-30
study_section: ZRD1-NURD-C(01)1
contact_pi_person_id: 2275110
contact_pi: BIEBERICH, ERHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-10-01
project_abstract:
Alzheimer's disease (AD) is characterized by build-up of A peptides forming amyloid plaques and hyper-phosphorylation of tau protein forming neurofibrillary tangles a two-fold protein aggregation process leading toprogressive neurodegeneration and cognitive decline. Epidemiological studies show that the risk of developingAD is 4-fold higher in persons who have experienced head trauma or traumatic brain injury (TBI) which isprevalent in Veterans returning from active combat. Reasons for this increased risk are unclear and no strategyto prevent AD pathology exists. A critical barrier to progress is the lack of understanding of how amyloid andtau are rendered neurotoxic and how TBI may induce or accelerate this process. Our goal is to understandand prevent amyloid and tau neurotoxicity and delay the onset and reduce neurodegeneration in ADparticularly when induced or accelerated by TBI in Veterans. Our central hypothesis is that TBI-inducedshear force shakes and repeatedly bends cilia in astrocytes which leads to calcium influx reprogramming ofceramide metabolism and sustained secretion of ceramide-enriched exosomes termed astrosomes(immediate effect). A42 and tau associate with ceramide and turn astrosomes into neurotoxic betasomeseven years after TBI (delayed effect). Betasomes also contain prostate apoptosis response 4 (PAR-4) aprotein sensitizing neurons to ceramide-induced apoptosis. Betasomes are transported to mitochondria wherethey enhance A42 and tau-mediated mitochondrial dysfunction and neurotoxicity. Consistent with ourhypothesis betasomes are detectable in serum from AD patients and 5xFAD mice and induce mitochondrialdamage caspase activation and tau aggregation in N2a cells and primary cultured neurons. Our hypothesispredicts that astrosome secretion association with A42 and tau and neurotoxicity are prevented by blockingTBI-induced calcium influx and ceramide generation. Our expected outcomes include 1) determiningenzymes in upregulation of ceramide and specific calcium channels that are activated by shear force; 2)defining a ceramide composition in astrosomes that induces interaction with A42 tau aggregation andmito/neurotoxicity; 3) identifying ceramide-modulating drugs and calcium channel blockers that preventastrosome secretion betasome formation mitochondrial dysfunction and tau aggregation and neurotoxicity;and 4) quantifying astrosomes and betasomes in serum that indicate severity of TBI-induced AD (TBI-AD) andsuccess of therapeutic treatment. The impact of this project on protection of Veterans and public health willinclude knowledge needed for the development of new treatment strategies that could delay and/or prevent theonset of progressive neurodegeneration in AD in particular when induced by mild TBI in Veterans.

project_terms:
Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease patient;Amyloid;Amyloid beta-42;Amyloid beta-Protein;Apoptosis;Astrocytes;Axon;Binding;Brain;Calcium;Calcium Channel;Calcium Channel Blockers;Caspase;Cells;Ceramides;Cilia;Closed head injuries;Craniocerebral Trauma;Development;Enzymes;Generations;Goals;Impaired cognition;Impairment;Interruption;Knowledge;Mediating;Metabolism;Mitochondria;Monitor;Mus;Nerve Degeneration;Neurofibrillary Tangles;Neurons;Outcome;Pathology;Patients;Peptides;Persons;Pharmaceutical Preparations;Prevention;Process;Prostate;Proteins;Public Health;Research;Risk;Senile Plaques;Serum;Severities;Testing;Therapeutic;Traumatic Brain Injury;Up-Regulation;Vesicle;Veterans;Voltage-Dependent Anion Channel;amyloid peptide;axonal degeneration;cell motility;ceramide 3;combat;cytochrome c;diagnostic biomarker;epidemiology study;exosome;experience;inhibitor;lipid metabolism;mild traumatic brain injury;mitochondrial dysfunction;mouse model;neuron loss;neurotoxic;neurotoxicity;novel diagnostics;prevent;progressive neurodegeneration;protein aggregation;protein folding;response;success;tau Proteins;tau aggregation;tau-1;treatment strategy;uptake

public_health_relevance:
Traumatic brain injury (TBI) resulting from combat is a prevalent head injury among Veterans. TBI can increasethe risk of developing Alzheimer's disease (AD) by 4-fold. AD is characterized by build-up of amyloid peptidesforming plaques and hyper-phosphorylation of tau protein forming neurofibrillary tangles a two-fold proteinaggregation process leading to neurodegeneration and cognitive decline. It is not known how TBI increases therisk of developing AD and how to prevent TBI-induced AD. Our research showed that even mild TBI elicitsshear forces in the brain that make particular cells secrete vesicles called exosomes. These TBI-inducedexosomes bind to amyloid peptide and tau protein and enhance their neurotoxicity. Our goal is to interrupt TBI-induced exosome secretion to prevent or delay the onset of AD in Veterans.


application_id: 10392316
project_number: 5I01BX003877-05
project_title: Targeting Platelet Endocytosis and Exocytosis to Control Thrombosis
administering_ic: VA
award_notice_date: 2021-10-26
opportunity_number: BX-16-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 003877
project_start_date: 2017-10-01
project_end_date: 2022-09-30
study_section: Hematology[HEMA]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-10-01
project_abstract:
World-wide spurious thrombosis accounts for 1 of 4 non-communicable disease deaths.Cardiovascular disease is a leading killer of aging US veterans and is the major cause of death in olderfemale veterans. Understanding how to modulate thrombosis will significantly aide the VA's mission toimprove veterans' health. Normally platelets respond to vascular damage and secrete granule cargothat are essential for recruiting more platelets and for generating a thrombus. This releasate promotesnormal sequelae but can also contribute to occlusive pathologies such as strokes and heart attacks. Inplatelets VAMPs SNAP-23 and Syntaxin-11 form a membrane-spanning complex that mediatesexocytosis. Formation of this complex requires a host of SNARE-regulators e.g. Munc18bSTXBP5/tomosyn-1 and granuphilin/SLP4; however the mechanisms by which these proteins controlthe complexity of the platelet release reaction (its rate extent and content) is uncertain. Platelets arealso capable of other cellular processes (i.e. RNA splicing translation glycosylation autophagy);however their effects on platelet function are still unknown. Our data suggest that endocytosis affectsthrombus growth by modulating platelet spreading and platelet-platelet contacts. Our goal is tomanipulate the membrane trafficking in platelets both endocytosis and exocytosis in order tomodulate occlusive thrombosis with only modest effects on hemostasis. To reach this goal wemust probe the molecular mechanisms of exocytosis. Our specific focus will be on Syntaxin-11regulators. We will also use an endocytosis defective mouse strain to define the roles of endocytosis inthrombosis and hemostasis. Two aims are proposed: 1) Define the network of protein-proteininteractions that affect Syntaxin-11-mediated membrane fusion and granule cargo release; and2) Determine the roles of platelet endocytosis in hemostasis. To complete these aims we willemploy biochemical assays to define the interactions between the SNARE regulators and in vitro andin vivo functional assays using transgenic mice to define the roles of the specific Syntaxin-11regulators and of endocytosis in thrombosis and hemostasis. Our results will expand the understandingof the molecular requirements and the sequence of protein-protein interactions controlling plateletexocytosis. We will also expand the mechanistic understanding of what cellular processes platelets canperform (i.e. endocytosis) and why they are important. Our results will be significant to the field sincethey will provide the needed mechanistic insights to identify potential targets for therapeutic interventionand to evaluate the relevance of the increasing volume of gene/risk associations that are guiding patienttreatment strategies. This will enhance the anti-thrombotic treatment options available for the care ofaging veterans.

project_terms:
Acute;Address;Adhesions;Affect;Age;Aging;Amino Acid Sequence;Autophagocytosis;Biochemical;Biological Assay;Blood Platelets;Blood Vessels;Cardiovascular Diseases;Caring;Carotid Artery Injuries;Cause of Death;Cell physiology;Cellular biology;Cessation of life;Clot retraction;Coagulation Process;Communicable Diseases;Complex;Cytoplasmic Granules;Data;Disease;Endocytosis;Equilibrium;Event;Exocytosis;Female;Fibrinogen;Gene Deletion;Goals;Growth;Guanosine Triphosphate Phosphohydrolases;Health;Hemorrhage;Hemostatic function;Hyperactivity;In Vitro;Infarction;Integrins;Knock-out;Knockout Mice;Knowledge;Mediating;Membrane;Membrane Fusion;Mission;Modeling;Molecular;Molecular Chaperones;Molecular Probes;Morbidity - disease rate;Mouse Strains;Mus;Myocardial Infarction;Pathology;Patients;Physicians;Precision Medicine Initiative;Process;Prognosis;Protein Biochemistry;Proteins;Publishing;RNA Splicing;Reaction;Risk;Risk Factors;Role;S-nitro-N-acetylpenicillamine;SNAP receptor;Sampling;Stroke;Tail;Therapeutic Intervention;Thrombosis;Thrombus;Transgenic Mice;Translations;Veterans;Work;base;clinically significant;experimental study;familial hemophagocytic lymphohistiocytosis;genome wide association study;glycosylation;granuphilin;health management;improved;in vitro Assay;in vivo;insight;male;military veteran;mortality;platelet function;protein protein interaction;recruit;response;restenosis;risk variant;synaptotagmin;syntaxin;syntaxin 11;syntaxin A;syntaxin-2;target SNARE proteins;targeted treatment;therapeutic target;thrombotic;trafficking;treatment strategy;vesicular SNARE proteins

public_health_relevance:
Relevance of the Project to Veterans' Health: Worldwide thrombotic events e.g. strokes and heart attacksaccount for 1 of 4 deaths not caused by communicable diseases. Thrombotic events are major killers of agingveterans especially female veterans. Platelets are essential for clot formation but targeting them to controlthrombosis requires a greater understanding of how platelet work. In this proposal we look at two aspects ofplatelet cell biology exocytosis and endocytosis to determine how and why platelets both release clottingcomponents and take them up them during clot formation. Our experiments will generate the critical mechanisticinsights needed to effectively control platelet function and thus limit thrombosis in aging veterans.


application_id: 10367171
project_number: 2I01CX001353-05A2
project_title: Modulation of mitochondrial respiration to treat colitis
administering_ic: VA
award_notice_date: 2022-02-01
opportunity_number: CX-21-001
application_type: 2
activity_code: I01
ic: CX
serial_number: 001353
suffix: A2
project_start_date: 2016-10-01
project_end_date: 2025-12-31
study_section: Special Emphasis Panel[ZRD1 GAST-L (01)]
contact_pi_person_id: 1883566
contact_pi: BARRETT, TERRENCE A.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The importance of mucosal healing in inflammatory bowel disease (IBD) derives from clinical data thatdemonstrate it to be a predictor of remission. Unfortunately many IBD patients remain refractory or loseresponsiveness to therapies leading to persistent mucosal ulceration. Prospective pediatric studies show thatreduced mitochondrial gene expression predict unfavorable outcomes in ulcerative colitis (UC). Consistentlyincreased expression of mitochondrial respiratory chain genes has been shown to predict favorable Crohnsdisease (CD) outcomes. Based on these results and our own data we hypothesize that a critical driver of chroniculceration in IBD is the failure of intestinal epithelial cells (IEC) to increase mitochondrial respiration. In studiesleading up to this submission we found that mitochondrial deficiency caused poor ulcer healing due to inadequatecrypt fissioning occurring at ulcer edges (Progress Report). These findings led us to develop a novel gold (Au)-based drug based on the current safe and effective gold therapy for Rheumatoid arthritis (Auranofin). This newdrug AuPhos localizes to mitochondria where it increases mitochondrial respiration and mitochondrial reactiveoxygen species (mtROS) production. Induction of low levels of endogenous mtROS are known to promotehealthy adaptive responses in cells including anti-oxidant enzyme activities (Background). In preliminarystudies we found that oral AuPhos 1) enhances mucosal repair in DSS colitis 2) increases IEC mitochondrialoxygen consumption rate (OCR) and oxidative phosphorylation (OXPHOS) 3) mtROS and H2O2 production inIEC as well as 4) phosphoinositides-3 kinase (PI3K) and nuclear factor erythroid 2-related factor (Nrf2) signalingwith 5) improved expression of proteins that induce mitochondrial biogenesis [peroxisome proliferator activatedreceptor- coactivator 1 alpha (PGC1) and transcription factor A mitochondrial (TFAM). Studies proposed inAim 1 interrogate mitochondrial function under baseline conditions to allow assessment of AuPhos-inducedchanges in mitochondrial mass activity (mtROS) and OCR ATP turnover electron transport chain (ETC) activityinduction of adaptive responses [anti-oxidant catalase MnSOD (superoxide dismutase) and glutathione(reduced/oxidized)] as well as assess changes in tissue oxidant stress (4HNE protein carbonylationnitrotyrosine IHC). Aim 2 will build upon these studies by evaluating AuPhos effects in TNF-stimulated smallbowel (SB) and colonic organoids from veterans (normal and IBD). Studies in 3D organoids will allow formechanistic testing of AuPhos-induced crypt budding and IEC gene expression. Results of Aim 2 will instructstudies in Aim 3A that study therapeutic effects of AuPhos on IEC gene expression and crypt fissioning thatheal ulcers in DSS colitis. In Aim 3B scRNAseq analysis of human biopsies incubated with AuPhos will allowus to examine induction of mitochondrial gene expression in discrete IEC clusters. Proposed studies are drivenby a novel hypothesis that restoration of IEC mitochondrial respiration is a key step in mucosal healing. Togetherthese preclinical studies with a VA-sponsored new drug (AuPhos) have the potential of transitioning this agentto the therapy of IBD in veterans.

project_terms:
3-Dimensional;3-nitrotyrosine;Antioxidants;Auranofin;Bioenergetics;Biogenesis;Biopsy;Cell Survival;Cells;Childhood;Chronic;Clinical;Clinical Data;Colitis;Crohn's disease;Data;Disease;Disease Outcome;Disease remission;Distant;Electron Transport;Epithelial Cells;Event;Failure;Gene Expression;Genes;Glutathione;Goals;Gold;Gold Compounds;Healthcare Systems;Human;Hydrogen Peroxide;Immunosuppression;In Vitro;Incubated;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Intestines;Messenger RNA;Mitochondria;Modeling;Morbidity - disease rate;Mucositis;Mucous Membrane;Mus;Oral;Organ;Organoids;Outcome;Oxidative Phosphorylation;Oxidative Stress;Oxides;Oxygen Consumption;PPAR gamma;Patients;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Phosphatidylinositols;Phosphotransferases;Production;Progress Reports;Proteins;Reactive Oxygen Species;Refractory;Research;Respiration;Respiratory Chain;Rheumatoid Arthritis;Risk;Role;SOD2 gene;Secondary to;Signal Transduction;Small Intestines;Superoxide Dismutase;TNF gene;Testing;Therapeutic;Therapeutic Effect;Therapeutic Studies;Tissues;Toxicology;Ulcer;Ulcerative Colitis;Veterans;Work;antioxidant enzyme;base;catalase;chronic ulcer;cytokine;dextran sulfate sodium induced colitis;enzyme activity;factor A;healing;improved;in vivo;innovation;intestinal crypt;intestinal epithelium;murine colitis;novel;novel therapeutics;nuclear factor-erythroid 2;oxidant stress;preclinical study;prospective;protein expression;repaired;response;restoration;transcription factor;uptake

public_health_relevance:
The increase in inflammatory bowel disease (IBD) among veterans in recent years presents a significantclinical problem in the VA healthcare system. Major concerns for IBD veteran patients are the increaseddisease morbidity and risk of therapies. Further research is needed to develop safe and effective agents thatenhance mucosal repair and reduce immune-suppression. Previous work from our lab has indicates thatmitochondrial respiration promotes ulcer healing. This finding led us to postulate that increasing mitochondrialrespiration constitutes a novel therapeutic goal in IBD. To improve mitochondrial function in IBD we developedAuPhos an oral agent that enhances mitochondrial electron transport that potentiates mitochondrialbio-energetics and mitochondrial reactive oxygen species (mtROS) production. The current project willascertain the impact of this novel gold compound (AuPhos) on mitochondrial function and ulcer healing inmouse models of colitis as well as biopsy tissue explants from veterans with IBD.


application_id: 10292945
project_number: 5I01BX004252-04
project_title: CD47 as a therapeutic target for obesity
administering_ic: VA
award_notice_date: 2021-10-26
opportunity_number: BX-17-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 004252
project_start_date: 2018-10-01
project_end_date: 2023-09-30
study_section: Endocriniology A[ENDA]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-10-01
project_abstract:
Brown adipose tissue (BAT) dissipates energy through UCP1-mediated uncoupled respiration and its activationmay represent a therapeutic strategy to combat obesity. Preliminary studies identified a novel role of CD47in regulating BAT function and its contribution to energy homeostasis and the development of obesity.CD47 a ubiquitously expressed cell membrane receptor implicated in self-recognition and immune functionwas upregulated in adipose tissue from obese animals. Moreover CD47 deficiency protected mice from diet-induced obesity (DIO) through activation of BAT function (e.g. enhanced mitochondria uncoupling and heatproduction) and increased energy expenditure. These data suggest that CD47 is a negative regulator of BATactivity. Therefore inhibition of CD47 signaling might be a novel anti-obesity strategy which is furthersupported by a recent human genome-wide study showing the association of single-nucleotide polymorphismsin CD47 gene with body weight and BMI. In this proposal the mechanisms by which CD47 downregulatesbrown fat cell function will be determined in Aim 1. The contribution of brown adipocyte specific CD47deficiency on obesity development will be determined in Aim 2. Whether inhibition of CD47 signaling by CD47-antisense oligo (ASO) treatment activates BAT and prevents/ameliorates obesity development in animalmodels will be determined in Aim 3. These studies will not only provide novel information on the mechanismsby which CD47 down-regulates brown fat function and its contribution to energy homeostasis and thedevelopment of obesity but also test the anti-obesity potential of a CD47-ASO in obese mouse models.Therefore these studies have clinical significance.

project_terms:
Adipocytes;Adipose tissue;Animal Model;Animals;Antisense Oligonucleotides;Attenuated;Body Weight;Body fat;Body mass index;Brown Fat;CD47 gene;Carnitine Palmitoyltransferase I;Cell Line;Cell membrane;Cell physiology;Cells;Complex;Cyclic AMP;Cyclic GMP;Data;Development;Diet;Eating;Energy Intake;Energy Metabolism;Exhibits;Fatty acid glycerol esters;Functional disorder;Genes;Genotype;High Fat Diet;Homeostasis;Human Genome;In Vitro;Insulin Resistance;Investigation;Knockout Mice;Mediating;Metabolic;Mitochondria;Modeling;Molecular;Mus;Nerve;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Obesity;Obesity Epidemic;Resistance;Respiration;Risk Factors;Rodent;Rodent Model;Role;Signal Pathway;Signal Transduction;Single Nucleotide Polymorphism;System;Testing;Therapeutic;Thermogenesis;Tissues;Wild Type Mouse;Work;base;blood glucose regulation;clinically significant;combat;comorbidity;diet-induced obesity;fatty liver disease;genome-wide analysis;human subject;immune function;improved;in vivo;knock-down;lipid biosynthesis;lipid metabolism;mouse model;novel;novel therapeutic intervention;obesity development;obesity genetics;obesity treatment;oxidation;prevent;receptor;therapeutic target;tool

public_health_relevance:
Obesity an imbalance of energy intake and energy expenditure is a major risk factor for the development ofinsulin resistance and type 2 diabetes. Preliminary studies identified that CD47 is a novel regulator of obesity-associated brown fat cell dysfunction. In this application while delineating mechanisms of CD47 to regulatebrown adipocyte function study will also focus on the development of novel therapeutic strategies in thetreatment of obesity and its associated metabolic complications.


application_id: 10292923
project_number: 5I01BX004639-03
project_title: HDL as a therapeutic target for sepsis
administering_ic: VA
award_notice_date: 2021-10-28
opportunity_number: BX-18-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 004639
project_start_date: 2019-10-01
project_end_date: 2023-09-30
study_section: ZRD1-SURG-P(01)
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-10-01
project_abstract:
Sepsis is a major health issues for public and for veterans. A recent study conducted in118 VA hospitals showed that 4.1% of patients undergoing surgery developedpostoperative sepsis. The mortality rate of sepsis is high exceeding 30% due to a lackof efficient therapy. A great barrier for sepsis therapy is that sepsis is a multi-factordisease involving endotoxin from bacteria dysregulated response in immune effectorcells all of which lead to cell damage and endothelial dysfunction resulting in organinjuries and septic death which may explain why extensive efforts (more than 100clinical trials) to block one or another component of the inflammatory or coagulationpathways have had little impact on patient survival. Here we propose that targeting anendogenous factor with multi-protective effects against sepsis may present a novelapproach for sepsis therapy and high density lipoprotein (HDL) is such a target. HDL isa major component of circulating blood with multi-protective properties in vascularendothelial cells and immune effector cells. However the levels of HDL decrease by 40-70% in septic patients which is associated with a poor prognosis. Using mice deficientin HDL we recently reported that mice lacking HDL are susceptible to cecal ligation andpuncture (CLP)-induced septic death and increase HDL levels protects CLP-inducedseptic death. These clinical and animal studies indicate that a decrease in HDL levels isa risk factor for sepsis and raising circulating HDL levels may provide an efficienttherapy for sepsis. Reconstituted or synthetic HDL (sHDL) is a new tool for promotingthe biological activity of HDL. In the preliminary study we generated a new type ofsHDL (YGZL3) and showed that the YGZL3 treatment significantly increases HDL levelsand protects mice from CLP- and bacterial-induced septic death indicating that sHDL(YGZL3) is a potential effective therapy for sepsis. Based on our preliminary data andexisting knowledge of HDL biology we hypothesize that sHDL therapy protects sepsisby restoring both HDL level and its multi-protective functions. The objectives of thisgrant are to understand the mechanism(s) underlying sHDL (YGZL3) protection againstsepsis to optimize the treatment regimen and to assess pharmacokinetics and toxicityof sHDL (YGZL3). Completion of this study will provide a body of mechanistic andpreclinical data for a novel sHDL-based therapy for sepsis and position it for futureInvestigational New Drug (IND) studies and rapid clinical translation which will improvethe health of public and veterans.

project_terms:
Animals;Bacteria;Biological;Biology;Blood;Cessation of life;Clinical;Clinical Data;Clinical Trials;Coagulation Process;Data;Disease;Dose;Drops;Drug Kinetics;Effector Cell;Endogenous Factors;Endothelial Cells;Endotoxins;Frequencies;Future;Generations;Grant;Health;High Density Lipoprotein therapy;High Density Lipoproteins;Hospitals;Immune;Immune response;Immunity;In Vitro;Infection;Inflammatory;Inflammatory Response;Investigational Drugs;Knockout Mice;Knowledge;Lead;Mediating;Modeling;Mus;Operative Surgical Procedures;Pathogenesis;Pathway interactions;Patients;Play;Positioning Attribute;Postoperative Period;Prognosis;Property;Public Health;Regimen;Reporting;Risk;Risk Factors;Role;Sepsis;Signal Transduction;Testing;Therapeutic;Toxic effect;Treatment Protocols;Vascular Endothelial Cell;Veterans;base;cecal ligation puncture;cell injury;clinical translation;drug development;effective therapy;endothelial dysfunction;experience;improved;in vivo;innovation;macrophage;mortality;neutrophil;novel;novel strategies;organ injury;overexpression;pre-clinical;protective effect;reconstitution;response;septic;septic patients;success;targeted treatment;therapeutic target;tool;treatment optimization

public_health_relevance:
Sepsis is a major health issues for public and for veterans. The mortality rate of sepsis is highexceeding 30% due to a lack of efficient therapy. A great barrier for sepsis therapy is that sepsis is amulti-factor disease which may explain why extensive efforts (more than 100 clinical trials) to block asingle component in inflammatory or coagulation pathways have had little impact on patient survival.Here we propose a new approach for sepsis therapy - targeting multiple factors in sepsis with a newtype of synthetic high density lipoprotein (sHDL YDZL3). Our proposal is well-supported by clinicalfindings the existing knowledge of HDL and our preliminary studies. Completion of this study willprovide a body of mechanistic and preclinical data for a novel sHDL-based therapy for sepsis andposition it for future Investigational New Drug (IND) studies and rapid clinical translation which willimprove the health of public and veterans.


application_id: 10266037
project_number: 5I01BX004275-03
project_title: Mechanisms linking obesity and abdominal aortic aneurysm
administering_ic: VA
award_notice_date: 2021-08-30
opportunity_number: BX-18-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 004275
project_start_date: 2019-07-01
project_end_date: 2023-06-30
study_section: ZRD1-CARB-R(01)1
contact_pi_person_id: 3123430
contact_pi: TANNOCK, LISA R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-07-01
project_abstract:
Obesity has emerged as a risk factor for human and angiotensin II (AngII)-induced abdominal aorticaneurysms (AAA). Obesity is highly prevalent in Veterans; the Veteran population also has high prevalence ofother risk factors for AAAs (male sex smoking hypertension). To date no single therapy has proven effectiveto blunt progressive growth of AAAs likely due to diverse etiologies underlying AAAs in the human population.Thus therapies must be individualized to target the relevant risk factor(s) such as obesity and itsmechanisms to effectively ameliorate AAA initiation and progression. We previously reported that obesitypromotes AngII-induced AAAs in mice through inflammation in the perivascular adipose tissue. We now havepreliminary data demonstrating that whole body deficiency of serum amyloid A (SAA) profoundly reducesAngII-induced AAAs in the setting of obesity. Moreover our recently published data demonstrate that SAAstimulates macrophage secretion of IL-1 an inflammatory cytokine implicated in both human and AngII-induced AAAs. In obese subjects adipocytes become a predominate source of local and systemic SAA. Wepropose that AngII periaortic fat and SAA come together in the setting of obesity to create a pro-inflammatoryenvironment immediately adjacent to the abdominal aorta which leads to AAA initiation and expansion. Thecentral hypothesis of this proposal is in the setting of obesity adipocyte-derived SAA activates the NLRP3inflammasome in macrophages to promote AAA development in obesity. Aim 1 will test the hypothesis thatadipocyte-derived SAA is central in creating the pro-inflammatory environment that promotes AngII-inducedAAA formation in obesity. In Aim 2 we will test the hypothesis that adipocyte-derived SAA promotes obesity-induced AAA by activating the NLRP3 inflammasome in macrophages. We have unique mouse models of SAAdeficiency as well as transgenic mice with tissue-specific SAA-overexpression in which we can overexpressSAA only in liver or only in fat. We will employ translational therapeutic approaches to prevent the formationand progression of AngII-induced AAAs in obesity. The impact of these studies is that we will identify SAA andperiaortic fat burden as biomarkers and risk factors for AAA development and progression in the obesepopulation which may identify precision-targeted AAA therapeutics.

project_terms:
Abdominal Aortic Aneurysm;Acute;Adipocytes;Adipose tissue;Age;Angiotensin II;Angiotensins;Biological Markers;C57BL/6 Mouse;Cause of Death;Consumption;Data;Development;Etiology;Fatty acid glycerol esters;Gender;Goals;Growth;Health;High Fat Diet;High Prevalence;Human;Hyperlipidemia;Hypertension;Inflammasome;Inflammation;Inflammatory;Interleukin-1 beta;Link;Liver;Mediator of activation protein;Modeling;Mus;Obese Mice;Obesity;Overweight;Phase;Population;Production;Protein Isoforms;Proteins;Publishing;Reporting;Resistance;Risk Factors;Role;Ruptured Abdominal Aortic Aneurysm;Serum amyloid A protein;Signal Transduction;Smoking;Source;Stimulus;Testing;Therapeutic;Tissues;Transgenic Mice;United States;United States Department of Veterans Affairs;Veterans;abdominal aorta;age group;cytokine;high risk;human very old age (85+);hypercholesterolemia;inflammatory milieu;macrophage;male;military veteran;mouse model;novel;novel therapeutic intervention;obese person;overexpression;prevent;sex;tool;vascular inflammation

public_health_relevance:
This project focuses on obesity as a risk factor for the formation and progressive growth of abdominalaortic aneurysms (AAAs). We focus on serum amyloid A (SAA) since levels of this protein increase withobesity. Our approach should delineate why obesity is a risk factor for AAAs and identify new therapeuticapproaches.


application_id: 10265394
project_number: 5IK6BX004199-04
project_title: BLR&D Research Career Scientist Award application
administering_ic: VA
award_notice_date: 2021-07-20
opportunity_number: BX-17-022
application_type: 5
activity_code: IK6
ic: BX
serial_number: 004199
project_start_date: 2018-04-01
project_end_date: 2023-03-31
study_section: Research Career Scientist[RCSR]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-04-01
project_abstract:
My research work largely explores the underlying physiologic questions regarding tiny vesicles calledexosomes. These exosomes are released from many different types of cells or food-derived exosome-likenanoparticles and I am investigating in VA patients the promising role of exosomes as therapeutic vehicles indelivering treatment for a diverse but specific group of medical conditions i.e.obesity/diabetes Nonalcoholicfatty liver disease (NASH) and cancer. There is a substantial population of veterans who are obese and/orhave cancer. Obesity and cancer pose special burdens on veterans who depend on VA care. Obesitycontributes to over 300000 deaths per year and increases the risk of NASH type 2 diabetes and severalcancers including colon prostate and kidney. Since receiving my initial Research Career Scientist award myresearch group has published more than 50 manuscripts on this subject. Collectively our findings supportcontinued funding of my team to investigate the following 3 aims: (1) Tumor exosomes play a role in: (a)immunosuppression through induction of myeloid-derived suppressor cells inhibition of dendritic celldifferentiation and inhibition of activation of NK cell immunotherapy; (b) by sorting suppressor miRNAs fromtumor cells into exosomes based on the oncogenic major vault protein (MVP) tumors grow faster (NatureCommunications. 2017 Feb 17;8:14448 Nature communications. 2015;6:6956); and (c) more recently wediscovered a novel nanoparticle (Oncotarget. 2016 May 12). Unlike other EVs this extracellular nanovesicle(named HG-NV HG-NV stands for HomoGenous nanovesicle as well as for Huang-Ge- nanovesicle) releasedfrom both mouse and human breast tumor cells is enriched with RNAs. Tumor-derived HG-NVs are morepotent in promoting tumor progression than exosomes. Molecules predominantly present in breast tumor HG-NVs have been identified and characterized. This discovery may have implications in advancing bothmicrovesicle biology research and clinical management including potential useas a biomarker (2). Exosomesreleased from non-tumor cells play a role in: (a) adipose tissue exosome-like vesicles mediating activation ofmacrophage-induced insulin resistance (Diabetes. 2009 Nov;58(11):2498-505); (b) we also found thatintestinal mucus-derived exosomes mediate activation of Wnt/-catenin signaling and play a role in inductionof liver NKT cell anergy (Hepatology 2013 57(3):1250-61); and (c) intestinal mucusderived exosomes carryprostaglandin E2 and suppress activation of liver NKT cells (J Immunol 2013 190(7):3579-89); (3). Exosome-like nanoparticles from edible plants have an effect and therapeutic application on mammalian cells: (a) weused mouse models to show that interspecies communication between plant and mouse gut host cells throughedible plant derived exosomelike nanoparticles by inducing expression of genes for anti-inflammationcytokines antioxidation and activation of Wnt signaling which are crucial for maintaining intestinalhomeostasis. This finding not only opens up a new avenue for investigating ELNs as a means to protect againstthe development of liver related diseases such as alcohol induced liver damage but sheds light on studyingthe cellular and molecular mechanisms underlying inter-species communication in the liver via edible plant-derived nanoparticles; (b) targeted drug/therapeutic miRNAs (Nature Communications. 2013;4:1867) deliveryto intestinal macrophages brain microglia cells (Molecular therapy: 2015 Volume 24 Issue 1 p96105) andinflammatory tumor sites (Cancer Research 2015;75:2520-9) by grapefruit ELN is possible; (c) Broccoli-Derived Nanoparticle Inhibits Mouse Colitis by Activating Dendritic Cell AMP-Activated Protein Kinase(Molecular Therapy. 2017 in press); and (d) Grape exosome-like nanoparticles induce intestinal stem cellsand protect mice from DSS-induced colitis (Molecular Therapy. 2013 Jul;21(7):1345-57).

project_terms:
5'-AMP-activated protein kinase;Adipose tissue;Alcoholic liver damage;Antibodies;Award;Biological;Biological Markers;Biology;Brain;Brain Injuries;Brain Neoplasms;Breast Cancer Cell;Broccoli - dietary;Cancer Patient;Caring;Cell Communication;Cell Differentiation Inhibition;Cell Differentiation process;Cells;Cessation of life;Chronic;Clinical;Clinical Management;Colitis;Colon;Colonic Neoplasms;Colorectal;Communication;Curcumin;Cutaneous Melanoma;DNA;Data;Dendritic Cells;Development;Diabetes Mellitus;Dinoprostone;Disease;Disease Progression;Drug Targeting;Edible Plants;Encephalitis;Explosion;Failure;Folic Acid;Food;Foundations;Funding;Gene Expression;Ginger;Goals;Grapefruit;Grapes;Health Status;Hepatocyte;Hepatology;High Fat Diet;Homeostasis;Homing;Human;Immunosuppression;Immunotherapy;Inflammation;Inflammatory;Insulin Resistance;International;Intestines;Journals;Kidney;Light;Link;Lipids;Liver;Long-Term Effects;Lung;Macrophage Activation;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mammalian Cell;Mammary Neoplasms;Manuscripts;Mediating;Medical;Methods;MicroRNAs;Microglia;Molecular;Mucous body substance;Mus;Myelogenous;Myeloid-derived suppressor cells;NK Cell Activation;Names;Nature;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oncogenes;Oncogenic;Oncoproteins;Overweight;Patients;Pharmaceutical Preparations;Physiological;Plants;Play;Prostate;Publishing;RNA;Radiation therapy;Research;Resistance;Risk;Role;Scientist;Signal Transduction;Site;Small Interfering RNA;Sorting - Cell Movement;Specificity;T-Lymphocyte;Therapeutic;Therapeutic Agents;Tissues;Traumatic Brain Injury;Tumor Promotion;Tumor Suppressor Proteins;Tumor-Derived;Vesicle;Veterans;WNT Signaling Pathway;War;Work;alcohol prevention;anergy;anticancer research;base;beta catenin;cancer cell;cancer diagnosis;cancer immunotherapy;cancer prevention;cancer therapy;cancer type;career;cell type;chemokine;chemokine receptor;cytokine;dextran sulfate sodium induced colitis;exosome;expression vector;extracellular;folate-binding protein;improved;in vivo;interspecies communication;intestinal homeostasis;liver development;liver inflammation;liver injury;macrophage;major vault protein;member;microvesicles;mild traumatic brain injury;military veteran;mortality;mouse model;nanoparticle;nanovector;nanovesicle;neoplastic cell;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel strategies;novel therapeutic intervention;nuclear factor-erythroid 2;patient population;pressure;prevent;side effect;sound;stem cells;targeted delivery;therapeutic development;therapeutic miRNA;translational study;treatment strategy;tumor;tumor progression

public_health_relevance:
The VA estimates that 78 percent of Veterans are overweight or obese. Obesity has been linked to excess riskfor type 2 diabetes and many cancers. Determining the precise mechanism(s) by which obesity contributes tothe development of cancer is essential for the development of therapeutic strategies against cancer. The focusof my career research is to characterize these mechanisms and then to determine whether targeting of thesemechanisms effectively blocks the induction of vesicles that can be caused by a high-fat diet.These vesiclespromote exosome-mediated development of cancer and I am pursuing therapies to treat obesity/diabetes andcancer in VA patients. More importantly development of novel strategies to block/reverse high-fat diet inducedand tumor exosome mediated immunosuppression would also yield a new and practical therapeutic method fortreating chronic inflammatory related diseases and thus improve the health status of members of the VA patientpopulation.


application_id: 10265350
project_number: 5I01BX004542-03
project_title: Optogenetics: A tool to probe mechanism and an agent to block TBI-induced epileptogenesis.
administering_ic: VA
award_notice_date: 2021-07-21
opportunity_number: BX-18-003
application_type: 5
activity_code: I01
ic: BX
serial_number: 004542
project_start_date: 2019-04-01
project_end_date: 2023-03-31
study_section: ZRD1-NURB-H(01)
contact_pi_person_id: 9405862
contact_pi: SLEVIN, JOHN T.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-04-01
project_abstract:
Over two million people are treated medically each year in the United States after sustaining atraumatic brain injury (TBI). Posttraumatic epilepsy (PTE) develops in up to 39% of patients with moderate tosevere non-penetrating TBI. As with other acquired epilepsies spontaneous recurrent seizures associatedwith PTE develop with a latency (>1 week and up to many years) after the initial injury. This seizure-free periodafter TBI represents the period of epileptogenesis during which the brain undergoes physiological anatomicalcellular and molecular changes leading to a state of chronically increased seizure susceptibility. This delaybetween the TBI and development of PTE also represents a period during which strategies might be employedto inhibit the reactive plasticity in the brain that leads to PTE but the molecular mechanisms underlying theepileptogenic process leading to acquired epilepsy are largely unknown and no anti-epileptogenic therapieshave been successfully developed to date. Animal models of posttraumatic epileptogenesis (PTEgenesis) pointto reactive plasticity of hippocampal networks with alteration in the balance of excitation/inhibition as a driverof permanent brain changes and the epileptic state. However the prime molecular and electrophysiologicaltransformations remain murky. The hypothesis to be tested: Post-injury activity and network changes in the hippocampus induced inpart by alterations in the vesicular neurotransmitter release machinery are primary drivers of PTEgenesis. TheSpecific Aims are to: 1) Use channelrhodopsin-2 (ChR2) to optogenetically drive neural activity and theprocess of PTEgenesis by depolarizing specific primary neuronal populations in dentate gyrus (DG). 2) Usehalorhodopsin (NpHR) to retard PTEgenesis induced using a standard method by optogenetically inhibitingneural activity in DG. Proven techniques will be integrated into a new and unique model to detect network andmolecular drivers of PTE and PTEgenesis. Using the controlled cortical impact (CCI) model of TBI ourproposed studies combine 1) unique microelectrode array electrochemistry (MEA) to monitor real-timeglutamate release and oxygen change as a metric of epileptiform activity; 2) immunohistochemistry to definechanges in specific cell phenotypes; and 3) slice electrophysiology with custom Western blot quantitation ofneurotransmitter release machinery on a novel optogenetically-modified hippocampal platform. Aim 1: Studies will be accomplished by AAV2/5 viral transfection of a ChR2-promotor construct intohippocampal DG of rats utilizing optogenetic activation of DG neurons of free-roaming rats after CCI-inducedTBI to enhance PTEgenesis. Extra-cellular glutamate electrophysiological immunohistochemical andvesicular release biochemical measures will be made on animals at discrete behavioral stages during theprogression of epileptogenesis. Aim 2: Studies will be accomplished by AAV2/5 viral transfection of an NpHR-promoter construct into hippocampal DG of rats prior to CCI injury and optogenetic inhibition of DG circuitsafter CCI to inhibit PTEgenesis. MEA electrophysiological immunohistochemical and biochemical measureswill be made. As one component of these studies transient glutamate surges and changes in oxygen in DGdetected by MEAs will trigger real-time optogenetic inhibition as a potential means to abort PTEgenesis. Our approach should allow network neuronal and presynaptic release changes to be clearly tied tobiochemical anatomical electrophysiological and behavioral outcomes associated with epileptogenesis. Thestudies in this proposal will pave the way to development of comprehensive novel analyses of the progressionof PTE and will provide preliminary data to support studies identifying causative effects of activity-dependentsynaptogenesis in the development of PTE. In addition these studies will test a potentially novel therapy forPTEgenesis. Thus this research is directly relevant to the care of a large proportion of service men andwomen veterans and the general population.

project_terms:
Acute;Anatomy;Animal Model;Animals;Antiepileptogenic;Behavioral;Biochemical;Brain;Caring;Cells;Chronic;Chronic Disease;Clinical Trials;Custom;Data;Development;Electrochemistry;Electrophysiology (science);Epilepsy;Epileptogenesis;Equilibrium;Excision;General Population;Glutamates;Goals;Halorhodopsins;Hippocampus (Brain);Human;Immunohistochemistry;Individual;Injury;Life;Measures;Medical;Methods;Microelectrodes;Modeling;Molecular;Neurons;Neurosurgical Procedures;Oxygen;Patients;Phenotype;Physiological;Population;Post-Traumatic Epilepsy;Predisposition;Process;Protein Biochemistry;Rattus;Recurrence;Research;Seizures;Services;Slice;Techniques;Testing;Therapeutic;Time;Transfection;Translations;Traumatic Brain Injury;United States;Veterans;Viral;Western Blotting;Woman;acquired epilepsy;behavioral outcome;controlled cortical impact;critical period;dentate gyrus;economic cost;extracellular;high risk;instrumentation;men;neurotransmitter release;novel;novel therapeutics;optogenetics;presynaptic;prevent;promoter;real time monitoring;relating to nervous system;standard of care;synaptogenesis;tool;vesicular release

public_health_relevance:
Human posttraumatic epilepsy (PTE) is defined as repeated unprovoked seizures beginning more than oneweek but up to years after a traumatic brain injury (TBI). During the seizure-free interval between TBI andPTE the brain undergoes changes leading to a state of chronically increased seizure susceptibility. Themolecular mechanisms and network changes underlying this posttraumatic epileptogenesis (PTEgenesis) arelargely unknown and there are no therapeutic strategies to prevent it. Our approach using microelectrodearrays immunohistochemistry slice electrophysiology quantitative protein biochemistry and optogenetics toanalyze this latent period should allow us to correlate network neuronal and presynaptic release changes tomolecular anatomical electrophysiological and behavioral outcomes associated with PTEgenesis. In additionthese studies will test a potentially novel therapy to retard/halt PTEgenesis. Thus this research is directlyrelevant to the care of a large proportion of service men and women veterans and the general population.


application_id: 10261081
project_number: 1I21RX003766-01
project_title: Developing Novel Models for Assessing Fundamental Mechanisms of Neuroma
administering_ic: VA
award_notice_date: 2021-10-12
opportunity_number: RX-20-009
application_type: 1
activity_code: I21
ic: RX
serial_number: 003766
project_start_date: 2021-10-01
project_end_date: 2023-09-30
study_section: Rehabilitation Research and Development SPiRE Program[RRDS]
contact_pi_person_id: 9011081
contact_pi: PETRUSKA, JEFFREY C
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-10-01
project_abstract:
Neuromas are painful tumors of nerve tissue that result from amputation or other nerve injury. Peripheral nerveinjury is the most-impactful comorbidity associated with the most common types of battlefield trauma andmany of these cases eventually result in formation of a painful neuroma. This condition often requiresadditional invasive surgery for our Veterans including resectioning of the injured nerve to remove theneuroma which may form again. Diabetes a chronic health problem that is a priority for VAMCs across thecountry is another common cause of amputation. Neuroma pain (or nerve pain as it is commonly called inthe amputee community) is also one of the major reasons patients reduce/stop use of assistive devicesincluding prosthetics. Further presence of neuroma can be a disqualifying factor for some prosthetics andnerve interfaces. Although treatments are available there is currently no clinical Standard of Care forprevention or treatment of neuroma because the available approaches are not sufficiently effective. Althoughessentially all unrepaired nerve injuries result in a neuroma not all neuromas are painful. Unfortunately thereis no safe window for neuromas  pain can begin at any point after the nerve injury which induced theneuroma. Neuromas continue to grow and their structure evolves over time likely introducing interactions thatwould not occur in normal tissue and developing emergent properties. These etiological factors suggest thatalthough sensory neurons are necessary for neuroma pain it is the neuroma structure itself that may establishthe physical relationships which lead to pain. Therefore understanding what factors control formation ofneuroma structure is necessary to develop approaches to prevent neuroma formation. Our plan to be pursued in subsequent MERIT applications will tests the hypothesis that it is regeneration ofinjured axons which controls neuroma formation and that subsequent aberrant coupling of sympathetic ormotor axons and/or immune cells with sensory axons is the major factor driving neuroma pain. To this end thisSPiRE proposal is designed to validate genetic models and experimental designs to enable us and the field toaddress fundamental questions which remain unanswered. This project will test the utility of a set of cell type-specific knockout and reporter mice for neuroma research. The premise for the proposed mouse lines is thatneuroma formation is apparently completely prevented by global knockout of a gene required for axonalregeneration. The premise for the new experimental design is that no existing animal models reflect the clinicalreality of the repeated nerve injury that occurs with neuroma resection and recurrence despite the fact that thecondition of repeated injury induces changes that differ from that of single injuries. This SPiRE project willprovide the animal lines visualization methods and preliminary data vital for MERIT projects to determinemechanisms and test treatments.

project_terms:
Address;Afferent Neurons;Amputation;Amputees;Animal Model;Animals;Automobile Driving;Axon;Basic Science;Biological;Biological Factors;Biological Models;Breeding;Cell Proliferation;Cells;Chronic;Clinical;Communities;Country;Coupling;Data;Dependence;Development;Devices;Diabetes Mellitus;Disease;Etiology;Excision;Experimental Designs;Future;Genes;Genetic Models;Goals;Growth;Health;Image;Immune;Injury;Investigation;Knock-out;Knockout Mice;Lead;Local Anesthetics;Methods;Modeling;Motor;Mus;Natural regeneration;Nerve;Nerve Pain;Nerve Tissue;Neuroma;Neurons;Normal tissue morphology;Operative Surgical Procedures;Pain;Patients;Peripheral;Peripheral nerve injury;Pharmacogenetics;Physical Rehabilitation;Physical therapy;Population;Prevention;Preventive therapy;Property;Prosthesis;Proteins;Quality of life;Recurrence;Rehabilitation therapy;Reporter;Research;Resources;Schwann Cells;Self-Help Devices;Sensory;Signal Transduction;Structure;Study models;Testing;Therapeutic;Time;Transgenic Mice;Trauma;Validation;Veterans;Visualization;Work;activating transcription factor 3;axon injury;axon regeneration;cell type;comorbidity;design;experimental study;improved;improved outcome;innovation;knockout gene;loss of function;model design;motor axon regeneration;nerve injury;novel;optogenetics;prevent;recruit;regenerative;response;standard of care;therapy design;therapy development;three dimensional structure;tool;translational approach;tumor

public_health_relevance:
The project aims to validate new genetic models for studying the mechanisms underlying painful neuromawhich occurs after nerve injury and seriously impacts Veterans quality of life engagement with rehabilitationand use of prosthetics. The causes of painful neuroma are not known which hinder development of treatmentsand preventions. The proposed work will take a basic science approach to enable new types of experiments toanswer some of the fundamental questions which will directly influence the design of translational strategies.


application_id: 10258072
project_number: 2I01BX005637-09A1
project_title: Lysophosphatidic Acid and Cardiovascular Disease Risk
administering_ic: VA
award_notice_date: 2021-04-06
opportunity_number: BX-20-001
application_type: 2
activity_code: I01
ic: BX
serial_number: 005637
suffix: A1
project_start_date: 2021-04-01
project_end_date: 2025-03-31
study_section: Special Emphasis Panel[ZRD1 CARB-R (01)]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: SMYTH, SUSAN S.
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Veterans have a higher incidence of cardiovascular disease than the general population. Valvular diseasesincluding Calcific Aortic Valve Disease (CAVD) are a particular concern for the aging Veteran Population. Atpresent there is no medical therapy to delay or reverse CAVD and the only treatment is valve replacement forsevere aortic valve stenosis. CAVD involves remodeling of the heart valve tissue as a consequence ofendothelial injury immune cell infiltration and myofibroblastic / osteogenic differentiation of cells that canultimately result in valve leaflet thickening and profound calcification. The fibrosis and calcification stiffen theleaflets and can result in leaflet fusion that reduces valve opening and causes valve stenosis. Understandingthe molecular mechanisms that drive these changes might lead to the development of much needed therapiesfor CAVD. In the past funding period we made mouse models to study the roles of a bioactive lipidlysophosphatidic acid (LPA) in cardiovascular and metabolic disease processes. In the course of these studieswe found that mice deficient in the enzyme autotaxin (ATX) that generates LPA were protected from valvecalcification and thickening in a commonly used experimental model. We also observed that mice lacking theenzyme lipid phosphate phosphatase 3 (LPP3) that can inactivate LPA exhibited greater valve calcification inthis model. These findings are likely translatable to humans because LPP3 levels are decreased duringdevelopment of human CAVD while ATX accumulates in the valve tissue and ATX binds to lipoprotein (a)particles which are themselves associated with CAVD risk. Valvular Interstitial Cells (VICs) are resident cells ofthe heart valve tissue that are normally responsible for maintaining the integrity of the heart valves. Pathologicaldifferentiation of these cells to myofibroblastic and osteogenic phenotypes is central to the development ofCAVD. Consistent with literature reports our preliminary data shows that mouse and human VICs express LPAselective cell surface receptors. Differentiation of these cells to an osteogenic phenotype and subsequentcalcification can be readily observed in culture medium containing serum which is a rich source of LPA.Pharmacological antagonism of LPA receptors blocks osteogenic differentiation and calcification of these cellsin culture. In the past funding period we characterized transcriptional circuits that regulate LPP3 expression tounderstand why expression is increased in inflammation and decreased by heritable variants that associate withincreased coronary artery disease risk. These studies provide reagents and a framework for understanding whyLPP3 expression is decreased in CAVD. Here we propose to test the broad hypothesis that LPA signalingpromotes CAVD. We will test this hypothesis by using mouse models with cell and tissue type selectiveinactivation of LPA receptors LPP3 and ATX to identify the cell and tissue types involved the permissive effectof LPA on CAVD with a particular interest in the possibility that secreted ATX and cell surface LPP3 could havenon cell autonomous effects on this process. As an orthogonal approach we will use well characterizedexperimental therapeutics (ATX inhibitors and LPA receptor antagonists) to validate results from these geneknockout models and evaluate their potential for pharmacological intervention in CAVD. Studies in mousemodels will be augmented by experiments using cultured mouse and human VICs where again cells with geneticdeficiencies or treatment with small molecule therapeutics can be used to define the role of LPA signaling inosteogenic differentiation and calcification. We will also examine how LPP3 expression is regulated during theseprocesses and test specific hypotheses about why LPP3 expression is decreased during development of CAVD.This research will provide important new information about a pharmacologically tractable lipid signaling pathwaythat appears to be central to the development of CAVD. This information could lead to new approaches for non-surgical management of CAVD in Veterans.

project_terms:
Adipose tissue;Aging;Alpha Particles;Aortic Valve Stenosis;Apolipoproteins;Apolipoproteins A;Atherosclerosis;Behavioral;Binding;Cardiovascular Diseases;Cardiovascular Models;Cell Culture System;Cell Differentiation process;Cell Surface Receptors;Cell surface;Cells;Coronary Arteriosclerosis;Cultured Cells;Data;Development;Diagnosis;Diet;Disease;Down-Regulation;Elderly;Endothelial Cells;Endothelium;Environmental Risk Factor;Enzymes;Exhibits;Experimental Models;Fibrosis;Funding;Gene Silencing;General Population;Generations;Genes;Genetic;Genetic Transcription;Heart;Heart Diseases;Heart Valves;Heritability;Human;Immune;Incidence;Infiltration;Inflammation;Inflammatory;Injury;Intervention;Investigational Therapies;LPAR4 gene;Lead;Link;Lipids;Lipoprotein (a);Literature;Low-Density Lipoproteins;Lysophosphatidic Acid Receptors;Mediating;Medical;Metabolic;Metabolic Diseases;Modeling;Molecular;Mus;NF-kappa B;Normal tissue morphology;Pathologic;Pharmaceutical Preparations;Pharmacology;Phenotype;Post-Translational Protein Processing;Process;Reagent;Receptor Activation;Recombinants;Reporting;Research;Risk;Role;Serum;Signal Pathway;Signal Transduction;Source;Stenosis;Stress;System;Testing;Therapeutic Intervention;Tissues;Variant;Vascular calcification;Veterans;aortic valve;aortic valve disorder;blood pump;bone;calcification;cardiovascular disorder risk;cell type;disorder risk;drug efficacy;experimental study;extracellular;genetic risk factor;heart cell;improved;inhibitor/antagonist;interest;interstitial cell;knockout gene;lipid phosphate phosphatase;lysophosphatidic acid;military veteran;mineralization;mortality;mouse model;novel strategies;osteogenic;prevent;promoter;receptor;response;small molecule;small molecule therapeutics;tissue/cell culture;transcription factor;valve replacement;vascular inflammation

public_health_relevance:
Veterans particularly the elderly have a higher incidence of heart diseases than the general populationincluding hardening of the valves of the heart which is a debilitating condition with no effective non-surgicaltreatment options. This disease involves the aortic valves becoming bone like and rigid which prevents thevalve from opening properly and stresses the heart as it tries to pump blood out the valve. This research willstudy the processes underlying these changes in the heart valve and evaluate the potential efficacy of drugs asinhibitors of hardening of the valves. These drugs might have benefit to protect Veterans from developing thiscondition or potentially reverse the condition in Veterans with established aortic valve disease.


application_id: 10223461
project_number: 5I21RX003173-02
project_title: Tuning Up Memory-related Brain Potentials using Real-time Neurofeedback in Older Veterans"
administering_ic: VA
award_notice_date: 2022-01-18
opportunity_number: RX-19-003
application_type: 5
activity_code: I21
ic: RX
serial_number: 003173
project_start_date: 2020-10-01
project_end_date: 2023-03-31
study_section: Rehabilitation Research and Development SPiRE Program[RRDS]
contact_pi_person_id: 7875188
contact_pi: JIANG, YANG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-10-01
project_abstract:
Military deployment is associated with increased risk of mild cognitive impairment (MCI).Combat stress related memory deficits has been well documented. Mild cognitive impairmentsuch as memory deficits are the most common and earliest symptoms of Alzheimers diseaseand related dementia (ADRD). The complaints about declined memory are common in healthyand cognitively intact civilian older adults but less understood in aging combat veterans. Braintraining strategies to enhance cognitive skills and especially memory processes are unmetneeds in aging combat veterans who are at additional risk for MCI induced by ADRD. Sincecurrently there is no effective drug treatment to stop cognitive decline noninvasive brain trainingto boost memory functions in older veterans is an increasingly attractive option to attenuatingdecline in memory. The proposed project is poised to investigate state-of-art neurofeedback (NF;biofeedback of brain activity) training for self-modulation of neural plasticity to boost memoryperformance in veterans. The recent advance of NF with Brian-Computer Interface (BCI) hasprovided a novel way to examine brain functions and plasticity. Thus far there has been limitedapplication in developing effective experimental and clinical paradigms for rehabilitation inveterans. Historically brainwave patterns during memory task performance have beenanalyzed offline a methodology which does not allow real-time NF modulation and training.The proposed project is poised to investigate state-of-art neurofeedback (NF; biofeedback ofbrain activity) training for self-modulation of neural plasticity to boost memory performance inveterans. The central hypothesis guiding this research is that optimal memory-related brainwavepatterns of a veteran can be trained. The online NF allows maximization of brainwave patternsassociated with healthier memory states. The development of efficient NF paradigms to augment memory performance is animportant first step for the application of this nonpharmacologic intervention to improve combatveterans memory functions and potential for treating MCI due to mild TBI or pain. We will usestate-of-the-art wearable wireless brain-computer interface headset which is affordable and canbe easily set up in VAMCs and eventually in remote assessment settings. This innovativecognitive neuroscience based nonpharmacologic intervention serves to revolutionize thediagnosis and treatment of combat veterans who are at risk for degenerative dementia.

project_terms:
Age;Aging;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease related dementia;Alzheimer's disease risk;Attenuated;Biofeedback;Biological Markers;Brain;Classification;Clinical;Cognitive;Computer Interface;Crossover Design;Dementia;Deposition;Development;Diagnosis;Elderly;Electrophysiology (science);Etiology;Functional disorder;Goals;Human;Impaired cognition;Individual;Intervention;Link;Measures;Memory;Memory Loss;Memory impairment;Mental disorders;Methodology;Methods;Military Personnel;Modeling;Neurocognitive;Neuronal Plasticity;Pain;Pattern;Performance;Persons;Pharmacotherapy;Physical Performance;Pilot Projects;Protocols documentation;Reaction Time;Rehabilitation therapy;Research;Research Design;Rest;Rewards;Risk;Sensory;Short-Term Memory;Signal Transduction;Stress;Symptoms;Synapses;Task Performances;Testing;Time;Training;Veterans;base;brain computer interface;cognitive enhancement;cognitive function;cognitive neuroscience;cognitive performance;cognitive rehabilitation;cognitive skill;cognitive testing;cognitive training;combat;combat veteran;community setting;effectiveness testing;high risk;improved;innovation;memory process;memory retrieval;mild cognitive impairment;mild traumatic brain injury;military veteran;neurofeedback;neuroregulation;novel;processing speed;rapid growth;rehabilitation paradigm;remote assessment;support network;tau Proteins;tau aggregation;wireless

public_health_relevance:
Military deployment is associated with increased risk of mild cognitive impairment such ascombat stress related memory deficits. The complaints about declined memory are common inhealthy and cognitively intact civilian older adults but less understood in aging combat veterans.The recent advances of wireless brain-computer interface and biofeedback of brain activity haveprovided novel ways to examine brain functions and plasticity. The proposed innovativecognitive neuroscience based non-pharmacologic intervention serves to revolutionize thediagnosis and treatment of combat veterans who are at risk for cognitive impairment anddementia.


application_id: 10158405
project_number: 5I01BX003274-04
project_title: The Vagus Nerve in Lung Disease
administering_ic: VA
award_notice_date: 2021-07-22
opportunity_number: BX-17-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 003274
project_start_date: 2018-04-01
project_end_date: 2023-03-31
study_section: Respiration[PULM]
contact_pi_person_id: 2084836
contact_pi: YU, JERRY (JUN)
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-04-01
project_abstract:
Pulmonary neuroendocrine (PNECs) cells are widely distributed throughout theairway mucosa. These cells can be solitary or aggregated to form neuroepithelialbodies (NEBs) which are richly innervated by the vagus nerve. PNECs/NEBs areimportant for early phases of lung development and also associated with stem cellniches in the airways. They are airway sensors. Airway sensory receptors arebiosensors that detect lung inflammation and injury through various mediators andcytokines. This information is transmitted through vagal afferents to the brain andproduces a host of responses that regulate the pathophysiological process.Increasing evidence suggests that the vagus nerve plays an important role in avariety of pulmonary diseases from asthma COPD ARDS to lung cancer.Pulmonary fibrosis (PF) can result from a variety of insults to the lung. Lung repairfollowing an insult-induced injury is a complex process involving both resident cellsand recruited cells. The progression of PF results from a network of interactionsamong mediators cytokines and growth factors derived from inflammatoryendothelial and epithelial cells which leads to lung remodeling deposition ofcollagen limitation of gas exchange and dyspnea. The vagus nerve is closelyrelated to each component of this network thus its function may influence theoutcome of PF. Since lung injury is a major component in the development of PFand harmful insults to the lung may stimulate the NEB-Vagal System (NVS) a novelhypothesis that activation of the NVS promotes lung fibrosis will be tested. [If thishypothesis is correct suppression of the NVS should attenuate fibrosis whereasstimulation of the NVS should promote fibrosis. By examining lung fibrosis inbleomycin treated mice in which the NVS is either stimulated or suppressed(vagotomy medication gene manipulation or cell adoptive transfer) and byassessing well-established cellular and molecular pathways that lead to PF withdifferent techniques (histology physiology cytology and biochemistry) theunderlying neural mechanisms will be delineated.] Successful completion of thestudies will establish a novel neural mechanism in the pathogenesis of PF. [Thispotentially may lead to a new pharmacological approach to treat or to limit chronicfibrotic diseases in the Veteran population.]

project_terms:
Acetylcholine;Address;Adoptive Cell Transfers;Adult Respiratory Distress Syndrome;Agonist;Asthma;Attenuated;Biochemical;Biochemistry;Biological;Biosensor;Brain;Bronchoalveolar Lavage;Cell Count;Cells;Cessation of life;Chronic;Chronic Obstructive Airway Disease;Cicatrix;Collagen;Complex;Cytology;Data;Deposition;Development;Disease;Dyspnea;Endothelial Cells;Epithelial Cells;Fibroblasts;Fibrosis;Gases;Gene Expression;Growth Factor;Histology;Hospitals;Immune response;Inflammatory;Injury;Lead;Lung;Lung Inflammation;Lung diseases;Malignant neoplasm of lung;Mammals;Mediating;Mediator of activation protein;Molecular;Mucous Membrane;Mus;Myofibroblast;Nerve;Nerve Block;Neural Pathways;Neuraxis;Neuroendocrine Cell;Neuroepithelial Bodies;Neuroimmune;Neurosecretory Systems;Outcome;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacology;Phase;Physiology;Plasma;Play;Process;Pulmonary Fibrosis;Research;Role;Sensory Receptors;Severities;System;Techniques;Testing;Transforming Growth Factor beta;Vagotomy;Vagus nerve structure;chemical release;cytokine;effective therapy;fibrogenesis;genetic manipulation;improved;indium-bleomycin;lung development;lung injury;lung repair;military veteran;mouse model;neuromechanism;novel;novel strategies;patient population;protein expression;receptor;recruit;sensor;stem cells;vagus nerve stimulation

public_health_relevance:
Lung diseases are a major cause of illness and death in the Veteran population. Many of thediseases are related to lung fibrosis (LF) which is due to increased collagen and has no effectivetreatment. In the lung there are specialized neuroendocrine cells connected to nerves forming aneuroendocrine system (NS). The NS is essential for lung repair and influences progression ofpulmonary diseases. We hypothesize that the NS promotes LF. We examined biochemistryphysiology and histology of both lungs in a mouse model for LF with one lung denervated andcompared severity of the LP. Indeed we found that a chemical released from the NS can promoteLF. In this application we will investigate the mechanism. Since pulmonary diseases related to LFform a major pulmonary patient population at VA hospitals successful completion of the studies willestablish a novel neural mechanism in the lung disease and may improve VA patient management.


application_id: 10137075
project_number: 5IK2BX004883-02
administering_ic: VA
award_notice_date: 2021-07-20
opportunity_number: BX-19-008
application_type: 5
activity_code: IK2
ic: BX
serial_number: 004883
project_start_date: 2020-04-01
project_end_date: 2025-03-31
study_section: ZRD1-NURE-E(01)
contact_pi_person_id: 11890992
contact_pi: YAMASAKI, TRITIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-04-01
budget_end_date: 2022-03-31
project_terms:
Affect;Aging;Antibodies;Area;Award;Basic Science;Binding;Biochemical;Biochemistry;Biological Assay;Biological Markers;Biosensor;Blood;Blood Platelets;Blood specimen;Braak's hypothesis;Brain;C-terminal;Cell-Free System;Cells;Characteristics;Clinic;Clinical;Clinical Research;Consent;DNA Sequence Alteration;Deep Brain Stimulation;Detection;Development;Diagnosis;Diagnostic;Disease;Disease Progression;Documentation;Early Diagnosis;Elderly;Engineering;Epitopes;Erythrocytes;Evaluation;Expenditure;Exposure to;FDA approved;Faculty;Fluorescence Resonance Energy Transfer;Gender;Genetic;Goals;Healthcare;Imaging Techniques;In Vitro;Investigative Techniques;Kentucky;Knowledge;Lead;Ligands;Liquid substance;Mentors;Methods;Modality;Molecular;Molecular Conformation;Motor;Movement;Movement Disorders;Multiple System Atrophy;Nerve Degeneration;Neuraxis;Neurodegenerative Disorders;Neurology;Parkinson Disease;Pathogenicity;Pathologic;Pathology;Patients;Peripheral;Plasma;Population;Positioning Attribute;Process;Prognosis;Property;Proteins;Publishing;Records;Research;Sampling;Seeds;Solubility;Structure;System;Techniques;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;Toxin;Training;Training Programs;Universities;Veterans;Whole Blood;Work;accurate diagnosis;alpha synuclein;amplification detection;base;career;cerebral atrophy;collaborative environment;detection method;disorder control;disorder risk;effective therapy;exosome;experience;genetic manipulation;imaging modality;insight;liquid biopsy;male;molecular imaging;novel;novel marker;patient population;prion-like;professor;prognostic;protein aggregation;rare condition;sensor;success;synuclein;synucleinopathy;translational scientist;transmission process


application_id: 10087790
project_number: 5IK2BX004618-02
project_title: Psychological deficits after low level blast exposure: role of neurovascular disruption
administering_ic: VA
award_notice_date: 2021-06-02
opportunity_number: BX-19-008
application_type: 5
activity_code: IK2
ic: BX
serial_number: 004618
project_start_date: 2020-01-01
project_end_date: 2024-12-31
study_section: ZRD1-NURC-H(01)
contact_pi_person_id: 14823099
contact_pi: HUBBARD, WILLIAM BRAD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-01-01
project_terms:
3-Dimensional;Acute;Address;Affect;Aggressive behavior;Aging;Amygdaloid structure;Animal Model;Animals;Anxiety;Behavior;Behavior assessment;Behavioral;Bioenergetics;Biological Assay;Biological Markers;Blast Injuries;Blood - brain barrier anatomy;Blood Platelets;Blood Vessels;Brain;Brain region;Cerebrovascular Circulation;Chronic;Chronic Post Traumatic Stress Disorder;Clinical;Coupled;Data;Development;Development Plans;Exposure to;Foundations;Functional disorder;Grant;Health;Image;Immunohistochemistry;Impairment;Investigation;Kentucky;Knowledge;Lead;Life;Literature;Matrix Metalloproteinases;Measures;Mentors;MicroRNAs;Military Personnel;Modeling;Nervous System Trauma;Neurocognitive;Neurologic Deficit;Neurologic Dysfunctions;Neurological outcome;Neurons;Neuropsychology;Occupational;Occupational Exposure;Outcome;Pathologic;Peripheral;Phenotype;Post-Traumatic Stress Disorders;Predisposition;Proteins;Publishing;Rattus;Recording of previous events;Recovery;Reporting;Research;Research Personnel;Risk;Rodent;Rodent Model;Role;Serum;Social Interaction;Soldier;Spin Labels;Stains;Symptoms;Techniques;Testing;Therapeutic;Time;Tissues;Training;Training Programs;Universities;Vascular Diseases;Veterans;Writing;base;behavior test;behavioral impairment;blast exposure;blood-based biomarker;blood-brain barrier disruption;career development;cerebrovascular;clinically relevant;cohort;depressive symptoms;exosome;experience;improved;inhibitor/antagonist;military veteran;multimodality;neuroimaging;neuropathology;neurovascular;neurovascular unit;novel;operation;phosphodiesterase V;pre-clinical;primary outcome;programs;psychologic;psychological outcomes;restoration;sildenafil;skills;stress related disorder;student mentoring;therapeutic target;time interval;trait


application_id: 10046275
project_number: 5I01BX004252-03
project_title: CD47 as a therapeutic target for obesity
administering_ic: VA
award_notice_date: 2020-10-28
opportunity_number: BX-17-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 004252
project_start_date: 2018-10-01
project_end_date: 2022-09-30
study_section: Endocriniology A[ENDA]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-10-01
project_abstract:
Brown adipose tissue (BAT) dissipates energy through UCP1-mediated uncoupled respiration and its activationmay represent a therapeutic strategy to combat obesity. Preliminary studies identified a novel role of CD47in regulating BAT function and its contribution to energy homeostasis and the development of obesity.CD47 a ubiquitously expressed cell membrane receptor implicated in self-recognition and immune functionwas upregulated in adipose tissue from obese animals. Moreover CD47 deficiency protected mice from diet-induced obesity (DIO) through activation of BAT function (e.g. enhanced mitochondria uncoupling and heatproduction) and increased energy expenditure. These data suggest that CD47 is a negative regulator of BATactivity. Therefore inhibition of CD47 signaling might be a novel anti-obesity strategy which is furthersupported by a recent human genome-wide study showing the association of single-nucleotide polymorphismsin CD47 gene with body weight and BMI. In this proposal the mechanisms by which CD47 downregulatesbrown fat cell function will be determined in Aim 1. The contribution of brown adipocyte specific CD47deficiency on obesity development will be determined in Aim 2. Whether inhibition of CD47 signaling by CD47-antisense oligo (ASO) treatment activates BAT and prevents/ameliorates obesity development in animalmodels will be determined in Aim 3. These studies will not only provide novel information on the mechanismsby which CD47 down-regulates brown fat function and its contribution to energy homeostasis and thedevelopment of obesity but also test the anti-obesity potential of a CD47-ASO in obese mouse models.Therefore these studies have clinical significance.

project_terms:
Adipocytes;Adipose tissue;Animal Model;Animals;Antisense Oligonucleotides;Attenuated;Body Weight;Body fat;Body mass index;Brown Fat;CD47 gene;Carnitine Palmitoyltransferase I;Cell Line;Cell membrane;Cell physiology;Cells;Complex;Cyclic AMP;Cyclic GMP;Data;Development;Diet;Eating;Energy Intake;Energy Metabolism;Exhibits;Fatty Liver;Fatty acid glycerol esters;Functional disorder;Genes;Genotype;High Fat Diet;Homeostasis;Human Genome;In Vitro;Insulin Resistance;Investigation;Knockout Mice;Liver diseases;Mediating;Metabolic;Mitochondria;Modeling;Molecular;Mus;Nerve;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Obesity;Obesity Epidemic;Resistance;Respiration;Risk Factors;Rodent;Rodent Model;Role;Signal Pathway;Signal Transduction;Single Nucleotide Polymorphism;System;Testing;Therapeutic;Thermogenesis;Tissues;Wild Type Mouse;Work;base;blood glucose regulation;clinically significant;combat;comorbidity;diet-induced obesity;genome-wide analysis;human subject;immune function;improved;in vivo;knock-down;lipid biosynthesis;lipid metabolism;mouse model;novel;novel therapeutic intervention;obesity development;obesity genetics;obesity treatment;oxidation;prevent;receptor;therapeutic target;tool

public_health_relevance:
Obesity an imbalance of energy intake and energy expenditure is a major risk factor for the development ofinsulin resistance and type 2 diabetes. Preliminary studies identified that CD47 is a novel regulator of obesity-associated brown fat cell dysfunction. In this application while delineating mechanisms of CD47 to regulatebrown adipocyte function study will also focus on the development of novel therapeutic strategies in thetreatment of obesity and its associated metabolic complications.


application_id: 10046272
project_number: 5I01BX003877-04
project_title: Targeting Platelet Endocytosis and Exocytosis to Control Thrombosis
administering_ic: VA
award_notice_date: 2021-04-13
opportunity_number: BX-16-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 003877
project_start_date: 2017-10-01
project_end_date: 2022-09-30
study_section: Hematology[HEMA]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-10-01
project_abstract:
World-wide spurious thrombosis accounts for 1 of 4 non-communicable disease deaths.Cardiovascular disease is a leading killer of aging US veterans and is the major cause of death in olderfemale veterans. Understanding how to modulate thrombosis will significantly aide the VA's mission toimprove veterans' health. Normally platelets respond to vascular damage and secrete granule cargothat are essential for recruiting more platelets and for generating a thrombus. This releasate promotesnormal sequelae but can also contribute to occlusive pathologies such as strokes and heart attacks. Inplatelets VAMPs SNAP-23 and Syntaxin-11 form a membrane-spanning complex that mediatesexocytosis. Formation of this complex requires a host of SNARE-regulators e.g. Munc18bSTXBP5/tomosyn-1 and granuphilin/SLP4; however the mechanisms by which these proteins controlthe complexity of the platelet release reaction (its rate extent and content) is uncertain. Platelets arealso capable of other cellular processes (i.e. RNA splicing translation glycosylation autophagy);however their effects on platelet function are still unknown. Our data suggest that endocytosis affectsthrombus growth by modulating platelet spreading and platelet-platelet contacts. Our goal is tomanipulate the membrane trafficking in platelets both endocytosis and exocytosis in order tomodulate occlusive thrombosis with only modest effects on hemostasis. To reach this goal wemust probe the molecular mechanisms of exocytosis. Our specific focus will be on Syntaxin-11regulators. We will also use an endocytosis defective mouse strain to define the roles of endocytosis inthrombosis and hemostasis. Two aims are proposed: 1) Define the network of protein-proteininteractions that affect Syntaxin-11-mediated membrane fusion and granule cargo release; and2) Determine the roles of platelet endocytosis in hemostasis. To complete these aims we willemploy biochemical assays to define the interactions between the SNARE regulators and in vitro andin vivo functional assays using transgenic mice to define the roles of the specific Syntaxin-11regulators and of endocytosis in thrombosis and hemostasis. Our results will expand the understandingof the molecular requirements and the sequence of protein-protein interactions controlling plateletexocytosis. We will also expand the mechanistic understanding of what cellular processes platelets canperform (i.e. endocytosis) and why they are important. Our results will be significant to the field sincethey will provide the needed mechanistic insights to identify potential targets for therapeutic interventionand to evaluate the relevance of the increasing volume of gene/risk associations that are guiding patienttreatment strategies. This will enhance the anti-thrombotic treatment options available for the care ofaging veterans.

project_terms:
Acute;Address;Adhesions;Affect;Age;Aging;Amino Acid Sequence;Autophagocytosis;Biochemical;Biological Assay;Blood Platelets;Blood Vessels;Cardiovascular Diseases;Caring;Carotid Artery Injuries;Cause of Death;Cell physiology;Cellular biology;Cessation of life;Clot retraction;Coagulation Process;Communicable Diseases;Complex;Cytoplasmic Granules;Data;Disease;Endocytosis;Equilibrium;Event;Exocytosis;Female;Fibrinogen;Gene Deletion;Goals;Growth;Guanosine Triphosphate Phosphohydrolases;Health;Hemorrhage;Hemostatic function;Hyperactivity;In Vitro;Infarction;Integrins;Knock-out;Knockout Mice;Knowledge;Mediating;Membrane;Membrane Fusion;Mission;Modeling;Molecular;Molecular Chaperones;Molecular Probes;Morbidity - disease rate;Mouse Strains;Mus;Myocardial Infarction;Pathology;Patients;Physicians;Precision Medicine Initiative;Process;Protein Biochemistry;Proteins;Publishing;RNA Splicing;Reaction;Risk;Risk Factors;Role;S-nitro-N-acetylpenicillamine;SNAP receptor;Sampling;Stroke;Tail;Therapeutic Intervention;Thrombosis;Thrombus;Transgenic Mice;Translations;Veterans;Work;base;clinically significant;experimental study;familial hemophagocytic lymphohistiocytosis;genome wide association study;glycosylation;granuphilin;health management;improved;in vitro Assay;in vivo;insight;male;military veteran;mortality;platelet function;protein protein interaction;recruit;response;restenosis;risk variant;synaptotagmin;syntaxin;syntaxin 11;syntaxin A;syntaxin-2;target SNARE proteins;targeted treatment;therapeutic target;thrombotic;trafficking;treatment strategy;vesicular SNARE proteins

public_health_relevance:
Relevance of the Project to Veterans' Health: Worldwide thrombotic events e.g. strokes and heart attacksaccount for 1 of 4 deaths not caused by communicable diseases. Thrombotic events are major killers of agingveterans especially female veterans. Platelets are essential for clot formation but targeting them to controlthrombosis requires a greater understanding of how platelet work. In this proposal we look at two aspects ofplatelet cell biology exocytosis and endocytosis to determine how and why platelets both release clottingcomponents and take them up them during clot formation. Our experiments will generate the critical mechanisticinsights needed to effectively control platelet function and thus limit thrombosis in aging veterans.


application_id: 10044406
project_number: 5I01BX003643-02
project_title: TBI-induced exosome release accelerates Alzheimer's disease pathology
administering_ic: VA
award_notice_date: 2021-05-27
opportunity_number: BX-18-004
application_type: 5
activity_code: I01
ic: BX
serial_number: 003643
project_start_date: 2019-10-01
project_end_date: 2023-09-30
study_section: ZRD1-NURD-C(01)1
contact_pi_person_id: 2275110
contact_pi: BIEBERICH, ERHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-10-01
project_abstract:
Alzheimer's disease (AD) is characterized by build-up of A peptides forming amyloid plaques and hyper-phosphorylation of tau protein forming neurofibrillary tangles a two-fold protein aggregation process leading toprogressive neurodegeneration and cognitive decline. Epidemiological studies show that the risk of developingAD is 4-fold higher in persons who have experienced head trauma or traumatic brain injury (TBI) which isprevalent in Veterans returning from active combat. Reasons for this increased risk are unclear and no strategyto prevent AD pathology exists. A critical barrier to progress is the lack of understanding of how amyloid andtau are rendered neurotoxic and how TBI may induce or accelerate this process. Our goal is to understandand prevent amyloid and tau neurotoxicity and delay the onset and reduce neurodegeneration in ADparticularly when induced or accelerated by TBI in Veterans. Our central hypothesis is that TBI-inducedshear force shakes and repeatedly bends cilia in astrocytes which leads to calcium influx reprogramming ofceramide metabolism and sustained secretion of ceramide-enriched exosomes termed astrosomes(immediate effect). A42 and tau associate with ceramide and turn astrosomes into neurotoxic betasomeseven years after TBI (delayed effect). Betasomes also contain prostate apoptosis response 4 (PAR-4) aprotein sensitizing neurons to ceramide-induced apoptosis. Betasomes are transported to mitochondria wherethey enhance A42 and tau-mediated mitochondrial dysfunction and neurotoxicity. Consistent with ourhypothesis betasomes are detectable in serum from AD patients and 5xFAD mice and induce mitochondrialdamage caspase activation and tau aggregation in N2a cells and primary cultured neurons. Our hypothesispredicts that astrosome secretion association with A42 and tau and neurotoxicity are prevented by blockingTBI-induced calcium influx and ceramide generation. Our expected outcomes include 1) determiningenzymes in upregulation of ceramide and specific calcium channels that are activated by shear force; 2)defining a ceramide composition in astrosomes that induces interaction with A42 tau aggregation andmito/neurotoxicity; 3) identifying ceramide-modulating drugs and calcium channel blockers that preventastrosome secretion betasome formation mitochondrial dysfunction and tau aggregation and neurotoxicity;and 4) quantifying astrosomes and betasomes in serum that indicate severity of TBI-induced AD (TBI-AD) andsuccess of therapeutic treatment. The impact of this project on protection of Veterans and public health willinclude knowledge needed for the development of new treatment strategies that could delay and/or prevent theonset of progressive neurodegeneration in AD in particular when induced by mild TBI in Veterans.

project_terms:
Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease patient;Amyloid;Amyloid beta-42;Amyloid beta-Protein;Apoptosis;Astrocytes;Axon;Binding;Brain;Calcium;Calcium Channel;Calcium Channel Blockers;Caspase;Cells;Ceramides;Cilia;Closed head injuries;Craniocerebral Trauma;Development;Enzymes;Generations;Goals;Impaired cognition;Impairment;Interruption;Knowledge;Mediating;Metabolism;Mitochondria;Monitor;Mus;Nerve Degeneration;Neurofibrillary Tangles;Neurons;Outcome;Pathology;Patients;Peptides;Persons;Pharmaceutical Preparations;Prevention;Process;Prostate;Proteins;Public Health;Research;Risk;Senile Plaques;Serum;Severities;Testing;Therapeutic;Traumatic Brain Injury;Up-Regulation;Vesicle;Veterans;Voltage-Dependent Anion Channel;amyloid peptide;axonal degeneration;cell motility;ceramide 3;combat;cytochrome c;diagnostic biomarker;epidemiology study;exosome;experience;inhibitor/antagonist;lipid metabolism;mild traumatic brain injury;mitochondrial dysfunction;mouse model;neuron loss;neurotoxic;neurotoxicity;novel diagnostics;prevent;progressive neurodegeneration;protein aggregation;protein folding;response;success;tau Proteins;tau aggregation;tau-1;treatment strategy;uptake

public_health_relevance:
Traumatic brain injury (TBI) resulting from combat is a prevalent head injury among Veterans. TBI can increasethe risk of developing Alzheimer's disease (AD) by 4-fold. AD is characterized by build-up of amyloid peptidesforming plaques and hyper-phosphorylation of tau protein forming neurofibrillary tangles a two-fold proteinaggregation process leading to neurodegeneration and cognitive decline. It is not known how TBI increases therisk of developing AD and how to prevent TBI-induced AD. Our research showed that even mild TBI elicitsshear forces in the brain that make particular cells secrete vesicles called exosomes. These TBI-inducedexosomes bind to amyloid peptide and tau protein and enhance their neurotoxicity. Our goal is to interrupt TBI-induced exosome secretion to prevent or delay the onset of AD in Veterans.


application_id: 10015496
project_number: 1I21RX003173-01A1
project_title: Tuning Up Memory-related Brain Potentials using Real-time Neurofeedback in Older Veterans"
administering_ic: VA
award_notice_date: 2020-07-23
opportunity_number: RX-19-003
application_type: 1
activity_code: I21
ic: RX
serial_number: 003173
suffix: A1
project_start_date: 2020-10-01
project_end_date: 2022-09-30
study_section: Rehabilitation Research and Development SPiRE Program[RRDS]
contact_pi_person_id: 7875188
contact_pi: JIANG, YANG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Age;Aging;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease related dementia;Alzheimer's disease risk;Attenuated;Biofeedback;Biological Markers;Brain;Classification;Clinical;Cognitive;Computer Interface;Crossover Design;Dementia;Deposition;Development;Diagnosis;Elderly;Electrophysiology (science);Etiology;Functional disorder;Goals;Human;Impaired cognition;Individual;Intervention;Link;Measures;Memory;Memory Loss;Memory impairment;Mental disorders;Methodology;Methods;Military Personnel;Modeling;Neurocognitive;Neuronal Plasticity;Pain;Pattern;Performance;Pharmacotherapy;Physical Performance;Pilot Projects;Population;Protocols documentation;Reaction Time;Rehabilitation therapy;Research;Research Design;Rest;Rewards;Risk;Sensory;Short-Term Memory;Signal Transduction;Stress;Symptoms;Synapses;Task Performances;Testing;Time;Training;Veterans;Wireless Technology;base;brain computer interface;cognitive enhancement;cognitive function;cognitive neuroscience;cognitive performance;cognitive rehabilitation;cognitive skill;cognitive testing;cognitive training;combat;community setting;effectiveness testing;high risk;improved;innovation;memory process;memory retrieval;mild cognitive impairment;mild traumatic brain injury;neurofeedback;neuroregulation;novel;processing speed;rapid growth;rehabilitation paradigm;support network;tau Proteins;tau aggregation


application_id: 10004812
project_number: 1I21RX003300-01A1
administering_ic: VA
award_notice_date: 2020-06-04
opportunity_number: RX-19-003
application_type: 1
activity_code: I21
ic: RX
serial_number: 003300
suffix: A1
project_start_date: 2020-06-01
project_end_date: 2022-05-31
study_section: Rehabilitation Research and Development SPiRE Program[RRDS]
contact_pi_person_id: 10388308
contact_pi: BAZRGARI, BABAK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-06-01
project_title:
The assessment of lower back mechanical behavior and spinal loads in veterans with non-specific low back pain: a feasibility study

project_abstract:
Low back pain (LBP) is strongly associated with opioid consumption among veterans and improved clinicalmanagement of LBP is likely to reduce reliance on opioid among veterans. Up to 60% of patients with an acuteepisode of non-specific LBP experience either symptom persistence or symptom relapse within one year. Thisis likely an indication of a failure in addressing the underlying mechanisms of pain or initiation of a newetiology; both may stem from a mismatch between patients and treatments. The overall goal of our researchis to develop validate and implement measures that are relevant to known mechanisms of LBP which canthen be used to holistically gauge the health status of patients lower backs beyond self-reporting of symptoms.More accurate measurements will help better match of patients with existing treatments or development ofmore effective new treatments. The specific objective of this study is to generate evidence in support of thefeasibility of our methods for 1) the evaluation of relative contribution of lower back tissues to spinal loads and2) the investigation of the resultant spinal loads in veterans with non-specific LBP. We have developed apowerful set of tools for the comprehensive assessment of spinal loads and lower back mechanical behavior(MB) that will enable us to examine the existence or development of abnormalities in spinal loads and lowerback MB in [five] groups of veterans with different experiences with non-specific LBP. These groups willinclude [1) veterans with chronic non-specific LBP and high level of disability (n=10) 2) veterans with chronicnon-specific LBP and low level of disability (n=10)] 3) veterans with non-chronic non-specific LBP (n=10) 4)asymptomatic veterans with a recent history (i.e. during the past year) of non-specific LBP (n=10) and 5)asymptomatic veterans without a recent history of non-specific LBP (n=10; serving as control group).Successful completion of this feasibility project will pave the way for future studies (merit grant applications)that will verify the role of abnormalities in lower back MB and spinal loads in the clinical presentation of LBP.Such an understanding has the potential to help the affected veterans with disabling non-specific LBP.Specifically measures of lower back MB and spinal loads can be used not only to identify veterans withmechanical abnormalities in their lower back who are likely to experience LBP in the future but also to guidenovel integrated physical and psychological preventative treatments aimed at improved lower back mechanics.Ultimately the goal and resultant improvement in clinical outcomes of treatment for non-specific LBPis to diminish reliance on opioids for the symptom management of particularly veterans with chronicLBP.

project_terms:
Activities of Daily Living;Acute;Address;Affect;Analgesics;Applications Grants;Back;Behavior;Biomechanics;Characteristics;Chronic;Chronic low back pain;Clinic;Clinical;Clinical Management;Control Groups;Development;Elements;Etiology;Evaluation;Failure;Feasibility Studies;Financial compensation;Future;Gender;Goals;Health Status;Individual;Investigation;Life;Low Back Pain;Manuals;Measurement;Measures;Mechanics;Medical center;Methods;Muscle;Nature;Opioid;Outcome;Pain;Participant;Patient Self-Report;Patients;Pelvis;Physical Function;Plant Roots;Population;Preventive treatment;Questionnaires;Recording of previous events;Recurrence;Reflex action;Relapse;Relaxation;Reporting;Research;Research Personnel;Risk;Role;Screening procedure;Source;Spinal;Stress;Surveys;Symptoms;Testing;Tissues;Treatment outcome;Vertebral column;Veterans;Walking;design;disability;effective intervention;effective therapy;experience;high risk;human model;improved;innovation;mechanical behavior;mechanical properties;neuromuscular;neuromusculoskeletal;novel;opioid use;opioid user;pain relief;psychologic;recruit;response;stem;symptom management;tool

public_health_relevance:
Low back pain is strongly associated with opioid consumption among veterans. This project will investigate thepresence of abnormalities in spinal loads and/or lower back mechanical behavior as potential contributingfactors to relapse or persistence of low back pain by examining five groups of veterans with differentexperiences of low back pain. Aiming at enhanced clinical management of low back pain our project has thepotential to help reduce reliance on opioid in veterans with disabling non-specific low back pain by enablingmore accurate assessment of lower back health status.


application_id: 9974276
project_number: 5I01BX004275-02
project_title: Mechanisms linking obesity and abdominal aortic aneurysm
administering_ic: VA
award_notice_date: 2020-09-18
opportunity_number: BX-18-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 004275
project_start_date: 2019-07-01
project_end_date: 2023-06-30
study_section: ZRD1-CARB-R(01)1
contact_pi_person_id: 3123430
contact_pi: TANNOCK, LISA R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
project_abstract:
Obesity has emerged as a risk factor for human and angiotensin II (AngII)-induced abdominal aorticaneurysms (AAA). Obesity is highly prevalent in Veterans; the Veteran population also has high prevalence ofother risk factors for AAAs (male sex smoking hypertension). To date no single therapy has proven effectiveto blunt progressive growth of AAAs likely due to diverse etiologies underlying AAAs in the human population.Thus therapies must be individualized to target the relevant risk factor(s) such as obesity and itsmechanisms to effectively ameliorate AAA initiation and progression. We previously reported that obesitypromotes AngII-induced AAAs in mice through inflammation in the perivascular adipose tissue. We now havepreliminary data demonstrating that whole body deficiency of serum amyloid A (SAA) profoundly reducesAngII-induced AAAs in the setting of obesity. Moreover our recently published data demonstrate that SAAstimulates macrophage secretion of IL-1 an inflammatory cytokine implicated in both human and AngII-induced AAAs. In obese subjects adipocytes become a predominate source of local and systemic SAA. Wepropose that AngII periaortic fat and SAA come together in the setting of obesity to create a pro-inflammatoryenvironment immediately adjacent to the abdominal aorta which leads to AAA initiation and expansion. Thecentral hypothesis of this proposal is in the setting of obesity adipocyte-derived SAA activates the NLRP3inflammasome in macrophages to promote AAA development in obesity. Aim 1 will test the hypothesis thatadipocyte-derived SAA is central in creating the pro-inflammatory environment that promotes AngII-inducedAAA formation in obesity. In Aim 2 we will test the hypothesis that adipocyte-derived SAA promotes obesity-induced AAA by activating the NLRP3 inflammasome in macrophages. We have unique mouse models of SAAdeficiency as well as transgenic mice with tissue-specific SAA-overexpression in which we can overexpressSAA only in liver or only in fat. We will employ translational therapeutic approaches to prevent the formationand progression of AngII-induced AAAs in obesity. The impact of these studies is that we will identify SAA andperiaortic fat burden as biomarkers and risk factors for AAA development and progression in the obesepopulation which may identify precision-targeted AAA therapeutics.

project_terms:
Abdominal Aortic Aneurysm;Acute;Adipocytes;Adipose tissue;Age;Angiotensin II;Angiotensins;Biological Markers;C57BL/6 Mouse;Cause of Death;Consumption;Data;Development;Etiology;Fatty acid glycerol esters;Gender;Goals;Growth;Health;High Fat Diet;High Prevalence;Human;Hyperlipidemia;Hypertension;Individual;Inflammasome;Inflammation;Inflammatory;Interleukin-1 beta;Link;Liver;Mediator of activation protein;Modeling;Mus;Obese Mice;Obesity;Overweight;Phase;Population;Production;Protein Isoforms;Proteins;Publishing;Reporting;Resistance;Risk Factors;Role;Ruptured Abdominal Aortic Aneurysm;Serum amyloid A protein;Signal Transduction;Smoking;Source;Stimulus;Testing;Therapeutic;Tissues;Transgenic Mice;United States;Veterans;abdominal aorta;age group;cytokine;high risk;human very old age (85+);hypercholesterolemia;inflammatory milieu;macrophage;male;mouse model;novel;novel therapeutic intervention;overexpression;prevent;sex;tool;vascular inflammation

public_health_relevance:
This project focuses on obesity as a risk factor for the formation and progressive growth of abdominalaortic aneurysms (AAAs). We focus on serum amyloid A (SAA) since levels of this protein increase withobesity. Our approach should delineate why obesity is a risk factor for AAAs and identify new therapeuticapproaches.


application_id: 9922659
project_number: 5I01BX004542-02
project_title: Optogenetics: A tool to probe mechanism and an agent to block TBI-induced epileptogenesis.
administering_ic: VA
award_notice_date: 2020-09-17
opportunity_number: BX-18-003
application_type: 5
activity_code: I01
ic: BX
serial_number: 004542
project_start_date: 2019-04-01
project_end_date: 2023-03-31
study_section: ZRD1-NURB-H(01)
contact_pi_person_id: 9405862
contact_pi: SLEVIN, JOHN T.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-04-01
project_abstract:
Over two million people are treated medically each year in the United States after sustaining atraumatic brain injury (TBI). Posttraumatic epilepsy (PTE) develops in up to 39% of patients with moderate tosevere non-penetrating TBI. As with other acquired epilepsies spontaneous recurrent seizures associatedwith PTE develop with a latency (>1 week and up to many years) after the initial injury. This seizure-free periodafter TBI represents the period of epileptogenesis during which the brain undergoes physiological anatomicalcellular and molecular changes leading to a state of chronically increased seizure susceptibility. This delaybetween the TBI and development of PTE also represents a period during which strategies might be employedto inhibit the reactive plasticity in the brain that leads to PTE but the molecular mechanisms underlying theepileptogenic process leading to acquired epilepsy are largely unknown and no anti-epileptogenic therapieshave been successfully developed to date. Animal models of posttraumatic epileptogenesis (PTEgenesis) pointto reactive plasticity of hippocampal networks with alteration in the balance of excitation/inhibition as a driverof permanent brain changes and the epileptic state. However the prime molecular and electrophysiologicaltransformations remain murky. The hypothesis to be tested: Post-injury activity and network changes in the hippocampus induced inpart by alterations in the vesicular neurotransmitter release machinery are primary drivers of PTEgenesis. TheSpecific Aims are to: 1) Use channelrhodopsin-2 (ChR2) to optogenetically drive neural activity and theprocess of PTEgenesis by depolarizing specific primary neuronal populations in dentate gyrus (DG). 2) Usehalorhodopsin (NpHR) to retard PTEgenesis induced using a standard method by optogenetically inhibitingneural activity in DG. Proven techniques will be integrated into a new and unique model to detect network andmolecular drivers of PTE and PTEgenesis. Using the controlled cortical impact (CCI) model of TBI ourproposed studies combine 1) unique microelectrode array electrochemistry (MEA) to monitor real-timeglutamate release and oxygen change as a metric of epileptiform activity; 2) immunohistochemistry to definechanges in specific cell phenotypes; and 3) slice electrophysiology with custom Western blot quantitation ofneurotransmitter release machinery on a novel optogenetically-modified hippocampal platform. Aim 1: Studies will be accomplished by AAV2/5 viral transfection of a ChR2-promotor construct intohippocampal DG of rats utilizing optogenetic activation of DG neurons of free-roaming rats after CCI-inducedTBI to enhance PTEgenesis. Extra-cellular glutamate electrophysiological immunohistochemical andvesicular release biochemical measures will be made on animals at discrete behavioral stages during theprogression of epileptogenesis. Aim 2: Studies will be accomplished by AAV2/5 viral transfection of an NpHR-promoter construct into hippocampal DG of rats prior to CCI injury and optogenetic inhibition of DG circuitsafter CCI to inhibit PTEgenesis. MEA electrophysiological immunohistochemical and biochemical measureswill be made. As one component of these studies transient glutamate surges and changes in oxygen in DGdetected by MEAs will trigger real-time optogenetic inhibition as a potential means to abort PTEgenesis. Our approach should allow network neuronal and presynaptic release changes to be clearly tied tobiochemical anatomical electrophysiological and behavioral outcomes associated with epileptogenesis. Thestudies in this proposal will pave the way to development of comprehensive novel analyses of the progressionof PTE and will provide preliminary data to support studies identifying causative effects of activity-dependentsynaptogenesis in the development of PTE. In addition these studies will test a potentially novel therapy forPTEgenesis. Thus this research is directly relevant to the care of a large proportion of service men andwomen veterans and the general population.

project_terms:
Acute;Anatomy;Animal Model;Animals;Antiepileptogenic;Behavioral;Biochemical;Brain;Caring;Cells;Chronic;Chronic Disease;Clinical Trials;Custom;Data;Development;Electrochemistry;Electrophysiology (science);Epilepsy;Epileptogenesis;Equilibrium;Excision;General Population;Glutamates;Goals;Halorhodopsins;Hippocampus (Brain);Human;Immunohistochemistry;Individual;Injury;Life;Measures;Medical;Methods;Microelectrodes;Modeling;Molecular;Neurons;Neurosurgical Procedures;Oxygen;Patients;Phenotype;Physiological;Population;Post-Traumatic Epilepsy;Predisposition;Process;Protein Biochemistry;Rattus;Recurrence;Research;Seizures;Services;Slice;Techniques;Testing;Therapeutic;Time;Transfection;Translations;Traumatic Brain Injury;United States;Veterans;Viral;Western Blotting;Woman;behavioral outcome;controlled cortical impact;critical period;dentate gyrus;economic cost;extracellular;high risk;instrumentation;men;neurotransmitter release;novel;novel therapeutics;optogenetics;presynaptic;prevent;promoter;real time monitoring;relating to nervous system;standard of care;synaptogenesis;tool;vesicular release

public_health_relevance:
Human posttraumatic epilepsy (PTE) is defined as repeated unprovoked seizures beginning more than oneweek but up to years after a traumatic brain injury (TBI). During the seizure-free interval between TBI andPTE the brain undergoes changes leading to a state of chronically increased seizure susceptibility. Themolecular mechanisms and network changes underlying this posttraumatic epileptogenesis (PTEgenesis) arelargely unknown and there are no therapeutic strategies to prevent it. Our approach using microelectrodearrays immunohistochemistry slice electrophysiology quantitative protein biochemistry and optogenetics toanalyze this latent period should allow us to correlate network neuronal and presynaptic release changes tomolecular anatomical electrophysiological and behavioral outcomes associated with PTEgenesis. In additionthese studies will test a potentially novel therapy to retard/halt PTEgenesis. Thus this research is directlyrelevant to the care of a large proportion of service men and women veterans and the general population.


application_id: 9899084
project_number: 5IK6BX004199-03
project_title: BLR&D Research Career Scientist Award application
administering_ic: VA
award_notice_date: 2020-09-17
opportunity_number: BX-17-022
application_type: 5
activity_code: IK6
ic: BX
serial_number: 004199
project_start_date: 2018-04-01
project_end_date: 2023-03-31
study_section: Research Career Scientist[RCSR]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-04-01
project_abstract:
My research work largely explores the underlying physiologic questions regarding tiny vesicles calledexosomes. These exosomes are released from many different types of cells or food-derived exosome-likenanoparticles and I am investigating in VA patients the promising role of exosomes as therapeutic vehicles indelivering treatment for a diverse but specific group of medical conditions i.e.obesity/diabetes Nonalcoholicfatty liver disease (NASH) and cancer. There is a substantial population of veterans who are obese and/orhave cancer. Obesity and cancer pose special burdens on veterans who depend on VA care. Obesitycontributes to over 300000 deaths per year and increases the risk of NASH type 2 diabetes and severalcancers including colon prostate and kidney. Since receiving my initial Research Career Scientist award myresearch group has published more than 50 manuscripts on this subject. Collectively our findings supportcontinued funding of my team to investigate the following 3 aims: (1) Tumor exosomes play a role in: (a)immunosuppression through induction of myeloid-derived suppressor cells inhibition of dendritic celldifferentiation and inhibition of activation of NK cell immunotherapy; (b) by sorting suppressor miRNAs fromtumor cells into exosomes based on the oncogenic major vault protein (MVP) tumors grow faster (NatureCommunications. 2017 Feb 17;8:14448 Nature communications. 2015;6:6956); and (c) more recently wediscovered a novel nanoparticle (Oncotarget. 2016 May 12). Unlike other EVs this extracellular nanovesicle(named HG-NV HG-NV stands for HomoGenous nanovesicle as well as for Huang-Ge- nanovesicle) releasedfrom both mouse and human breast tumor cells is enriched with RNAs. Tumor-derived HG-NVs are morepotent in promoting tumor progression than exosomes. Molecules predominantly present in breast tumor HG-NVs have been identified and characterized. This discovery may have implications in advancing bothmicrovesicle biology research and clinical management including potential useas a biomarker (2). Exosomesreleased from non-tumor cells play a role in: (a) adipose tissue exosome-like vesicles mediating activation ofmacrophage-induced insulin resistance (Diabetes. 2009 Nov;58(11):2498-505); (b) we also found thatintestinal mucus-derived exosomes mediate activation of Wnt/-catenin signaling and play a role in inductionof liver NKT cell anergy (Hepatology 2013 57(3):1250-61); and (c) intestinal mucusderived exosomes carryprostaglandin E2 and suppress activation of liver NKT cells (J Immunol 2013 190(7):3579-89); (3). Exosome-like nanoparticles from edible plants have an effect and therapeutic application on mammalian cells: (a) weused mouse models to show that interspecies communication between plant and mouse gut host cells throughedible plant derived exosomelike nanoparticles by inducing expression of genes for anti-inflammationcytokines antioxidation and activation of Wnt signaling which are crucial for maintaining intestinalhomeostasis. This finding not only opens up a new avenue for investigating ELNs as a means to protect againstthe development of liver related diseases such as alcohol induced liver damage but sheds light on studyingthe cellular and molecular mechanisms underlying inter-species communication in the liver via edible plant-derived nanoparticles; (b) targeted drug/therapeutic miRNAs (Nature Communications. 2013;4:1867) deliveryto intestinal macrophages brain microglia cells (Molecular therapy: 2015 Volume 24 Issue 1 p96105) andinflammatory tumor sites (Cancer Research 2015;75:2520-9) by grapefruit ELN is possible; (c) Broccoli-Derived Nanoparticle Inhibits Mouse Colitis by Activating Dendritic Cell AMP-Activated Protein Kinase(Molecular Therapy. 2017 in press); and (d) Grape exosome-like nanoparticles induce intestinal stem cellsand protect mice from DSS-induced colitis (Molecular Therapy. 2013 Jul;21(7):1345-57).

project_terms:
5'-AMP-activated protein kinase;Adipose tissue;Alcoholic liver damage;Antibodies;Award;Biological;Biological Markers;Biology;Brain;Brain Injuries;Brain Neoplasms;Breast Cancer Cell;Broccoli - dietary;Cancer Patient;Caring;Cell Communication;Cell Differentiation Inhibition;Cell Differentiation process;Cells;Cessation of life;Chronic;Clinical;Clinical Management;Colitis;Colon;Colonic Neoplasms;Colorectal;Communication;Curcumin;Cutaneous Melanoma;DNA;Data;Dendritic Cells;Development;Diabetes Mellitus;Dinoprostone;Disease;Disease Progression;Drug Targeting;Edible Plants;Encephalitis;Explosion;Failure;Folic Acid;Food;Foundations;Funding;Gene Expression;Ginger;Goals;Grapefruit;Grapes;Health Status;Hepatocyte;Hepatology;High Fat Diet;Homeostasis;Homing;Human;Immunosuppression;Immunotherapy;Inflammation;Inflammatory;Insulin Resistance;International;Intestines;Journals;Kidney;Light;Link;Lipids;Liver;Long-Term Effects;Lung;Macrophage Activation;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mammalian Cell;Mammary Neoplasms;Manuscripts;Mediating;Medical;Methods;MicroRNAs;Microglia;Molecular;Mucous body substance;Mus;Myelogenous;Myeloid-derived suppressor cells;NK Cell Activation;Names;Nature;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oncogenes;Oncogenic;Oncoproteins;Overweight;Patients;Pharmaceutical Preparations;Physiological;Plants;Play;Population;Prostate;Publishing;RNA;Radiation therapy;Research;Resistance;Risk;Role;Scientist;Signal Transduction;Site;Small Interfering RNA;Sorting - Cell Movement;Specificity;T-Lymphocyte;Therapeutic;Therapeutic Agents;Tissues;Traumatic Brain Injury;Tumor Promotion;Tumor Suppressor Proteins;Tumor-Derived;Vesicle;Veterans;WNT Signaling Pathway;War;Work;alcohol prevention;anergy;anticancer research;base;beta catenin;cancer cell;cancer diagnosis;cancer immunotherapy;cancer prevention;cancer therapy;cancer type;career;cell type;chemokine;chemokine receptor;cytokine;dextran sulfate sodium induced colitis;exosome;expression vector;extracellular;folate-binding protein;improved;in vivo;interspecies communication;intestinal homeostasis;liver development;liver inflammation;liver injury;macrophage;major vault protein;member;microvesicles;mild traumatic brain injury;mortality;mouse model;nanoparticle;nanovector;nanovesicle;neoplastic cell;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel strategies;novel therapeutic intervention;nuclear factor-erythroid 2;patient population;pressure;prevent;side effect;sound;stem cells;targeted delivery;therapeutic development;therapeutic miRNA;translational study;treatment strategy;tumor;tumor progression

public_health_relevance:
The VA estimates that 78 percent of Veterans are overweight or obese. Obesity has been linked to excess riskfor type 2 diabetes and many cancers. Determining the precise mechanism(s) by which obesity contributes tothe development of cancer is essential for the development of therapeutic strategies against cancer. The focusof my career research is to characterize these mechanisms and then to determine whether targeting of thesemechanisms effectively blocks the induction of vesicles that can be caused by a high-fat diet.These vesiclespromote exosome-mediated development of cancer and I am pursuing therapies to treat obesity/diabetes andcancer in VA patients. More importantly development of novel strategies to block/reverse high-fat diet inducedand tumor exosome mediated immunosuppression would also yield a new and practical therapeutic method fortreating chronic inflammatory related diseases and thus improve the health status of members of the VA patientpopulation.


application_id: 9898233
project_number: 5I01BX003274-03
project_title: The Vagus Nerve in Lung Disease
administering_ic: VA
award_notice_date: 2020-05-04
opportunity_number: BX-17-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 003274
project_start_date: 2018-04-01
project_end_date: 2022-03-31
study_section: Respiration[PULM]
contact_pi_person_id: 2084836
contact_pi: YU, JERRY (JUN)
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-04-01
project_terms:
Acetylcholine;Address;Adoptive Cell Transfers;Adult Respiratory Distress Syndrome;Agonist;Asthma;Attenuated;Biochemical;Biochemistry;Biological;Biosensor;Brain;Bronchoalveolar Lavage;Cell Count;Cells;Cessation of life;Chronic;Chronic Obstructive Airway Disease;Cicatrix;Collagen;Complex;Cytology;Data;Deposition;Development;Disease;Dyspnea;Endothelial Cells;Epithelial Cells;Fibroblasts;Fibrosis;Gases;Gene Expression;Growth Factor;Histology;Hospitals;Immune response;Inflammatory;Injury;Lead;Lung;Lung Inflammation;Lung diseases;Malignant neoplasm of lung;Mammals;Mediating;Mediator of activation protein;Molecular;Mucous Membrane;Mus;Myofibroblast;Nerve;Nerve Block;Neural Pathways;Neuraxis;Neuroendocrine Cell;Neuroepithelial Bodies;Neuroimmune;Neurosecretory Systems;Outcome;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacology;Phase;Physiology;Plasma;Play;Population;Process;Pulmonary Fibrosis;Research;Role;Sensory Receptors;Severities;System;Techniques;Testing;Transforming Growth Factor beta;Vagotomy;Vagus nerve structure;Veterans;chemical release;cytokine;effective therapy;fibrogenesis;genetic manipulation;improved;indium-bleomycin;lung development;lung injury;lung repair;mouse model;neuromechanism;novel;novel strategies;patient population;protein expression;receptor;recruit;sensor;stem cells;vagus nerve stimulation


application_id: 9892565
project_number: 2I01BX002149-05
project_title: FUS Protein Homeostasis in ALS
administering_ic: VA
award_notice_date: 2020-02-19
opportunity_number: BX-19-004
application_type: 2
activity_code: I01
ic: BX
serial_number: 002149
project_start_date: 2015-10-01
project_end_date: 2024-03-31
study_section: Special Emphasis Panel[ZRD1 NURE-E (01)]
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-04-01
project_abstract:
Amyotrophic lateral sclerosis (ALS) is a poorly understood neurodegenerative disease with no effectivetreatment. ALS is connected with military service and veterans are at a higher risk of developing this debilitatingdisease. Mutations in several genes have been discovered to cause a subset of familial ALS including copper-zinc superoxide dismutase (SOD1) Fused in Sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43).Studying familial ALS using the well-defined genetic models will provide critical insights into the diseasepathology as well as novel targets for future therapeutic development. This project is focused on the RNA binding protein FUS that has been implicated in both familial andsporadic ALS. ALS-related mutations in FUS cause a liquid-liquid phase separation (LLPS) of the FUS proteinforming liquid droplets in vitro. In neurons mutant FUS accumulates in the cytoplasm forming ribonucleoproteingranules and inclusions eventually leading to neurotoxicity. We recently identified cellular proteins in FUS-positive inclusions and a bioinformatics analysis revealed two previously unknown pathways affected by mutantFUS: protein translation and mRNA surveillance. We also demonstrated that ALS FUS mutations indeedsuppressed protein translation and hyper-activated the nonsense-mediated decay (NMD) of mRNAs. Ouroverarching hypothesis is that the dysregulation of protein translation and mRNA nonsense-mediated decaycontributes to FUS toxicity and motor neuron dysfunction. Since little is known about how the mutant FUS-induced dysregulation of protein translation and NMD cause toxicity in neurons discoveries in this project will fillthis knowledge gap and advance the field significantly. Three specific aims are designed to test the hypothesis. Aim 1 is to determine what properties of mutantFUS drive the dysregulation of protein translation and NMD. We will use different domain truncations of FUS tomanipulate LLPS and examine the relationship between LLPS and mutant FUS dysregulation. In addition we willmanipulate RNA binding of FUS and test whether RNA binding is a significant contributor to mutant FUSdysfunction. We will also use FUS knockout models to examine whether FUS plays a role in in protein translationand NMD under physiological conditions. Aim 2 is to determine whether mutant FUS impairs translation ofspecific proteins and NMD of specific mRNAs. We will employ specialized proteomic and transcriptomicapproaches to identify changes of nascent protein biosynthesis and mRNA turnover rate as a consequence ofmutant FUS. Differentially altered proteins and mRNAs will be validated in animal models as well as iPSC andinduced motor neurons derived from familial ALS patients. Results from these -omics approaches will beintegrated to determine whether mutant FUS impairs specific molecular and cellular function and pathways. Aim3 is to examine whether attenuation of NMD hyperactivity can restore protein translation and mitigate FUSneurotoxicity. We will use genetic and pharmacological approaches to attenuate NMD hyperactivity anddetermine whether the intervention can restore the balance and mitigate FUS toxicity in vitro and in vivo models. The proposed studies are highly innovative both conceptually and technically. The proposal is based ona number of novel observations regarding the impact of ALS mutant FUS on protein translation and mRNAdecay. The results from this project are expected to produce new mechanistic insights into FUS ALS laying afoundation for future therapeutic development of new ALS treatment(s).

project_terms:
ALS patients;Address;Affect;Agonist;Amyotrophic Lateral Sclerosis;Animal Model;Attenuated;Bioinformatics;Categories;Cell Line;Cell Nucleus;Cell physiology;Cells;Cessation of life;Contracts;Cytoplasm;Cytoplasmic Granules;DNA Binding;Defect;Diagnosis;Disease;Drosophila genus;Endoplasmic Reticulum;Equilibrium;Familial Amyotrophic Lateral Sclerosis;Foundations;Functional disorder;Future;Genes;Genetic;Genetic Models;Health;Healthcare;Hydrogels;Hyperactive behavior;Impairment;In Vitro;Inclusion Bodies;Intervention;Knock-out;Knowledge;Liquid substance;Mediating;Membrane Proteins;Messenger RNA;Military Personnel;Modeling;Molecular;Motor Neurons;Mutation;N-terminal;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Nonsense-Mediated Decay;Pathologic;Pathology;Pathway interactions;Pharmacology;Phase;Phenotype;Physiological;Play;Post-Translational Protein Processing;Property;Protein Biosynthesis;Proteins;Proteome;Proteomics;Publishing;RNA;RNA Binding;RNA Decay;RNA-Binding Proteins;Rattus;Reporting;Ribonucleoproteins;Role;Services;Specificity;Testing;Toxic effect;Transgenic Mice;Transgenic Organisms;Translations;Veterans;attenuation;base;care costs;copper zinc superoxide dismutase;cost;design;disability;effective therapy;high risk;improved;in vivo;in vivo Model;induced pluripotent stem cell;inhibitor/antagonist;innovation;insight;mRNA Decay;mRNA Surveillance;mutant;neuron loss;neurotoxicity;novel;overexpression;prion-like;protein TDP-43;proteostasis;sarcoma;tau Proteins;therapeutic development;transcriptome;transcriptomics;unpublished works

public_health_relevance:
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease and currently there is no cure.Veterans are at a higher risk of being affected with the disorder thus ALS has been listed as a disease entitled topresumptive service connection. All veterans diagnosed with ALS have received full disability lifetime health anddeath benefits costing VA an estimated $505 million over 10 years. Mutations in the gene encoding Fused inSarcoma (FUS) cause a subset of familial ALS. This project is to use the well-defined genetic model to determinethe mechanisms how mutant FUS suppresses protein translation hyper-activates RNA nonsense-mediateddecay and induces downstream cellular toxicity. We will also test whether attenuating these pathways canmitigate FUS toxicity. The results from studying the mutant FUS mediated familial ALS will provide critical insightsinto the pathology of all types of ALS. Our project will likely identify novel targets for future therapeuticdevelopments thus improving the healthcare of veterans and reducing the cost of caring for these veterans.


application_id: 9890542
project_number: 1IK2BX004883-01
administering_ic: VA
award_notice_date: 2020-04-01
opportunity_number: BX-19-008
application_type: 1
activity_code: IK2
ic: BX
serial_number: 004883
project_start_date: 2020-04-01
project_end_date: 2025-03-31
study_section: Special Emphasis Panel[ZRD1 NURE-E (01)]
contact_pi_person_id: 11890992
contact_pi: YAMASAKI, TRITIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-04-01
budget_end_date: 2021-03-31
project_terms:
Affect;Aging;Antibodies;Area;Award;Basic Science;Binding;Biochemical;Biochemistry;Biological Assay;Biological Markers;Biosensor;Blood;Blood Platelets;Blood specimen;Brain;C-terminal;Cell-Free System;Cells;Characteristics;Clinic;Clinical;Clinical Markers;Clinical Research;Consent;DNA Sequence Alteration;Deep Brain Stimulation;Detection;Development;Diagnosis;Diagnostic;Disease;Disease Progression;Documentation;Early Diagnosis;Elderly;Engineering;Epitopes;Erythrocytes;Evaluation;Expenditure;Exposure to;FDA approved;Faculty;Fluorescence Resonance Energy Transfer;Gender;Genetic;Goals;Healthcare;Imaging Techniques;In Vitro;Investigative Techniques;Kentucky;Knowledge;Lead;Ligands;Liquid substance;Mentors;Methods;Modality;Molecular;Molecular Conformation;Motor;Movement;Movement Disorders;Multiple System Atrophy;Nerve Degeneration;Neuraxis;Neurodegenerative Disorders;Neurology;Parkinson Disease;Pathogenicity;Pathologic;Pathology;Patients;Peripheral;Plasma;Population;Positioning Attribute;Process;Property;Proteins;Publishing;Records;Research;Sampling;Seeds;Solubility;Structure;System;Techniques;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;Toxin;Training;Training Programs;Universities;Veterans;Whole Blood;Work;accurate diagnosis;alpha synuclein;amplification detection;base;career;cerebral atrophy;collaborative environment;disorder control;disorder risk;effective therapy;exosome;experience;genetic manipulation;imaging modality;insight;liquid biopsy;male;molecular imaging;novel;novel marker;outcome forecast;patient population;prion-like;professor;prognostic;protein aggregation;rare condition;sensor;success;synuclein;synucleinopathy;translational scientist;transmission process


application_id: 9890125
project_number: 1IK2BX004618-01A1
project_title: Psychological deficits after low level blast exposure: role of neurovascular disruption
administering_ic: VA
award_notice_date: 2020-01-22
opportunity_number: BX-19-008
application_type: 1
activity_code: IK2
ic: BX
serial_number: 004618
suffix: A1
project_start_date: 2020-01-01
project_end_date: 2024-12-31
study_section: Special Emphasis Panel[ZRD1 NURC-H (01)]
contact_pi_person_id: 14823099
contact_pi: HUBBARD, WILLIAM BRAD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_terms:
3-Dimensional;Acute;Address;Affect;Aggressive behavior;Aging;Amygdaloid structure;Animal Model;Animals;Anxiety;Behavior;Behavior assessment;Behavioral;Bioenergetics;Biological Assay;Biological Markers;Blast Injuries;Blood - brain barrier anatomy;Blood Platelets;Blood Vessels;Brain;Brain region;Cerebrovascular Circulation;Chronic;Chronic Post Traumatic Stress Disorder;Clinical;Coupled;Data;Development;Development Plans;Exposure to;Foundations;Functional disorder;Grant;Health;Image;Immunohistochemistry;Impairment;Investigation;Kentucky;Knowledge;Lead;Life;Literature;Matrix Metalloproteinases;Measures;Mentors;MicroRNAs;Military Personnel;Modeling;Nervous System Trauma;Neurocognitive;Neurologic Deficit;Neurologic Dysfunctions;Neurological outcome;Neurons;Neuropsychology;Occupational;Occupational Exposure;Outcome;Pathologic;Peripheral;Phenotype;Population;Post-Traumatic Stress Disorders;Predisposition;Proteins;Publishing;Rattus;Recording of previous events;Recovery;Reporting;Research;Research Personnel;Risk;Rodent;Rodent Model;Role;Serum;Social Interaction;Soldier;Spin Labels;Stains;Symptoms;Techniques;Testing;Therapeutic;Time;Tissues;Training;Training Programs;Universities;Vascular Diseases;Veterans;Writing;base;behavior test;behavioral impairment;blood-based biomarker;blood-brain barrier disruption;career development;cerebrovascular;clinically relevant;cohort;depressive symptoms;exosome;experience;improved;inhibitor/antagonist;multimodality;neuroimaging;neuropathology;neurovascular;neurovascular unit;novel;operation;phosphodiesterase V;pre-clinical;primary outcome;programs;psychologic;psychological outcomes;restoration;sildenafil;skills;stress related disorder;student mentoring;therapeutic target;time interval;trait


application_id: 9888883
project_number: 1I01BX004671-01A1
project_title: Serum Amyloid as a Critical mediator between inflammation and thrombosis
administering_ic: VA
award_notice_date: 2020-02-12
opportunity_number: BX-19-001
application_type: 1
activity_code: I01
ic: BX
serial_number: 004671
suffix: A1
project_start_date: 2020-04-01
project_end_date: 2024-03-31
study_section: Special Emphasis Panel[ZRD1 HEMA-I (01)]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Acute and chronic inflammation contributes significantly to poor health most notably as a risk factor forthe development of atherosclerotic vascular disease and its complications such as myocardialinfarction/acute coronary syndromes (ACS) strokes and limb ischemia. The medical costs associatedwith atherosclerosis contribute to preventable death and serious disability which strain the VA healthcare system. Despite the well-established relationship between inflammation atherosclerotic diseaseand ACS treatment strategies are limited due in part to a lack of understanding of the mechanism(s)by which inflammation stimulates thrombosis. The ability of statin therapy to lower ACS in patients withelevated C-reactive protein and the recent results from the CANTOS trial suggest that it may bepossible to prevent arterial thrombosis by targeting inflammation. A better understanding of theinflammatory signals that contribute to acute thrombosis could provide a more precise strategy forfuture interventions. In this proposal we provide evidence that the acute phase reactant serum amyloidA (SAA) has direct effects on platelet function. SAA levels increase dramatically with acuteinflammation and myocardial injury and are modestly elevated with chronic inflammation. Based on ourfindings we suggest the central hypothesis that SAA serves as a key link between inflammation andthrombosis. To test this hypothesis we have assembled an exceptional group of VA investigators withcomplimentary expertise in inflammation and thrombosis and unique model systems and reagents.Importantly we have gain and loss of function animal models in which SAA levels can be modulatedindependent of inflammation and following different inflammatory challenges. We will apply theseresources to accomplish the following two specific aims: (1) to identify the role of SAA in modulatingplatelet aggregation and thrombosis and the molecular mechanism(s) involved and (2) to elucidate therole of SAA in promoting platelet secretion and leukocyte interactions during inflammation. The aims ofthis grant provide a vehicle to address a major unresolved issue in the field namely identification ofspecific inflammatory mediators that influence thrombosis through effects on platelet function and thesignaling pathways involved. These results will be significant because they are expected to provideinnovative targets and provide proof-of-concept for novel inhibitors that may be used for prevention andtreatment for the complications of inflammation in humans.

project_terms:
Acute;Acute myocardial infarction;Acute-Phase Proteins;Address;Adhesives;Agonist;Amyloid;Animal Model;Arterial Injury;Atherosclerosis;Biochemical;Biological Models;Biology;Blood Platelets;C-reactive protein;Cardiovascular Diseases;Cardiovascular system;Chronic;Clinical Trials;Collaborations;Cues;Data;Development;Diagnosis;Event;Experimental Models;Future;Genetic;Goals;Grant;Health;Healthcare Systems;Hemostatic function;Human;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Intervention;Knowledge;Leukocytes;Link;Literature;Mediating;Mediator of activation protein;Medical Care Costs;Molecular;Morbidity - disease rate;Mus;Myocardial Infarction;P-Selectin;Pathologic;Pathway interactions;Patients;Pharmacology;Physiological;Plasma;Platelet Activation;Platelet aggregation;Play;Pre-Clinical Model;Prevention;Reagent;Research;Research Personnel;Resources;Risk Factors;Role;Serum;Serum amyloid A protein;Signal Pathway;Signal Transduction;Stroke;Techniques;Testing;Thrombosis;Veterans;Work;acute coronary syndrome;base;disability;improved;inhibitor/antagonist;innovation;limb ischemia;loss of function;mortality;myocardial injury;novel;overexpression;platelet function;preclinical study;prevent;preventable death;response;response to injury;synergism;thromboinflammation;tissue injury;treatment strategy;vascular injury

public_health_relevance:
Acute and chronic inflammation contributes significantly to poor health most notably as a risk factor for thedevelopment of atherosclerotic vascular disease and its complications such as heart attacks strokes and limbischemia that are substantial causes of morbidity and mortality in veterans. Evidence from preclinical studiesand a recent large clinical trial suggest that targeting inflammation can reduce arterial thrombosis andmyocardial infarction. However the precise mechanism(s) that link inflammation to thrombosis remainunknown. In this proposal we will test the hypothesis that the acute phase reactant serum amyloid A plays anovel role in accelerating thrombosis through a direct effect on platelet function. We will define the signalingpathways involved and their contributions to thromboinflammatory conditions using preclinical models. Ourwork could define a unique signaling pathway that links inflammation to thrombosis and may suggestinnovative targets to prevent devastating cardiovascular complications.


