# projects

application_id: 8824016
project_number: 3R01CA131075-05S1
project_title: The role of Mc1r in melanocytic UV-induced DNA damage and repair responses
administering_ic: NCI
award_notice_date: 2014-04-30
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: CA
serial_number: 131075
suffix: S1
program_official: LIN, ALISON J
project_start_date: 2010-07-01
project_end_date: 2016-04-14
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN A
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
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
project_abstract:
DESCRIPTION (provided by applicant): We seek to understand the molecular responses that occur when skin is exposed to UV radiation in order to devise novel strategies to protect against damage and carcinogenesis. In this proposal we will examine two major risk factors for skin cancer: UV radiation and pigment (melanin) phenotype. Our studies focus on the melanocyte and its cell surface receptor the melanocortin-1 receptor (Mc1r) which regulates melanin synthesis. We hypothesize that Mc1r protects melanocytes against UV-mediated mutagenesis and transformation by modulating melanization and recovery from UV-mediated cellular injury. Loss-of-function polymorphisms in Mc1r correlate with fair skin and a high incidence of melanoma while robust Mc1r function correlates with darker skin and UV resistance. We have developed a novel genetically-matched murine model of human skin as well as a protocol for growing primary melanocytes from these mice. These isogenic melanocytes span eumelanotic pheomelanotic and amelanotic melanin composition will serve a unique and potent tool to delineate the role of Mc1r function in response to UV. Using our unique animal model and primary melanocytes derived thereof we propose the following aims: Aim 1. Characterize the mechanism of Mc1r-mediated enhancement of nucleotide excision repair (NER); Aim 2. Determine whether Mc1r signaling protects against UV-mediated oxidative damage; and Aim 3. Determine the ability of pharmacologic Mc1r rescue to protect against UV damage. With respect to Aim 1 we will examine the role of Mc1r in the repair of UV-induced photolesions by southwestern and flow cytometric analysis and determine the influence of Mc1r on cellular levels of nucleotide excision repair enzymes by qRT-PCR and Western analysis. We will investigate a molecular link between Mc1r signaling and enhanced repair enzyme levels by examining expression of the NER enzymes basally and in the setting of UV irradiation and by investigating the ability of cAMP-responsive transcription factors downstream of Mc1r signaling (namely Mitf and CREB) to bind to and induce transcription of NER enzyme promoters. In Aim 2 we will study whether pheomelanin which is produced as a result of low Mc1r function promotes oxidative damage in melanocytes by complementary measures of oxidative load (DCF-mediated fluorescence flow cytometry Southwestern blotting hOGG1-adapted Comet assay TBARS assay and direct quantification of oxidative DNA adducts by GC/MS). Importantly we will directly test whether  pheomelanin functions as a pro-carcinogen by an HPRT-based forward mutagenesis approach in primary melanocytes. Finally we will directly test the ability of forskolin an activator of adenylyl cyclase to bypass defective Mc1r function to enhance recovery from UV-mediated DNA damage and to rescue UV protection in melanocytes and in whole skin. Together these studies will lay the foundation for future translational studies designed to develop novel small molecule-based approaches for UV and cancer protection to prevent many cases of melanoma.

project_terms:
Address;Adenylate Cyclase;Animal Model;Automobile Driving;Binding (Molecular Function);Biological Assay;Bypass;CREB1 gene;Carcinogens;Cell Line;Cell Surface Receptors;Cells;Comet Assay;Cyclic AMP;DNA;DNA Adducts;DNA Damage;DNA Repair;Defect;Exposure to;Flow Cytometry;Fluorescence;Forskolin;Foundations;Future;Genes;Genetic Polymorphism;Genetic Transcription;Goals;Health;Human;In Vitro;Incidence;Individual;Injury;Link;Malignant - descriptor;Malignant Neoplasms;Measures;Mediating;Melanins;Melanocyte stimulating hormone;Methods;Modeling;Molecular;Monophenol Monooxygenase;Mus;Mutagenesis;Nucleotide Excision Repair;Phenotype;Pigmentation physiologic function;Pigments;Primary Cell Cultures;Promotor (Genetics);Protocols documentation;Receptor Signaling;Receptor Melanocortin Type 1;Recovery;Research Design;Resistance;Risk Factors;Role;Skin;Skin Cancer;Skin Pigmentation;Southwestern Blotting;Sun Exposure;Surface;System;Testing;The Sun;UV induced;UV induced DNA damage;UV protection;UV response;Ultraviolet B Radiation;Ultraviolet Rays;Variant;alpha-Melanocyte stimulating hormone;base;carcinogenesis;cell injury;congenic;defined contribution;eumelanin;high risk;loss of function;melanocyte;melanoma;novel;novel strategies;oxidative damage;pheomelanin;photolesion;prevent;receptor;receptor binding;receptor function;repair enzyme;repaired;research study;response;small molecule;synthetic enzyme;tool;transcription factor;translational study;ultraviolet damage;ultraviolet irradiation

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Though it has long been known that people with functional defects of the melanocortin 1 receptor (Mc1r) protein are at high risk of developing melanoma the way(s) in which Mc1r protects against melanoma are not understood. Using pigment cells known as melanocytes we will study how the Mc1r protein influences UV- mediated DNA and cellular damage in melanocytes and contributes to melanoma resistance. Our goal is to develop the strategy of pharmacologic Mc1r rescue toward translational applicability so that many cases of melanoma can be prevented.


application_id: 8822900
project_number: 5R01HL056652-17
project_title: Molecular Mechanism of Platelet Exocytosis
administering_ic: NHLBI
award_notice_date: 2015-03-17
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 056652
program_official: SARKAR, RITA
project_start_date: 1996-07-01
project_end_date: 2017-03-31
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
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
project_abstract:
DESCRIPTION (provided by applicant): Platelets are central to hemostasis because they respond to vascular damage and secrete a variety of granule cargo molecules which are critical to thrombosis and its normal as well as pathogenic sequellae. This property makes platelets a target for modulation of hemostasis but it also raises questions about how these anucleated cell fragments function. Are platelets an active participant specifically releasing context-appropriate material or are they random delivery devises? The overall goal of this proposal is to understand the process of platelet secretion at the cellular and molecular level. The first Aim addresses one of the most important questions facing the field. Is platelet secretion thematically responsive? The experiments in Aim 1 will characterize the heterogeneity in cargo release from activated platelets. The goal is to determine if platelet secretion is thematic stochastic or controlled kinetically. Micro-ELISA assays will be used to measure the secretion of several released molecules and detailed mathematical analysis of the release kinetics will be used to identify patterns. The second Aim seeks to dissect a novel signaling cascade that directly controls platelet secretion. The goal is to identify the signaling pathways that activate IkB Kinase to phosphorylate SNAP-23 and to determine how the modification affects platelet secretion. This Aim focuses on the role that IkB Kinase (IKK) plays in regulating platelet secretion by probing both how the kinase is activated and how SNAP-23 phosphorylation affects platelet secretion. Additional studies will determine if IKK inhibitors can be used as anti-thrombotic agents. The final Aim focuses on the mechanism of a limiting element of the platelet secretory machinery Munc13-4. The goal will be to define the mechanism by which Munc13-4 mediates platelet secretion. The experiments in this Aim will characterize the molecular mechanisms of Munc13-4 by probing its interactions and their roles in secretion. Since Munc13-4 is a limiting factor in platelets and is required for normal hemostasis it is an attractive target for therapeutic intervention. The experiments in the final Aim will yield the detailed molecular characterization required for such targeting. In sum the data gained for the proposed experiments will illuminate the process of platelet secretion and thus set the constraints for future models of platelet function in the vasculature. The experiments will also identify aspects of the secretory machinery that can be exploited for therapeutic intervention to modulate thrombosis. Cardiovascular disease is the #1 cause of death in the US and is estimated to cost $500 billion in medical expenses and lost productivity in 2010 (AHA Fact Sheet). These staggering statistics underline the need for new therapeutic agents designed to ameliorate the pathologies associated with platelet dysfunction. The insights gained from the proposed experiments and their potential for identifying novel targets will clearly benefit the search for such agents.

project_terms:
Address;Adhesions;Affect;Agonist;Atherosclerosis;Attenuated;Basic Science;Biochemical;Biochemistry;Biological Assay;Blood Platelets;Blood Vessels;Blood coagulation;Blood flow;Cardiovascular Diseases;Cause of Death;Cell membrane;Cells;Cellular biology;Cessation of life;Clinical;Coagulation Process;Complex;Cytoplasmic Granules;Data;Defect;Development;Disease;Docking;Elements;Enzyme-Linked Immunosorbent Assay;Event;Exocytosis;Functional disorder;Future;Goals;Hemorrhage;Hemostatic function;Heterogeneity;In Vitro;Inflammation;Integral Membrane Protein;Kinetics;Knockout Mice;Knowledge;Lead;Learning;Measures;Mediating;Medical;Membrane Fusion;Modeling;Modification;Molecular;Monitor;Mus;Myocardial Infarction;Participant;Pathology;Pathway interactions;Pattern;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Physicians;Platelet Activation;Play;Process;Productivity;Property;Publishing;Reaction;Risk;Role;S-nitro-N-acetylpenicillamine;SNAP receptor;Signal Pathway;Signal Transduction;Site;Sum;System;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Thrombosis;Time;United States;Work;Wound Healing;angiogenesis;base;cohort;cost;design;disability;enhancing factor;in vivo;insight;kinase inhibitor;mathematical analysis;neurotransmitter release;novel;novel therapeutics;outcome forecast;protein protein interaction;research study;response;statistics;stroke;target SNARE proteins;therapeutic target;wound

public_health_relevance:
Strokes and heart attacks are major killers in the United States and both are caused by a loss of blood flow usually because a blood clot has formed in the wrong place. This application focuses on how platelets release molecules that cause clot formation. This work is critical because it will direct the development of future drugs needed to decrease the risk of spurious clot formation.


application_id: 8822875
project_number: 5R21EY024347-02
project_title: Impact of EOM specific myosin loss on extraocular muscle structure and function
administering_ic: NEI
award_notice_date: 2015-03-19
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: EY
serial_number: 024347
program_official: ARAJ, HOUMAM H
project_start_date: 2014-04-01
project_end_date: 2017-03-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 6197585
contact_pi: ANDRADE, FRANCISCO H
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
project_abstract:
DESCRIPTION (provided by applicant):  Strabismus is a common condition in children that frequently leads to permanent visual impairment. Available treatment options target the extraocular muscles when they are not fully developed. The extraocular muscles are different from other muscles; they even have their own tissue-specific myosin isoform EOM-specific myosin which appears soon after birth during a period of postnatal extraocular muscle development linked to visual experience: absence of vision during this time disrupts EOM-specific myosin expression and alters the contractile properties of the extraocular muscles perhaps permanently. The same changes occur in strabismus patients and may explain the need for multiple surgeries to restore normal eye position in many of them. This project will answer two questions: to what extent EOM-specific myosin defines normal extraocular muscle function and how eye muscle function changes when the expression of this tissue-specific myosin is altered. To address these issues we will ablate or restore the EOM-specific myosin gene to test the relevance of this myosin isoform to extraocular muscle function and integrity. The experimental approach relies on our recently developed mouse strains that permit control of the expression of the EOM-specific myosin gene and will test the hypothesis that EOM-specific myosin is necessary for normal development of extraocular muscle structure and function and its appearance after its normal postnatal window does not restore muscle function. Specific Aim 2 will determine the consequences of EOM-specific myosin gene ablation on the postnatal development of mouse extraocular muscle structure and function. Specific Aim 2 will test whether the recovery of EOM-specific myosin expression in the adult mouse restores extraocular muscle function. The answers that will result from the completion of this project will inform the timing of surgical and medical treatment for congenital strabismus.

project_terms:
6 year old;ATP phosphohydrolase;Ablation;Address;Adult;Affect;Amblyopia;Appearance;Biochemical;Birth;Characteristics;Child;Data;Defect;Depth Perception;Development;Esotropia;Eye;Eye Movements;Failure (biologic function);Genes;Goals;Health;Human;Incidence;Intervention;Knockout Mice;Limb structure;Link;Medical;Messenger RNA;Mouse Strains;Mus;Muscle;Muscle Development;Muscle Fibers;Muscle function;Myosin ATPase;Myosin Heavy Chains;Operative Surgical Procedures;Pathway interactions;Patients;Phenotype;Physiological;Positioning Attribute;Property;Protein Isoforms;Proteins;Recovery;Respiratory Muscles;Specimen;Strabismus;Structure;Testing;Therapeutic;Time;Tissues;Vision;Visual;Visual impairment;Work;base;experience;interest;mouse development;muscle form;muscular structure;novel;orbit muscle;postnatal;research study

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  The extraocular muscles are the small muscles that move the eyes to keep them on the visual target of interest; one of their defining characteristics is tht they have a unique form of myosin EOM-specific myosin a special protein that influences how these muscles work. This protein is lost in patients with strabismus (crossed eyes). This project will determine what happens to eye muscle function when this protein is absent. The results from these studies will be important for our understanding of extraocular muscle function and how it is affected in congenital and acquired strabismus.


application_id: 8822451
project_number: 1R21AR064896-01A1
project_title: Ribosome specialization in adult skeletal muscle
administering_ic: NIAMS
award_notice_date: 2014-09-01
opportunity_number: PA-12-209
application_type: 1
activity_code: R21
ic: AR
serial_number: 064896
suffix: A1
program_official: BOYCE, AMANDA T
project_start_date: 2014-09-01
project_end_date: 2016-08-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
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
project_abstract:
DESCRIPTION (provided by applicant): The ribosome has generally been considered to have no cell-specific function but rather serves in a "housekeeping" capacity. This view has been challenged by evidence showing heterogeneity in the protein composition of the ribosome resulting in the functional specialization of the ribosome. Ribosome specialization alters the intrinsic translational activity of the ribosome thereby affecting the translation of a particular et of mRNAs. Expression profiling of ribosomal proteins in adult tissues showed that ribosomal protein L3 (Rpl3) is highly expressed in all tissues except in striated muscle; in contrast the expression of the Rpl3-like is exactly the opposite being highly expressed only in striated muscle skeletal muscle in particular. Preliminary data revealed that during periods of significant
muscle hypertrophy such as post-natal development and in response to synergist ablation the expression pattern of these two genes is completely reversed such that Rpl3 is highly-expressed and Rpl3-like is dramatically down-regulated in skeletal muscle. Consistent with these observations we found that over-expression of RPL3-like promotes significant myotube atrophy associated with a lower fusion index. While Rpl3 is necessary for ribosome assembly and peptidyl transferase activity of the ribosome the ribosomal function of Rpl3-like remains completely unknown. Based on our preliminary data we hypothesize that Rpl3-like acts to limit muscle size by altering the intrinsic translational activity of skeletal muscle ribosomes. To test the idea of ribosome specialization in skeletal muscle and its regulation the following objectives
will be pursued: 1) Determine how muscle-specific Rpl3-like alters ribosome function and 2) Determine the mechanisms regulating the muscle-specific pattern of expression of Rpl3 and Rpl3-like. We have developed a Tet-On system to compare translational fidelity of ribosomes containing Rpl3 versus Rpl3- like. Ribosome function will be examined by assessing programmed ribosomal frameshifting stop codon read- through near- and non-cognate tRNA utilization and IRES-mediated translation. Based on preliminary data we will test the hypothesis that the muscle-specific microRNA-1 represses Rpl3 expression in skeletal muscle by using 32-UTR reporter assay with mutagenesis in gain- and loss-of-function studies using miR-1 mimic and antimiR respectively. Next we will test the hypothesis that MyoD regulates the muscle-specific expression of Rpl3-like through promoter analysis mutagenesis EMSA and ChIP assay. The fact that there is a muscle- specific Rpl3 strongly suggests ribosomes have become specialized in skeletal muscle - understanding why this is so is the long-term goal of this project In the short-term the goal is to better understand the function and regulation of Rpl3-like as the
basis for a future R01 grant application investigating the role of ribosome specialization in skeletal muscle plasticity and disease.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Adult;Affect;Aging;Applications Grants;Atrophic;Biological Assay;Cachexia;Cells;Chronic;Clinical;Data;Databases;Deterioration;Development;Disease;EMSA;Embryonic Development;Future;Gene Expression;Gene Expression Regulation;Genes;Genetic Translation;Goals;Growth;HIV;Health;Heart failure;Heterogeneity;Housekeeping;Immobilization;In Vitro;Internal Ribosome Entry Site;Limb structure;Malignant Neoplasms;Mammals;Mediating;Messenger RNA;MicroRNAs;Molecular;Molecular Profiling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle;Muscle Fibers;Muscle function;Mutagenesis;Myogenic Regulatory Factors;Nature;Pattern;Peptidyltransferase;Play;Process;Promotor (Genetics);Proteins;Quality of life;Reading;Regulation;Reporter;Repression;Rheumatoid Arthritis;Ribosomal Frameshifting;Ribosomal Proteins;Ribosomes;Risk;Role;Sepsis;Skeletal muscle structure;Striated Muscles;System;Systemic disease;Terminator Codon;Testing;Tetanus Helper Peptide;Tissues;Transcript;Transfer RNA;Translating;Translations;Untranslated Regions;base;effective therapy;indexing;interest;loss of function;muscle form;muscle hypertrophy;neurotensin mimic 1;novel;patient population;prevent;programs;public health relevance;research study;response;ribosomal protein L3;sarcopenia;skeletal muscle plasticity

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The loss of skeletal muscle mass is of clinical importance because it is associated with increased morbidity and mortality as well as a marked deterioration in the quality of life. A broad patient population is affected by significant losses n muscle mass including those afflicted by various systemic diseases (cancer sepsis HIV- AIDS heart failure) chronic physical inactivity rheumatoid arthritis limb immobilization and sarcopenia. A better of understanding of the molecular mechanisms that regulate skeletal muscle mass will provide the basis for more effective therapies to prevent or restore muscle mass. The focus of the current proposal is to investigate the regulation and function of ribosome specialization in adult skeletal muscle and the role it plays in skeletal muscle health and disease.


application_id: 8822338
project_number: 5F32NS083182-03
project_title: Role of beta catenin mediated neural stem cell and astrocyte proliferation in TBI
administering_ic: NINDS
award_notice_date: 2015-03-27
opportunity_number: PA-11-113
application_type: 5
activity_code: F32
ic: NS
serial_number: 083182
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2013-04-15
project_end_date: 2016-01-04
study_section: Special Emphasis Panel[ZRG1-F01-F(20)L]
contact_pi_person_id: 9632738
contact_pi: SAMA, DIANA M.
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
project_abstract:
DESCRIPTION (provided by applicant): Approximately 1.5 million traumatic brain injuries (TBIs) occur in the United States annually. Although much research has focused on neuronal death following TBI TBI also initiates a proliferative response in some cell types including neural progenitor cells (NPCs) and astrocytes. Proliferating NPCs are thought to replace dying neurons through neurogenesis but the function of astrocyte proliferation is more controversial. Both normally rely on -catenin for proliferation but the importance of the -catenin pathway in posttraumatic proliferation has not yet been established. Because quiescent NPCs and astrocytes express glial fibrillary acidic protein (GFAP) this study utilizes a novel transgenic mouse in which -catenin signaling is conditionally knocked-out using the Cre-lox system under the GFAP promoter (GFAP-tta/Tet-O-Cre/-cateninflox/flox; cat-KO) allowing for the specific manipulation of NPCs and astrocytes after trauma. The central hypothesis is that -catenin- mediated NPC and astrocyte proliferation promotes recovery after contusion brain injury. The main goals of this proposal are to understand the extent to which -catenin signaling affects NPC and astrocyte proliferation after controlled cortical impact (CCI) brain injury (Aim 1) and toassess the role of dividing NPCs and astrocytes in the injured brain (Aim 2). Aim 1 tests the hypothesis that -catenin signaling is critical for NPC and astrocyte proliferation following CCI. cat-KO and wild-type (WT) mice will receive moderate CCI injury and injection of 5-bromo-2-deoxyuridine (BrdU a thymidine analog) to label dividing cells. Immunostaining will be used to compare numbers of BrdU-positive NPCs and astrocytes in cat-KO and WT mice. Aim 2 tests the hypothesis that eliminating -catenin-dependent proliferation in GFAP-positive NPCs and astrocytes will impair spontaneous recovery after CCI. Astrocytes are normally key regulators of blood-brain barrier (BBB) integrity and dendritic/synaptic outgrowth. Because -catenin affects astrocyte proliferation it is expected that cat-KO mice will show greater deficits than WT mice inBBB integrity (assessed by IgG or Evan's blue extravasation) and dendritic/synaptic recovery (assessed through immunostaining and Golgi staining). Because -catenin affects NPC proliferation recovery of immature neuronal populations in the hippocampus (evaluated with doublecortin immunolabeling) is expected to be impaired in cat-KO mice compared to WT mice. The combined loss of astrocyte and NPC proliferation are predicted to result in greater cognitive impairment which will be evaluated using a Morris Water Maze learning paradigm and Novel Object Recognition (memory) Task. These studies will provide novel insights on NPC and astrocyte proliferation in posttraumatic recovery thereby identifying new therapeutic targets for posttraumatic intervention. The proposed studies will greatly enhance my training in the pathobiology of TBI and my technical expertise for studying neurodegenerative conditions.

project_terms:
Address;Adult;Affect;Age;Animals;Astrocytes;Blood - brain barrier anatomy;Brain;Brain Injuries;Bromodeoxyuridine;Cause of Death;Cell Communication;Cell Cycle;Cell Differentiation process;Cell Proliferation;Cell division;Cells;Cessation of life;Contusions;DLG4 gene;Data;Deoxyuridine;Evans blue stain;Exhibits;Extravasation;Felis catus;Glial Fibrillary Acidic Protein;Goals;Golgi Apparatus;Growth;Health;Hippocampus (Brain);Immunoglobulin G;Impaired cognition;Injection of therapeutic agent;Injury;Intervention;Knock-out;Label;Life;Link;Maze Learning;Measures;Mediating;Memory;Modeling;Monitor;Mus;Nerve Degeneration;Neurons;Pathway interactions;Perfusion;Permeability;Population;Production;Proliferating;Promotor (Genetics);Proteins;Recovery;Research;Role;Signal Transduction;Staining method;Stains;Stem cells;Synapses;Synaptophysin;System;Technical Expertise;Testing;Tetanus Helper Peptide;Thymidine;Time;Training;Transgenic Mice;Trauma;Traumatic Brain Injury;United States;Vertebral column;Vulnerable Populations;Wild Type Mouse;analog;astrocyte progenitor;behavioral impairment;behavioral outcome;beta catenin;cell type;cognitive recovery;cohort;controlled cortical impact;disability;functional loss;improved;injured;insight;morris water maze;nerve stem cell;neurogenesis;neuron loss;new therapeutic target;novel;object recognition;repaired;research study;response;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Traumatic brain injury is the leading cause of death and disability under age 45. This research study will establish how proliferation of neural stem cells and astrocytes in the brain after trauma contributes to repair of the injured brain ultimately leading to improved behavioral outcome.


application_id: 8821772
project_number: 1R03AG047452-01A1
project_title: Increasing PKG activity protects aging kidney from ischemic-reperfusion induced injury
administering_ic: NIA
award_notice_date: 2015-02-13
opportunity_number: PA-13-142
application_type: 1
activity_code: R03
ic: AG
serial_number: 047452
suffix: A1
program_official: MACCHIARINI, FRANCESCA
project_start_date: 2015-03-01
project_end_date: 2017-02-28
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
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
project_abstract:
DESCRIPTION (provided by applicant): Aging is associated with increased incidence of acute kidney injury (AKI). This age-dependent increase in susceptibility to AKI is linked to a decreased renal functional recovery and even progression to advanced chronic kidney disease a severe health problem worldwide. Despite advances in our understanding of the cellular and molecular aspects of AKI in recent years the relationship between aging and AKI remains poorly understood and requires further mechanistic studies. Preliminary studies demonstrated that nitric oxide (NO) and its downstream signaling pathway cGMP and cGMP-dependent protein kinase (PKG) was down-regulated in aging kidney which was associated with aging-related renal functional changes. Moreover preliminary data identified a novel inhibitory effect of PKG on tubular cell necrosis and apoptosis following renal ischemia reperfusion (IR) induced AKI in young mice and an inhibitory effect of PKG on macrophage migration suggesting a therapeutic potential of PKG for renal IR injury. In this proposal we will test the hypothesis that down-regulation of NO/cGMP/PKG signaling in the kidney contributes to increased susceptibility to ischemia reperfusion-mediated AKI in older individuals. We will determine whether genetically or pharmacologically increased PKG activity reduces the susceptibility of old animals to ischemia mediated AKI in Aim 1. The mechanisms of reduced NO/cGMP/PKG signaling in aging kidney will be determined in Aim 2. These studies will establish the significance of PKG in acute kidney injury in aging population. Importantly we will test a novel potential application of sildenafil fr AKI in older population. Sildenafil is an inhibitor of cGMP specific phosphodiesterase 5 (PDE5) and a FDA approved drug for treatment of pulmonary hypertension and erectile dysfunction. Hopefully these proposed studies will lead to new therapeutic strategy for acute kidney injury in aging population.

project_terms:
Acute Renal Failure with Renal Papillary Necrosis;Aging;Animals;Antibodies;Apoptosis;CD47 gene;Cell Proliferation Regulation;Cell physiology;Cells;Chronic Kidney Failure;Cyclic GMP;Cyclic GMP-Dependent Protein Kinases;Data;Development;Down-Regulation;Elderly;Erectile dysfunction;FDA approved;Genetic;Genotype;Glomerular Filtration Rate;Guanylate Cyclase;Health;Healthcare Systems;Incidence;Individual;Inflammation;Injury;Ischemia;Kidney;Knockout Mice;Lead;Link;Mediating;Mediator of activation protein;Molecular;Mus;Necrosis;Nitric Oxide;Older Population;Outcome;Pathway interactions;Pharmaceutical Preparations;Play;Predisposition;Production;Protein Binding;Pulmonary Hypertension;Recovery;Recovery of Function;Regulation;Renal Blood Flow;Renal function;Reperfusion Injury;Reperfusion Therapy;Role;Signal Pathway;Signal Transduction;Signaling Molecule;System;Testing;Therapeutic;Transgenic Mice;Tubular formation;Up-Regulation (Physiology);age related;aging population;atrial natriuretic factor prohormone (31-67);base;genetic approach;improved;inhibitor/antagonist;juvenile animal;macrophage;male;migration;normal aging;novel;novel therapeutics;phosphodiesterase V;public health relevance;receptor;renal ischemia;sildenafil

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Aging is associated with increased incidence of acute kidney injury. The proposed studies will provide novel information on the mechanisms of aging mediated down-regulation of renal nitric oxide/cGMP/PKG signaling and its contribution to increased susceptibility of old animals to acute kidney injury. These studies may lead to new therapeutic strategy for acute kidney injury in aging population.


application_id: 8821568
project_number: 5R01AI093450-06
project_title: Development of New Bivalent Cross-Protective Arenaviral Vaccines
administering_ic: NIAID
award_notice_date: 2015-03-13
opportunity_number: RFA-AI-10-003
application_type: 5
activity_code: R01
ic: AI
serial_number: 093450
program_official: REPIK, PATRICIA M
project_start_date: 2011-04-01
project_end_date: 2018-03-31
study_section: ZAI1-NLE-M(J3)
contact_pi_person_id: 6955101
contact_pi: LUKASHEVICH, IGOR S.
other_pis: PUSHKO, PETER M.
congressional_district: 03
department: PHARMACOLOGY
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:
DESCRIPTION (provided by applicant): Highly pathogenic arenaviruses Lassa Junun Machupo are dominant viral species among NIAID Category A Priority Pathogens. The development of safe and efficacious vaccines against these pathogens with particular emphasis on multivalent and cross protective strategy and advanced platform technology is one of the priorities of NIH/NIAID. The main goal of this project is an advanced development and optimization of alphavirus-based VLPV (virus-like-particle-vectors) technology (patent is pending) as a generic platform for preventive biodefense vaccines against highly pathogenic arenaviruses. Using this technology and rational vaccine design we will develop: (i) a bivalent LASV vaccine with enhanced immunogenicity and cross-protective potential against distantly-related LASV genotypes and (ii) a bivalent JUNV&MACV vaccine. The VLPV technology will be transferred to a manufacturing environment and scaled-up to produce GLP-grade vaccines for preclinical testing in nonhuman primates. SPECIFIC AIM I: Rational Design of Multivalent VLPV Expressing Arenaviral Glycoproteins with Enhanced Immunogenicity and Cross-Reactivity. The goal of this aim is to design: (i) VLPV expressing LASV GP able to induce strong CD8+ T cell responses to distantly-related LASV lineages I and IV through the conventional MHC I peptide presentation and through cross-priming; ii) VLPV expressing JUNV&MACV GP to induce neutralizing Abs against both pathogens; and iii) to optimize alphavirus bi-cistronic replicon structures for product development. SPECIFIC AIM II: Selection of Immunogenic and Cross-Reactive Recombinant VLPV Vaccines in Experimental Animals. In-process Safety Testing. SPECIFIC AIM III: Pre-Clinical Safety Immunogenicity and Efficacy in NHP. Tox Lot vaccine products will be tested for Safety Immunogenicity and Efficacy in the NHP challenge model we recently developed. The main goal of this project is an advanced development and optimization of Virus-Like-Particle-Vectors technology as a generic platform for preventive biodefense vaccines against highly pathogenic arenaviruses Lassa-Junin-Machupo. The VLPV technology will be transferred to a manufacturing environment and scaled-up to produce GLP-grade vaccines for Safety Immunogenicity and Efficacy Studies in non-human primates

project_terms:
Advanced Development;Adverse event;Affect;Africa;Alphavirus;Am 80;Animals;Antigen-Presenting Cells;Antigens;Arenavirus;Attenuated Live Virus Vaccine;Bolivian Hemorrhagic Fever Virus;CD8B1 gene;Categories;Cavia;Cells;Cessation of life;Cross-Priming;DNA;Development;Ebola virus;Ensure;Environment;Equilibrium;Filovirus;Frequencies (time pattern);Generic Drugs;Genes;Genetic;Genotype;Geographic Distribution;Glycoproteins;Goals;Human;Immunization;Individual;Junin virus;Lassa Fever;Lassa virus;Lead;Legal patent;Lujo virus;Modeling;Mus;National Institute of Allergy and Infectious Disease;Nucleoproteins;Old World Arenaviruses;Peptides;Preclinical Testing;Preventive;Process;Production;Promotor (Genetics);Recombinants;Replicon;Safety;South Africa;Structural Protein;Structure;T cell response;Tacaribe Complex Viruses;Technology;Technology Transfer;Testing;United States National Institutes of Health;Vaccination;Vaccine Design;Vaccines;Viral;Viral Hemorrhagic Fevers;Virus;Virus-like particle;base;biodefense;cross reactivity;design;environmental change;immunogenic;immunogenicity;neutralizing antibody;next generation;nonhuman primate;particle;pathogen;peptide I;pre-clinical;product development;public health medicine (field);recombinant virus;safety testing;scale up;vaccine safety;vector;vector vaccine

public_health_relevance:
The main goal of this project is an advanced development and optimization of Virus-Like-Particle-Vectors technology as a generic platform for preventive biodefensevaccines against highly pathogenic arenaviruses Lassa-Junin-Machupo. The VLPVtechnology will be transferred to a manufacturing environment and scaled-up to produceGLP-grade vaccines for Safety Immunogenicity and Efficacy Studies in non-humanprimates


application_id: 8819437
project_number: 5R13CA168316-04
project_title: Advancing Health Communication Research through the KCHC-DCHC Conference Series
administering_ic: NCI
award_notice_date: 2015-01-30
opportunity_number: PA-10-071
application_type: 5
activity_code: R13
ic: CA
serial_number: 168316
program_official: BLAKE, KELLY D
project_start_date: 2012-04-19
project_end_date: 2015-12-31
study_section: ZCA1-PCRB-G(F2)
contact_pi_person_id: 1974135
contact_pi: HARRINGTON, NANCY GRANT
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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This R13 application requests support for the Kentucky Conference on Health Communication (KCHC)- District of Columbia Health Communication (DCHC) conference series which currently is planning its 13th meeting to be held April 19-21 2012. The overall goal of the annual KCHC-DCHC conference series is to promote health communication research and practice in order to advance our understanding of behavioral and communication science; such advanced understanding will through translational research subsequently enhance the effectiveness of interventions designed to promote health and prevent illness. The specific aims of this R13 are to increase the impact of KCHC-DCHC through 1) expanding dissemination; 2) increasing participation by early career researchers and graduate students; 3) increasing participation from underrepresented groups; and 4) continuing emphasis on scholarly excellence. Across all four aims our goal is to positively influence the field of health communication and increase its impact by enhancing dissemination of leading research and promoting the career development of early career scientists particularly those from underrepresented groups. Our emphasis on health message design and dissemination is relevant to the mission of the National Institutes of Health (NIH) given our goal to apply our knowledge "to enhance health lengthen life and reduce the burdens of illness and disability" [1]. This scientific focus is consistent with the aims of the U.S. government which has recognized the importance of communication in promoting the health and well-being of our nation in its Healthy People publications. The timeliness of our conference series is especially reflected by the theme the of 2012 conference Health Literacy Research and Practice a theme that addresses the number one Healthy People 2020 [2] health communication objective: health literacy. Our three- day international interdisciplinary conference encompasses several disciplines representing communication social behavioral and health sciences. Topics addressed at the conference include interventions designed for health risk behavior reduction in areas such as cancer diabetes substance abuse and HIV/AIDS; community media and technology-related issues; and methodological issues in behavioral/social science research. Such health communication-focused inquiry is now recognized as instrumental in promoting public health [3]. Past conference attendance has averaged approximately 200 participants. The audience primarily includes graduate postdoctoral and academic faculty researchers; we emphasize participation by graduate students and early career scientists. This audience composition allows the conference series to support one of NIH's goals: "to develop maintain and renew scientific human...resources that will ensure the Nation's capability to prevent disease" [1].

project_terms:
AIDS/HIV problem;Address;Area;Behavioral;Behavioral Genetics;Behavioral Sciences;Communication;Communication Research;Communities;Diabetes Mellitus;Discipline;Discipline of Nursing;Disease;District of Columbia;Effectiveness of Interventions;Ensure;Event;Faculty;Goals;Government;Growth;Health;Health Communication;Health Personnel;Health Promotion;Health Sciences;Healthy People 2020;Human Resources;Interdisciplinary Study;International;Internet;Kentucky;Knowledge;Life;Malignant Neoplasms;Medical Informatics;Medicine;Mission;Participant;Personal Satisfaction;Persuasive Communication;Process;Psychology;Publications;Publishing;Request for Applications;Research;Research Personnel;Risk;Risk Reduction Behavior;Scholarship;Science;Scientist;Series;Sister;Social Sciences;Sociology;Students;Substance abuse problem;Technology;Translational Research;Travel;Underrepresented Minority;United States National Institutes of Health;Work;behavioral/social science;burden of illness;career;career development;design;disability;disorder prevention;drug abuse prevention;graduate student;health information technology;health literacy;interest;meetings;member;prevent;public health medicine (field);public health relevance;skills;social;social science research;substance abuse prevention;symposium;therapy design

public_health_relevance:
The Kentucky Conference on Health Communication (KCHC)-District of Columbia Health Communication (DCHC) conference series will advance health communication research and practice in order to reduce the burden of pressing public health problems such as cancer diabetes substance abuse and HIV/AIDS. The conference will promote career development in the social and behavioral sciences through support of early career researchers and graduate students increasing the number of professionals with expertise in health communication.


application_id: 8819132
project_number: 5R21EY024313-02
project_title: Hypoxia-induced reprogramming to RPE stem cells
administering_ic: NEI
award_notice_date: 2015-05-01
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: EY
serial_number: 024313
program_official: NEUHOLD, LISA
project_start_date: 2014-04-01
project_end_date: 2017-03-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 1877760
contact_pi: DEAN, DOUGLAS CHASE
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
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:
DESCRIPTION (provided by applicant): In urodeles and anurans a major component of retinal regeneration is transdifferentiation of RPE to neural retina. But regeneration is limited in mammals leaving them susceptible to retinal injury and blinding diseases. Recent studies identified a population of RPE stem cells (RPESC) among cultures of human RPE. These RPESC show unrestricted proliferation and their differentiation potential closely resembled mesenchymal stem cells (MSC) which share a common neuroepithelial origin with RPE. Although RPESC differentiated to express neuronal markers they failed to induce photoreceptor markers such as RHO. Thus these RPESC may not represent an intermediate in transdifferentiation of mammalian RPE into photoreceptors. We examined cultures of adult mouse RPE for cells with the differentiation capacity of RPESC but we failed to identify such cells. However we found that cells with properties of RPESC can be efficiently and stably induced from RPE (iRPESC) through a hypoxia-dependent pathway similar to that described for maintenance and induction of MSC. Hypoxia causes RPE damage and is linked to neovascularization and AMD. Key to this iRPESC reprogramming pathway is superinduction of hypoxia inducible factor 1a (Hif1a) to a threshold sufficient to bind and activate the Oct4 stem cell gene promoter. Oct4 in turn induces Dnmt1 which silences cell cycle blocking cyclin dependent kinase inhibitors leading to unrestricted proliferation. These iRPESC are resistant to hypoxia and importantly as opposed to human RPESC they differentiate into Rho+ cells-indeed this differentiation to Rho+ cells is more efficient than seen with embryonic stem cells or induced pluripotent stem cells. Furthermore iRPESC do not undergo the typical epithelial-mesenchymal transition (EMT) seen when RPE are placed in culture providing the potential for retaining an RPE phenotype as the cells are expanded. Because blinding diseases such as AMD are highlighted by loss of both functional RPE and photoreceptors the ability of the iRPESC to undergo photoreceptor differentiation and to resist EMT-initiated loss of phenotype suggest a unique therapeutic potential for the cells. During the two year period of this R21 proposal we aim to investigate the iRPESC reprogramming pathway on a molecular level. The purpose of these studies is to provide a foundation for experiments designed to optimize photoreceptor differentiation from iRPESC and to maintain a function RPE phenotype as iRPESC are expanded so in the future we can begin testing the effectiveness of the differentiated iRPESC in transplantation experiments. A second point of this molecular analysis is to identify pathway markers that can ultimately be used for detection of iRPESC in vivo and to understand factors that might be used in the future to stimulate iRPESC generation from RPE in situ.

project_terms:
Adult;Binding (Molecular Function);Cell Aging;Cell Cycle;Cell Differentiation process;Cells;Cessation of life;Cyclin-Dependent Kinase Inhibitor;Detection;Development;Disease;Effectiveness;Embryo;Environment;Epithelial;Foundations;Future;Generations;Genes;Goals;Health;Hemostatic function;Human;Hypoxia;Hypoxia Inducible Factor;In Situ;Injury;Knowledge;Left;Link;Maintenance;Mammals;Mesenchymal;Mesenchymal Stem Cells;Mitotic;Molecular;Molecular Analysis;Mus;Natural regeneration;Neural Retina;Neuroepithelial;Neuronal Differentiation;Neurons;Newts;Optics;Organ;Pathway interactions;Phenotype;Photoreceptors;Play;Population;Proliferating;Promotor (Genetics);Property;Protocols documentation;Rana (genus);Repression;Resistance;Retinal;Retinal Diseases;Rodent;Rods (Retina);Role;Salamander;Stem cells;Structure of retinal pigment epithelium;Suspension substance;Suspensions;Testing;Therapeutic;Tissues;Transplantation;adult stem cell;design;diencephalon;embryonic stem cell;in vivo;induced pluripotent stem cell;inhibitor/antagonist;monolayer;neovascularization;neuroepithelium;pluripotency;prevent;progenitor;repaired;research study;response;restoration;retinal regeneration;rho;senescence;toad;transdifferentiation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Retinal pigment epithelium (RPE) can efficiently transdifferentiate to replace damaged neural retina in newts and frogs and to a more limited degree in embryonic chick and rodents. However RPE transdifferentiation does not occur in adult mammals and regeneration is limited leaving mammals susceptible to retinal injury and blinding diseases. Recent studies have provided the first evidence of RPE stem cells (RPESC) in cultures of human RPE. This important finding raises the possibility that these RPESC may serve as a reservoir for replacement of damaged RPE in diseases such as AMD and they may represent an intermediate in transdifferentiation of RPE to photoreceptor in mammals. However even though these human RPESC closely resembled mesemchymal stem cells (MSC) in their differentiation potential and they showed evidence of neuronal differentiation they failed to induce markers of photoreceptor differentiation. We have examined adult mouse RPE for cells with properties of RPESC. Although we did not detect RPESC we found instead that cells with properties of RPESC could be stably and efficiently induced from RPE (iRPESC) through a hypoxia-dependent pathway similar to that described for maintenance and induction of MSC. Key to this iRPESC reprogramming pathway is superinduction of hypoxia inducible factor 1a (Hif1a) to a threshold sufficient to bind and activate the Oct4 stem cell gene promoter. Oct4 in turn induces Dnmt1 which silences cell cycle blocking cyclin dependent kinase inhibitors leading to unrestricted proliferation. These iRPESC are resistant to hypoxia and importantly as opposed to human RPESC they differentiate into Rho+ cells-indeed this differentiation to Rho+ cells is more efficient than seen with embryonic stem cells or induced pluripotent stem cells. These results with iRPESC demonstrate induction of RPESC under hypoxic conditions that have been linked to RPE damage in retinal disease (e.g. neovascularization and AMD). Because iRPESC can efficiently differentiate to express rod photoreceptor makers they can act as a stable intermediate for transition of mammalian RPE to cells expressing markers of photoreceptors. We propose studies of the molecular pathway leading to iRPESC reprogramming during the two year period of the R21.


application_id: 8817431
project_number: 1R01EY024051-01A1
project_title: The danger signals in autoimmune uveitis
administering_ic: NEI
award_notice_date: 2014-11-25
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: EY
serial_number: 024051
suffix: A1
program_official: MCKIE, GEORGE ANN
project_start_date: 2014-12-01
project_end_date: 2018-11-30
study_section: Diseases and Pathophysiology of the Visual System Study Section[DPVS]
contact_pi_person_id: 6193432
contact_pi: SHAO, HUI
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
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
project_terms:
Adoptive Transfer;Affect;Anti-Inflammatory Agents;Anti-inflammatory;Antigen-Presenting Cells;Antigens;Apoptotic;Astrocytes;Blindness;CD95 Antigens;Cell Death;Cell physiology;Cells;Chronic;Disease;Eye;Frequencies (time pattern);Functional disorder;Generations;Goals;HMGB1 gene;Human;Immunity;Inflammation;Inflammatory;Intervention;Local Therapy;MAPK14 gene;MAPK8 gene;Maintenance;Mediating;Memory;Modeling;Molecular;Mus;Pathogenesis;Pathogenicity;Phenotype;Population;Proteins;Regulatory T-Lymphocyte;Relative (related person);Resistance;Retinal;Role;Signal Transduction;Systemic Therapy;T memory cell;T-Lymphocyte;Testing;Th1 Cells;Uveitis;Western World;Work;autoimmune uveitis;caspase;chemokine;cytokine;inhibitor/antagonist;interstitial retinol-binding protein;novel;novel therapeutic intervention;public health relevance;research study;response


application_id: 8817310
project_number: 5R01HL107326-04
project_title: Sex Differences in Angiotensin-Induced Vascular Diseases
administering_ic: NHLBI
award_notice_date: 2015-03-06
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 107326
program_official: VARAGIC, JASMINA
project_start_date: 2012-03-21
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1-VH-D(90)]
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
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
project_abstract:
DESCRIPTION (provided by applicant): Abdominal aortic aneurysms (AAAs) are a common life-threatening disorder with no therapeutic strategies that effectively blunt growth and progression of the disease. Male sex is a strong risk factor for AAAs. Similarly AAAs induced by infusion of angiotensin II (AngII) exhibit marked sexual dimorphism with a 4-fold higher prevalence in male compared to female mice. Previous results demonstrated that testosterone exhibits region-specific regulation of angiotensin type 1a receptor (AT1aR) expression in abdominal aortas to promote AngII-induced AAAs. We also demonstrated that exposures of neonatal females to testosterone induced permanent increases in adult susceptibility to AAAs. This model of female androgenization which mimics surges in testosterone shortly after birth in males resulted in increased AT1aR expression in abdominal aortas and markedly enhanced AAA susceptibility of adult females. Since males require continued testosterone exposures to exhibit high AAA susceptibility our results demonstrate that males and females respond differently to testosterone during development. We propose that sex hormones as well as sex chromosomes mediate sexual dimorphism of AngII-induced AAAs. The central hypothesis of this proposal is that testosterone effects (developmental and/or adult) at pivotal cell types in addition to sex chromosome effects promote region- specific increases in aortic AT1aR expression and AngII-induced AAAs. Aim 1 will define the cell-specific role of androgen receptors in developmental and/or adult effects of testosterone on abdominal aortic AT1aR expression and AngII-induced AAAs. Aim 2 will define the relative contribution of sex hormones versus sex chromosomes in developmental and/or adult effects of testosterone on abdominal aortic AT1aR expression and AngII-induced AAAs. In both aims approaches will include studies designed to quantify effects on AAA formation versus progression. In addition to identifying mechanisms for sexual dimorphism of AngII-induced AAAs results from these studies may identify targets amenable to therapy that either protect (females) or augment (males) AAA susceptibility.

project_terms:
Abdomen;Abdominal Aortic Aneurysm;Adult;Affect;Aging;Androgen Receptor;Androgenization;Angiotensin II;Angiotensin Type 1a Receptor;Angiotensins;Aorta;Aortic Aneurysm;Apolipoprotein E;Atherosclerosis;Birth;Blood Pressure;Blood Vessels;Cardiovascular system;Cells;Cessation of life;Chromosomes;Development;Disease;Disease Progression;Dose;Early Intervention;Embryo;Employee Strikes;Exhibits;Exposure to;Female;Genes;Genotype;Goals;Gonadal Steroid Hormones;Growth;High Prevalence;Infusion procedures;Life;Low-Density Lipoproteins;Medial;Mediating;Mediator of activation protein;Mesoderm;Mesoderm Cell;Messenger RNA;Modeling;Mus;Neonatal;Operative Surgical Procedures;Pathology;Predisposition;Prevalence;Regulation;Relative (related person);Research;Research Design;Risk Factors;Role;Rupture;Sex Characteristics;Sex Chromosomes;Site;Smooth Muscle Myocytes;Smooth muscle (tissue);Testing;Testosterone;Therapeutic;Thoracic aorta;Vascular Diseases;abdominal aorta;aged;base;blastomere structure;cell type;effective therapy;human disease;interest;male;mouse model;neonatal exposure;novel;prevent;receptor expression;response;sex;sexual dimorphism

public_health_relevance:
The proposed research will define mechanisms for sex differences in susceptibility to abdominal aortic aneurysms (AAAs). A unique and relevant aspect of these studies is a focus on effects of male sex hormone exposures during development as a mediator of greater susceptibility to AAAs in adult males. This shift in focus to development may identify novel interventions early in life that can prevent or decrease vascular disease in aging males and females. In addition these are the first studies to define the role of sex chromosomes as mediators of the pronounced sexual dimorphism in AAA formation and/or progression.


application_id: 8816499
project_number: 1R01HD075829-01A1
project_title: The development of emotion processing in infancy
administering_ic: NICHD
award_notice_date: 2015-04-01
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: HD
serial_number: 075829
suffix: A1
program_official: FREUND, LISA S
project_start_date: 2015-04-01
project_end_date: 2020-02-29
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 8534513
contact_pi: BHATT, RAMESH S
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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Adult;Affect;Age-Months;Age-Years;Anger;Autistic Disorder;Behavior;Categories;Conduct Disorder;Cues;Development;Disease;Emotional;Emotions;Face;Feeling;Fright;Gestures;Human;Human body;Infant;Infant Development;Intention;Knowledge;Learning;Life;Literature;Mental disorders;Modality;Modeling;Motor;Movement;Nature;Organism;Perception;Perceptual learning;Persons;Play;Posture;Process;Psychopathology;Research;Role;Scanning;Signal Transduction;Social Functioning;Social Interaction;Social Perception;Sorting - Cell Movement;Source;Testing;Visual;Visuospatial;Walkers;Work;autism spectrum disorder;base;cognitive function;developmental disease/disorder;emotional behavior;experience;infancy;object perception;public health relevance;research study;showing emotion;social;theories


application_id: 8816202
project_number: 1R01NR012967-01A1
administering_ic: NINR
award_notice_date: 2014-09-24
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: NR
serial_number: 012967
suffix: A1
program_official: HUSS, KAREN
project_start_date: 2014-09-26
project_end_date: 2019-07-31
study_section: Behavioral Medicine, Interventions and Outcomes Study Section[BMIO]
contact_pi_person_id: 8446344
contact_pi: CHUNG, MISOOK LEE
other_pis: Not Applicable
congressional_district: 06
department: NONE
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 NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Address;Adherence (attribute);Adult;Affect;Age;Analysis of Variance;Attitude;Behavior;Cardiovascular system;Caregivers;Caring;Chronic;Chronically Ill;Complex;Control Groups;Data;Desire for food;Diet;Dietary Sodium;Distress;Eating;Educational Intervention;Educational aspects;Educational process of instructing;Elderly;Electronics;Enrollment;Epidemic;Excretory function;Face;Family;Family Caregiver;Family member;Feeling;Food;Food Labeling;Food Preferences;Goals;Health;Health Care Costs;Health Status;Heart failure;Hospitalization;Hour;Individual;Intake;Intervention;Intervention Studies;Knowledge;Lead;Long-Term Effects;Measures;Medical;Modeling;Monitor;Outcome;Patients;Perception;Physiological;Play;Prevalence;Quality of life;Questionnaires;Randomized;Randomized Controlled Trials;Reading;Recommendation;Research;Research Personnel;Resources;Role;Self Care;Self Management;Sensory;Social support;Sodium;Sodium Chloride;Sodium-Restricted Diet;Source;Symptoms;Tablets;Taste Buds;Taste Perception;Testing;Time;Urine;Videoconferences;Videoconferencing;Wit;Work;base;care giving burden;caregiving;design;follow-up;group intervention;hedonic;improved;innovation;intervention program;longitudinal analysis;meetings;member;monitoring device;outcome forecast;preference;prevent;programs;public health medicine (field);public health relevance;skills;success;treatment as usual;urinary


application_id: 8816090
project_number: 5K01DK096042-03
project_title: Enhancement of NAFLD risk by vinyl chloride: interaction of gut-liver-adipose axi
administering_ic: NIDDK
award_notice_date: 2015-02-26
opportunity_number: PAR-12-020
application_type: 5
activity_code: K01
ic: DK
serial_number: 096042
program_official: SASLOWSKY, DAVID E
project_start_date: 2013-04-01
project_end_date: 2016-03-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 10438358
contact_pi: BEIER, JULIANE I
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
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:
DESCRIPTION (provided by applicant): Obesity and its metabolic complications are major health problems in the United States and worldwide. A major disease associated with obesity is non-alcoholic fatty liver disease (NAFLD). Indeed obesity may influence individual susceptibility to other environmental exposures such as vinyl chloride (VC). Specifically we hypothesize that experimental NAFLD sensitizes the liver to VC as a 2nd hit. Recent studies indicate that intestinal barrier function and GI tract flora play a key role in the development of NAFLD. Supplementation with probiotics has been shown to decrease induced gut permeability and liver injury. We therefore propose that VC via altering intracellular signaling cascades impairs barrier function integrity in NAFLD and that probiotic supplementation [Lactobacillus rhamnosus Gorbach-Goldin (LGG)] will attenuate these effects. Aim 1. To test the hypothesis that VC exposure exacerbates liver injury caused by HFD. It is well-known that liver injury is increased by high fat (HFD) diet. It has been shown that VC is hepatotoxic. We propose here that VC exposure will exacerbate liver injury caused by experimental NAFLD (HFD) in mice. Subaims will determine: a) the minimal low dose VC exposure conditions that exacerbate fatty liver due to HFD; b) potential mechanisms by which VC exposure enhances liver damage caused HFD. Aim 2. To determine mechanisms by which VC accentuates fatty liver disease caused by HFD. It is known that there is a critical crosstalk between the GI tract the adipose tissue and the liver tha plays an important role in the development of NAFLD (i.e. the 'gut-liver-adipose axis'). The purpose of this Aim is to determine the effect of VC metabolites on responses in in vitro paradigms of the gut-liver-adipose axis. Subaims will characterize the response of: a) hepatocytes to cytotoxic stimuli b) response of macrophages to inflammatory stimuli and c) stimulus of adipocytes to produce adipogenic mediators. Aim 3. To test the hypothesis that VC exposure exacerbates intestinal permeability caused by HFD. It is known that intestinal permeability is increased after HFD feeding. The barrier function of the intestinal epithelium is also dependent on the gut microbiota profile. Probiotic microorganisms have been shown to improve barrier integrity of the intestinal epithelium. We propose here that VC exposure will exacerbate gut permeability due to HFD in mice and that gut microbiota play an important role in gut permeability and VC-induced toxicity in HF-fed mice. We will further determine if probiotics [e.g. lactobacillus rhamnosus GG (LGG)] will decrease VC-induced toxicity in HF-fed mice via improvement of gut permeability and TJ integrity. Subaims will determine: a) the combined effect of VC and HFD on intestinal integrity in vivo (mice) and in vitro (Caco-2 cells); b) the effct of VC and dietary fatty acids on mRNA and surface expression of key tight junction proteins and the role of SAPK signaling in this process in Caco-2 cells; c) if HFD and VC synergistically impair TJ barrier functions in vivo; and d) the protective effect of probiotic LGG on HFD and VC-induced gut permeability.

project_terms:
Accounting;Adipocytes;Adipose tissue;Attenuated;Caco-2 Cells;Chemicals;Data;Development;Diet;Dietary Fatty Acid;Disease;Dose;Endotoxemia;Environmental Exposure;Environmental Pollutants;Fatty Liver;Fatty acid glycerol esters;Gastrointestinal tract structure;Health;Hepatocyte;Human;In Vitro;Individual;Inflammatory;Inflammatory Response;Intestines;Lactobacillus casei rhamnosus;Liver;Liver diseases;Mediating;Mediator of activation protein;Messenger RNA;Metabolic;Modeling;Mus;Nutrient;Obesity;Permeability;Play;Population;Predisposition;Probiotics;Process;Production;Proteins;Relative (related person);Relative Risks;Risk;Risk Factors;Role;SAPK;Safety;Signal Transduction;Stimulus;Supplementation;Surface;Testing;Tight Junctions;Toxic effect;Toxin;Treatment Protocols;United States;Vinyl Chloride;Work;cytokine;cytotoxic;disorder risk;feeding;gut microbiota;improved;in vivo;in vivo Model;intestinal epithelium;liver injury;macrophage;microorganism;non-alcoholic fatty liver;nonalcoholic steatohepatitis;novel;protective effect;response;toxicant

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  We propose that vinyl chloride exposure even below levels that are overtly hepatotoxic may increase the stimulated inflammatory response in the liver potentially adding another risk factor to the development of liver disease associated with obesity (i.e. non-alcoholic fatty liver disease). The project will focus on the individual and combined effects of vinyl chloride and diet on gut-liver-adipose axis in experimental NAFLD.


application_id: 8815324
project_number: 5K99EY024336-02
project_title: Non-canonical NLRP3 Inflammasome Activation in Geographic Atrophy
administering_ic: NEI
award_notice_date: 2015-03-19
opportunity_number: PA-11-197
application_type: 5
activity_code: K99
ic: EY
serial_number: 024336
program_official: AGARWAL, NEERAJ
project_start_date: 2014-04-01
project_end_date: 2015-12-31
study_section: ZEY1-VSN(02)
contact_pi_person_id: 11044965
contact_pi: KERUR, NAGARAJ
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
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): This K99/R00 grant will facilitate the applicant's (Dr. Nagaraj Kerur) long-term goal to develop as an independent investigator in vision research. Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) characterized by central loss of vision due to retinal pigmented epithelium (RPE) degeneration. Currently there is no therapy available for GA because of its unclear etiology. We recently discovered that DICER1 deficit causes a pathologic accumulation of Alu RNA transcripts in the RPE of human GA eyes and that the accumulated Alu RNAs activate the NLRP3 inflammasome which in turn leads to IL- 18/MyD88-dependent RPE cell death (Kaneko et al. Nature 2011; Tarallo et al. Cell 2012). In exciting new preliminary studies we have discovered that Alu RNA-induced NLRP3 inflammasome activation occurs in a non-canonical fashion- a newly described pathway in which caspase 4 (aka caspase 11 in mouse) is required for the NLRP3 inflammasome activation (in contrast the canonical inflammasome activation is independent of caspase 4). The central goal of the proposed research is to define role of caspase 4-mediated non-canonical NLRP3 inflammasome activation in the context of GA and to identify critical signaling pathways regulating caspase 4 activation via the following aims: (1) Define the signaling pathways that regulate caspase 4 (aka caspase 11 in mouse) activation by Alu RNA; (2) Elucidate the mechanisms of caspase 4 (aka caspase 11 in mouse) activation of the NLRP3 inflammasome; and (3) Measure the activation of these non-canonical inflammasome signaling pathways in human GA. These studies will illuminate the molecular foundation of GA unravel novel regulatory checkpoints of NLRP3 inflammasome activation and provide a strong molecular foundation for exploiting new therapeutic targets in AMD. During the mentored phase (K99) the applicant will carry out the proposed studies under direct supervision of the mentor Dr. Jayakrishna Ambati at the University of Kentucky. In addition an advisory committee consisting of co-mentor Dr. Katherine Fitzgerald and the faculty members at the Department of Ophthalmology and Visual Sciences will monitor the applicant's research progress and offer assistance in advancing the applicant's transition towards independent investigator. The Ambati Group at the University of Kentucky as well as the Fitzgerald Laboratory at the University of Massachusetts Medical School both offer scientifically enriching environments and resources necessary for the advancement of the applicant's scientific career. The major focus of K99 phase will include: (1) mentored research to define molecular insights into the caspase 4 activation mechanism and to optimize experimental conditions for studies to be carried out in the R00 phase; and (2) training activities consisting of formal course work seminars workshops on grant writing and acquisition of other skill-sets required for successfully developing and leading an independent research program. During the R00 phase the focus will be on: (1) deciphering the mechanisms by which caspase 4 regulates NLRP3 inflammasome activation; and (2) quantifying the activation of non-canonical inflammasome signaling pathways in human GA eyes. Overall this proposal will not only unravel the novel molecular mechanisms of RPE degeneration in GA but will also equip the applicant with suitable skills to transition int an independent career in vision research.

project_terms:
Advisory Committees;Age related macular degeneration;Atrophic;Blindness;CASP1 gene;Caspase-1;Cell Culture Techniques;Cell Death;Cells;Cellular biology;Cessation of life;DICER1 gene;Dependency (Psychology);Development;Disease;Educational workshop;Environment;Etiology;Eye;Faculty;Foundations;Goals;Grant;Health;Human;IL18 gene;Immune;Interferons;Interleukin-1;Interleukin-18;Investigation;Kentucky;Laboratories;Massachusetts;Measures;Mediating;Mentors;Modeling;Molecular;Monitor;Mus;Nature;Ophthalmology;Pathogenesis;Pathologic;Pathway interactions;Phase;Pilot Projects;Play;Proteomics;RNA;Regulation;Regulatory Pathway;Research;Research Personnel;Resources;Role;Scaffolding Protein;Signal Pathway;Signal Transduction;Structure of retinal pigment epithelium;Supervision;Therapeutic;Tissue Model;Training Activity;Transcript;Universities;Vision research;Work;Writing;age related;career;caspase;cytokine;geographic atrophy;human CASP4 protein;human DICER1 protein;human tissue;insight;macula;medical schools;member;mouse model;new therapeutic target;novel;procaspase-1;programs;skills;vision science

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Recently we have discovered that the over-activation of the NLRP3 inflammasome pathway plays an essential role in the development of geographic atrophy (GA) an untreatable cause of blindness. However the mechanisms that govern inflammasome activation in GA are poorly understood. Our proposed research will help gain a deeper understanding of these inflammasome-regulatory pathways to identify novel critical molecules that can be targeted for treating GA and other inflammasomopathies.


application_id: 8814536
project_number: 2R01DE017921-05
project_title: Role of JAKs in innate responses to P. gingivalis
administering_ic: NIDCR
award_notice_date: 2014-12-09
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: DE
serial_number: 017921
program_official: CHANDER, PREETHI
project_start_date: 2010-06-23
project_end_date: 2019-12-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
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 DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Inflammatory responses to pathogenic bacteria are essential for protection of the host and control of bacterial infection. However inflammatory responses that are sustained in duration and intensity can be damaging to susceptible tissues. To limit the ferocity of inflammation and curtail possible tissue damage a number of pathways exist that dampen the innate immune response. Our studies have focused on a tyrosine kinase of the Janus kinase (JAK) family JAK3. We have found that that challenge with the periodontal pathogen P. gingivalis increases both the activation state and the amount of JAK3 in human monocytes and murine bone marrow derived macrophages. Moreover JAK3 inhibition enhances the production of pro-inflammatory cytokines upon P. gingivalis stimulation and concurrently diminishes levels of the anti-inflammatory cytokine IL-10. Thus we have identified a novel role for JAK3 as a negative regulator of inflammation and propose that stimulation of this endogenous anti-inflammatory pathway in the host will help limit or prevent P. gingivalis- induced tissue destruction. The specific hypothesis to be tested in this application is that P. gingivalis-modified JAK3 activation in innate immune cells directs negative regulation of inflammation and ultimately controls alveolar bone loss through dedicated downstream signaling pathways. We will challenge this hypothesis with three specific Aims: 1) To characterize JAK3 signaling pathways that control anti-inflammatory responses induced by P. gingivalis; 2) To functionally dissect P. gingivalis modification of JAK3 expression and activation
in innate immune cells; 3) To determine the effect of JAK3 inhibition in vivo on inflammatory responses and the disease process induced by P. gingivalis using a mouse chamber model and bone loss model. Successful completion of these studies will define for the first time the host anti-inflammatory responses to P. gingivalis that flow through JAK3. In addition this work will characterize an important but relatively understudied aspect of the overall host-P. gingivalis interaction and increase our understanding both of the role of JAK3 in innate immune cells and of anti-inflammatory mechanisms in general. This work could be translated into the identification of novel targets for therapeutic intervention designed to enhance anti-inflammatory signaling and prevent or limit tissue destruction. Such an approach has relevance both for periodontal disease and for chronic inflammatory conditions in general.

project_terms:
Adopted;Affect;Agonist;Alveolar Bone Loss;Anti-Inflammatory Agents;Anti-inflammatory;Autocrine Communication;Bacteria;Bacterial Infections;Bone Marrow;Cells;Chronic;Data;Disease;Equilibrium;Event;Family;Gingiva;Goals;Health;Homeostasis;Human;Immune;Immune response;Inflammation;Inflammatory;Inflammatory Response;Interleukin-10;Interleukin-4;JAK3 gene;Janus kinase;Knockout Mice;Mass Spectrum Analysis;Mediating;Microbe;Modeling;Modification;Mus;Natural Immunity;Neutrophil Infiltration;Organism;Pathway interactions;Pattern;Periodontal Diseases;Periodontitis;Periodontium;Phosphorylation;Phosphotransferases;Porphyromonas gingivalis;Process;Production;Protein Tyrosine Kinase;Proto-Oncogene Proteins c-akt;Reaction;Regulation;Role;Signal Pathway;Signal Transduction;Signaling Protein;Site-Directed Mutagenesis;Testing;Therapeutic Intervention;Time;Tissues;Translating;Work;bone loss;cytokine;design;in vivo;macrophage;member;microbial;microbial community;monocyte;novel;oral infection;pathogen;pathogenic bacteria;prevent;public health relevance;response;therapy design


application_id: 8814446
project_number: 1R21CA192003-01
project_title: Deciphering the pathogenesis of pediatric high-grade gliomas
administering_ic: NCI
award_notice_date: 2014-12-01
opportunity_number: PAR-13-146
application_type: 1
activity_code: R21
ic: CA
serial_number: 192003
program_official: OKANO, PAUL
project_start_date: 2014-12-01
project_end_date: 2015-07-31
study_section: Special Emphasis Panel[ZCA1 RPRB-C (O1)]
contact_pi_person_id: 7875365
contact_pi: LI, GUO-MIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
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 long-term goal of this project is to elucidate the molecular pathogenesis underlying pediatric high- grade gliomas (HGGs). Glioblastoma is the most common and lethal type of primary brain tumor in humans which accounts for 52% of all functional tissue brain tumor cases. Despite decades of concerted therapeutic efforts gliomas remain incurable. The major problem is that the real pathogenesis underlying this disease is essentially unknown. Recent studies have linked pediatric and young adult HGGs with mutations in SETD2 and Gly34Arg/Val (G34R/V) substitutions in histone H3.3 but the molecular mechanism(s) by which the altered SETD2 and H3.3 drive malignancy of pediatric and young adult HGGs are not elucidated. Because SETD2 encodes the only known methyltransferase specific for histone H3 lysine36 trimethylation (H3K36me3) and H3.3G34R/V mutations lead to significant decrease in H3K36me3 levels these observations have pointed the true culprit of pediatric and young adult HGGs to a mechanism that is regulated by H3K36me3. Strikingly we have recently shown that H3K36me3 is essential for a critical genome-maintenance system called DNA mismatch repair (MMR) by recruiting mismatch recognition protein hMutS? to chromatin through its direct interaction with hMutS? and that cells depleted of SETD2/H3K36me3 display a mutator phenotype usually seen in cells defective in MMR genes. We therefore hypothesize that abnormal SETD2 and H3.3 promote pediatric and young adult HGG tumorigenesis by inactivating the MMR function via blocking H3K36 trimethylation. To test this hypothesis two specific aims are proposed in this application. Specific Aim 1 is to directly determine H3K36me3 levels and mutator phenotype in pediatric HGGs with SETD2 or H3.3G34R/V mutations. Specific Aim 2 is to measure genomic instability and the dynamic interaction between H3K36me3 and hMutS? in glioma cell lines expressing G34R/V H3.3. A successful completion of the proposed study will reveal the real pathogenesis of pediatric HGGs providing a novel biomarker for cancer detection. More importantly since tumor cells defective in MMR are highly resistant to many chemotherapeutic drugs including temozolomide which is widely used for and causes resistance in glioma therapy this study will also offer new strategies to improve glioma therapy.

project_terms:
Accounting;Biological Assay;Biological Markers;Brain Neoplasms;Cancer Detection;Cell Line;Cells;Childhood;Chromatin;Co-Immunoprecipitations;DNA;DNA Sequence;Detection;Disease;Exhibits;Genes;Genome;Genomic Instability;Gerda brand of difluprednate;Glioblastoma;Glioma;Goals;Histone H3;Histone H3.3;Human;Immunofluorescence Immunologic;Immunohistochemistry;Lead;Link;Maintenance;Malignant - descriptor;Malignant Childhood Neoplasm;Measures;Methyltransferase;Microsatellite Instability;Mismatch Repair;Molecular;Mutation;Pathogenesis;Patients;Pharmaceutical Preparations;Phenotype;Primary Brain Neoplasms;Proteins;Recruitment Activity;Research;Resistance;System;Testing;Therapeutic;Tissues;Tumor Cell Line;genome sequencing;glioma cell line;improved;in vivo;neoplastic cell;novel;outcome forecast;public health relevance;research study;temozolomide;tumorigenesis;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Despite decades of concerted therapeutic efforts on glioblastoma (GBM) the most common and lethal type of primary brain tumor few GBM patients can achieve more than 2-year survival. A major reason is that the cause of the disease is unknown. This application aims to identify the pathogenesis of pediatric high-grade gliomas to improve GBM detection and treatment.


application_id: 8814389
project_number: 1R21CA178753-01A1
project_title: Epigenetic regulation of S100A4/Metastasin
administering_ic: NCI
award_notice_date: 2014-12-01
opportunity_number: PAR-13-146
application_type: 1
activity_code: R21
ic: CA
serial_number: 178753
suffix: A1
program_official: AULT, GRACE S
project_start_date: 2014-12-01
project_end_date: 2016-11-30
study_section: Special Emphasis Panel[ZCA1 SRB-1 (O1)]
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
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
project_abstract:
DESCRIPTION (provided by applicant): Epigenetic modulation of gene expression is an important mediator of cancer progression. It is well understood that tumor suppressors can be inactivated by the methylation of their promoters which can contribute to tumor progression. However select promoters of pro-invasive and pro-metastatic genes can be selectively demethylated and thus activated during tumor progression. S100A4 is one such gene that contributes to tumor metastasis in several cancer types and its expression is tightly controlled by promoter methylation. We have found that the integrin 64 can control S100A4 expression in breast cancer by stimulating the demethylation of the S100A4 promoter. Based on our preliminary data and supporting literature we propose a novel mechanism of producing sncRNAs through transcriptional regulation of antisense RNAs. We postulate that these sncRNAs are generated by double stranded RNAs created through hybridization of sense and antisense transcripts from a given promoter. In the case of the S100A4 promoter the region that governs the methylation status of the promoter is located in a non-coding alternatively spliced exon. Notably sncRNAs corresponding to this alternatively spliced exon of S100A4 are present in cells expressing high S100A4 but not in cells lacking S100A4 according to public databases. Furthermore we provide evidence that integrin 64 controls the expression of an antisense transcript to S100A4. We propose that these sncRNAs then direct methylcytosine modifying enzymes and DNA repair molecules to the site of specific DNA demethylation. Accordingly the central hypothesis of this application is that integrin 64 stimulates S100A4 promoter demethylation through non-coding RNA-guided modification of methylated cytosines and subsequent DNA mismatch repair. We will test our central hypothesis through completion of the following three aims: 1) Define how integrin 64 directs DNA demethylation of the S100A4 promoter through generation of antisense RNAs and sncRNAs 2) Determine the involvement of DNA repair in DNA demethylation of the S100A4 promoter which will aid us in defining the molecules that drive removal of repressive CpG methylation marks and 3) Define changes in DNA methylation caused by integrin 64 signaling on a genomic scale. If our model is proven largely correct it will represent a new paradigm of how integrins non-coding RNAs and RNA processing transmit oncogenic signals. Furthermore understanding how epigenetic modulation of an invasive and metastatic phenotype is controlled will give us the power to target it therapeutically.

project_terms:
Antisense RNA;Bioinformatics;Cells;Cleaved cell;Complementary DNA;Coupled;Cues;Cytosine;Cytosine deaminase;DNA;DNA Methylation;DNA Repair;DNA Repair Enzymes;DNA Repair Pathway;DNA glycosylase;Data;Databases;Dicer Pathway;Double-Stranded RNA;ECM receptor;Elements;Environment;Enzymes;Epigenetic Process;Event;Excision;Exons;Gene Expression;Gene Expression Profile;Generations;Genes;Genomics;Health;Integrins;Literature;Malignant Neoplasms;Mammalian Cell;Mediating;Mediator of activation protein;Methodology;Methylation;Mismatch Repair;Modeling;Modification;Nature;Neoplasm Metastasis;Oncogenic;Phenotype;Process;Promoter Regions (Genetics);Promotor (Genetics);Publishing;RNA Interference;RNA Processing;RNA Splicing;Reaction;Regulation;Reporting;Role;Signal Transduction;Site;Solid;Specificity;System;Testing;Thymidine;Transcript;Transcriptional Regulation;Tumor Suppressor Proteins;Untranslated RNA;Up-Regulation (Physiology);Variant;Work;Zebrafish;base;cancer type;demethylation;epigenetic regulation;epigenome;genome-wide;human DICER1 protein;inhibitor/antagonist;innovation;insight;malignant breast neoplasm;methylome;next generation sequencing;novel;receptor;transcription factor;tumor;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: In this study we will use the collective expertise of our team and take advantage of the recent progress in the field of DNA demethylation to understand how integrin 64 contributes to promoter demethylation of pro-invasive and pro-metastatic genes thus demonstrating how specificity of demethylation is achieved. Specifically we will determine how sncRNAs and the DNA repair pathway epigenetically control the S100A4 promoter and how these specific sncRNAs are generated. Ultimately if our model is proven largely correct it will uncover a new paradigm of how integrins non-coding RNAs and RNA processing transmit oncogenic signals that will give us the power to target these epigenetic events therapeutically.


application_id: 8813885
project_number: 1P20GM113226-01
project_title: Alterations and Renovations
administering_ic: NIGMS
award_notice_date: 2016-06-09
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZGM1 TWD-A (C1)]
subproject_number: 6177
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID W
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
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: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The administrative and many of the faculty offices and laboratories in the Department of Pharmacology andToxicology are housed on the 13th and 14th floors of the research tower located within a 10 min walk from theClinical and Translational Research Building where the COBRE is centered. Funds are requested forrenovation of the northeast quadrant of the 14th floor of the research tower. Few renovations to the originaloffice and laboratory space have been undertaken on the 14th floor since the research tower was constructedand occupied over 40 years ago. The northeast quadrant of the 14th floor consists of approximately 1300 sq.ft. of net usable space presently divided into 7 separate rooms ranging in size from about100 to 200 sq. ft.each. The space will be completely renovated to meet current standards for laboratory research including: 1)general demolition of existing casework & tops fittings floor tile fume hoods & ducts and lighting; 2) newmetal casework for utility fittings sinks faucets electrical outlets and fume hoods; and 3) architecturalmechanical plumbing and electrical aspects of the reconstruction. Similar renovations recently werecompleted on the sixth floor of the research tower and pictures are provided to illustrate comparisons of pre-renovated (14th floor) versus renovated space (6th floor) in the research tower (the 6th and 14th floors arenearly identical). The renovated space will result in a wet lab (871 sq. ft.) with two adjoining offices (120 sq. ft.each) and tissue culture rooms (96 sq. ft each). Additional adjoining space on the 14th floor also will beavailable for equipment microscopy cold rooms etc for which renovation costs will be funded from othersources. The renovated space is designed to accommodate two faculty members who will receive tenure trackappointments in the Department of Pharmacology and Toxicology following receipt of independent funding andtransition from COBRE funding. Their current space in the Clinical and Translational Research Building will inturn be reallocated to the replacement COBRE mentees. The overall strategy facilitates the expected growthof the COBRE program.

project_terms:
Appointment;Centers of Research Excellence;Chairperson;Clinical;Clinical Research;Duct (organ) structure;Equipment;Faculty;Floor;Funding;Growth;Health Sciences;Housing;Laboratories;Laboratory Research;Lighting;Mechanics;Mentors;Metals;Microscopy;Pharmacology and Toxicology;Plumbing;Positioning Attribute;Principal Investigator;Request for Proposals;Research;Running;Services;Source;Toxicology;Translational Research;Walking;career development;cost;design;improved;meetings;member;programs;reconstruction;square foot;success;tenure track;tissue culture


application_id: 8813884
project_number: 1P20GM113226-01
project_title: Effects of Dietary Fat on the Hepatotoxicity of Environmental Arsenic
administering_ic: NIGMS
award_notice_date: 2016-06-09
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZGM1 TWD-A (C1)]
subproject_number: 6176
contact_pi_person_id: 1902836
contact_pi: WATSON, WALTER H
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
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: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acetylation;Adult;Affect;American;Animal Model;Arginine;Arsenic;Arsenites;Benign;Binding;Cells;Centers of Research Excellence;ChIP-seq;Chemicals;Cirrhosis;Clinical;Consumption;Cysteine;DNA;DNA Binding;DNA Binding Domain;Diet;Dietary Fats;Disease;Disease Progression;Disease model;Environment;Etiology;FDA approved;Fatty Liver;Fatty acid glycerol esters;Fibrosis;Gene Expression;Genes;Genetic;Hepatic;Hepatotoxicity;High Fat Diet;In Vitro;Incubated;Individual;Inflammation;Inflammatory;Injury;Knowledge;Liver;Liver diseases;Lysine;Mediating;Methylation;Modeling;Modification;Mus;Obesity;Pathway interactions;Play;Population;Post-Translational Protein Processing;Process;Proteins;Proteomics;Request for Proposals;Response Elements;Risk Factors;Role;Signal Pathway;Staging;Steatohepatitis;Techniques;Testing;Tissues;Toxic effect;Toxicology;Transactivation;Translating;United States;Zinc;Zinc Fingers;cell injury;contaminated drinking water;drinking water;feeding;follow-up;genetic regulatory protein;innovation;lipid metabolism;liver injury;non-alcoholic fatty liver;novel;oxidation;promoter;research study;response;saturated fat;transcription factor;transcriptome sequencing


application_id: 8813883
project_number: 1P20GM113226-01
project_title: Mechanisms of Probiotics in Alcoholic Liver Disease
administering_ic: NIGMS
award_notice_date: 2016-06-09
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZGM1 TWD-A (C1)]
subproject_number: 6175
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
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: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Alcohol abuse;Alcohol consumption;Alcohol-Induced Disorders;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Attenuated;Bacteria;Bacterial Translocation;Biological Assay;Butyrates;Butyric Acids;Carbohydrates;Cell Culture Techniques;Cell Line;Centers of Research Excellence;Chronic;Cirrhosis;Data;Development;Disease Progression;Endotoxins;Enzymes;Epithelial;Epithelial Cells;Experimental Models;Fatty Liver;Functional disorder;Future;Goals;Goblet Cells;Health;Histology;Histones;Homeostasis;Human;Hypoxia Inducible Factor;Immune response;Inflammation;Injury;Intervention;Intestinal Diseases;Intestines;Knockout Mice;Laboratories;Lactobacillus casei rhamnosus;Life;Link;Liver;Liver diseases;Mediating;Metagenomics;Morbidity - disease rate;Mucous body substance;Mus;Oral Administration;Patients;Permeability;Pilot Projects;Plasma;Play;Prevention;Probiotics;Process;Production;Proteins;Proteomics;Recombinants;Regulation;Reporting;Request for Proposals;Rodent;Role;Sampling;Supplementation;Testing;Therapeutic;Tight Junctions;Toxicology;Volatile Fatty Acids;Work;alcohol exposure;bacterial metabolism;base;cathelicidin antimicrobial peptide;comparative efficacy;feeding;gastrointestinal epithelium;gut microbiota;improved;in vivo;lipid metabolism;liver inflammation;liver injury;metabolomics;mortality;mouse model;novel therapeutic intervention;occludin;prevent;protective effect;repaired;research study;transcription factor;trefoil factor


application_id: 8813882
project_number: 1P20GM113226-01
project_title: High fat diet induced hepatocyte exosomes-promoted hepatic inflammation and tumorigenesis
administering_ic: NIGMS
award_notice_date: 2016-06-09
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZGM1 TWD-A (C1)]
subproject_number: 6174
contact_pi_person_id: 11629370
contact_pi: DENG, ZHONG-BIN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
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: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acceleration;Address;Anti-Inflammatory Agents;Binding Sites;C57BL/6 Mouse;COPS5 gene;Cells;Centers of Research Excellence;Chemoprevention;Chronic;Curcumin;Data;Development;Diet;Diethylnitrosamine;Disease;Elements;Enzymes;Equilibrium;Fatty acid glycerol esters;Fruit;Goals;Growth;Hepatic;Hepatocyte;High Fat Diet;Human;ITGAM gene;Immunosuppressive Agents;In Vitro;Individual;Inflammation;Inflammatory;Inflammatory Response;Lead;Link;Liver;Liver Extract;Liver neoplasms;MAPK3 gene;Malignant Neoplasms;Malignant neoplasm of liver;Mediating;Membrane;Modeling;Molecular Target;Mus;Mutation;Myelogenous;Myeloid Cells;Natural Killer Cells;Natural immunosuppression;Obese Mice;Obesity;Pathway interactions;Phosphorylation Site;Phosphotransferases;Play;Prevention;Process;Production;Property;Request for Proposals;Role;Safety;Signal Pathway;Signal Transduction;Site;Small Interfering RNA;T-Lymphocyte;Technology;Testing;Toxicology;Vesicle;base;cancer therapy;cell growth;chemotherapy;clinically relevant;cytokine;exosome;feeding;in vitro testing;in vivo;knock-down;macrophage;mouse model;nanoparticle;neoplastic cell;novel;peripheral blood;prevent;response;tumor;tumor growth;tumor progression;tumorigenesis


application_id: 8813881
project_number: 1P20GM113226-01
project_title: Pathogenic role of PDE4 in hepatic stellate cell activation and TGF signaling
administering_ic: NIGMS
award_notice_date: 2016-06-09
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZGM1 TWD-A (C1)]
subproject_number: 6173
contact_pi_person_id: 11058066
contact_pi: GOBEJISHVILI, LEILA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
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: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Attenuated;Cells;Centers of Research Excellence;Cirrhosis;Collagen;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;DNA Modification Process;Development;Enzymes;Epigenetic Process;Etiology;FDA approved;Family;Fibrosis;Funding;Genes;Hepatic Stellate Cell;Hepatocyte;In Vitro;Inflammation;Injury;Knockout Mice;Liver Fibrosis;Mass Spectrum Analysis;Mediating;Modeling;Modification;Myofibroblast;PDE4B;Peroxisome Proliferator-Activated Receptors;Phenotype;Phosphorylation;Play;Post-Translational Protein Processing;Prevention strategy;Primary carcinoma of the liver cells;Process;Promoter Regions;Protein Isoforms;Proteins;Proteomics;Rattus;Regulation;Request for Proposals;Role;Rolipram;Second Messenger Systems;Signal Transduction;Therapeutic;Toxicology;Transcriptional Activation;Wound Healing;base;cell transformation;cytokine;experimental analysis;histone modification;in vivo;inhibitor/antagonist;liver injury;member;phosphodiesterase IV;promoter;second messenger;translational study


application_id: 8813880
project_number: 1P20GM113226-01
project_title: Role of oxidized linoleic acid metabolites in the pathogenesis of alcoholic liver disease
administering_ic: NIGMS
award_notice_date: 2016-06-09
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZGM1 TWD-A (C1)]
subproject_number: 6172
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA A.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
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: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Arachidonate 15-Lipoxygenase;Attenuated;Cations;Centers of Research Excellence;Cessation of life;Chronic;Data;Development;Diet;Dietary Intervention;Enzymes;Experimental Animal Model;FDA approved;Fatty Liver;Heavy Drinking;Hepatic;Hepatocyte;Human;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Interleukin-1;Interleukin-18;Intestines;Knockout Mice;Kupffer Cells;Laboratories;Lead;Ligands;Linoleic Acids;Liver;Mediating;Molecular;Morbidity - disease rate;Mus;Pathogenesis;Pathway interactions;Patients;Permeability;Plasma;Play;Production;Publishing;Request for Proposals;Role;Signal Pathway;Signal Transduction;Staging;Testing;Toxicology;Translating;Unsaturated Fats;Up-Regulation;Vanilloid;Whole Blood;base;cytokine;human study;in vitro testing;in vivo;knockout animal;liver inflammation;liver injury;macrophage;mitochondrial dysfunction;monocyte;mortality;mouse model;new therapeutic target;octadecadienoic acid;oxidation;peripheral blood;receptor;stressor;therapeutic target


application_id: 8813879
project_number: 1P20GM113226-01
project_title: ANIMAL MODEL AND BIOREPOSITORY CORE
administering_ic: NIGMS
award_notice_date: 2016-06-09
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZGM1 TWD-A (C1)]
subproject_number: 6171
contact_pi_person_id: 2047731
contact_pi: ARTEEL, GAVIN E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
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: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Animal Husbandry;Animal Model;Animals;Attention;Autopsy;Basic Science;Biological Assay;Cataloging;Catalogs;Centers of Research Excellence;Characteristics;Clinical;Data;Data Analyses;Development;Endothelial Cells;Ensure;Equipment;Fee-for-Service Plans;Fostering;Future;Goals;Hepatic;Hepatocyte;Human;Human Resources;In Vitro;Individual;Institution;Libraries;Liver;Liver diseases;Maintenance;Measurement;Measures;Methods;Mission;Modeling;Operative Surgical Procedures;Phenotype;Physiology;Procedures;Protocols documentation;Request for Proposals;Research;Research Activity;Research Infrastructure;Research Personnel;Resolution;Resources;Sampling;Services;Techniques;Tissue Banks;Tissues;Toxicology;Training;Training and Education;Translational Research;Translations;Work;base;biobank;career;career development;design;experience;flexibility;interest;investigator training;liver injury;meetings;member;mouse model;operation;research study;success


application_id: 8813878
project_number: 1P20GM113226-01
project_title: ANALYTICAL CORE
administering_ic: NIGMS
award_notice_date: 2016-06-09
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZGM1 TWD-A (C1)]
subproject_number: 6170
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
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: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Area;Attention;Award;Bioenergetics;Biological;Biological Assay;Cells;Centers of Research Excellence;Clinical Research;Communities;Continuing Education;Core Facility;Core Grant;Data Analyses;Detection;Development;Drug Interactions;Ensure;Environment;Equipment;Evaluation;Extramural Activities;Faculty;Fee-for-Service Plans;Fostering;Funding;Future;Genus Hippocampus;Glutathione;Goals;HIV;High Pressure Liquid Chromatography;In Vitro;Individual;Institution;Journals;Kentucky;Laboratories;Liver;Liver diseases;Measurement;Measures;Metabolism;Microscope;Mission;Molecular;Molecular Target;Performance;Phase;Play;Population;Proteins;Protocols documentation;Reader;Reagent;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Role;Running;S-Adenosylmethionine;Sampling;Services;Signal Pathway;Specimen;System;Techniques;Technology;Time;Tissues;Toxicology;Training and Education;Translational Research;United States National Institutes of Health;Universities;Whole Organism;base;career development;complex biological systems;cytokine;design;experience;extracellular;innovation;instrumentation;interest;investigator training;liver injury;meetings;member;metabolic abnormality assessment;multidisciplinary;novel;programs;protocol development;research facility;research study;screening;success;time use;toxicant


application_id: 8813877
project_number: 1P20GM113226-01
project_title: OMICS CORE
administering_ic: NIGMS
award_notice_date: 2016-06-09
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZGM1 TWD-A (C1)]
subproject_number: 6169
contact_pi_person_id: 8487327
contact_pi: ZHANG, XIANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
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: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Ablation;Acetylation;Affinity;Alcohols;Arsenic;Binding;Bioinformatics;Biological;Blood;Centers of Research Excellence;Chemicals;Complex Mixtures;Curcumin;Cysteine;DNA Binding Domain;Diet;Drug Interactions;Environment;Ethanol;Event;Feces;Gas Chromatography;Gel;Goals;Hepatic;Hepatic Stellate Cell;High Fat Diet;Immunoprecipitation;Inductively Coupled Plasma Mass Spectrometry;Inflammation;Injury;Intestines;Iodoacetamide;Iodoacetic Acid;Ions;Label;Lactobacillus casei rhamnosus;Large Intestine;Lasers;Linoleic Acids;Liquid Chromatography;Liver;Liver diseases;Mass Spectrum Analysis;Measurement;Measures;Mediating;Metals;Methods;Methylation;Mus;Pathology;Phenotype;Phosphopeptides;Phosphorylation;Plasma;Post-Translational Protein Processing;Production;Protein Fragment;Protein Isoforms;Proteins;Proteomics;Recombinant Proteins;Regulation;Request for Proposals;Research;Resolution;Role;Sampling;Science;Site;Small Intestines;Stable Isotope Labeling;Steatohepatitis;Techniques;Technology;Time;Tissue Sample;Tissues;Toxicology;Toxin;Unsaturated Fatty Acids;Urine;Volatile Fatty Acids;Zinc;exosome;feeding;liquid chromatography mass spectrometry;liver inflammation;liver injury;mass spectrometer;meetings;metabolomics;non-alcoholic fatty liver;novel;nutrition;oxidation;phosphodiesterase IV;protein complex;protein metabolite;recombinant peptide;research study;response;transcription factor;tumor growth;two-dimensional;zinc-binding protein


application_id: 8813876
project_number: 1P20GM113226-01
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2016-06-09
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZGM1 TWD-A (C1)]
subproject_number: 6168
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
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: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adult;Affect;Alcoholic Liver Diseases;Alcohols;Area;Basic Science;Bioinformatics;Budgets;Centers of Research Excellence;Child;Cirrhosis;Clinical;Clinical Trials;Communities;Community Outreach;Complex;Conflict (Psychology);Country;Development;Diabetes Mellitus;Disease;Doctor of Philosophy;Drug Delivery Systems;Drug Interactions;Ensure;Environment;Environmental Health;Extramural Activities;Faculty;Funding;Grant;Health;Healthcare;Hepatitis B;Hepatitis C;Hepatology;Individual;Industry;Intellectual Property;Kansas;Kentucky;Leadership;Left;Link;Liver;Liver Failure;Liver diseases;Malignant Neoplasms;Malignant neoplasm of liver;Marketing;Mentors;Metabolic syndrome;Metabolism;Names;National Institute of Environmental Health Sciences;National Institute on Alcohol Abuse and Alcoholism;Nuclear Receptors;Obesity;Organ;Overweight;Pharmaceutical Preparations;Pharmacology and Toxicology;Population;Positioning Attribute;Primary carcinoma of the liver cells;Process;Public Health;Qualifying;Recruitment Activity;Request for Proposals;Research;Research Infrastructure;Research Personnel;Research Training;Retirement;Rural;Signal Recognition Particle;Structure;Superfund;Teacher Professional Development;Toxic Environmental Substances;Toxicology;Training;United States National Institutes of Health;Universities;Work;drinking;drug development;drug metabolism;faculty mentor;improved;liver injury;liver metabolism;liver transplantation;multidisciplinary;non-alcoholic fatty liver;nonalcoholic steatohepatitis;novel therapeutics;personalized medicine;problem drinker;programs;ranpirnase;senior faculty;toxicant


application_id: 8813875
project_number: 1P20GM113226-01
project_title: Hepatobiology and Toxicology COBRE
administering_ic: NIGMS
award_notice_date: 2016-06-09
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 113226
program_official: GOROSPE, RAFAEL
project_start_date: 2016-06-10
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZGM1 TWD-A (C1)]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
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:
DESCRIPTION (provided by applicant): The University of Louisville (UofL) Hepatobiology and Toxicology COBRE is a unique thematic research center. The UofL COBRE scientists comprise a multidisciplinary group senior mentors and junior investigators focusing on the mechanisms and therapy for liver injury nutrition and gut:liver interactions and liver:environment/toxin/dru interactions. The liver is the largest internal organ in the body and is possibly the most complex
organ in terms of metabolism. Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) is the most common liver disease affecting about 1/3 of adults and over 10% of children in the US. NAFLD arises most commonly among overweight/obese individuals and is highly linked to the Metabolic Syndrome. Alcoholic Liver Disease (ALD) remains a common problem among those who drink. Environmental Toxicant Induced Liver Injury is an increasingly recognized problem and Louisville has been a leader in this area. Hepatitis B and C remain important causes of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Personalized Medicine is an increasingly important factor in medication efficacy. Drug-Induced Liver Injury (DILI) is the most common reason drugs are removed from the market and an important cause of liver failure. This COBRE brings together experienced senior mentors and promising junior investigators from across UofL in collaboration with scientists across the U.S./World to perform cross-cutting research on the unique topics of Hepatobiology and Toxicology. The Specific Aims of the Hepatobiology and Toxicology COBRE are to: 1. Develop a thematically-focused program in Hepatobiology and Toxicology that strengthens the overall research infrastructure at UofL. 2. Create a multidisciplinary program in research education mentoring and career development in Hepatobiology and Toxicology. 3. Provide the necessary research resources and translational science/basic technologies to support and sustain state-of-the-art research in Hepatobiology and Toxicology. 4. Discover new mechanisms/molecular targets and effective means for preventing and/or treating liver diseases/toxicant exposures and communicate our findings to the public.

project_terms:
Acute Liver Failure;Address;Adult;Affect;Alcohol-Induced Disorders;Alcoholic Liver Diseases;Alcohols;American;Area;Back;Blood Circulation;Carbohydrates;Centers of Research Excellence;Child;Cirrhosis;Collaborations;Communities;Complex;Core Facility;County;Data Analyses;Development;Diabetes Mellitus;Drug Interactions;Endotoxins;Environment;Enzymes;Evaluation;FDA approved;Fatty acid glycerol esters;Fostering;Goals;Health;Hepatitis B;Hepatitis C;Hepatitis C virus;Hepatotoxicity;Home environment;Immune Tolerance;Individual;Industry;Kentucky;Link;Liver;Liver Failure;Liver diseases;Marketing;Medical History;Mentors;Metabolic syndrome;Metabolism;Micronutrients;Molecular Target;Monitor;National Institute on Alcohol Abuse and Alcoholism;Neighborhoods;Obesity;Organ;Overweight;Patients;Pharmaceutical Preparations;Pharmacotherapy;Play;Prevention;Primary carcinoma of the liver cells;Process;Production;Proteins;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Role;Scientist;Site;Specimen;Strategic Planning;Structure;Technology;Toxic Environmental Substances;Toxicant exposure;Toxicology;Toxin;Translational Research;United States National Institutes of Health;Universities;biobank;career development;drinking;education research;experience;liver injury;liver transplantation;medical complication;multidisciplinary;non-alcoholic fatty liver;nonalcoholic steatohepatitis;novel;novel therapeutics;nutrition;personalized medicine;prevent;programs;public health relevance;toxicant


application_id: 8813782
project_number: 1R21CA191683-01
project_title: CCR2 mediated inflammation and gut microbiota in promoting intestinal cancer
administering_ic: NCI
award_notice_date: 2014-12-24
opportunity_number: PAR-13-146
application_type: 1
activity_code: R21
ic: CA
serial_number: 191683
program_official: DASCHNER, PHILLIP J
project_start_date: 2015-01-01
project_end_date: 2016-12-31
study_section: Special Emphasis Panel[ZCA1 RTRB-Z (O1)]
contact_pi_person_id: 9246960
contact_pi: JALA, VENKATAKRISHNA RAO
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
project_abstract:
DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is strongly associated with inflammation accompanied by increased infiltration of leukocytes. CCR2 a seven transmembrane G-protein coupled chemokine receptor mediates several biological functions including chemotaxis of leukocytes upon binding to its ligand CCL2 (MCP1). CCR2 is expressed on peripheral blood monocytes/macrophages as well as on activated T-cells B-cells immature dendritic cells and mast cells. Elevated expression of CCL2 in tumor cells is very well correlated with increased metastasis and poor prognosis in several types of human cancers. Recently it was shown in animal models that CCL2-CCR2 axis play an important role in promotion of colon tumorigenesis. Our preliminary data showed that CCR2-/- mice in the ApcMin/+ (a spontaneous intestinal cancer mouse model) background developed significantly fewer and smaller size small intestinal and colon tumors and showed substantial survival advantage compared to ApcMin/+ mice. Further polyps in CCR2-/-ApcMin/+ displayed decreased tumor infiltrating F4/80+ cells decreased inflammatory molecules (e.g. IL-1 SOCS1) increased apoptosis and CD8 levels compared to ApcMin/+ mice. Interestingly inflammatory cytokines IL-23 and IL-17 were significantly reduced in CCR2-/-ApcMin/+. Our gut microbiota analysis revealed that tumor promoting Bacteroides genus are significantly reduced in CCR2-/-ApcMin/+ mice compared to ApcMin/+ mice.  Based on these preliminary data we hypothesize that CCR2/CCL2 mediated recruitment of tumor associated macrophages (TAMs) and Th17 cells modulate inflammation and microbiota in the tumor microenvironment to promote intestinal tumors and blocking CCR2-CCL2 axis would reduce the tumor burden. To test this hypothesis we propose two specific aims. In AIM 1 we will determine the requirement of CCR2 for recruitment and activation of IL-23 (TAMs DCs) and IL-17 (Th17  T-cells) producing cells during intestinal tumorigenesis. In AIM 2 we will determine the influence of gut microflora on CCR2 dependent production of IL-23 and IL-17 to promote intestinal tumorigenesis. The current proposal will also examine the efficacy of existing CCR2 inhibitors in colon cancer progression to translate our basic observation in pre-clinical models. Determining the molecular cellular mechanisms and complex inter-relationship between immune system-microbiota in the context of cancer will have a strong impact on our basic understanding of intestinal carcinogenesis as well as potential for developing novel therapeutic strategies.

project_terms:
Adoptive Transfer;Animal Model;Antibiotics;ApcMin/+ mice;Apoptosis;B-Lymphocytes;Bacteria;Bacteroides;Bacteroides fragilis;Binding (Molecular Function);Biological Process;CCL2 gene;CD4 Positive T Lymphocytes;CD8B1 gene;Cancer Etiology;Cells;Cessation of life;Chemotaxis;Colitis;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Complex;Coupled;Data;Dendritic Cells;Development;Epithelial;Epithelial Cells;Equilibrium;Event;Family;Figs - dietary;GTP-Binding Proteins;Genes;Genetic;Granzyme;Human;IL8 gene;Immune;Immune system;Individual;Infiltration;Inflammation;Inflammatory;Interferon Type II;Interleukin-17;Interleukin-6;Intestinal Cancer;Intestinal Neoplasms;Intestines;Lactobacillus acidophilus;Lamina Propria;Leukocyte Chemotaxis;Leukocytes;Ligands;Link;Lymphoid Cell;Malignant Neoplasms;Mediating;Methods;Modeling;Molecular;Monocyte Chemoattractant Proteins;Mus;Mutation;Myeloid Cells;NF-kappa B;Neoplasm Metastasis;Pathway interactions;Play;Polyps;Pre-Clinical Model;Probiotics;Process;Production;Recruitment Activity;Role;STAT3 gene;Signal Transduction;Spleen;T-Cell Proliferation;T-Lymphocyte;TNF gene;Testing;Translating;Transplantation;Tumor Burden;base;carcinogenesis;cell motility;chemokine;chemokine receptor;colon tumorigenesis;commensal microbes;cytokine;design;gut microbiota;gut microflora;inhibitor/antagonist;interleukin-23;macrophage;mast cell;monocyte;mouse model;neoplastic cell;next generation sequencing;novel therapeutic intervention;novel therapeutics;outcome forecast;peripheral blood;proxigermanium;public health relevance;research study;response;seven-transmembrane G-protein-coupled receptor;small molecule;transcription factor;tumor;tumor microenvironment;tumor progression;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Monocyte chemoattractant protein (MCP1/CCL2) is a classic chemokine that mediates its directed cell migration via CCR2. Our data suggested that deficiency of CCR2 reduced the progression of spontaneous intestinal tumors and increased survival in the context of Min mutation in the Apc gene. This proposal investigates role of CCL2-CCR2 axis in balancing the inter-relationship between immune system and microbiota in colon tumorigenesis and successful completion of this project would provide new level of understanding to design potential novel therapeutic approaches for the treatment of colon cancer.


application_id: 8813575
project_number: 5R01EY012716-16
project_title: Functional State of Developing Retinogeniculate Synapse
administering_ic: NEI
award_notice_date: 2015-02-27
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: EY
serial_number: 012716
program_official: GREENWELL, THOMAS
project_start_date: 2001-05-01
project_end_date: 2016-02-29
study_section: Special Emphasis Panel[ZRG1-IFCN-Q(02)M]
contact_pi_person_id: 1864719
contact_pi: GUIDO, WILLIAM
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
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:
DESCRIPTION (provided by applicant): We have developed a powerful mouse model to study visual circuit development in the dorsal lateral geniculate nucleus (dLGN) the thalamic relay of retinal information to the visual cortex. To date studies have focused largely on the retinogeniculate pathway and the refinement of connections between retinal ganglion cells and dLGN neurons. While many of the changes in retinogeniculate axon patterning and connectivity have been delineated information about two fundamental aspects of organization is still lacking. One relates to the cell- class specificity of connections between RGCs and dLGN cells and the other pertains to the source of connections to dLGN cells namely the wealth of input that arises from nonretinal projections. Both aspects are critical for a contemporary understanding of thalamic function which is to provide a faithful relay of retinal signals but at the same time to modulate the gain of transmission based on changes in behavioral state. The goals of this proposal are to assess how retinogeniculate refinement relates to class specific connections whether retinogeniculate refinement proceeds in a way that establishes separable parallel visual channels to determine when nonretinal projections develop in dLGN and to assess how such input coordinates with the innervation and refinement of the retinogeniculate pathway. To address these issues we will conduct anatomical electrophysiological and optogenetic experiments in transgenic mice that allow for the visualization and experimental isolation of specific cell types arising from the retina or from such nonretinal sources as layer VI of visual cortex the thalamic reticular nucleus and cholinergic nuclei of the brainstem. These studies willprovide valuable information about how the developing brain forms precise patterns of connections and offer further insight into the study and treatment of developmental and neurological disorders that result from the formation of abnormal patterns of connectivity.

project_terms:
3-Dimensional;Address;Adopted;Age;Architecture;Axon;Behavioral;Biological Models;Brain;Brain Stem;Cell Nucleus;Cells;Cholera Toxin Protomer B;Deafferentation procedure;Development;Disease;Dorsal;Event;Exhibits;Eye;Felis catus;Genetic;Goals;Health;Imagery;In Vitro;Injection of therapeutic agent;Injury;Interneurons;Knowledge;Label;Lateral Geniculate Body;Life;Light;Mus;Neurons;Optic Nerve;Pathway interactions;Pattern;Preparation;Retina;Retinal;Retinal Ganglion Cells;Rhodopsin;Signal Transduction;Slice;Source;Specificity;Synapses;Testing;Thalamic structure;Time;Transgenic Mice;Transgenic Organisms;Trees;Variant;Viral;Visual;Visual Cortex;base;biocytin;cell type;cholinergic;developmental disease/disorder;insight;loss of function;monocular;mouse model;mutant;nerve supply;nervous system disorder;optogenetics;postnatal;preference;reconstruction;research study;response;retinal axon;retinal progenitor cell;retinogeniculate;synaptogenesis;transcription factor;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE: These studies will provide valuable information about how the developing brain forms precise patterns of connections and offer further insight into the study and treatment of developmental and neurological disorders that result from the formation of abnormal patterns of connectivity. Knowledge gained from these studies will also have important implications for understanding and predicting how thalamic circuits involving retinal and nonretinal projections respond to disease or injury.


application_id: 8812803
project_number: 5R01DK093496-04
project_title: MIF: a pro-inflammatory cytokine as a novel target to reduce bladder inflammation
administering_ic: NIDDK
award_notice_date: 2015-03-04
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: DK
serial_number: 093496
program_official: KIRKALI, ZIYA
project_start_date: 2012-04-01
project_end_date: 2016-03-31
study_section: Urologic and Kidney Development and Genitourinary Diseases Study Section[UKGD]
contact_pi_person_id: 8093598
contact_pi: VERA, PEDRO L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078344581
primary_uei: JCSKALYM8HU6
duns_number: 078344581
uei: JCSKALYM8HU6
fips: US
organization_id: 10030991
organization_name: LEXINGTON BIOMEDICAL RESEARCH INSTITUTE
organization_city: LEXINGTON
organization_state: KY
organization_type: Research Institutes
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Experimental evidence supports the pro-inflammatory effect of Macrophage Migration Inhibitory Factor (MIF) in bladder inflammation but how MIF mediates bladder inflammation is poorly understood. The long-term goal is to understand the mechanisms of MIF-mediated bladder inflammation with the aim of altering these processes to reduce or abolish bladder inflammation in patients with chronic painful conditions of the lower urinary tract. The overall objective of this proposal is to determine the contribution of specific urothelial receptors to MIF release and to MIF-mediated signaling and bladder inflammation. The central hypothesis is that there are two components to inflammation involving MIF: 1) increased release of MIF; and 2) upregulation of MIF receptors and subsequent increased signaling via MIF/receptor interactions that enhances and/or maintains inflammation. This hypothesis has been formulated based on preliminary data generated in the applicants' laboratory. The rationale for propos- ing these studies is that by increasing our understanding of signaling events both upstream and downstream of MIF in the bladder will identify potential therapeutic targets.  The hypothesis will be tested by the following specific aims: 1) Determine the contribution of urothelial Protease Activated Receptors (PAR) to a novel mechanism of urothelial MIF release: Agonists with specificity for different PAR receptors will be used to induce MIF release from urothelial cells (both human in vitro and in vivo using mice) to determine which receptors are involved in MIF release. To determine the contribution of MIF to PAR-mediated bladder inflammation in vivo bladder inflammation will be induced in mice by instilling specific PAR agonists while simultaneously antagonizing MIF. Physiological histological and molecular changes in the bladder will be measured. 2) Identify the contribution of urothelial MIF receptors (CD74; CXCR4) to MIF signaling and cystitis: MIF receptor blockade will be used to examine changes in MIF-mediated signaling during a well-established model of cystitis (cyclophosphamide) in mice. These experiments will also determine the effect of MIF receptor blockade on mediating cystitis by measuring physiological histological and molecular changes in the bladder. 3) Determine MIF and MIF receptor levels in clinical conditions with bladder inflammation: Urinary MIF levels will be determined in UTI radiation cystitis and PBS/IC (Hunner ulcer vs non-Hunner ulcer) patients. MIF CD74 and CXCR4 urothelial immunostaining will be examined in PBS/IC (Hunner ulcer vs non-Hunner ulcer) and MIF-mediated cytokine production in human detrusor smooth muscle cells from PBS/IC patients will be examined.  This proposal is innovative because it focuses on MIF a novel mediator of bladder inflammation. The pro- posed research is significant because a greater understanding of the mechanisms of MIF release during bladder inflammation and of the signaling pathways activated by MIF binding to urothelial MIF receptors is expected to result in the identification of novel therapeutic targets for inflammatory conditions of the lower urinary tract.

project_terms:
Acute;Agonist;Binding (Molecular Function);Biology;Bladder;Bladder Tissue;CXCR4 gene;Chronic;Clinical;Complex;Cyclophosphamide;Cystitis;Data;Development;Disease;Etiology;Event;F2R gene;Goals;Human;In Vitro;In-Migration;Inflammation;Inflammation Mediators;Inflammatory;Interstitial Cystitis;Knock-out;Laboratories;Lesion;Link;Lower urinary tract;Maintenance;Measures;Mediating;Mediator of activation protein;Migration Inhibitory Factor;Modeling;Molecular;Mus;Outcome;PAWR gene;Pain;Patients;Phosphotransferases;Physiological;Play;Process;Production;Proteinase-Activated Receptors;Quality of life;Radiation;Recurrence;Regulation;Research;Role;Signal Pathway;Signal Transduction;Smooth Muscle Myocytes;Specificity;Spinal cord injury;System;Testing;Tetracyclines;Therapeutic;Therapeutic Intervention;Thrombin;Transgenic Mice;Ulcer;Up-Regulation (Physiology);Urinary tract infection;Urination;Urine;Urothelial Cell;Urothelium;Work;base;chronic pain;cytokine;in vivo;innovation;insight;new therapeutic target;novel;novel strategies;phenylpyruvate tautomerase;prevent;receptor;research study;therapeutic development;therapeutic target;urinary

public_health_relevance:
Inflammation of the lower urinary tract occurs in several diseases including urinary tract infections radiation cystitis and chronic painful conditions such as Painful Bladder Syndrome/Interstitial Cystitis. This proposal will examine Macrophage Migration Inhibitory Factor a novel regulator of bladder inflammation and will describe new potential targets to decrease or abolish bladder inflammation. Research into the mechanisms of bladder inflammation will provide new information that may benefit a large group of patients suffering from this condition and may suggest potential targets for ameliorating this disease.


application_id: 8812760
project_number: 5R01AA015407-11
project_title: GSK3beta a mediator of ethanol neurotoxicity
administering_ic: NIAAA
award_notice_date: 2015-02-16
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AA
serial_number: 015407
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2005-08-01
project_end_date: 2016-07-31
study_section: Special Emphasis Panel[ZRG1-IFCN-C(02)M]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: SHI, XIANGLIN
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
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):  Alcohol is a neuroteratogen; alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD) among which fetal alcohol syndrome (FAS) is the most severe form. The depletion of neurons in the developing CNS is the most deteriorating effect of ethanol. The loss of CNS neurons may underlie many of the behavioral deficits observed in FASD. Glycogen synthase kinase 3 (GSK3) a serine/threonine kinase is an important mediator of neuron degeneration. We have demonstrated that ethanol activates GSK3 and the activation of GSK3 leads to neuronal death. Oxidative stress is also considered an important contributor to ethanol-induced neurotoxicity. We have purified a potent antioxidant from blackberries cyanidin-3-glucoside (C3G). Our study indicates that C3G inhibits GSK3 activity and alleviates oxidative stress in cultured neuronal cells. In addition C3G protects neuronal cells against ethanol-induced cell death. C3G-mediated neuroprotection is much more potent than other antioxidants and GSK3 inhibitors. C3G can cross the blood brain barrier (BBB) and distribute in the brain. C3G diminishes ethanol-induced activation of caspase-3 and Bax in the developing brain. Pharmacologically relevant concentrations of C3G are achievable through oral administration or intravenous (iv) injection in animals and no adverse effect is observed. These findings suggest that C3G is a promising neuroprotective agent that may ameliorate/prevent ethanol-induced neuronal damage. We hypothesize that C3G's potent protection against ethanol-induced neuronal loss is mediated by the combined action of its antioxidant property and inhibition of pro-apoptotic signaling GSK3/Bax pathways. To test the hypothesis we will (1) investigate the antioxidant property of C3G and its metabolites and their effects on GSK3 activity; (2) determine whether C3G protection against ethanol- induced neuronal loss is mediated by the combined action of its antioxidant property and the inhibition of GSK3; (3) determine whether C3G ameliorates ethanol-induced behavioral deficits.  C3G is a potent natural antioxidant and has diverse potential benefits for human health. It is a promising neuroprotective agent against ethanol toxicity due to its dual functions as an antioxidant and a GSK3 inhibitor. As a unit the proposed experiments will elucidate the novel role of C3G and provide an important basis for future clinical trials to evaluate the feasibility of C3G to treat ethanol neurotoxicity. Our study will potentially offer a new therapeutic strategy.

project_terms:
Acids;Acute;Adverse effects;Alcohol-Induced Disorders;Alcohol-Induced Neurotoxicity;Alcohols;Animals;Anthocyanins;Antioxidants;Apoptotic;Behavior;Behavioral;Blood - brain barrier anatomy;Brain;C57BL/6 Mouse;Cell Death;Cells;Cerebellum;Cerebral cortex;Cessation of life;Clinical Trials;Drug Kinetics;Electron Spin Resonance Spectroscopy;Episodic memory;Equilibrium;Ethanol;Ethanol toxicity;Exposure to;Family;Fetal Alcohol Spectrum Disorder;Fetal Alcohol Syndrome;Funding;Future;Generations;Glucosides;Glycogen Synthase Kinase 3;Glycogen Synthase Kinases;Health;Hippocampus (Brain);Human;Hydrogen Peroxide;Hydroxyl Radical;Hyperactive behavior;In Vitro;Learning;Life;Mediating;Mediator of activation protein;Memory;Mental Retardation;Microglia;Modeling;Motor;Mus;Neonatal Alcohol Exposure;Nerve Degeneration;Neuraxis;Neurons;Neuroprotective Agents;North America;Oral;Oral Administration;Oxidative Stress;Pathway interactions;Production;Property;Protein-Serine-Threonine Kinases;RAPGEF1 gene;Role;Signal Transduction;Superoxides;Testing;Therapeutic;Third Pregnancy Trimester;alcohol behavior;alcohol consumption during pregnancy;alcohol effect;alcohol exposure;base;caspase-3;free radical oxygen;in vivo;in vivo Model;inhibitor/antagonist;intravenous administration;intravenous injection;member;neuroblastoma cell;neuron apoptosis;neuron loss;neuroprotection;neurotoxicity;novel;novel therapeutics;postnatal;prenatal;prevent;research study

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD) among which fetal alcohol syndrome (FAS) is the most severe form. The developing central nervous system (CNS) is particularly sensitive to ethanol. The loss of CNS neurons may underlie many of the behavioral deficits observed in FASD. Both glycogen synthase kinase 3 (GSK3) and oxidative stress contributes to ethanol neurotoxicity. We have purified a potent antioxidant from blackberries cyanidin-3-glucoside (C3G) which can also inhibit GSK3 and reduce oxidative stress. The current study is to determine whether C3G ameliorates ethanol-induced neuronal loss as well as behavioral deficits. The proposal will potentially develop a new therapeutic strategy.


application_id: 8811952
project_number: 5R01ES021375-04
project_title: PCBs worsen obesity/metabolic syndrome through 'toxic metabolic endotoxemia'
administering_ic: NIEHS
award_notice_date: 2015-02-25
opportunity_number: PAR-11-170
application_type: 5
activity_code: R01
ic: ES
serial_number: 021375
program_official: HEINDEL, JERROLD
project_start_date: 2012-05-08
project_end_date: 2016-02-29
study_section: Special Emphasis Panel[ZRG1-EMNR-D(55)R]
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
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:
DESCRIPTION (provided by applicant): 68% of US adults are either overweight or obese and more than 100 million Americans have diabetes or pre- diabetes. These conditions may lead to cardiovascular disease and cancer. Recent research indicates a potential role for polychlorinated biphenyls (PCBs) which are persistent organic pollutants in obesity and diabetes. PCBs were previously used in electrical transformers. Although they were banned over 30 years ago PCBs are still present in the US food supply and in all adult Americans. Preliminary research performed by our group and others suggests that PCBs cause a "leaky gut" to disrupt the gut:liver:adipose axis. Subsequently intestinal-derived bacterial products enter the bloodstream causing inflammation liver disease and contribute to obesity and diabetes. We call this problem "toxic-metabolic endotoxemia". We hypothesize that PCBs interact with high fat or high carbohydrate diets through toxic metabolic endotoxemia to worsen obesity and diabetes; and studying this hypothesis is the overall objective of this grant. The specific aims of this novel nutrient:toxin interaction translational project are to:1) Determine in mice mechanisms by which PCBs disrupt the gut:liver:adipose axis to increase metabolic endotoxemia and worsen diet-induced obesity/insulin resistance. 2) Determine the potential role of cellular receptors in PCBs-associated toxic-metabolic endotoxemia in mice and cell culture models. 3) Study mechanisms of toxic metabolic endotoxemia in stored blood samples from a large group of highly PCB-exposed humans. We expect to find that PCBs activate receptors perturb the gut:liver:adipose axis and worsen obesity/diabetes via toxic metabolic endotoxemia in mice and in humans. This innovative project is the first to study PCB- related endotoxemia in obesity/diabetes and is expected to lead to a new understanding of these conditions. The proposal is relevant to all overweight/obese people exposed to environmental pollution.

project_terms:
Adipose tissue;Adult;Alabama;American;Animal Model;Antioxidants;Archives;Attenuated;Binding (Molecular Function);Biological Assay;Biological Markers;Blood Circulation;Blood specimen;Body fat;C57BL/6 Mouse;Carbohydrates;Cardiovascular Diseases;Cell Culture Techniques;Cells;Chemicals;Cytokeratin 18;Data;Diabetes Mellitus;Diet;Dose;Endotoxemia;Endotoxins;Environmental Pollution;Epidemiologic Studies;Exposure to;Fatty Liver;Fatty acid glycerol esters;Food Supply;Fructose;General Population;Genetic;Glutathione;Grant;Hepatocarcinogenesis;Hormones;Human;Inflammation;Inflammatory;Insulin Resistance;Intestines;Lead;Ligands;Liver;Liver diseases;Malignant Neoplasms;Measures;Metabolic;Metabolic syndrome;Modeling;Mus;Nutrient;Obesity;Occupational Exposure;Organ;Overweight;Oxidative Stress;Pathogenesis;Permeability;Plants;Polychlorinated Biphenyls;Prediabetes syndrome;Production;Proteins;Research;Role;Sampling;Serum;Site;Steatohepatitis;TLR4 gene;Tight Junctions;Toll-like receptors;Toxin;Wild Type Mouse;base;clinically relevant;cohort;cost;cytokine;driving force;feeding;gut microbiota;gut microflora;innovation;macrophage;member;mutant;non-alcoholic fatty liver;nonalcoholic steatohepatitis;novel;pollutant;receptor;receptor expression;research study;toxicant

public_health_relevance:
We expect to find that PCBs worsen obesity/diabetes via toxic metabolic endotoxemia in mice and in humans. This innovative project is the first to study PCB-related endotoxemia in obesity/diabetes and is expected to lead to a new understanding of these conditions. The proposal is relevant to all overweight/obese people exposed to environmental pollution.


application_id: 8811153
project_number: 5UM1HL113530-04
project_title: University of Louisville Regional Clinical Center for the CCTRN
administering_ic: NHLBI
award_notice_date: 2015-03-23
opportunity_number: RFA-HL-12-026
application_type: 5
activity_code: UM1
ic: HL
serial_number: 113530
program_official: EBERT, RAY F
project_start_date: 2012-03-22
project_end_date: 2016-02-29
study_section: ZHL1-CSR-O(F2)
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
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_terms:
Activities of Daily Living;Address;Affect;Area;Basic Science;CD34 gene;Cardiac;Cardiac Surgery procedures;Cardiomyopathies;Cardiovascular Surgical Procedures;Cardiovascular system;Cell Therapy;Cell physiology;Cells;Cellular biology;Characteristics;Clinical;Clinical Research;Collaborations;Coupled;Effectiveness;Embryo;Enrollment;Environment;Event;Faculty;Goals;Heart failure;Hospitals;Human;Human Resources;Implant;In Vitro;Infarction;Institution;Left;Letters;Life;Medicine;Motivation;Multicenter Trials;Myocardial;Myocardial Ischemia;Myocardium;Names;Natural regeneration;Patients;Performance;Personnel Staffing;Phase;Population;Positioning Attribute;Postdoctoral Fellow;Proto-Oncogene Protein c-kit;Quality of life;Recovery;Reporting;Research;Research Infrastructure;Research Personnel;Resources;Safety;Staging;Stem cells;Testing;Therapeutic;Thoracic Surgical Procedures;Time;Universities;Work;base;clinical infrastructure;control trial;follower of religion Jewish;human study;implantation;improved;in vivo;injured;insight;member;novel;outcome forecast;phase 1 study;phase 2 study;phase 3 study;pre-clinical research;preclinical study;programs;repaired;stem cell population;stem cell therapy;success;ventricular assist device


application_id: 8811108
project_number: 5R01DA035552-03
project_title: Long-lasting cocaine-metabolizing enzyme for cocaine addiction treatment
administering_ic: NIDA
award_notice_date: 2015-02-18
opportunity_number: RFA-DA-13-004
application_type: 5
activity_code: R01
ic: DA
serial_number: 035552
program_official: KLINE, RICHARD
project_start_date: 2013-04-01
project_end_date: 2018-02-28
study_section: ZDA1-GXM-A(11)S
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
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 PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cocaine abuse is a major medical and public health problem. There is still no FDA-approved anti-cocaine medication. Disastrous medical and social consequences of cocaine abuse have made the development of an anti-cocaine medication a high priority. Enhancing cocaine metabolism by administration of human butyrylcholinesterase (BChE) is recognized as an efficient treatment strategy for cocaine overdose and addiction. However the catalytic efficiency (kcat/KM) of wild-type BChE against the naturally occurring (-)- cocaine is low (kcat = 4.1 min-1 and KM = 4.5 M). Nevertheless we have recently designed and discovered a set of BChE mutants known as cocaine hydrolases (CocHs) with >1000-fold improved catalytic efficiency against (-)-cocaine compared to wild-type BChE. In vivo evidences and clinical data for the first one of our discovered and patented CocHs have demonstrated that our discovered CocHs are promising candidates for development of an anti-cocaine medication. Our recently designed discovered and patented CocHs are significantly more potent. Built on our success in rational design and discovery of the CocHs the currently proposed investigation is focused on rational design preparation and preclinical testing of a novel type of long-lastingCocH entities denoted as Fc-CocH obtained from fusion of CocH with Fc portion of human antibody IgG1. The specific aims are: (1) to design new molecular entities of Fc-CocH that potentially have not only a high catalytic efficiency against (-)-cocaine but also a long biologicl half-life; (2) to prepare and test the designed Fc-CocHs for their in vitro activities; (3) to characterize the in vivo potency pharmacokinetics and immunogenicity of Fc-CocHs in rats and rhesus monkeys; (4) to evaluate the actual effects of the promising Fc-CocHs (identified in Aim 3) on the physiological and behavior responses of animals to cocaine by performing cardiovascular assays and self-administration assays in rhesus monkeys. Accomplishment of this proposed investigation will result in the identification and development of the best possible Fc-CocH entity that has not only a high in vivo potency in blocking physiological effects of cocaine but also a long biological half- life without immunogenicity. The long-lasting Fc-CocH entity optimized in this investigation is expected to be highly effective and safe as a novel exogenous enzyme suitable for cocaine addiction treatment in humans.

project_terms:
Animals;Antibodies;Binding (Molecular Function);Binding Sites;Biological;Biological Assay;Butyrylcholinesterase;Cardiovascular system;Clinical;Clinical Data;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Computer Simulation;Data;Development;Dose;Drug Kinetics;Enzymes;FDA approved;Goals;Half-Life;Health;Human;Hydrolase;IgG1;Immunoglobulin G;In Vitro;Investigation;Investigational Drugs;Lead;Legal patent;Macaca mulatta;Medical;Metabolism;Molecular;Neuraxis;Neurons;Pharmaceutical Preparations;Pharmacodynamics;Physiological;Plasma;Preclinical Testing;Preparation;Proteins;Rattus;Schedule;Self Administration;Testing;Vaccines;addiction;base;behavioral response;cocaine overdose;design;immunogenicity;improved;in vitro Assay;in vitro activity;in vivo;large scale production;mutant;novel;novel therapeutics;public health medicine (field);small molecule;social;stable cell line;success;therapy development;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Accelerating cocaine metabolism has been recognized as a promising treatment strategy for cocaine overdose and abuse. The long-lasting cocaine-metabolizing enzymes to be tested in this project are promising candidates for an efficient anti-cocaine medication.


application_id: 8811077
project_number: 5R01AG037868-05
project_title: Psychosocial stress interactions with electrophysiology and brain aging
administering_ic: NIA
award_notice_date: 2015-02-27
opportunity_number: PA-09-216
application_type: 5
activity_code: R01
ic: AG
serial_number: 037868
program_official: WISE, BRADLEY C
project_start_date: 2011-03-01
project_end_date: 2017-02-28
study_section: Neuroendocrinology, Neuroimmunology, and Behavior Study Section[NNB]
contact_pi_person_id: 8915754
contact_pi: BLALOCK, ERIC
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
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): This application proposes to address a fundamental unresolved question in the field of psychosocial stress and brain aging the nature of the neurobiological pathways through which psychosocial stress promotes unhealthy brain aging (UBA). The focus of the studies will be on brain aging markers developing near the age of divergence of unhealthy from healthy brain aging as these seem particularly likely to be susceptible to stress. This project will also test the hypothesis that midlife changes in the brain's responses to stress promote the emergence of UBA. This view derives from our recent work with both electrophysiological and microarray techniques showing that stress hormone-sensitive markers of brain aging emerge around midlife in rats the same age range in which unhealthy cognitive aging begins to appear. The proposed studies will comprise a large multidisciplinary project aimed at obtaining a unique integrated perspective on neurobiological pathways affected by psychosocial stress in an established rat model of aging. It will involve state-of-the-art intracellular electrophysiology in brain slices immunohistochemistry with a battery of stains separate microarray analysis of individual rat brains EEG monitoring of sleep patterns and behavioral testing. Multiple techniques will be applied in each animal. These studies will pursue the aims of correlating electrophysiological and genomic markers of unhealthy brain aging in the same animals and will relate exposure to psychosocial stress to the development of UBA as a function of age and under acute vs. chronic conditions. Importantly behavioral and pharmacological interventions to reduce stress and protect sleep patterns will be used to test whether the course of UBA can be altered in long-term studies. Aged animals subjected to psychosocial stress-reducing and sleep-promoting interventions will be evaluated on a battery of behavioral electrophysiological sleep monitoring microarray and immunohistochemical analyses to test the proposition that conversion these interventions may reduce/reverse UBA symptoms and if so to determine through which brain pathways this occurred. Overall these studies should substantially elucidate neurobiological pathways through which psychosocial stress influences brain aging markers and should importantly determine the role of age in modulating stress impact. Further the proposed intervention studies should have direct translational relevance.

project_terms:
21 year old;Accounting;Acute;Address;Adrenal Glands;Affect;Age;Age-Months;Aging;Animals;Area;Behavioral;Blood;Brain;Chronic;Chronic stress;Cognition;Cognitive aging;Development;Electroencephalography;Electrophysiology (science);Ensure;Exhibits;Exposure to;Gene Expression;Genomics;Glial Fibrillary Acidic Protein;Health;Hippocampus (Brain);Hormones;Human;Immunohistochemistry;Inbred F344 Rats;Individual;Inflammatory;Intervention;Intervention Studies;Killings;Link;Literature;Longitudinal Studies;Mediating;Microarray Analysis;Mifepristone;Modeling;Monitor;NIH Program Announcements;Nature;Neurobiology;Outcome;Outcome Measure;Pathway interactions;Pattern;Polysomnography;Predisposition;Process;Psychosocial Stress;RU-486;Rattus;Research;Resistance;Role;Sleep;Sleep disturbances;Slice;Staining method;Stains;Steroids;Stress;Symptoms;Techniques;Testing;Therapeutic;Time;Trazodone;Wireless Technology;Work;age group;age related;aged;aging brain;behavior test;biological adaptation to stress;brain pathway;combat;environmental enrichment for laboratory animals;functional outcomes;genome-wide;interdisciplinary approach;interest;intervention effect;middle age;morris water maze;multidisciplinary;novel;prevent;research study;response;restraint;restraint stress;serotonergic regulation;steroid hormone;stressor;transmission process;voltage clamp;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This proposed research will investigate the impact of acute and chronic psychosocial stress on brain function in an established rat model of aging. These studies will elucidate neurobiological markers of and processes influencing the divergence of healthy and unhealthy brain aging focusing on changes beginning around midlife and will also evaluate stress reducing and sleep promoting interventions' ability to combat the effects of psychosocial stress. Therefore the proposed studies should have both predictive and therapeutic value in determining the course of human brain aging.


application_id: 8808726
project_number: 5K02AG033629-04
project_title: Self-Regulation and Aging: Substrates and Health Consequences
administering_ic: NIA
award_notice_date: 2015-02-27
opportunity_number: PA-10-057
application_type: 5
activity_code: K02
ic: AG
serial_number: 033629
program_official: NIELSEN, LISBETH
project_start_date: 2012-03-15
project_end_date: 2016-02-29
study_section: Behavior and Social Science of Aging Study Section[NIA-S]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Suzanne C. Segerstrom is an independent investigator (PhD 1997) who has established a productive research program in personality self-regulation and physiology. The application proposes to protect a high level of research effort (80%) by releasing her from teaching service and administrative responsibilities. This support will facilitate an expansion of her research program in the interactions among self-regulation physiology well-being and health in older adults. The application has three foci: (i) executive cognitive function and heart rate variability are predicted to covary with self-regulatory success (ii) self-regulatory success across domains (e.g. control of repetitive thought acquisition of social or status resources) is predicted to correlate with mental and physical health and (iii) social resources will have disproportionate effects on health with increasing age as predicted by socioemotional selectivity theory. Career development activities under the award will include didactic and experiential training in aging longitudinal design and analysis and the responsible conduct of research; collaborations with dedicated aging researchers in cognition neuropsychology immunology neurology and methodology; and spearheading special projects and meetings. Research activities will include analysis of the relationship between executive function and self- regulation in her existing R01-funded longitudinal research with community-dwelling older adults (N = 150) and studies of self-regulation and health in the R01 sample a cross-sectional study of younger and older women focusing on immunosenescence (N=76) a longitudinal follow-up in a study of middle-aged adults (N = 96) that began in 1994 and a longitudinal study of amyotrophic lateral sclerosis patients and caregivers (N = 266). Proposed studies illustrating future directions examine the role of goal selection and optimization in promoting psychological and physiological well-being in older women with pain and the role of self-regulation in socioemotional selectivity and the contributions of executive cognitive function and heart rate variability to this relationship in older adults. The University of Kentucky and the Department of Psychology provide a rich environment for the development of this work. It is expected that K02 support would allow Dr. Segerstrom to acquire additional expertise in cognition physiology and aging; produce and disseminate cutting-edge research in self-regulation aging and health; expand her grant portfolio to continue this line of research; and train PhD students in the conduct of this research.

project_terms:
Adult;Age;Aging;Amyotrophic Lateral Sclerosis;Attention;Award;Behavior;Caregivers;Cognition;Collaborations;Communities;Cross-Sectional Studies;Data Collection;Databases;Development;Disease Progression;Doctor of Philosophy;Educational process of instructing;Elderly;Emotional;Emotions;Environment;Failure (biologic function);Funding;Future;Goals;Grant;Health;Health Resources;Hydrocortisone;Immune response;Immunology;Individual;Individual Differences;Inflammation;Informal Social Control;Interleukin-6;Kentucky;Lead;Longevity;Longitudinal Studies;Medical;Memory;Mental Depression;Mental Health;Methodology;Neurology;Neuropsychology;Pain;Patients;Peripheral;Personal Satisfaction;Personality;Physiological;Physiology;Process;Psychology;Regimen;Regulation;Research;Research Activity;Research Personnel;Resources;Rest;Risk;Role;Sampling;Science;Self-control as a personality trait;Series;Services;Social Interaction;Social status;Students;Testing;Thinking function;Time;Training;United States National Institutes of Health;Universities;Vaccination;Work;behavior change;beta-2 Microglobulin;career development;cognitive function;executive function;falls;follow-up;heart rate variability;immune activation;immunosenescence;longitudinal analysis;longitudinal design;meetings;middle age;older women;physical conditioning;programs;psychologic;psychosocial;public health medicine (field);research study;response;responsible research conduct;satisfaction;social;success;theories;thought control;vaccine trial;young woman

public_health_relevance:
NARRATIVE Older adults' ability to control thoughts emotions and behaviors - that is to self-regulate - is important for acquiring and maintaining resources such as social relationships as well as meeting other demands such as compliance with medical regimens. Understanding the underlying resources for self-regulation such as cognitive function as well as the psychological social and physical consequences of self-regulatory ability and success is important for optimizing older adults' health and well-being.


application_id: 8806351
project_number: 1R21DE024804-01
project_title: Antimicrobial and inflammatory epithelial responses modulated by P. gingivalis-induced PLA2-IIA
administering_ic: NIDCR
award_notice_date: 2014-11-23
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: DE
serial_number: 024804
program_official: MELILLO, AMANDA A
project_start_date: 2014-12-01
project_end_date: 2016-11-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 9641157
contact_pi: GONZALEZ, OCTAVIO ALBERTO
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
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 DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Although specific oral pathogenic bacterial species [i.e. P. gingivalis (Pg)] have been related to established periodontal lesions and can recapitulate disease in animal models the early events associated with epithelial-oral pathogen interactions in a complex microbial ecology that creates a microenvironment enabling the initiation of periodontitis (i.e. periodontal dysbiosis) remain unclear. Current studies in our laboratory identifying global gene expression profiles of immunoinflammatory genes in oral epithelial cells (OECs) exposed to oral bacteria species indicated that Pg is able to induce a remarkable increase in the transcription of secreted phospholipase A2-group IIA (PLA2G2A) whose expression levels clearly exceeded 20-30 times those of classical immunoinflammatory mediators (e.g. cytokines/chemokines and antimicrobial peptides). Protein levels determination indicated that PLA2-IIA expression appears to be Pg-specific response since other oral G+ and G- bacterial species failed to induce similar PLA2-IIA responses. PLA2-IIA is a highly cationic lipolytic enzyme produced by multiple cells and plays a critical role in infection and inflammation
through its potent antimicrobial properties (especially against Gram-positive bacteria) as well as
its effects on activating inflammatory cells and lipid mediator production. Moreover evidence indicates that Notch-1 is a central regulator of mucosal immune responses and is involved in PLA2-IIA expression by intestinal epithelial cells. Consistently we observed that Pg induced the expression of the NOTCH1 gene and its activation in OECs. Thus modulation of epithelial PLA2-IIA levels particularly at mucosal surfaces could be a plausible strategy for pathogenic bacterial species to break the host-microbiota symbiotic interactions leading to inflammatory disease. Therefore we hypothesize that antimicrobial and immunoinflammatory responses of OECs are modulated by P. gingivalis through differential activation of PLA2-IIA in a mechanism that involves the Notch-1 receptor. To test this hypothesis we propose the following two specific aims: (i) to identify the OEC signaling pathways involved in P. gingivalis-induced PLA2-IIA and (ii) to determine the cellular location and function of OEC- produced PLA2-IIA in response to P. gingivalis. To address these knowledge gaps we will use oral epithelial cell culture models as well as different Pg strains combined with neutralization experiments using monoclonal antibodies chemical inhibitors or siRNA approaches to: (i) identify OEC receptors/pathways involved in Pg-induced PLA2-IIA and (ii) determine the cellular location and function of OEC-produced PLA2-IIA after Pg challenge to more fully understand the potential role of this interesting molecule in the initial states of infection and inflammation of the oral mucosa. This contribution's significance will enable a better understanding of the cellular and molecular mechanisms involved in Pg-induced PLA2-IIA as a potential mechanism involved in Pg-induced dysbiosis. The results are expected to contribute to a strong evidence-based foundation for future studies designed to identify molecular target(s) associated with Pg-induced epithelial PLA2-IIA production in vitro (using primary OECs and organotypic cultures) and in vivo (using a nonhuman primate model) that could increase the risk for oral mucosa dysbiosis. More focused control of this dysbiosis process should ultimately provide new opportunities for the development of innovative approaches to prevent/treat periodontitis.

project_terms:
Address;Affect;Animal Model;Atherosclerosis;Bacteria;Blood Platelets;CCAAT-Enhancer-Binding Proteins;Cell Culture Techniques;Cell membrane;Cells;Chemicals;Complement;Complex;Crohn's disease;Cytokine Signaling;Development;Disease;ES01;Ecology;Endothelial Cells;Environment;Enzymes;Epithelial;Epithelial Cells;Epithelial Receptor Cell;Event;Foundations;Future;Gene Expression;Genes;Genetic Transcription;Gram-Positive Bacteria;Health;Heparan Sulfate Proteoglycan;Hepatocyte;Host Defense;Human;Immune response;In Vitro;Infection;Inflammation;Inflammatory;Inorganic Sulfates;Interleukin-1;Intestines;Invaded;Knowledge;Laboratories;Lesion;Link;Location;Mediating;Mediator of activation protein;Membrane;Microbe;Modeling;Molecular;Molecular Profiling;Molecular Target;Monoclonal Antibodies;Mucosal Immune Responses;Mucositis;NOTCH1 gene;Nutrient;Oral;Oral mucous membrane structure;PLA2G2A gene;Paneth Cells;Pathogenesis;Pathway interactions;Pattern Recognition;Periodontal Diseases;Periodontitis;Phospholipase A2;Play;Porphyromonas gingivalis;Process;Production;Property;Proteins;Proteoglycan;Receptor Up-Regulation;Regulation;Research;Research Design;Rheumatoid Arthritis;Risk;Role;SP1 gene;Signal Pathway;Signal Transduction;Small Interfering RNA;Solid;Subgroup;Surface;Symbiosis;TNF gene;Testing;Time;Translating;Unspecified or Sulfate Ion Sulfates;Up-Regulation (Physiology);Virulence Factors;antimicrobial;antimicrobial peptide;autocrine;cell type;chemokine;cytokine;design;evidence base;extracellular;human PLA2G2A protein;in vivo;inhibitor/antagonist;innovation;interest;lipid mediator;macrophage;member;microbial;microbial host;nonhuman primate;notch protein;oral bacteria;oral pathogen;pathogen;prevent;public health medicine (field);public health relevance;receptor;research study;response;translational study

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This research is relevant to public health because it will provide an evidence- based mechanistic foundation for further translational studies designed to identify molecular target(s) mediating the Pg-induced PLA2-IIA by oral epithelial cells. This potential early event in the pathogenesis of periodontitis should provide new opportunities for the development of innovative approaches to prevent/treat periodontal disease and its contribution to adverse systemic health. In addition this research will create a foundation for future studies focused on evaluating similar Pg- related PLA2-IIA responses in other cell types (e.g. human endothelial cells) that may help to elucidate the potential role of Pg in other systemic disorders such as atherosclerosis.


application_id: 8806238
project_number: 3R01DK091338-02S1
project_title: Metabolomics study on the preventive mechanisms for LDR on diabetic nephropathy
administering_ic: NIDDK
award_notice_date: 2014-09-08
opportunity_number: PA-14-003
application_type: 3
activity_code: R01
ic: DK
serial_number: 091338
suffix: S1
program_official: FLESSNER, MICHAEL FRANCIS
project_start_date: 2013-09-15
project_end_date: 2016-08-31
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 6879103
contact_pi: CAI, LU
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
project_abstract:
DESCRIPTION (provided by applicant):    The goal of this study is to develop low-dose radiation (LDR) as a new tool to prevent and treat diabetic nephropathy. Currently no effective preventive or therapeutic approaches are available to treat diabetic nephropathy which is the most common cause of renal failure. We have been investigating the biological effects of LDR including its hormesis and adaptive response in vitroand in vivo. A major advantage of LDR is that it activates many genes in antioxidant and anti-inflammatory pathways rather than just single protective gene potentially making LDR a very potent and novel therapeutic approach. This was borne out by our preliminary studies that show that LDR at 25 mGy decreases diabetic nephropathy by significantly reducing diabetes-induced renal oxidative damage and inflammation. Our latest preliminary data show up-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression and protein kinase B (also called Akt) phosphorylation in the kidney of diabetic mice also exposed to LDR at 25 mGy. NRF2 is a transcription factor involved in expression of a broad range of protective genes. Therefore our central hypothesis is that exposure of diabetic animals to LDR can prevent and treat diabetic nephropathy by activation of many protective genes through stimulation of the Nrf2 pathway.  This hypothesis will be tested through three specific Aims: (1) LDR at the optimal condition not only prevents but also delay diabetic nephropathy; (2) the optimal LDR is safe for diabetic subjects; (3) the renal protection by the optimal LDR is predominantly mediated by up- regulating Nrf2-mediated multiple antioxidant components.  The great advantage of LDR is that it offers a highly controllable non-invasive method for eliciting endogenous synergistic tissue protection and repair mechanisms. This innovative approach will be particularly valuable for the diabetic patient who already has significantly decreased renal function that increases the toxicityof invasive drugs. Therefore this project will open a new avenue for the prevention and treatment of diabetic complications.

project_terms:
Adverse effects;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Apoptotic;Biological;Cell Death;Cell Nucleus;Cell Proliferation;Complications of Diabetes Mellitus;Cytogenetics;Cytosol;Data;Diabetes Mellitus;Diabetic Nephropathy;Diabetic mouse;Disease;Dose;Drug Combinations;Drug Targeting;Drug usage;Frequencies (time pattern);Genes;Germ Cells;Glycogen Synthase Kinase 3;Goals;Harvest;In Vitro;Inflammation;Kidney;Kidney Diseases;Kidney Failure;Low Dose Radiation;Mediating;Methods;Modality;Modeling;Mus;Organ;Pathway interactions;Pharmaceutical Preparations;Phosphorylation;Prevention;Preventive;Protein Tyrosine Kinase;Proto-Oncogene Proteins c-akt;Proto-Oncogenes;Radiation;Radiation therapy;Reactive Oxygen Species;Renal function;Renin-Angiotensin System;Risk;Rodent;Role;Safety;Streptozocin;Testing;Therapeutic;Therapeutic Effect;Tissues;Toxic effect;Up-Regulation (Physiology);Work;cytotoxic;diabetic;diabetic patient;in vivo;innovation;metabolomics;mouse model;novel strategies;novel therapeutic intervention;nuclear factor-erythroid 2;oxidative damage;prevent;public health relevance;repaired;response;safety testing;tool;transcription factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    The objective of this study is to apply low-dose radiation (LDR) as a new and non-invasive tool to prevent and treat diabetic nephropathy through stimulation of renal multiple protective mechanisms against oxidative damage and inflammation. We will firstly define the optimal condition of LDR to prevent and treat diabetic nephropathy with type 1 and type 2 diabetic mouse models and then determine the safety for diabetic subjects to expose to LDR and underlying mechanisms for the renal protection from diabetes by LDR. This project represents a unique approach to apply LDR to activate multiple protective pathways unlike most currently- used drugs only working on a single pathway.


application_id: 8804950
project_number: 5R01HL107640-04
project_title: Mechanisms of Mitochondrial Dysfunction in Brain Vasculature
administering_ic: NHLBI
award_notice_date: 2015-03-06
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 107640
program_official: REID, DIANE M
project_start_date: 2012-03-01
project_end_date: 2016-02-29
study_section: Special Emphasis Panel[ZRG1-VH-J(02)]
contact_pi_person_id: 9959914
contact_pi: TYAGI, NEETU
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
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:
DESCRIPTION (provided by applicant): Clinical data suggest an association between elevated levels of Hcy also known as hyperhomocysteine-mia (HHcy) and stroke. HHcy is generated due to increase in de-methylation of methionine by S-adenosine- homocysteine hydrolase (SAHH) and a decrease in methyltetrahydrofolate reductase (MTHFR) and cystathionine-y-lyase (CSE an enzyme responsible for Hcy metabolism to H2S a most potent vasodilator antioxidant and anti-hypertensive agent) contribute to mitochondria dysfunction (mitophagy) and ischemic stroke. Cytochrome-C transports electrons and facilitates mitochondrial bioenergetics. Interestingly during HHcy cytochrome-C becomes homocysteinylated (N-Hcy-cyt-c). However it's consequence to mitophagy and stroke is unclear. The long-term goal of this project is to understand the mechanism of mitophagy mitochondrial repair and permeability in brain vasculature during I/R injury. Our preliminary studies suggest that during I/R total Hcy levels increases causes N-Hcy-cyt-C  increases mitochondrial matrix metalloproteinase-9 (mtMMP-9) in-part degradation of mt-matrix (connexin and tight junction protein TJP) which led to mitophagy and permeability in brain vasculature. Interestingly THC decreases Hcy level and mitigates brain damage. Tetra hydro-curcumin (THC) a major herbal antioxidant and anti-inflammatory agent has shown to protect brain against I/R injury. The central hypothesis of this proposal is that HHcy contributes to mitophagy mediated brain damage through N-Hcy-cyt-C in part by increasing oxidative stress mtMMP-9 degrades connexin-43 and TJP (Figure 1). The treatment with THC CSE gene and SAHH shRNA gene transfer attenuates mitophagy and permeability. We will test this hypothesis by following three specific aims: Specific Aim #1: To determine whether the Hcy contributes to mitophagy in part by inducing oxidative stress exacerbating homocysteinylation of cytochrome-c in ischemia reperfusion and if THC CSE and SAHH shRNA gene therapy mitigates these changes. Specific Aim #2: To determine whether the homocysteinylation of cytochrome-c activates mt-MMP-9 disruption of collagen/elastin ratio mtCxn43 and mt-tight junction proteins in ischemia reperfusion and if THC CSE and SAHH shRNA gene therapy ameliorate. Specific Aim #3: To determine whether Hcy alters mitochondrial (mt) bioenergetics and cerebro-vascular remodeling in ischemia reperfusion and if THC CSE and SAHH shRNA gene therapy alleviate. These studies will demonstrate the novel mechanism of cerebrovascular remodeling and have therapeutic ramifications for mitochondrial repair in cerebral ischemic stroke.

project_terms:
ATP Synthesis Pathway;Adenosine;Albumins;Angiography;Anti-Inflammatory Agents;Antihypertensive Agents;Antioxidants;Attenuated;Bioenergetics;Blood Vessels;Blood flow;Brain;Brain Injuries;Brain Stem;Caliber;Cerebrum;Clinical Data;Co-Immunoprecipitations;Cognitive;Collagen;Collagen Type IV;Connexin 43;Connexins;Curcumin;Cystathionine;Cytochromes;DNA;DNA Methylation;Diet;Dyes;Elastin;Electron Transport;Enzymes;Event;Extravasation;Functional disorder;Gel;Gelatin;Gelatinase B;Gene Transfer;Genes;Goals;Histocytochemistry;Homocysteine;Homocystine;Hydrolase;In Situ;Injection of therapeutic agent;Injury;Ischemia;Ischemic Stroke;Label;Lyase;Matrix Metalloproteinases;Measures;Mediating;Membrane Potentials;Messenger RNA;Metabolism;Methionine;Methylation;Mitochondria;Mitochondrial DNA;Mitochondrial Matrix;Mus;Operative Surgical Procedures;Oxidants;Oxidation-Reduction;Oxidative Stress;Oxidoreductase;Oxygen Consumption;Pathway interactions;Permeability;Plasmids;Production;Proteins;Proteolysis;Proteome;Reperfusion Injury;Reperfusion Therapy;Respiration;Reverse Transcriptase Polymerase Chain Reaction;Stress;Testing;Therapeutic;Tight Junctions;Time;Vascular remodeling;Vasodilator Agents;Western Blotting;calcein AM;cerebrovascular;cytochrome c;gene therapy;middle cerebral artery;mitochondrial dysfunction;mitochondrial membrane;novel;prevent;repaired;response;sham surgery;small hairpin RNA;stroke;tetrahydrocurcumin

public_health_relevance:
These studies will delineate the mechanisms of mitophagy and cerebrovascular remodeling in brain vasculature. The treatment with dietary herbal antioxidant tetrahydrocurcumin naked CSE DNA and SAHH shRNA gene therapy mediated stabilization of mitochondrial membrane potential by inhibition of mitochondrial DNA methylation; oxidant and proteolysis stress via novel mechanistic pathways will be powerful therapeutic strategy for preventing ischemic stroke.


application_id: 8804067
project_number: 6R44DK085810-03
project_title: Hollow Fiber Catheter for Drug Delivery into the Prostate
administering_ic: NIDDK
award_notice_date: 2014-02-26
opportunity_number: PA-12-088
application_type: 6
activity_code: R44
ic: DK
serial_number: 085810
program_official: KIRKALI, ZIYA
project_start_date: 2010-06-01
project_end_date: 2015-06-30
study_section: Urologic and Genitourinary Physiology and Pathology[UGPP]
contact_pi_person_id: 8714039
contact_pi: STICE, JIM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079228773
duns_number: 079228773
fips: US
organization_id: 10035571
organization_name: TWIN STAR TDS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071968
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-02-01
budget_end_date: 2014-06-30
project_abstract:
DESCRIPTION (provided by applicant): The significance of the proposed research is based on the growing demand for healthcare resources to treat and manage prostatic disease in particular benign prostatic hyperplasia (BPH) and cancer. Prostate cancer is the second-leading cause of cancer deaths among men in the U.S and both the disease's incidence and cost of treatment for BPH and its complications are growing rapidly with the aging U.S. population. There is a clear need for minimally invasive cost-effective therapies to match the outcomes of surgical treatment options which are associated with significant morbidity and complications. Prostate injections have not become standard of care due to inadequate drug distribution with needles. The applicants have developed a microporous hollow fiber catheter (MiHFC) for improved injection distribution in the prostate. Phase II innovations focus on combining existing treatment planning methods with MiHFC for drug delivery injections into human prostates with the objective that the system developed will be ready for human clinical use. Hypothesis: The injection system being developed in Phase II including MiHFC and treatment planning software will give urologists and researchers a more reliable tool to plan and deliver injection therapies into the human prostate. The same MiHFC device with small changes would be adaptable for use in many other human clinical applications needing improved injection systems such as liver kidney and other solid organs. This would allow researchers to use MiHFC devices for other research projects involving human drug injections with or without treatment planning. Preliminary Data: In Phase I research the innovative use of applicant's microporous hollow fiber catheters (MiHFC) to improve injection drug delivery into the prostate was successful with MiHFC significantly improving ethanol distribution in canine prostates as compared to needle injections. Specific Aims: The objective of this Phase II proposal is to further develop the applicant's innovative drug delivery system for improved prostate disease therapies and to provide the bench and animal study data to accelerate its clinical use. Aim 1: Finalize human study catheter design. The Phase I MiHFC design will be optimized to meet human use specifications established from user requirements. Aim 2: Infusion studies and analysis. Human ex vivo and baboon in vivo studies will be conducted to assess agent distribution for the development of a treatment planning system. Aim 3: Design verification and 510(k) submission. FDA 510(k) clearance will facilitate clinical adoption and commercialization.

public_health_relevance:
There is a significant demand for healthcare resources to treat and manage prostate diseases. The objective of this Phase II proposal is to develop an innovative drug delivery system for improved prostate disease therapies and to provide the bench and animal study data to accelerate its clinical use.


application_id: 8803767
project_number: 5R21AI108260-02
project_title: Hendra virus trafficking and assembly
administering_ic: NIAID
award_notice_date: 2015-01-20
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: AI
serial_number: 108260
program_official: CHALLBERG, MARK D
project_start_date: 2014-02-10
project_end_date: 2017-01-31
study_section: Special Emphasis Panel[ZRG1-IDM-S(02)M]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
other_pis: SCHMITT, ANTHONY P
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
project_abstract:
DESCRIPTION (provided by applicant): Hendra virus (HeV) and Nipah virus members of the Henipavirus genus of the paramyxovirus family are zoonotic viruses with high mortality rates in humans. Henipavirus particle assembly is coordinated by the viral matrix (M) proteins which link together the viral glycoproteins and the viral ribonucleoproteins. The Dutch lab recently defined a novel mechanism for proteolytic cleavage of the Henipavirus fusion (F) proteins. In contrast to other paramyxovirus F proteins Henipavirus F proteins reach the cell surface in the inactive uncleaved form are endocytosed from the plasma membrane (PM) and encounter cathepsin proteases within early endosomes (EEs). Following cathepsin cleavage F is routed through Rab11-containing recycling endosomes (REs) before returning to the PM for incorporation into budding virus particles. The Schmitt lab recently identified interactions between Henipavirus matrix (M) proteins and the beta subunit of AP-3 adapter complexes which are involved in endosomal trafficking. M protein localized in Rab11 compartments and this localization was disrupted upon expression of M- binding AP3B1-derived inhibitory polypeptides. To explore the significance of M and F protein convergence in Rab11-positive REs the Dutch and Schmitt labs have now combined their efforts and discovered that an F mutant defective in endocytic trafficking fails to participate in VLP assembly and that introduction of a dominant negative Rab11 protein dramatically inhibits Hendra VLP production. We therefore hypothesize that Rab-11 containing endosomal compartments serve as a critical assembly site for key viral proteins prior to viral budding. In Aim 1 we will examine the role of HeV virus F protein trafficking in vius assembly through use of a comprehensive set of trafficking-altered F protein mutants and will analyze F- M interactions in Rab11 REs using a sensitive proximity ligation assay. Our second aim will build on the exciting preliminary data defining an interaction between HeV M protein and the beta subunit of the AP-3 adapter complex examining the role of this interaction in M trafficking delineating the trafficking pathway and examining the role of this interaction in apial targeting of the HeV M protein. Finally in Aim 3 we will address the role of HeV G protein interactions with M or F on G assembly testing the hypothesis that G protein assembly into VLPs is mediated by redundant interactions with M and F proteins. These experiments will provide critical new information on HeV assembly and test the novel hypothesis that Rab11 REs may serve as viral assembly sites. If this hypothesis is correct Rab11 RE components involved in membrane bending may serve as novel host factors for non-ESCRT mediated budding.

project_terms:
Address;Antiviral Agents;Apical;Binding (Molecular Function);Biological Assay;Cathepsins;Cell membrane;Cell surface;Cells;Complex;Cytoplasmic Tail;Data;Defect;Development;Dominant-Negative Mutation;Early Endosome;Endocytosis;Endosomes;Family;GTP-Binding Proteins;Glycoproteins;Health;Hendra Virus;Henipavirus;Henipavirus Infections;Human;Integration Host Factors;Lead;Ligation;Link;Measures;Mediating;Membrane;Mortality Vital Statistics;Nipah Virus;Paramyxovirus;Pathway interactions;Peptide Hydrolases;Process;Production;Proteins;Reagent;Recycling;Ribonucleoproteins;Role;Series;Site;Surface;Testing;Ubiquitination;Vaccines;Viral;Viral Proteins;Virion;Virus;Virus Assembly;member;multiple myeloma M Protein;mutant;novel;particle;pathogen;polarized cell;polypeptide;protein transport;rab11 protein;research study;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The highly pathogenic Hendra and Nipah viruses are recently emerged human pathogens for which no vaccines or antivirals for human use are available. The proposed experiments will provide new understanding of the process of Hendra virus assembly and budding and could lead to development of new antiviral reagents.


application_id: 8802964
project_number: 1R01GM113832-01
project_title: Synthetic HDL_a potential sepsis therapy
administering_ic: NIGMS
award_notice_date: 2014-12-31
opportunity_number: RFA-HL-14-028
application_type: 1
activity_code: R01
ic: GM
serial_number: 113832
program_official: DUNSMORE, SARAH
project_start_date: 2015-01-01
project_end_date: 2019-11-30
study_section: Special Emphasis Panel[ZHL1 CSR-O (S1)]
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
other_pis: SCHWENDEMAN, ANNA
congressional_district: 06
department: PEDIATRICS
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_terms:
Animals;Bacteria;Biodistribution;Biological;Biology;Blood;Blood Vessels;Cardiovascular Diseases;Cessation of life;Chemicals;Clinical;Clinical Data;Data;Dose;Drops;Drug Kinetics;Effector Cell;Endothelial Cells;Endotoxins;Event;Extravasation;Figs - dietary;Frequencies (time pattern);Generations;Goals;Grant;High Density Lipoprotein therapy;High Density Lipoproteins;Immune;Immunity;Immunocompromised Host;In Vitro;Inflammatory;Inflammatory Response;Knockout Mice;Knowledge;Lead;Ligation;Lipids;Lipoprotein (a);Mediating;Modeling;Mortality Vital Statistics;Mus;Pathogenesis;Pathway interactions;Patients;Peptides;Play;Positioning Attribute;Proteins;Puncture procedure;Regimen;Reporting;Research Personnel;Risk Factors;Role;Safety;Sepsis;Shapes;Signal Transduction;Testing;Therapeutic;Time;Translations;Treatment Protocols;Vascular Endothelial Cell;aged;base;cytokine;design;effective therapy;endothelial dysfunction;experience;in vitro Assay;in vivo;innovation;macrophage;mechanistic (body);multidisciplinary;novel;outcome forecast;overexpression;pre-clinical;preclinical study;reconstitution;septic;success;tool;treatment strategy;vascular endothelial dysfunction


application_id: 8802869
project_number: 5R21DC013343-02
project_title: Odorant Receptor Gene Regulation
administering_ic: NIDCD
award_notice_date: 2015-02-12
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: DC
serial_number: 013343
program_official: SULLIVAN, SUSAN L
project_start_date: 2014-03-01
project_end_date: 2016-07-31
study_section: Special Emphasis Panel[ZRG1-SCS-N(09)]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
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
project_abstract:
DESCRIPTION (provided by applicant): This project investigates the actions of two homeodomain transcription factors that help control expression of nearly all of the more than 1000 mouse odorant receptor genes expression so finely regulated that each olfactory nerve cell expresses just one allele of one odorant receptor gene. The overarching hypothesis for the project proposes that homeodomain transcription factor stimulation of odorant receptor gene transcription triggers local positive feedback acting through active chromatin modifications while simultaneously enhancing global negative feedback acting through repressive chromatin modifications competing events capable of explaining the singularity of odorant receptor expression. This project tests whether the transcription factors act directly at promoters and enhancers of odorant receptor genes and whether these events are associated with selected active chromatin modifications at odorant receptor genes.

project_terms:
Alleles;Back;Binding (Molecular Function);Cells;Chemicals;Chromatin;Code;Complex;Data;Development;Discrimination (Psychology);Disease;Enhancers;Equilibrium;Event;Family;Feedback;Future;Gene Expression;Gene Expression Regulation;Gene Family;Genes;Genetic Predisposition to Disease;Genetic Transcription;Health;Histones;In Vitro;Mammals;Modeling;Modification;Molecular;Mus;Mutant Strains Mice;Mutation;Neurons;Odorant Receptors;Odors;Olfactory Nerve;Outcome;Process;Promotor (Genetics);Property;Receptor Gene;Recruitment Activity;Reporter Genes;Repression;Role;Site;Specificity;Testing;Transcription Initiation;Work;afferent nerve;base;cancer genetics;chromatin modification;coping;emx2 protein;genetic discrimination;homeodomain;in vivo;interest;neuron development;olfactory sensory neurons;receptor expression;selective expression;transcription factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Expression of odorant receptors which are the largest family of mammalian genes is so specific that each olfactory sensory nerve cell expresses only one allele of one odorant receptor gene. Mechanisms controlling gene expression are broadly interesting given their fundamental involvement in normal development cancer and genetic susceptibility to diseases and the odorant receptors represent the most extreme and exquisite example of how cells achieve specificity of expression from a large gene family. Though poorly understood odorant receptor gene expression does appear to depend on two homeodomain transcription factors whose actions are the focus of this project.


application_id: 8798770
project_number: 1R01ES024771-01
project_title: Community-Engaged Research and Action to Reduce Respiratory Disease in Appalachia
administering_ic: NIEHS
award_notice_date: 2015-04-14
opportunity_number: PA-12-153
application_type: 1
activity_code: R01
ic: ES
serial_number: 024771
program_official: FINN, SYMMA
project_start_date: 2015-04-15
project_end_date: 2020-01-31
study_section: Health Disparities and Equity Promotion Study Section[HDEP]
contact_pi_person_id: 1939811
contact_pi: BROWNING, STEVEN R
other_pis: SCHOENBERG, NANCY E.
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
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 PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Rural Appalachian residents experience the nation's highest rates of serious respiratory illnesses with Appalachian Kentuckians twice as likely to be diagnosed with adult asthma and chronic obstructive pulmonary disease as their national counterparts. In response to community concern and to address the critical need to reduce respiratory health disparities in Appalachia we draw on our decade-long community-academic partnership to undertake three aims and activities: (1) to investigate the extent nature and source of respiratory health inequities we will implement a community-engaged assessment of environmental and individual-level exposures; (2) to enhance community knowledge about respiratory illness and refine a culturally appropriate environmental public health action strategy
(EPHAS) we will disseminate results from the epidemiologic assessment and gather input to refine the EPHAS; and (3) to test the efficacy of the EPHAS we will implement and evaluate a three arm RCT involving self-management and home modification. Outcomes include appropriate health care use; improvement in quality of life pulmonary function respiratory illness knowledge and self-efficacy; extent of community participation; and programmatic satisfaction. The proposed application is responsive to "Research to Action: Assessing and Addressing Community Exposures to Environmental Contaminants" (PA-12-153) encouraging "community-engagement projects designed to investigate the potential health risks of environmental exposures of concern to a community and to implement an environmental public health action plan based on research findings." The proposed community-academic effort represents the first of its kind to undertake a comprehensive environmental behavioral and social determinants assessment leading to a community-endorsed environmental public health action strategy to rectify Appalachian respiratory health inequities.

project_terms:
Accounting;Action Research;Address;Adult;Adult asthma;Affect;Age;Air;Air Pollutants;Appalachian Region;Area;Asthma;Back;Behavioral;Chronic Obstructive Airway Disease;Coal Mining;Collaborations;Communities;Community Participation;Data;Development;Diagnosis;Diet;Environmental Exposure;Environmental Pollution;Environmental Risk Factor;Epidemiologic Studies;Epidemiology;Evaluation;Exposure to;Gender;Goals;Health;Health education;Healthcare;Home environment;Individual;Intervention;Kentucky;Knowledge;Lead;Lung diseases;Measurement;Measures;Modification;Nature;Neighborhoods;Occupations;Outcome;Outcome Assessment (Health Care);Physical activity;Population;Process;Quality of life;Randomized;Reporting;Research;Research Design;Research Personnel;Risk;Risk Factors;Role;Rural;Self Efficacy;Self Management;Smoking;Source;Symptoms;Testing;Voice;arm;base;community organizations;design;efficacy testing;environmental justice;experience;health disparity;improved;innovation;low socioeconomic status;meetings;member;programs;public health medicine (field);public health relevance;pulmonary function;residence;respiratory;respiratory health;response;satisfaction;social


application_id: 8798667
project_number: 5R01EY022238-04
project_title: Functional studies of DICER1 and Alu RNA in geographic atrophy
administering_ic: NEI
award_notice_date: 2015-01-30
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: EY
serial_number: 022238
program_official: SHEN, GRACE L
project_start_date: 2012-02-01
project_end_date: 2016-01-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
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:
SummaryGeographic atrophy (GA) is an untreatable advanced form of age-related macular degeneration(AMD) that is characterized by degeneration of the retinal pigmented epithelium (RPE). Neitherthe mechanisms that promote this RPE degeneration nor the basis for the centrifugal expansionof GA that can ultimately lead to blindness have been resolved. This enigmatic nature of GApathogenesis has precluded the development of any FDA-approved therapy for the one millionAmericans diagnosed with GA and the millions more at risk of developing GA. In new andexciting studies we made the surprising observation that there is an abundance of Alu repetitiveRNA in the RPE of human eyes with GA that accumulates in response to a dramatic deficiencyin the RNase DICER1 and induces RPE degeneration (Kaneko et al. Nature 2011). Ourfindings which introduce a novel cell survival function for DICER1 independent of its canonicalmiRNA biogenesis function and the concept that Alu RNA can directly promote humanpathology provide new mechanistic insights into GA pathogenesis. However we still lack anintegrated understanding of how DICER1 is dysregulated in GA and precisely how Alu RNAinduces RPE degeneration. A rigorous definition of these mechanisms is crucial to enhancingour understanding of the molecular drivers of GA and to developing rational treatments. We willprovide novel functional insights into how DICER1/Alu RNA dysregulation contributes to GApathogenesis and develop a novel therapeutic strategy via the following Aims: (1) Generate aspatiotemporal map of DICER1 and Alu RNA in relation to the locus of pathology in GA andearly AMD eyes; (2) Decipher the mechanisms by which Alu RNA triggers a new inflammatorycell death pathway we have identified; (3) Define the molecular regulation of DICER1 in theRPE in the context of GA and the function of a novel DICER1 splice variant; (4) Create a newanimal model of GA having human-like features of the disease and validate an antisensetherapeutic strategy targeting Alu RNA. These studies will illuminate novel aspects of themolecular and biochemical bases of GA and help validate a molecular targeting strategy thatcould be translated into clinical trials. As such this proposal is perfectly aligned with the 5-yeargoals of the NEI's Retinal Diseases Program strategic plan.

project_terms:
Accounting;Affect;Age related macular degeneration;American;Animal Model;Antisense Oligonucleotides;Biochemical;Biogenesis;Blindness;Blood Vessels;Cell Death;Cell Survival;Cells;Cellular Stress;Characteristics;Choroidal Neovascularization;Clinical Trials;DICER1 gene;Data;Developed Countries;Development;Diagnosis;Disease;Down-Regulation;Economics;Elements;Etiology;Eye;FDA approved;Functional disorder;Goals;Health;Health Expenditures;Human;Human Pathology;Immune;Inflammatory;Lead;Link;Maps;Mediator of activation protein;MicroRNAs;Modeling;Molecular;Molecular Target;Nature;Pathogenesis;Pathology;Pathway interactions;Patients;Pattern;Prevalence;Process;Productivity;Proteins;RNA;RNA Splicing;Regulation;Retina;Retinal Diseases;Retrotransposon;Ribonucleases;Risk;Signal Pathway;Stimulus;Strategic Planning;Structure of retinal pigment epithelium;Testing;Therapeutic;Toll-like receptors;Transcript;Translating;Variant;Vision;base;cytotoxic;cytotoxicity;drug testing;effective therapy;geographic atrophy;immune activation;improved;insight;member;nonhuman primate;novel;novel therapeutics;prevent;programs;response;spatiotemporal

public_health_relevance:
NarrativeThere is no FDA-approved treatment for the one million Americans with geographicatrophy (GA) or for the millions more who are at risk of developing GA. We recentlydiscovered an enzymatic deficiency that leads to accumulation of toxic RNA moleculesin the eyes of patients with GA. The goal of this project is to understand how this newlydiscovered pathway causes GA and to test drugs that will be suitable for entry intoclinical trials.


application_id: 8798551
project_number: 5R21AA022189-02
project_title: The role of hepatocyte cAMP/PDE4 in alcohol-induced liver steatosis and injury
administering_ic: NIAAA
award_notice_date: 2015-01-21
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: AA
serial_number: 022189
program_official: RADAEVA, SVETLANA
project_start_date: 2014-02-05
project_end_date: 2017-01-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 11058066
contact_pi: GOBEJISHVILI, LEILA
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
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:
DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the United States. Steatosis is the initial most frequent hepatic manifestation that occurs in response to acute as well as chronic ethanol consumption. Although steatosis is reversible it is now established that the severity of steatosis predicts theprogression of liver disease to more advanced stages including fibrosis and cirrhosis. Alcohol causes hepatic steatosis by enhancing de novo lipogenesis and impairing fatty acid beta-oxidation system with subsequent susceptibility to injury by inflammatory cytokines particularly TNF. However gaps remain in our understanding of alcohol-responsive mechanisms that contribute to dysregulation of genes involved in hepatic steatosis and subsequent cytokine hepatotoxicity. Cyclic AMP (cAMP) through activation of protein kinase A (PKA) has been shown to modulate genes involved in lipid metabolism and apoptosis. cAMP levels are tightly regulated through biosynthesis by adenyl cylases (ACs) and hydrolysis by phosphodiesterases (PDEs). Our earlier work shows that expression of cAMP-specific PDE4 is significantly increased in response to alcohol exposure in monocytes/macrophages including hepatic Kupffer cells. Notably our recent preliminary data suggest that ethanol exposure of primary mouse hepatocytes leads to a significant up-regulation of the PDE4 sub-family of enzymes PDEA B and D. Based on these findings we postulate that chronic ethanol feeding decreases cAMP levels in hepatocytes in a PDE4-dependent manner. There is no FDA-approved therapy for any stage of alcoholic liver disease (ALD). The most widely-used (off-label) drug therapies are glucocorticoids and pentoxifylline (PTX). Unfortunately an important subset of AH patients treated with glucocorticoids have "steroid resistance" and some patients have contraindications to steroid therapy. PTX is a broad spectrum PDE inhibitor with only a weak PDE4 inhibitor activity and the data available from the limited studies suggest a positive intervention effect. Hence a more directed intervention aimed at inhibiting PDE4 may be significantly more effective. In this regard our recent preliminary data show that treatment with PDE4 specific inhibitor rolipram markedly inhibits hepatic steatosis in ethanol-fed animals. Our central hypothesis is that alcohol exposure increases cAMP degrading PDE4 expression in hepatocytes lowering cAMP levels with a resultant increase in lipogenesis and a decrease in fatty acid beta oxidation leading to the development of steatosis and sensitization to TNF-induced toxicity. Importantly as a corollary lowering PDE4 activity may provide a significant therapeutic approach. The specific objectives of these mechanistic as well as translational studies are 1) to examine the effect of alcohol exposure on hepatocyte PDE4 expression cAMP metabolism and development of hepatic steatosis and injury and 2) to determine the role of PDE4 subclasses and effect of PDE4 inhibition on the development of alcohol induced hepatic steatosis and injury. Our future goal is to provide a conceptual basis for targeting PDE4 activity as a clinical treatment for alcoholic patients.

project_terms:
ADD-1 protein;Acute;Adenylate Cyclase;Affect;Alcoholic Liver Diseases;Alcohols;Anabolism;Animal Feed;Apoptosis;Apoptotic;Cause of Death;Cell physiology;Cessation of life;Chronic;Cirrhosis;Clinical Treatment;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Cyclic AMP-Responsive DNA-Binding Protein;Data;Development;Endotoxins;Enzymes;Ethanol;FDA approved;Family;Fatty Acids;Fatty Liver;Fibrosis;Future;Genes;Glucocorticoids;Goals;Health;Hepatic;Hepatocyte;Hepatorenal Syndrome;Hepatotoxicity;Homeostasis;Hydrolysis;In Vitro;Individual;Inflammatory;Injury;Injury to Liver;Intervention;Knock-out;Kupffer Cells;Label;Liver;Liver diseases;Metabolism;Mortality Vital Statistics;Mus;Patients;Pentoxifylline;Peroxisome Proliferator-Activated Receptors;Pharmacotherapy;Phosphodiesterase Inhibitors;Phosphorylation;Play;Predisposition;Prevention;Regulation;Role;Rolipram;Second Messenger Systems;Severities;Staging;Steroid Resistance;Steroid therapy;Stimulus;System;TNF gene;Therapeutic;Toxic effect;United States;Up-Regulation (Physiology);Work;alcohol effect;alcohol exposure;alcohol response;base;chronic alcohol ingestion;cytokine;fatty acid oxidation;feeding;in vivo;inhibitor/antagonist;intervention effect;lipid biosynthesis;lipid metabolism;liver injury;macrophage;monocyte;oxidation;phosphoric diester hydrolase;problem drinker;receptor;response;second messenger;translational study

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This project will determine the contributing role of dysregulated hepatocyte PDE4/cAMP homeostasis in the development of alcohol-induced hepatic steatosis and injury and examine the efficacy of PDE4 inhibition in the prevention and treatment of alcoholic liver disease.


application_id: 8797357
project_number: 5R21NS083692-02
project_title: Leptin Obesity and Stroke
administering_ic: NINDS
award_notice_date: 2015-01-23
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: NS
serial_number: 083692
program_official: CORRIVEAU, RODERICK A
project_start_date: 2014-02-15
project_end_date: 2016-01-31
study_section: Special Emphasis Panel[ZRG1-BINP-Y(08)F]
contact_pi_person_id: 8535896
contact_pi: MURPHY, MICHAEL PAUL
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
project_abstract:
DESCRIPTION (provided by applicant): Metabolic disease is linked to obesity - especially mid-life obesity - a persistent problem in our society. An unexplained connection exists between type 2 diabetes mellitus and neurologic disorders such as vascular dementia (VaD) and Alzheimer's disease (AD). The biological mechanism underlying this link is not known. As our population demographics shift towards an older average age the potential confluence of obesity diabetes and age related neurological dysfunction represents a potential public health disaster. The form of dementia afflicting individuals with a history of obesity and diabetes combines vascular pathology strokes and AD related neuropathology including amyloid deposits. It is not known if amyloid either in the brain parenchyma or deposited within the cerebrovasculature causes the vascular pathology or if some other aspect of diabetes and obesity is reponsible. This proposal grew out of the possibility that this connection may be related to leptin resistance. Leptin is an adipocyte-derived peptide hormone that regulates satiety and hunger via signaling through the leptin receptor which is expressed throughout the brain. Obese individuals are resistant to leptin. In preliminary experiments we discovered that leptin is a strong regulator of -secretase particularly PS1 expression at the mRNA level. To investigate this problem we created a line of knock-in mice that become rapidly obese and diabetic and develop amyloid pathology with increasing age. The most remarkable feature of this unique mouse model (db/AD) is that it develops a striking phenotype of cerebrovascular pathology including aneurysms and strokes and displays a profound cognitive impairment. This mouse line does not overexpress disease related proteins or use artificial promoter systems making it an ideal system for the study of how aberant gene regulation in metabolic disease can influence brain pathology. We believe that we have created a mouse model of VaD an understudied neurological disorder with limited treatment options. We propose to use our unique db/AD model to determine the mechanistic connection between aberrant leptin signaling and the development of aneurysms strokes and other aspects of cerebrovascular pathology. We will track the development of pathology longitudinally using state-of-the-art magnetic resonance imaging combined with two approaches currently in human clinical trials to treat dementia. Since these approaches have been shown to have a good safety profile in human trials the clinical implications for the outcome of this study are significant. The major strengths of this proposal are the use of a novel mouse model with unique features and an innovative approach to determine the mechanism driving the development of pathology. This project has the potential to significantly advance our understanding of the major underlying causes of VaD and has significant implications for the treatment and prevention of age-related cerebrovascular disease.

project_terms:
Adipocytes;Affect;Age;Alzheimer's Disease;Alzheimer's disease model;Amyloid;Aneurysm;Automobile Driving;Biological;Biological Factors;Blood Vessels;Brain;Brain Pathology;Cell Density;Cerebrovascular Disorders;Characteristics;Clinical;Clinical Trials;Dementia;Deposition;Development;Diabetes Mellitus;Disasters;Disease;Electron Microscopy;Employee Strikes;Endothelial Cells;Excision;Exhibits;Foundations;Functional disorder;Future;Gene Expression Regulation;Health;Human;Hunger;Image;Impaired cognition;Individual;Knock-in Mouse;Leptin;Leptin resistance;Lesion;Link;Magnetic Resonance Imaging;Messenger RNA;Metabolic Diseases;Modeling;Mus;Neurodegenerative Disorders;Neurologic Dysfunctions;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Outcome Study;Pathology;Peptides;Phenotype;Population;Prevention;Prevention strategy;Production;Promotor (Genetics);Proteins;Recording of previous events;Resistance;Risk;Role;Safety;Satiation;Signal Transduction;Societies;System;Testing;Vascular Dementia;age related;amyloid pathology;amyloid peptide;angiogenesis;base;cerebrovascular;demographics;density;diabetic;inhibitor/antagonist;innovation;leptin receptor;light microscopy;middle age;mouse model;nervous system disorder;neuropathology;notch protein;novel;overexpression;peptide A;peptide hormone;presenilin-1;prevent;public health medicine (field);research study;secretase;small molecule;stroke;therapeutic development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: A strong connection exists between risk for vascular dementia Alzheimer's disease type 2 diabetes and obesity but the mechanisms are unknown. The connection may involve strokes and other forms of cerebrovascular pathology. This project will explore the mechanism of this link and provide a strong foundation for future therapeutic development.


application_id: 8797281
project_number: 3T32DA035200-17S1
project_title: Research Training in Drug Abuse Behavior
project_terms: Behavior;Drug abuse;Research Training
administering_ic: NIDA
award_notice_date: 2014-06-25
opportunity_number: PA-12-100
application_type: 3
activity_code: T32
ic: DA
serial_number: 035200
suffix: S1
program_official: KAUTZ, MARY A
project_start_date: 1998-08-01
project_end_date: 2018-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
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
public_health_relevance:
The purpose of this application is to continue a highly successful 15-year training program in translational and interdisciplinary drug-abuse research. The program offers translational and interdisciplinary research training on bio-behavioral factors in drug abuse at the pre-doctoral and post-doctoral levels. Graduates of this program are actively involved in research teaching publishing articles and becoming independent drug abuse researchers. We aim to continue this record of success in the next funding period because the need for a translational or interdisciplinary program is greater today than ever before and the proposed training program fills a unique niche in drug abuse research.


application_id: 8796085
project_number: 1R01NS089515-01
project_title: The Role of Perlecan Domain V in Vascular Dementia
administering_ic: NINDS
award_notice_date: 2014-08-25
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: NS
serial_number: 089515
program_official: CORRIVEAU, RODERICK A
project_start_date: 2014-09-01
project_end_date: 2019-07-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7568819
contact_pi: BIX, GREGORY JAYE
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
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_terms:
APP-PS1;Acute;Aftercare;Age;Alzheimer's Disease;Alzheimer's disease model;Animal Model;Animals;Arteriovenous malformation;Astrocytes;Autopsy;Bilateral;Biochemical;Blood;Blood Vessels;Brain;Brain Part;Brain region;Carotid Stenosis;Cell Communication;Cell physiology;Cerebral Amyloid Angiopathy;Cognitive;Complex;Coupling;Dementia;Development;Endothelial Cells;Etiology;Experimental Animal Model;Extracellular Matrix;Failure (biologic function);Functional disorder;Gene Expression;Generations;Growth;Growth Factor;Health;Heparan Sulfate Proteoglycan;Homo;Human;Immunohistochemistry;Impaired cognition;Infarction;Injury;Integrins;Ischemic Stroke;Knock-in Mouse;Methods;Mus;Neurons;Outcome;Pathologic;Pathology;Patients;Pericytes;Phenotype;Play;Prevalence;Process;Protein Fragment;Proteins;Relative (related person);Replacement Therapy;Role;Therapeutic;Time;Vascular Dementia;angiogenesis;cerebrovascular;cognitive function;combat;diabetic;gray matter;hypoperfusion;improved;mouse model;neurovascular unit;novel;perlecan;post stroke;prevent;receptor;response;response to injury;stroke;white matter


application_id: 8795712
project_number: 5R01DE022597-03
project_title: Bacterial peptidylarginine deiminase a link between gums and joint disease
administering_ic: NIDCR
award_notice_date: 2015-01-12
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DE
serial_number: 022597
program_official: CHANDER, PREETHI
project_start_date: 2013-02-01
project_end_date: 2016-01-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
other_pis: Not Applicable
congressional_district: 03
department: NONE
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 DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Porphyromonas gingivalis is a leading pathogen in chronic periodontitis a disease process involving progressive destruction of tissues that support the teeth. Recently the organism has been reported to produce a unique bacterial enzyme P. gingivalis peptidylarginine deiminase (PPAD) which has the ability to convert arginine residues in proteins to citrulline. Protein citrullination alters protein structure and function hence PPA may be involved in dysregulation of the host's signaling network for immune evasion. Further accumulating evidence has revealed the role of autoimmunity against citrullinated proteins in the development of rheumatoid arthritis (RA). As inflammatory conditions in the lungs of cigarette smokers contributes to the breakdown of immune tolerance to citrullinated epitopes chronic exposure to citrullinated proteins at periodontitis sites may also predispose susceptible individuals to the development of autoantibodies and initiation of RA. Thus PPAD may represent the mechanistic link between periodontitis and rheumatoid arthritis - diseases that are known to be significantly associated to each other at the epidemiological level.  We hypothesize that citrullination of bacterial and host proteins in periodontal/gingival tissues by PPAD within the chronic inflammatory environment and immune system stimulation by bacteria- derived "danger signals" leads to the initial break of immune tolerance to citrullinated proteins and peptides. In addition PPAD may manipulate immune responses in inflamed periodontal tissues by modifying important effector molecules of the innate immunity including C3a and C5a anaphylatoxins and bradykinin. Biological activity of these peptides depends on the C-terminal arginine which is also a preferential target for PPAD. Hence this research proposal will investigate the important and innovative concept that PPAD as a virulence factor of P. gingivalis and mechanistic link between periodontitis and RA with the following specific aims: (i) in vivo and ex vivo examination of PPAD's role in the pathogenesis of RA; (ii) functional and structural studies of various forms of PPAD; and (iii) investigate the immunomodulatory effect of PPAD that is relevant to the pathogenesis of periodontal disease. Thus the proposed research will illuminate the PPAD's contribution to chronic inflammation driven by P. gingivalis infection and shed light on the possible link between periodontal disease and rheumatoid arthritis. This knowledge will create new perspectives in the treatment of periodontitis and prevention of rheumatoid arthritis in susceptible individuals.

project_terms:
Affect;Anaphylatoxins;Antibodies;Arginine;Atherosclerosis;Autoantibodies;Autoimmune Responses;Autoimmunity;Bacteria;Bioinformatics;Biological;Bone Resorption;Bradykinin;C-terminal;CAP18 lipopolysaccharide-binding protein;Chronic;Cigarette Smoker;Citrulline;Clinical;Collagen-Induced Arthritis;Complement;Complement 3a;Complement 5a;Complex;Connective Tissue;Data;Dental Plaque;Development;Disease;Environment;Enzymes;Epidemiology;Epitopes;Exposure to;Forsythia;Generations;Gingiva;Gingival Crevicular Fluid;Health;Homeostasis;Homologous Gene;Human;Immune;Immune Tolerance;Immune response;Immune system;Individual;Infection;Inflammation;Inflammatory;Intervention;Joints;Kinins;Knowledge;Lesion;Light;Link;Lung;Microbial Genome Sequencing;Molecular;Natural Immunity;Organism;Pathogenesis;Pathogenicity;Pathology;Patients;Peptides;Peptidoglycan;Periodontal Diseases;Periodontitis;Physiological;Population;Porphyromonas gingivalis;Post-Translational Protein Processing;Predisposition;Prevention;Process;Properdin;Protein-arginine deiminase;Proteins;Reaction;Reporting;Research;Research Proposals;Resistance;Rheumatoid Arthritis;Role;Serum;Signal Transduction;Site;Source;Substrate Specificity;Synovial Fluid;System;TNFRSF10A gene;Tissues;Tooth Loss;Tooth structure;Transgenic Mice;Treponema denticola;Validation;Virulence Factors;alveolar bone;arthropathies;bactericide;base;caspase;citrullinated protein;complement pathway;fimbria;gingipain;in vivo;innovation;interest;microbial;novel strategies;pathogen;pathogenic bacteria;polypeptide;preference;protein structure function;three dimensional structure;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis is characterized by the development of autoantibodies against citrullinated proteins within the joints in susceptible individuals. Porphyromonas gingivalis a known periodontal pathogen is the only known bacterium which produces an enzyme (PPAD) that is capable of converting arginine residues in proteins into citrullin. It is hypothesized that PPAD activity in inflamed infected periodontal tissues not onlycontributes to the pathology of periodontitis but also may promote breakdown of immunotolerance and initiates the development of rheumatoid arthritis.


application_id: 8795231
project_number: 5R01NS084857-02
project_title: Carbonyl Scavenging for Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2015-01-08
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: NS
serial_number: 084857
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2014-02-01
project_end_date: 2018-01-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
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): Our laboratory has documented that generation of the potent reactive nitrogen species (RNS) peroxynitrite (PN) is responsible for oxidative damage by lipid peroxidation (LP) and neurotoxic protein modification by binding of LP-derived carbonyl-containing aldehydes such as 4-hydroxynoneal (4-HNE) and acrolein to mitochondrial and other cellular elements during the first 72 hrs after traumatic brain injury (TBI). This oxidative damagecauses brain mitochondrial respiratory compromise and decreased calcium (Ca++) buffering which worsens post-TBI neuronal intracellular Ca++ overload calpain-mediated neuronal cytoskeletal degradation neurodegeneration and neurological impairment. Recently a novel antioxidant approach for post-central nervous system (CNS) injury for decreasing and possibly reversing oxidative damage has been identified that involves scavenging the LP-derived carbonyl compounds ("carbonyl scavenging") preventing their neurotoxic effects. Preliminary support from other laboratories and our own has shown that certain clinically used drugs that contain hydrazine function groups can covalently bind to 4-HNE or acrolein and prevent their neurotoxicity. The proposed 3 Aim project will employ phenelzine a long used hydrazine-containing anti-depressant that contains has been found to be an effective carbonyl scavenger as a tool to investigate the antioxidant neuroprotective effects of carbonyl scavenging in isolatedrat brain mitochondria and the rat controlled cortical impact TBI model. Specifcally the project will define the neuroprotective pharmacology (e.g. mechanism of action dose-response and therapeutic window) of phenelzine's "carbonyl scavenging" in terms of neuronal mitochondrial and cytoskeletal protection along with the ability to improve chronic motor and cognitive recovery and to decrease post-traumatic neurodegeneration. Since phenelzine has a long history of clinical use and a well understood human safety profile the translation of the drug's use into clinical TBI trials would be facilitated.

project_terms:
4 hydroxynonenal;Acrolein;Acute;Aldehydes;Antihypertensive Agents;Antioxidants;Binding (Molecular Function);Brain;Brain Injuries;Buffers;Calcium;Calpain;Cell Culture Techniques;Cell membrane;Chemicals;Chronic;Clinical;Data;Dose;Drug usage;Elements;Exposure to;Functional disorder;Generations;Health;Human;Hydralazine;Hydrazine;Impairment;Injury;Ischemia;Laboratories;Lesion;Lipid Peroxidation;Lipids;Mediating;Membrane Lipids;Mitochondria;Mitochondrial Proteins;Modeling;Modification;Mortality Vital Statistics;Motor;Mus;Nerve Degeneration;Neurologic;Neurons;Patients;Peroxonitrite;Pharmacology;Phase;Phase III Clinical Trials;Phenelzine;Polyunsaturated Fatty Acids;Post-Translational Protein Processing;Rattus;Reaction;Reactive Nitrogen Species;Reactive Oxygen Species;Recording of previous events;Regimen;Reperfusion Therapy;Reporting;Research Personnel;Safety;Spinal cord injury;Staging;Stress;Testing;Therapeutic;Time;Tissues;Toxic effect;Translations;Traumatic Brain Injury;Traumatic Subarachnoid Hemorrhage;Treatment Efficacy;attenuation;axonal degeneration;base;carbonyl compound;carbonyl group;central nervous system injury;clinically relevant;cognitive function;cognitive recovery;controlled cortical impact;cytotoxic;improved;in vivo;injured;lipid peroxidation inhibitor;morris water maze;motor function improvement;motor recovery;nerve injury;neurotoxic;neurotoxicity;novel;oxidative damage;perhydroxyl radical;prevent;protective effect;respiratory;response;stroke;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This project will examine the neuroprotective effects of phenelzine a long-used anti-depressant compound that has recently been discovered to also be a scavenger of lipid peroxidation-derived carbonyl-containing aldehydes such as 4-hydroxynonenal and acrolein in the rat controlled cortical impact traumatic brain injury model (CCI-TBI). Preliminary data has demonstrated that phenelzine can protect brain mitochchondria from impairment of their function an effect that is correlated with a lessened 4-hydroxynonenal modification of mitochondrial proteins and to decrease post-TBI brain damage. This proposal will expand our understanding of the neuroprotective pharmacology (e.g. mechanism of action dose-response and therapeutic window) of phenelzine's "carbonyl scavenging" in terms of neuronal mitochondrial and cytoskeletal protection along with the ability to improve chronic motor and cognitive recovery and to decrease post-traumatic neurodegeneration.


application_id: 8795230
project_number: 5R21NS084088-02
project_title: Novel Biomarkers of TBI Identified Using Phage Display
administering_ic: NINDS
award_notice_date: 2015-01-08
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: NS
serial_number: 084088
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2014-02-01
project_end_date: 2017-01-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W.
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
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): Traumatic brain injury (TBI) can be frustratingly difficult to diagnose particularly for mild cases which can result in inadequate or improper treatment. As a result there has been considerable interest in identifying biochemical markers of TBI to aid in diagnosis and evaluation of treatment efficacy. CSF and serum alterations in several proteins have been investigated in both animal models and clinical studies but these appear to be best suited for severe TBI cases. Urgently needed are biomarkers for mild TBI which represents the majority of the cases and which are the most difficult to diagnose. To identify novel serum and CSF biomarkers for mild and moderate TBI we propose an unbiased approach utilizing phage display. Phage display is a powerful tool for selecting peptides proteins or antibodies with specific binding properties. It uses bacteriophages in which DNA encoding a peptide or protein is inserted into the gene encoding a coat protein of a filamentous phage such as M13 phage. The encoded protein or peptide is expressed on the cell surface of the phage and used to attract and bind proteins of interest. We propose to use engineered phage display peptide libraries in which >2 million independent clones express random sequences of 7 or 12 amino acid peptides. In Aim 1 three different phage libraries will be screened to identify phages that bind to the serum and CSF obtained from rats with mild TBI produced using the lateral fluid percussion model. The biofluids will be collected at 6h and 24h after injury. We will utilize a subtractive panning technique in which phage libraries are first bound to the biofluid (CSF or serum) from uninjured mice to remove non- specific phages then incubated with injury biofluids to identify injury-selective phages. Preliminary data demonstrate the feasibility of this approach using serum from a mouse TBI model at 6h postinjury. Aim 2 will use sequence and identify the proteins which bind to the phages selective for the injury biofluids. Together the above results will identify novel biomarkers of mild TBI to assist in the diagnosis of TBI determination of injury severity evaluation of recovery and therapeutic efficacy and prediction of outcomes.

project_terms:
Address;Amino Acids;Animal Model;Antibodies;Bacteriophage M13;Bacteriophages;Binding (Molecular Function);Binding Proteins;Biochemical Markers;Biological Markers;Biomechanics;Brain Concussion;Brain Injuries;Capsid Proteins;Cell surface;Clinical;Clinical Research;DNA;DNA Sequence;Data;Diagnosis;Diagnostic;Discrimination (Psychology);Disease;Dizziness;Engineering;Evaluation;Genes;Head;Headache;Health;Image;Incubated;Individual;Inflammatory;Injury;Inovirus;Lateral;Libraries;Link;Liquid substance;Magnetism;Mass Spectrum Analysis;Modeling;Mus;Nausea;Nervous System Physiology;Outcome;Peptide Phage Display Library;Peptides;Percussion;Phage Display;Phase;Post-Concussion Syndrome;Property;Proteins;Protocols documentation;Radiology Specialty;Rattus;Recombinants;Recovery;Sensitivity and Specificity;Serum;Severities;Symptoms;Techniques;Technology;Time;Translating;Translations;Traumatic Brain Injury;Treatment Efficacy;Unconscious State;base;diagnosis evaluation;fluid percussion injury;injured;instrument;interest;mild traumatic brain injury;mouse model;novel;research study;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Over 1 million individuals sustain a traumatic brain injury in a given year with the majority being concussions or similar mild forms. However diagnosis of such brain injury is difficult. Biomarkers with sufficient sensitivity and specificity would assistnot only with the diagnosis of brain injury but also with determination of injury severity evaluationof recovery and therapeutic efficacy and prediction of outcomes.


application_id: 8795163
project_number: 5K23AR062069-03
project_title: Prolonged alterations to muscle following knee surgery and physical therapy
administering_ic: NIAMS
award_notice_date: 2015-02-20
opportunity_number: PA-11-194
application_type: 5
activity_code: K23
ic: AR
serial_number: 062069
program_official: BOYCE, AMANDA T
project_start_date: 2013-02-01
project_end_date: 2016-01-31
study_section: ZAR1-CHW(M1)
contact_pi_person_id: 10137938
contact_pi: NOEHREN, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
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: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Anterior;Architecture;Area;Award;Biology;Biomechanics;Biophysics;Biopsy;Clinical;Clinical Research;Clinical Trials;Coupled;Data;Data Analyses;Degenerative polyarthritis;Development;Diffusion;Disease;Effectiveness;Fascicle;Fiber;Fibrosis;Future;Goals;Growth;Head;Health;Health Sciences;Individual;Intervention;Joints;Kentucky;Knee;Laboratories;Left;Leg;Length;Ligaments;Link;Magnetic Resonance Imaging;Measurement;Measures;Mechanics;Mentored Patient-Oriented Research Career Development Award;Mentors;Mentorship;Methods;Microscopic;Molecular;Morphology;Muscle;Muscle Fibers;Muscle Weakness;Muscle function;Operative Surgical Procedures;Outcome;Patient Outcomes Assessments;Patients;Physical therapy;Physiological;Physiology;Positioning Attribute;Process;Production;Property;Protocols documentation;Quadriceps Muscle of the Thigh;Recovery;Rehabilitation therapy;Research;Research Design;Research Personnel;Scientist;Senior Scientist;Structure;Testing;Time;Tissues;Training;Translating;United States National Institutes of Health;Universities;anterior cruciate ligament reconstruction;base;clinically significant;cohort;college;evidence base;experience;follow-up;functional outcomes;improved;innovation;interest;joint loading;muscular structure;non-invasive imaging;novel;professor;reconstruction;rehabilitation strategy;response to injury;skills;strength training;vastus lateralis


application_id: 8795142
project_number: 5R25AA022823-02
project_title: Basic and Applied Summer Training in Alcohol Research
administering_ic: NIAAA
award_notice_date: 2015-01-21
opportunity_number: PAR-13-104
application_type: 5
activity_code: R25
ic: AA
serial_number: 022823
program_official: GRANDISON, LINDSEY
project_start_date: 2014-02-01
project_end_date: 2019-01-31
study_section: Epidemiology, Prevention and Behavior Research Study Section[AA-2]
contact_pi_person_id: 1869834
contact_pi: NIXON, KIMBERLY
other_pis: PRENDERGAST, MARK A
congressional_district: 06
department: PHARMACOLOGY
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 PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Advertising;Alcohol consumption;Alcohols;Arts;Behavioral Sciences;Biomedical Research;Brain Injuries;Career Choice;Cellular biology;Development;Domestic Violence;Engineering;Evaluation;Faculty;Goals;Hand;Health;Institution;Kentucky;Laboratories;Laboratory Personnel;Mathematics;Nerve Degeneration;Pharmacologic Substance;Play;Qualifying;Research;Research Infrastructure;Role;STEM field;Schools;Science;Students;Supervision;Surveys;Technology;Training;Underrepresented Minority;Universities;Work;addiction;alcohol research;bench to bedside;career;college;experience;peer;programs;responsible research conduct;scientific organization;success;symposium;undergraduate research;undergraduate student;web site


application_id: 8793994
project_number: 1P40OD019794-01
project_title: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2015-03-01
opportunity_number: PAR-14-005
application_type: 1
activity_code: P40
ic: OD
serial_number: 019794
program_official: CONTRERAS, MIGUEL A
project_start_date: 2015-03-01
project_end_date: 2020-02-29
study_section: Special Emphasis Panel[ZRG1 BBBP-Y (45)]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adolescent;Adult;Advisory Committees;Ambystoma;Ambystoma mexicanum;Applied Research;Area;Behavior;Biological;Biomedical Research;Body part;Brain;Breeding;Cells;Cellular biology;Collection;Communities;Community Services;Computers;Custom;Data;Development;Embryo;Embryonic Development;Ensure;Equipment;Evolution;Funding;Genes;Genetic;Genome;Genomics;Health;Heart;Hour;Housing;Human;IACUC;Informatics;Injection of therapeutic agent;Institution;Jaw;Kentucky;Knock-in Mouse;Learning;Life;Limb structure;Methods;Microinjections;Mission;Modeling;Monitor;Natural regeneration;Neurobiology;Organism;Physiology;Population;Preparation;Procedures;Production;Protocols documentation;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Retina;Services;Site;Site-Directed Mutagenesis;Speed (motion);Spinal Cord;System;Tail;Time;Tissues;Transgenic Organisms;Translating;United States National Institutes of Health;Universities;Vertebrates;Visit;Work;animal resource;base;experience;gene function;innovation;knowledge base;meetings;operation;organ regeneration;public health relevance;tissue repair;web site


application_id: 8793804
project_number: 5R01HL112085-03
project_title: Effects of Sleep Deprivation on Infection Induced Organ Failure
administering_ic: NHLBI
award_notice_date: 2015-01-26
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 112085
program_official: LAPOSKY, AARON D
project_start_date: 2013-02-15
project_end_date: 2016-01-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 6210708
contact_pi: CALLAHAN, LEIGH A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
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): Recent studies indicate that critically ill patients experience poor sleep frequent disruptions loss of circadian rhythm and a marked reduction of the percentage of sleep time spent in restorative stages. Importantly sleep deprivation in these patients may have adverse consequences. In keeping with this concept two recent animal studies found that sleep deprivation markedly increases death in sepsis but the mechanisms responsible for this phenomenon are completely unknown. We will test the specific hypotheses that sleep deprivation interacts with infection to activate endoplasmic reticulum (ER) stress pathways and that ER stress pathway activation in turn causes failure of multiple organs. Aim 1 will determine if infection and sleep deprivation synergistically induce ER stress in multiple tissues and if ER stress pathway activation produces organ failure. Studies will be performed using animal models of sepsis (cecal ligation and puncture CLP) and sleep deprivation (SD). Experiment 1.1 will test the hypothesis that sepsis and sleep deprivation interact to induce ER stress with ER stress pathways activated in parallel with development of organ failure. Experiment 1.2 will test the hypothesis that chemical activation of ER stress triggers pathological alterations (e.g. activation of downstream proteolytic pathways) that produce organ dysfunction. Aim 2 will elucidate the upstream mechanisms by which sepsis and sleep deprivation activate ER stress pathways. Experiment 2.1 will test the hypothesis that cytokine-induced production of reactive oxygen species (ROS) is the key upstream trigger that activates ER stress in sepsis. Experiment 2.2 will test the hypothesis that upstream alterations in peripheral tissue clock gene function activate ER stress pathways in response to sleep deprivation. Experiment 2.3 will test the hypothesis that disruption of peripheral tissue clock function increases ROS generation and activates ER stress pathways. Aim 3 will determine if administration of pharmacological inhibitors of ER stress pathways improves organ function in sepsis and sleep deprivation. Experiments 3.1 3.2 and 3.3 will test the hypothesis that either z-ATAD-fmk (a caspase 12 inhibitor) salubrinal (a selective inhibitor of eIF2 dephosphorylation) or melatonin (an endogenous hormone that inhibits the IRE1 pathway) will block ER stress pathway dependent cell damage and improve organ function in CLP+SD. Experiment 3.4 will test the hypothesis that delayed administration of the pharmacologic agent to found to produce the best therapeutic effect will block ER stress pathway dependent cell damage and improve organ function in CLP+SD.

project_terms:
Animal Model;Animals;Area;Cause of Death;Cells;Cessation of life;Chemicals;Circadian Rhythms;Cognitive;Complex;Critical Illness;Data;Development;Diagnostic tests;Disease;Functional disorder;Generations;Genes;Goals;Heart Diseases;Hormones;Hospitalization;Infection;Ligation;Light;Malignant Neoplasms;Melatonin;Modeling;Mortality Vital Statistics;Multiple Organ Failure;Noise;Organ;Organ failure;Pathway interactions;Patients;Peripheral;Pharmaceutical Preparations;Physiological;Population;Production;Protein Dephosphorylation;Puncture procedure;Reactive Oxygen Species;Recovery;Risk;Sepsis;Sleep;Sleep Deprivation;Staging;Survivors;Testing;Therapeutic Effect;Time;Tissues;United States;adverse outcome;caspase 12;cell injury;cytokine;endoplasmic reticulum stress;experience;gene function;improved;inhibitor/antagonist;novel therapeutics;nursing intervention;psychologic;public health relevance;research study;response;septic

public_health_relevance:
PUBLIC HEALTH RELEVANCE: During hospitalization patients' sleep is constantly disrupted due to diagnostic tests frequent nursing interventions noise from alarms and changes in light levels. Recent studies show that sleep deprivation increases death when combined with infection but how this occurs is not known. We have discovered that sleep disruption during infection activates pathways that cause several of the body's organs to fail so the purpose of our proposal is to determine the cellular mechanisms responsible for the interaction of sleep deprivation and infection and to define new treatments which may improve survival and recovery in hospitalized patients.


application_id: 8792925
project_number: 1R01HL125228-01
project_title: Mineralocorticoid receptor and abdominal aortic aneurysm
administering_ic: NHLBI
award_notice_date: 2014-11-13
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: HL
serial_number: 125228
program_official: TOLUNAY, ESER
project_start_date: 2014-11-15
project_end_date: 2018-10-31
study_section: Special Emphasis Panel[ZRG1 VH-A (03)]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: GUO, ZHENHENG
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
project_abstract:
DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) is a vascular disease with rising prevalence and a high mortality rate. Current treatment is limited to open or endovascular surgery a procedure for which only 10% of AAA patients are eligible highlighting an urgent need for new mechanistic understandings of AAA. With a long term goal to identify new therapeutic targets for AAA the current proposal will investigate the pathological roles of aldosterone (Aldo) mineralocorticoid receptor (MR) and high salt intake in AAA. Elevated plasma Aldo and high salt intake have been linked to a spectrum of cardiovascular diseases. MR antagonists have been shown to be effective in reducing cardiovascular mortality and hospitalizations for heart failure. However little is known of the roles of Aldo MR and high sal intake in AAA. Recently the applicants discovered that administration of MR agonists deoxycorticosterone acetate (DOCA) or Aldo to C57BL/6 male mice induced AAA in the presence of high salt. Importantly DOCA- or Aldo-salt-induced AAA mimicked human AAA with respect to oxidative stress vascular inflammation smooth muscle cell (SMC) degeneration metalloproteinase (MMP) activation and elastin degradation. Treatment of mice with spironolactone or eplerenone two clinically used MR antagonists effectively attenuated DOC- or Aldo-salt-induced aortic aneurysm formation and rupture. Building on these exciting and novel findings the applicants further demonstrated that in isolated mouse aorta administration of pathological plasma concentrations of Aldo and sodium activated MMP2 and induced oxidative stress suggesting a direct pathological effect of Aldo and salt on aorta. Interestingly
denuding endothelial cells from isolated aorta had no effect on Aldo-salt-induced MMP2 activation and oxidative stress indicating that MR in SMC (SMC-MR) is involved. Consistent with this concept the applicants found that p47phox a component of NADPH oxidase that has been implicated in human AAA was markedly upregulated by Aldo-salt in the medial layer of abdominal aortic wall and co-localized with SMC a-Actin which was completely abolished by treatment of mice with eplerenone. Moreover treatment of mice with temporal a free radical scavenger diminished DOCA-salt-induced AAA. Therefore the applicants hypothesize that increased plasma Aldo and salt activate SMC-MR and p47phox and thus result in oxidative stress MMP activation vascular inflammation SMC degeneration and elastin degradation thereby contributing to AAA. Three specific aims are: 1) test the hypothesis that SMC-MR is required for Aldo-salt-induced AAA; 2) define the mechanism by which SMC-MR targets p47phox to induce AAA; 3) determine whether targeting the Aldo/MR/salt axis is effective for treatment of AAA. To achieve these aims genetic animal models (SMC- specific MR knockout mice and global p47phox knockout mice) and various molecular biochemical and physiopathological approaches will be used. If proposed studies are successful they will have a profound impact on current basic researches and clinical practices on the etiology diagnosis and treatment of AAA.

project_terms:
2266-tetramethyl-4-piperidinol-N-oxyl;Abdomen;Abdominal Aortic Aneurysm;Accounting;Acetates;Actins;Affect;Age;Agonist;Aldosterone;Aldosterone Antagonists;Animal Model;Aorta;Aortic Aneurysm;Attenuated;Basic Science;Binding (Molecular Function);Biochemical;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Clinic;Country;Deoxycorticosterone;Diagnosis;Disease;Elastin;Endothelial Cells;Etiology;Free Radical Scavengers;Genetic;Goals;Heart failure;Hospitalization;Human;Hypertension;Intake;Kidney;Knockout Mice;Left Ventricular Hypertrophy;Link;MMP2 gene;MMP9 gene;Matrix Metalloproteinases;Medial;Membrane;Messenger RNA;Metalloproteases;Mineralocorticoid Receptor;Molecular;Mortality Vital Statistics;Mus;Myocardial Infarction;NADPH Oxidase;Operative Surgical Procedures;Oxidative Stress;Patients;Pharmaceutical Preparations;Plasma;Prevalence;Procedures;Promotor (Genetics);Role;Rupture;Ruptured Abdominal Aortic Aneurysm;Scheme;Smooth Muscle Myocytes;Sodium;Sodium Chloride;Spironolactone;Stress;Tamoxifen;Testing;Time;Vascular Diseases;Withdrawal;Woman;abdominal aorta;age related;clinical practice;diagnosis evaluation;effective therapy;eplerenone;insight;loss of function;male;men;mouse model;new therapeutic target;novel;novel therapeutics;prevent;public health relevance;salt intake;stroke;vascular inflammation


application_id: 8792349
project_number: 5R01CA167181-03
project_title: Novel Mechanism of Genome Instability in Colorectal Cancer
administering_ic: NCI
award_notice_date: 2014-12-22
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 167181
program_official: OKANO, PAUL
project_start_date: 2013-02-15
project_end_date: 2015-07-31
study_section: Molecular Genetics B Study Section[MGB]
contact_pi_person_id: 7875365
contact_pi: LI, GUO-MIN
other_pis: GU, LIYA
congressional_district: 06
department: PHARMACOLOGY
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 long-term goal of this project is to study how post-translational modifications of DNA mismatch repair (MMR) proteins impact genome integrity and cancer development. MMR maintains genome stability by removing mismatches in the newly synthesized strand during DNA replication. The MMR reaction involves mismatch recognition by the initiation factors (MutS MutL and PCNA) mismatch removal by nucleases and DNA gap-filling by DNA polymerases. The importance of MMR is under- scored by the fact that MMR defects lead to hypermutations and susceptibility to both hereditary and sporadic colorectal cancers (CRCs). Exhibiting elevated instability in simple repeats called microsatellite instability (MSI) is a hallmark of MMR-deficient CRCs. However only ~70% of hereditary and sporadic CRC cases that display MSI have identifiable mutations in MMR genes suggesting that other mechanism(s) are responsible for the MSI phenotype in the remaining 30% of the cases. We recently showed that CRC cells containing high levels of PCNA tyrosine phosphorylation are defective in MMR in vitro. We therefore hypothesize that PCNA phosphorylation inhibits MMR leading to genome instability and CRC development. To test this hypothesis three Specific Aims are proposed. Aim 1 is to determine how phosphorylated PCNA inhibits MMR. A well-defined in vitro MMR reaction will be conducted in both a nuclear extract system and a reconstituted system in the presence or absence of phosphorylated PCNA and analysis of the repair products will allow determination of the specific step(s) of the reaction tht is blocked. Aim 2 is to determine hypermutability and MMR proficiency in cells stably expressing phosphorylated PCNA mimics while suppressed for endogenous PCNA expression. Aim 3 is to analyze tumorigenesis in transgenic mice expressing phosphorylated PCNA. A successful completion of the proposed work will establish PCNA tyrosine phosphorylation as a novel biomarker for cancer etiology and progression.

project_terms:
Adult;American;Biological Assay;Biological Markers;Cancer Etiology;Cell Line;Cell Proliferation;Cells;Cessation of life;Colorectal Cancer;DNA;DNA biosynthesis;DNA-Directed DNA Polymerase;Defect;Deoxyribonucleases;Development;Disease;EGFR Protein Overexpression;Epidermal Growth Factor Receptor;Excision;Exhibits;Family;Gene Mutation;Gene Proteins;Genes;Genetic;Genome;Genome Stability;Genomic Instability;Goals;Health;In Vitro;Inherited;Laboratories;Lead;Link;Maintenance;Malignant Neoplasms;Measures;Mediating;Microsatellite Instability;Mismatch Repair;Molecular;Monitor;Mutation;Nuclear Antigens;Nuclear Extract;Nucleotides;Peptide Initiation Factors;Phenotype;Phosphorylation;Play;Polymers;Post-Translational Protein Processing;Predisposition;Proliferating;Proteins;Reaction;Receptor Protein-Tyrosine Kinases;Role;Surgical incisions;System;Testing;Transgenic Animals;Transgenic Mice;Tyrosine;Tyrosine Phosphorylation;United States;Work;cancer cell;cancer therapy;colon cancer cell line;colorectal cancer screening;genome integrity;improved;in vivo;member;novel;nuclease;overexpression;public health relevance;reconstitution;repaired;stable cell line;tumor progression;tumorigenesis

public_health_relevance:
Despite that great progress has been made in colorectal cancer (CRC) therapy the disease is still the second leading cause of cancer deaths among adults in the United States. A major reason for this is that the factors that cause a significant fraction of CRC are not fully understood. To improve the health of Americans this application aims to identify these factors which will improve both CRC screening and treatment.


application_id: 8792347
project_number: 5R01CA165469-03
project_title: Role of Tcl1 and Par-4 in regulation of chronic lymphocytic leukemia
administering_ic: NCI
award_notice_date: 2015-01-21
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 165469
program_official: JHAPPAN, CHAMELLI
project_start_date: 2013-02-07
project_end_date: 2016-01-31
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 7739669
contact_pi: BONDADA, SUBBARAO
other_pis: RANGNEKAR, VIVEK M
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
project_abstract:
DESCRIPTION (provided by applicant):  Chronic lymphocytic leukemia (CLL) also known as small cell lymphoma constitutes almost 30% of all cases of non-Hodgkin's lymphoma. It is the most common adult leukemia. Despite advances in chemotherapy treatment options for CLL patients are limited with only a modest efficacy especially for patients with unmutated types of B cell receptors (BCR) del (17p13.1) and p53 mutations. Tcl-1 an oncogene initially found to be translocated in T-cell leukemias has been found to be expressed at higher levels in CLL phenotypes that are classified as aggressive. A mouse model for CLL has been generated by expressing the Tcl-1 oncogene in B cells using immunoglobulin promoter and the E enhancer. These mice reproducibly develop CLL in 13-18 months and have been shown to be excellent models for human CLL. Par-4 is a pro-apoptotic tumor suppressor discovered by us that induces apoptosis in cancer but not normal cells using both the Fas pathway and by inhibiting NF-B. We made four novel observations. First the B-cell receptor signaling pathway is active both in the human CLL cells and in the E-Tcl-1 mouse model of CLL as reflected by constitutive activation of Src family protein tyrosine kinases (SFK). Second we discovered that expression of Tcl1 is down regulated upon inhibition of SFK suggesting a role for BCR signaling in Tcl1 expression. Third we found that expression of Par-4 is down-regulated in E-Tcl1 CLL cells compared to normal mice while its expression has been found to be variable in human CLL cells. Fourth we discovered that E-Tcl1 cells are killed by soluble Par-4 and SAC a specific domain of Par-4 that is cytotoxic only to tumor cells. Based on these observations we hypothesize that a balance between Tcl1 and Par-4 regulated by BCR signaling decides the fate of CLL cells between survival and death. We have three specific aims. Aim 1 will determine the importance of BCR signaling and the role of specific SFKs in the regulation of Tcl-1 and Par-4 expression using the E-Tcl-1 mouse model of CLL. Aim 2 will investigate the importance of Par-4 overexpression for CLL development using a newly generated inducible Par-4 transgenic mice mouse model and the E-Tcl-1 mice. Aim 2 will involve preclinical studies to test the efficacy of extracellular Par-4 and SAC to inhibit CLL growth in the E-Tcl-1 mouse model. The relative importance of Tcl-1 and Par-4 will be studied in Aim 3 with primary CLL cells from patients thus translating the basic research findings in Aims 1 and 2 to clinical samples. The collaboration between UK and OSU provides us an opportunity to integrate the basic science and pre-clinical findings from the first two Aims with studies in Aim 3 using patient derived CLL cells. The exciting aspect of these studies is the possibility that soluble Par-4 or SAC can be developed into a treatment strategy for CLL cells either in isolation or in combination with SFK inhibitors or other targets that are currently being investigated in our laboratories.

project_terms:
17p13.1;A Mouse;Affect;Animal Model;Apoptosis;Apoptotic;B lymphoid malignancy;B-Cell Lymphomas;B-Lymphocytes;Basic Science;Biology;Bone Marrow;Cell Aging;Cell Survival;Cells;Cessation of life;Chromosomal translocation;Chronic Lymphocytic Leukemia;Clinical;Clinical Data;Clinical Investigator;Clinical Trials;Collaborations;Development;Disease;Down-Regulation;Elderly;Enhancers;Equilibrium;Family;Family member;GRP gene;GRP78;Genes;Goals;Grant;Growth;Health;Human;Immunoglobulins;In Vitro;Induction of Apoptosis;Killings;Laboratories;Leukemic Cell;Lymphoid;Malignant Neoplasms;Mediating;Modality;Modeling;Mus;Mutation;Nature;Non-Hodgkin's Lymphoma;Normal Cell;Oncogenes;Organ;PAWR gene;Pathway interactions;Patients;Peptides;Phenotype;Play;Predisposition;Promotor (Genetics);Protein Tyrosine Kinase;Proteins;Receptor Signaling;Receptors Antigen B-Cell;Regulation;Relative (related person);Resistance;Role;Sampling;Signal Pathway;Signaling Molecule;Small Interfering RNA;Small-Cell Lymphoma;Surface;T-Cell Leukemia;T-Cell Receptor;T-Lymphocyte;Testing;Therapeutic;Therapeutic Effect;Transcription Factor AP-1;Transgenic Mice;Transgenic Organisms;Translating;Tumor Suppressor Proteins;Western World;Whole Blood;adult leukemia;base;cancer cell;cell age;cell killing;chemotherapy;clinically relevant;cytotoxic;efficacy testing;extracellular;genetic approach;in vivo;inhibitor/antagonist;member;molecular marker;mouse model;neoplastic cell;novel;outcome forecast;overexpression;peripheral blood;pre-clinical;preclinical study;pro-apoptotic protein;receptor;response;therapy development;transcription factor;treatment strategy;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  The efficacy of existing therapeutic modalities for Chronic lymphocytic leukemias which affect mainly older adults is not high and new therapies for this disease are not yet available. The proposed studies will focus on two novel molecules Tcl-1 and Par-4 that have antagonistic roles in survival of CLL cells and may provide new avenues that can be developed into therapeutic strategies.


application_id: 8791173
project_number: 4R44AG044157-02
project_title: Circulating Blood-Based Diagnostic for Mild Cognitive Impaired Victims
administering_ic: NIA
award_notice_date: 2014-03-31
opportunity_number: PA-12-088
application_type: 4
activity_code: R44
ic: AG
serial_number: 044157
program_official: HSIAO, JOHN
project_start_date: 2014-04-01
project_end_date: 2015-12-31
study_section: Special Emphasis Panel[ZRG1-ETTN-M(11)B]
contact_pi_person_id: 1860379
contact_pi: WANG, EUGENIA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 805479370
primary_uei: KPMEKJJTDUS5
duns_number: 805479370
uei: KPMEKJJTDUS5
fips: US
organization_id: 10020610
organization_name: ADVANCED GENOMIC TECHNOLOGY, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402416052
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This project aims to generate blood tests for: 1. mild cognitive impairment (MCI) and 2. conversion risk from MCI to full-blown Alzheimer's disease (AD). We have reported that systemic footprints increases in key micro- RNA (miR) levels are identifiable in AD blood samples; here we suggest that this is also true for MCI the pre- AD phase. Our recent results suggest two stages of cognitive decline continuum: Stage 1 for key microRNAs increased from circulating blood of normal elderly controls (NEC) to that of MCI patients but not further to AD; and Stage 2 for specific circulating blood microRNA increases from MCI to AD. This led us to suggest our mo- del: Stage 1 circulating microRNAs as MCI-specific biomarkers and Stage 2 circulating microRNAs as biomark- ers for conversion of MCI to AD. Prototypes of these biomarkers are: Stage 1 miR-181b increases from NEC to MCI levels but not further in AD plasma samples; Stage 2 increased miR-34a & miR-34c levels observed only from MCI to AD but not from NEC to MCI plasma. These results suggest that the MCI cognitive decline may start with increased Stage 1 microRNAs' expression then Stage 2 increases add insult to injury; the for- mer being MCI-specific biomarkers and the latter specificfor AD and/or converter patients. Our goal is then to establish two sets of stage-specific biomarkers based on: a. highly reproducible data for identified blood micro- RNAs; b. training datasets for next-stage development for FDA approval; and c. validated specificity for de- mentia due to AD in contrast to other types of dementia. Toward this end Phase I will study 30 archived sam- ples each of MCI NEC and AD blood to attain: Aim 1 establishing the reproducibility of our protocol for opti- mal blood microRNA assays and identifying lead microRNAs' origins by determining concordance and/or dis- cordance among the above three microRNAs' increases in three circulating blood compartments: peripheral blood mononuclear cells (PBMC) plasma/serum and its derivative exosomes; and Aim 2 identifying other members of four lead array-profiled and PCR-validated microRNA families: miR-34 -181 200 & Let-7 to expand our pool of candidate Stage 1 and Stage 2 biomarkers. In Phase II Aim 1 expands to a larger cohort of 200 MCI patients' samples to establish a Stage 1 biomarker training dataset tracing 21 microRNAs of these 4 families; Aim 2 establishes a repertoire of Stage 2 biomarkers in archived specimens from 22 MCI subjects in our study 12 of whom have converted to AD within the past decade by comparing freshly collected with archived blood samples from converters versus non-converters by qPCR assays of the 21 listed miRNAs and array profiling to identify additional novel ones; and Aim 3 establishes the identified biomarkers as specific for AD in contrast with non-AD dementias i.e. Frontotemporal (FTD) Lewy body (LBD) and Parkinson's disease (PD) with dementia (PDD). Success of this project will provide blood miRNA-based diagnostics for MCI and predict conversion from MCI to AD unprecedented tests to monitor disease onset progression and drug efficacy for novel therapies to retard the decline of MCI to bona fide AD.

project_terms:
Alzheimer's Disease;Archives;Biological Assay;Biological Markers;Bipolar Disorder;Blood;Blood Tests;Blood specimen;Boxing;Brain;Cancer Diagnostics;Cardiovascular Diseases;Cells;Central Nervous System Diseases;Cerebrospinal Fluid;Clinical;Cognitive;Companions;Comparative Study;Data;Data Quality;Data Set;Dementia;Development;Diagnosis;Diagnostic;Disease;Disease Progression;Elderly;Family;Frontotemporal Dementia;Funding;Genomics;Goals;Grant;Health;Healthcare;Healthcare Systems;Huntington Disease;Image;Impaired cognition;Individual;Injury;Lead;Lewy Bodies;Lewy Body Dementia;Magnetic Resonance Imaging;Measurable;Measurement;Messenger RNA;Metric;MicroRNAs;Mind;Mission;Monitor;Nature;Nerve Degeneration;Onset of illness;Parkinson Disease;Parkinson's Dementia;Pathogenesis;Patients;Peripheral Blood Mononuclear Cell;Phase;Plasma;Population;Pregnancy Trimesters;Proteins;Protocols documentation;Reporting;Reproducibility;Risk;Risk Assessment;Sampling;Small Business Innovation Research Grant;Specificity;Specimen;Staging;Technology;Testing;Training;Validation;Work;aging population;base;cohort;commercialization;cost effective;drug efficacy;indexing;member;mental state;mild cognitive impairment;neuropsychological;novel;outcome forecast;prototype;success;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Like Alzheimer's disease (AD) health care mild cognitive impairment (MCI) due to AD suffers from the lack of a noninvasive blood test which is a major roadblock to MCI diagnosis; in its absence the disease is largely de- fined by neuropsychological assessment and costly MRI imaging and secondarily by identified cerebrospinal fluid biomarkers a less ideal approach due to its invasive nature. This project aims to generate cost-effective noninvasive blood tests for serial diagnosis and staging of MCI and its conversion to full-blown AD based on unique biomarkers microRNA expressions whose levels in circulating blood are 'footprints' of disease patho- genesis reflecting cognitive declin in brain. Quantitative metrics of circulating key microRNAs may serve as numerical indices for diagnosis of MCI and prognosis of conversion to AD as well as objective drug efficacy measurements for novel therapies to retard the further decline of these victims from developing full-blown Alzheimer's disease and thus halting the tidal wave of a fast-increasing aging population suffering this devastating mind-robbing peril.


application_id: 8790688
project_number: 5F32NS084605-02
project_title: Dysregulated neuroinflammation: a novel target for neurodegeneration after TBI
administering_ic: NINDS
award_notice_date: 2014-06-26
opportunity_number: PA-11-113
application_type: 5
activity_code: F32
ic: NS
serial_number: 084605
program_official: CORRIVEAU, RODERICK A
project_start_date: 2013-07-01
project_end_date: 2016-06-30
study_section: Special Emphasis Panel[ZRG1-F01-F(20)L]
contact_pi_person_id: 9651320
contact_pi: WEBSTER, SCOTT J
other_pis: Not Applicable
congressional_district: 06
department: NONE
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: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Traumatic brain injury (TBI) constitutes a major worldwide public health problem with a great socio-economic impact on our society and is a leading cause of long-term disability. TBI initiates complex pathophysiological events secondary to the immediate injury which have been shown to enhance susceptibility to subsequent age-related neurodegenerative disease such as Alzheimer's disease (AD). The exact mechanism of this enhanced susceptibility to AD following TBI is not known. However clinical data from AD and human head injury patients suggest that excessive proinflammatory responses from activated microglia contribute to the pathogenesis of both disorders and could potentially be the driving force that links these two conditions. Further there exists strong clinical and basic sciences evidence to suggest that even a single TBI can induce chronic inflammatory signaling in the brain for months to years after the initial insult. This chronic enhanced neuroinflammatory response can increase damage from future stressors placed on the brain and contribute to the development of neurodegenerative disease. This proposal will test the hypothesis that it is this chronically enhanced neuroinflammatory response that leads to the enhanced susceptibility and poorer AD-related outcomes clinically observed for TBI patients. In aim 1 we will test whether acute treatment targeting this neuroinflammatory response can protect against the neuropathology and behavioral impairments following TBI in an APP/PS1 knock-in mouse model of AD (preventing the chronically heightened inflammatory response from developing). This aim is designed to model the clinical scenario of an individual who receives acute treatment following a TBI. However clinically many TBIs are never reported and fail to receive acute treatment. Aim 2 is designed to model the clinical scenario where an initial TBI is untreated and to answer the question of whether these patients could still potentially benefit from late onset treatment aimed at correcting the chronically heightened inflammatory response that exists after TBI. Successful completion of this project will provide insight into the
link between TBI and the subsequent development of future neurodegenerative complications. Further successful completion of this project has important clinical implications by demonstrating a potential novel therapy for an important clinical need that has no currently available treatment. A Career Development Plan has been formalized and includes specialty workshop participation regular presentations of proposed research plans and results at the laboratory and research group level presentation of independent research results in seminar format participation in national and international scientific meetings preparation of research proposals and publications and development of additional career enhancing skills. An experienced mentor a rich scientific environment and an organized educational and training plan will assure that the applicant has optimal opportunities for scientific growth career enhancement and development into an independent academic investigator.

project_terms:
APP-PS1;Acute;Alzheimer's Disease;Basic Science;Behavioral;Brain;Cessation of life;Chronic;Clinical;Clinical Data;Clinical Sciences;Complex;Craniocerebral Trauma;Data;Development;Development Plans;Disease;Educational workshop;Elderly;Environment;Epidemiologic Studies;Event;Functional disorder;Future;Growth;Hour;Human;Individual;Inflammation;Inflammatory;Inflammatory Response;Injury;International;Intervention;Knock-in Mouse;Laboratory Research;Life;Link;Mentors;Microglia;Modeling;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Outcome;Pathogenesis;Pathologic;Pathology;Patients;Pharmaceutical Preparations;Predisposition;Preparation;Production;Proteins;Publications;Reporting;Research;Research Personnel;Research Proposals;Secondary to;Signal Transduction;Societies;Symptoms;Synapses;Testing;Training;Traumatic Brain Injury;age related;behavioral impairment;career;career development;cytokine;design;disability;driving force;early onset;economic impact;efficacy testing;experience;functional outcomes;improved;insight;medical specialties;meetings;middle age;mouse model;neuroinflammation;neuropathology;normal aging;novel;novel therapeutics;prevent;public health medicine (field);public health relevance;response;skills;socioeconomics;stressor

public_health_relevance:
It is becoming increasingly clear that traumatic brain injury (TBI) is associated with the subsequent development of late life neurodegenerative disease (i.e. Alzheimer's disease). Clinical data from Alzheimer's disease and TBI patients suggest that excessive proinflammatory responses in the brain could potentially be the link between these two conditions. Successful completion of this project will provide insight into this link as well a demonstrate the potential value of a novel therapeutic treatment to prevent the development of neurodegenerative disease following TBI.


application_id: 8789793
project_number: 5R01NS073584-05
project_title: ER stress and oligodendrocyte survival after spinal cord injury
administering_ic: NINDS
award_notice_date: 2015-01-15
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: NS
serial_number: 073584
program_official: JAKEMAN, LYN B
project_start_date: 2011-02-01
project_end_date: 2017-01-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: HETMAN, MICHAL
congressional_district: 03
department: NEUROSURGERY
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:
DESCRIPTION (provided by applicant): The endoplasmic reticulum (ER) is the intracellular organelle in which secretory and membrane proteins are synthesized and folded by resident chaperone proteins. The ER stress response (ERSR) is an evolutionarily conserved cell defense mechanism that protects against excessive accumulation of malfolded proteins in the ER. These malfolded proteins are translocated to the cytoplasm by the machinery of the ER- associated degredation (ERAD) where they are degraded. The ERSR is initiated after multiple cellular stresses including hypoxia inflammation trauma excitotoxicity and oxidative damage. The ERSR is initially protective but if malfolded proteins cannot be cleared apoptotic cell death initiates. The 3 pathways involved in the ERSR involve PERK IRE1/XBP-1 and ATF6 signaling. Preliminary data demonstrate upregulation of all 3 ERSR pathways following SCI. Mice null for CHOP a pro-apoptotic transcription factor that is downstream of PERK and activated during ERSR showed enhanced functional recovery after SCI and we identified oligodendrocytes as highly vulnerable to ER stress. We hypothesize that enhancing the protective or inhibiting the apoptotic aspects of the ERSR will enhance functional recovery after SCI. In Aim 1 we will potentiate the protective effectors of ERSR and in Aim 2 suppress those that initiate oligodendrocyte apoptosis. We will use a combination of pharmacological agents constitutive and conditional null mice as well as cell culture studies using wild type (WT) and available null oligodendrocyte precursor cells (OPCs) and/or siRNAs to address these questions.

project_terms:
Acute;Address;Apoptosis;Apoptotic;Cell Culture Techniques;Cell Death;Cell Survival;Cells;Cellular Stress;Cessation of life;Chemicals;Chemosensitization;Chronic;Coculture Techniques;Cytoplasm;Cytoprotection;Data;Defense Mechanisms;Disease;Endoplasmic Reticulum;Family;Functional disorder;Genes;Genetic;Grant;Hand;Health;Hypoxia;In Vitro;Inflammation;Injury;Knockout Mice;Locomotor Recovery;Mediating;Mediator of activation protein;Membrane Proteins;Methods;Modeling;Molecular Chaperones;Mus;Neurons;Oligodendroglia;Organelles;Pathology;Pathway interactions;Patients;Phosphorylation;Protein Dephosphorylation;Proteins;Recovery of Function;Role;Signal Transduction;Small Interfering RNA;Spinal Cord;Spinal Ganglia;Spinal cord injury;TNFRSF10B gene;Translational Repression;Translations;Trauma;Traumatic CNS injury;Tunicamycin;Up-Regulation (Physiology);arm;biological adaptation to stress;cytotoxic;effective therapy;endoplasmic reticulum stress;excitotoxicity;improved;in vitro Assay;in vivo;inhibitor/antagonist;insight;loss of function;nervous system disorder;new therapeutic target;novel;oligodendrocyte precursor;oxidative damage;precursor cell;protective effect;research study;response;secretory protein;tauroursodeoxycholic acid;therapeutic target;transcription factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Spinal cord injury (SCI) is a devastating injury for both patients and their families and at present there is no effective treatment either acutely or for chronic patients. This grant examines the role of the endoplasmic reticulum stress response a cellular defense mechanism induced in every spinal cord cell after SCI in mediating survival or death of myelinating oligodendrocytes after SCI. We expect to identify new acute therapeutic targets that will hopefully extend beyond SCI to other CNS trauma and neurological disease treatment.


application_id: 8789131
project_number: 7R01DK093462-03
project_title: Role of Ceramide-induced Kidney Cell Death in Acute Kidney Injury
administering_ic: NIDDK
award_notice_date: 2014-02-19
opportunity_number: PA-11-260
application_type: 7
activity_code: R01
ic: DK
serial_number: 093462
program_official: RYS-SIKORA, KRYSTYNA E
project_start_date: 2012-09-17
project_end_date: 2017-04-30
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 6769757
contact_pi: SISKIND, LEAH J
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
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:
DESCRIPTION (provided by applicant): Rhabdomyolysis is a significant cause of acute kidney injury (AKI) and apoptosis and necrosis are known to play major roles in rhabdomyolysis-induced AKI but there is a fundamental knowledge gap of the factors that lead to their induction in the kidney. Continued existence of this gap represents a significant problem as AKI has a high mortality rate and there are very few therapeutic interventions to alter the clinical course of this disease. The long-term goal is to uncover the mechanisms involved in rhabdomyolysis-induced AKI for the development of novel therapeutics to protect the kidney. Ceramides regulate apoptosis and necrosis and are elevated in the kidney during AKI. The factors that regulate production of ceramides during kidney apoptosis and necrosis and whether ceramides lead to apoptotic versus necrotic kidney cell death are completely unknown. Likewise there are many different ceramide species and the roles for particular ceramide species in AKI have not been determined. This proposal will answer these questions to achieve the objective of developing ceramides as novel therapeutic approaches for the treatment of AKI following rhabdomyolysis. Preliminary data demonstrate that: (i) C16-ceramide is generated via de novo synthesis during kidney cell apoptosis and blocking its generation inhibits apoptosis; (ii) the pro-apoptotic BCL-2 protein BAK is a key regulator of ceramide synthases (CerS) and long-chain ceramide generation during kidney cell apoptosis; (iii) acid sphingomyelinase (SMase) generated C26-ceramide occurs in kidney cell necrosis; and (iv) rat kidney cortical CerS and acid SMase are activated and specific ceramides elevated more than 5-fold in a rat model of rhabdomyolysis-induced AKI. This expanding and developing body of work has led us to propose the following hypothesis: nephrotoxic stimuli elevate specific species of kidney ceramides through CerS and SMase- mediated pathways inducing kidney cell death and ultimately kidney failure. This hypothesis will be tested with three specific aims: (1) determine the mechanism by which BAK regulates CerS activity and generation of specific long-chain ceramides during kidney cell apoptosis; (2) determine the contribution of SMase-generated ceramide to kidney cell necrosis; and (3) determine the in vivo contribution of specific ceramides to rhabdomyolysis-induced AKI and kidney failure in rats. The approach is innovative because it utilizes novel methodologies to identify the specific role of individual ceramide species in AKI namely the quantification of the individual ceramide species in the kidney cortex and in vivo knockdown of the expression of particular CerS isoforms specifically within the kidney. The proposed research is significant as it advances our current knowledge of mechanisms of AKI by identifying factors that regulate generation of specific ceramide species during kidney apoptosis and necrosis. Ultimately such knowledge has the potential to greatly improve the treatment of AKI.

public_health_relevance:
This proposal will advance current knowledge of mechanisms of acute kidney injury by identifying factors that regulate generation of specific ceramide species during kidney apoptosis and necrosis. The proposed research is relevant to public health because acute kidney injury has a high mortality rate with very few therapeutic interventions. Thus information gained from the enclosed studies has the potential to greatly improve the treatment of acute kidney injury.


application_id: 8788827
project_number: 5R37DE011111-22
project_title: P.gingivalis interactions with gingival epithelial cells
administering_ic: NIDCR
award_notice_date: 2014-12-08
opportunity_number: PA-07-070
application_type: 5
activity_code: R37
ic: DE
serial_number: 011111
program_official: LUNSFORD, DWAYNE
project_start_date: 2014-01-01
project_end_date: 2018-12-31
study_section: NSS
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
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: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Periodontal diseases are one of the most common bacterial infections of humans and impose a significantburden on the health care system. One of the predominant pathogens in periodontal disease is P.gingivalis; however P. gingivalis can also inhabit the oral cavity in the absence of disease. The interactionbetween P. gingivalis and gingival epithelial cells makes a significant contribution to the degree ofequilibrium between host and microbe and to overall gingival health status. P. gingivalis can manipulateepithelial cell signal transduction pathways in order to direct entry into the host cell and to reprogram hostinnate immunity. One of the effector molecules of P. gingivalis is the HAD family serine phosphatase SerB.The goal of this proposal is define the outcomes of the interaction between P. gingivalis and gingivalepithelial cells as they relate colonization of the organism and the generation of immune dysbiosis. We shallalso continue our major focus on the role of the functionally versatile SerB invasin and modulin of P.gingivalis. Cofilin an actin depolymerizing protein is required for P. gingivalis invasion. We will examinethe ability of SerB to dephosphorylate and inactivate LIMK kinase which will lead to activation of cofilin. Wewill then investigate the impact of P. gingivalis on ROCK PAK1 and MK2 pathways that lead to activation of LIMK. These interactions will be observed within the cell by live cell imaging. P..gingivalis can suppressIL-8 production in part through regulation of actin dynamics. We shall study the cofilin dependent actinmediated suppression of IL-8 by P. gingivalis. The immune disruptive ability of P. gingivalis also extends toT-cell chemokines and the mechanism of suppression of IP-10 ITAC and Mig will be studied. We will alsobegin to assess biological relevance by examining T-cell migration in response to epithelial cells infectedwith P. gingivalis. These studies will provide a detailed molecular analysis of the targeting of host signaltransduction by P. gingivalis along with the role of a specific effector phosphatase. Ultimately the knowledge gained could be developed into strategies that could be utilized to intervene in the P.gingivalis-epithelial cell interaction to ensure that the outcome is non-harmful to the host.RELEVANCE (See instructions):P. gingivalis is a cause of periodontal diseases that afflict millions of Americans. In this study we willexamine the interactions between P. gingivalis and the human cells that are colonized by the organism. Theinformation to be gathered could be used to identify targets for novel therapeutic agents designed tointerfere with the colonization and survival strategies of P. gingivalis.

project_terms:
Actins;American;Bacterial Infections;Binding (Molecular Function);Biological;Biological Assay;CXCL10 gene;Cell Communication;Cells;Complement;Data;Development;Disease;Elements;Ensure;Epithelial Cells;Equilibrium;Family;Generations;Gingiva;Goals;Health Status;Healthcare Systems;Human;I-kappa B Proteins;IL8 gene;IRF1 gene;Immune;Immunologic Surveillance;Instruction;Interferons;Knowledge;LIM Domain Kinase 1;LIMK1 gene;Label;Lead;Life;Location;Luciferases;MEK inhibition;MEKs;Measurement;Measures;Mediating;Microbe;Molecular;Molecular Analysis;Natural Immunity;Nuclear Translocation;Oral cavity;Organism;Outcome;Pathway interactions;Periodontal Diseases;Phospho-Specific Antibodies;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Plasmids;Porphyromonas gingivalis;Process;Production;Promotor (Genetics);Protein Dephosphorylation;Proteins;ROCK1 gene;Regulation;Reporter;Role;Serine;Signal Transduction;Signal Transduction Pathway;Signaling Molecule;Small Interfering RNA;Structure;T-Lymphocyte;Testing;Therapeutic Agents;Tumor Necrosis Factor-alpha;Variant;actin depolymerizing proteins;cell motility;cellular imaging;chemokine;cofilin;design;in vivo;mutant;novel;novel therapeutics;overexpression;p65;pathogen;prevent;response;transcription factor


application_id: 8788695
project_number: 5R03CA172954-02
project_title: Evaluation of T Cell Response to Cisplatin Resistant NSCLC
administering_ic: NCI
award_notice_date: 2015-01-09
opportunity_number: PAR-11-079
application_type: 5
activity_code: R03
ic: CA
serial_number: 172954
program_official: PERLOFF, MARJORIE
project_start_date: 2014-01-01
project_end_date: 2016-12-31
study_section: ZCA1-SRLB-J(O1)
contact_pi_person_id: 1870178
contact_pi: YANNELLI, JOHN R.
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
project_abstract:
DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is a leading killer of men and women around the world. Most patients present in the clinic with advanced stage disease at a point where surgery is not an option and conventional chemotherapy and radiation therapy are limited in their effectiveness. Novel therapies are needed for this patient population.Continued failure to significantly impact NSCLC patients with conventional therapy will tax the health care system and remain a financial burden for families and society. Interestingly while NSCLC is responsive to chemotherapeutic agents such as cisplatin tumor is often observed to recur or progress in additional anatomic sites. It is known that NSCLC as well as other solid tumors develop mechanisms of drug resistance. Thus continued exposure to cisplatin remains ineffective. In the current study we propose to investigate whether Immunotherapy which exploits the patient's immune system to recognize and eliminate cancer should be considered to address the issue of chemo-resistance. We are asking the question that following cisplatin therapy in NSCLC patients what role can immunotherapy play in preventing the growth of chemo-resistant tumor cell clones which likely result in tumor recurrence and progression? Our hypothesis is that proteins which characterize cisplatin chemo-resistance can be targeted by vaccine therapy. To address this hypothesis we will build on the expertise of our group in developing and delivering vaccines in lung cancer. The current proposal is a proof of principle study which will investigate the existence of novel shared tumor associated antigens which are immunogenic and define the chemo-resistant phenotype. A unique methodology is proposed to identify HLA-A2 restricted cisplatin resistant CTL in normal donors based on specific antigen stimulation and TCR-Vbeta analysis. Understanding preferential usage of Vbetas in normal donors will be applied to the analysis of archived PBMC derived from -A2+ patients with NSCLC. Using this methodology we will determine if the precursor frequency for CTL specific for peptides characteristic of the cisplatin resistant state will be higher in patients previously exposed to cisplatin. If true in a future clinical study we hypothesize that NSCLC patients can be immunized against these peptides before cisplatin therapy. Following an appropriate period of rest NSCLC patients given boost vaccine injections with the peptides derived from the chemo-resistant proteins are expected to generate a potent immune response allowing the recognition and destruction of chemo-resistant tumor cells; thus preventing recurrence and progression. All required reagents for this proof of principle analysis are available to the applicant.

project_terms:
Accounting;Address;Adjuvant;Advocate;Allogenic;Anatomy;Antigens;Apoptotic;Archives;Autologous Dendritic Cells;Brain;Breast;CD8B1 gene;Cancer Patient;Cancer cell line;Cell Line;Cell Survival;Cells;Centers for Disease Control and Prevention (U.S.);Cessation of life;Characteristics;Cisplatin;Clinic;Clinical Research;Colon;Colon Carcinoma;Cytotoxic T-Lymphocytes;Data;Disease;Drug Targeting;Drug resistance;Drug toxicity;Effectiveness;Evaluation;Exposure to;Failure (biologic function);Family;Flow Cytometry;Frequencies (time pattern);Funding;Future;Growth;HLA-A2 Antigen;Habits;Health;Healthcare Systems;Household;Immune response;Immune system;Immunity;Immunotherapeutic agent;Immunotherapy;In Vitro;Injection of therapeutic agent;Investigation;Kentucky;Laboratories;Lead;Link;Literature;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Methodology;Necrosis;Non-Small-Cell Lung Carcinoma;Oncologist;Operative Surgical Procedures;Outcome;Patients;Peptides;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phenotype;Play;Population;Primary Health Care;Prostate;Proteins;Quality of life;Radiation;Radiation therapy;Reagent;Recurrence;Resistance;Rest;Role;Site;Smoke;Smoking;Societies;Solid Neoplasm;Source;Specificity;Staging;Supportive care;Survival Rate;Symptoms;T cell response;T-Lymphocyte;Taxes;Therapeutic;Tumor Antigens;Universities;Vaccine Therapy;Vaccines;Variant;Woman;base;beta-Glucans;bone;chemotherapeutic agent;chemotherapy;conventional therapy;design;disease diagnosis;immunogenic;immunogenicity;improved;lymph nodes;malignant breast neoplasm;men;neoplastic cell;never smoker;novel;novel vaccines;outcome forecast;patient population;prevent;research clinical testing;tumor;vaccine development;vaccine evaluation;vaccine trial

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Prognosis of advanced stage NSCLC is grim. While some oncologists advocate therapeutic nihilism for advanced NSCLC based on excessive drug toxicity and universally poor outcomes chemotherapy can reduce symptoms improve quality of life and result in small improvement in survival when compared to best supportive care. This application describes Proof of Principle studies for the improvement of an already proven cellular vaccine for NSCLC.


application_id: 8788308
project_number: 7R01AI065530-10
project_title: Type III exported effectors of Chlamydia trachomatis
administering_ic: NIAID
award_notice_date: 2014-01-06
opportunity_number: PA-07-070
application_type: 7
activity_code: R01
ic: AI
serial_number: 065530
program_official: HILTKE, THOMAS J
project_start_date: 2005-06-01
project_end_date: 2015-04-30
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 7726964
contact_pi: FIELDS, KENNETH A
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
project_abstract:
DESCRIPTION (provided by applicant): The human pathogen Chlamydia trachomatis is a significant concern in the United States due to its prevalence and the combined health and socioeconomic impact of acute and chronic disease. Chlamydiae are obligate intracellular pathogens and possess the ability to modulate host-cell functions while sequestered within a membrane-bound vacuole. Expression of a virulence-associated type III secretion system (T3SS) represents one mechanism employed to modulate critical host cell pathways. During the past funding cycle we identified multiple chlamydial T3S substrates capable of influencing these host cellular processes. The C. trachomatis locus containing the identified effector protein CT694 contains multiple substrates that are deployed by infectious particles during or subsequent to the invasion process. We propose to elucidate molecular mechanisms regarding the anti-host activities of these proteins and delineate the consequences of effector activity on the ability of Chlamydiae to establish and maintain a specialized intracellular niche. A combination of methods designed to identify interactions of chlamydial proteins with host targets will be employed to establish relevant functions. The consequences of these interactions will be investigated in both a tissue culture infection model and a murine model of acute chlamydial infection. We furthermore propose to evaluate whether differences in these effectors among chlamydial species account for any of the distinct species-specific events related to early chlamydial development. The chlamydial type III secretion system represents an attractive yet relatively unexplored mechanism to achieve modulation of host cell activities. Given the comparative difficulty associated with study of obligate intracellular bacteria investigation of host pathways specifically targeted by the type III secretion mechanism continues to represent a productive approach to elucidate novel pathogenic mechanisms. These studies will lead to an enhanced understanding of Chlamydia-mediated disease and have the potential to yield novel preventative and treatment therapies.

public_health_relevance:
Chlamydia trachomatis an agent of sexually transmitted disease relies on a specializedsecretion mechanism to deploy proteins exerting anti-host activities essential to pathogenesis.This proposal contains work designed to identify these anti-host proteins and determine theirspecific contributions to chlamydial disease.


application_id: 8787456
project_number: 5R03CA176777-02
project_title: Modulation of colitis-associated cancer by cyclosporine A
administering_ic: NCI
award_notice_date: 2014-12-08
opportunity_number: PAR-12-144
application_type: 5
activity_code: R03
ic: CA
serial_number: 176777
program_official: DASCHNER, PHILLIP J
project_start_date: 2014-01-01
project_end_date: 2016-12-31
study_section: ZCA1-RTRB-Z(O1)
contact_pi_person_id: 1878476
contact_pi: COHEN, DONALD A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
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): Patients with inflammatory bowel disease (IBD) develop malignancies of the intestinal tract at an increased frequency compared to the normal population. This is thought to be due in part to the chronic inflammation associated with this debilitating disease. Cyclosporine A (CsA) is an effective treatment for patients with severe steroid-refractory IBD especially ulcerative colitis (UC). However the use of CsA in animal models has been associated with enhanced spread of colorectal cancer cells. We have shown that treatment of bone marrow transplanted (BMT) mice with CsA leads to a colitis-like disease similar to other models of IBD. Importantly recent studies have demonstrated a role for the inflammasome in intestinal homeostasis and the development of colitis-associated intestinal tumors. IBD patients have decreased inflammasome activity which may contribute to the development of clinical disease and animals with deficiencies in the inflammasome develop enhanced colitis and colon tumors. We have documented that CsA-treatment of BMT mice inhibited the activation of the inflammasome and may have participated in the development of colitis-like disease making suspect the clinical use of CsA in refractory IBD. Given these findings two specific aims will be proposed to test the hypothesis that cyclosporine treatment willalter intestinal homeostasis via inhibition of inflammasome function resulting in enhanced tumor growth in the azoxymethane (AOM)/dextran sulfate sodium (DSS) model of colitis-associated colon cancer (CAC). Aim 1 will determine if treatment of AOM/DSS- treated animals with a therapeutic dose of CsA will enhance the severity of colitis and the development of CAC. Inflammasome expression and activity will be determined in CsA-treated mice after induction of AOM/DSS CAC. Preliminary results show that CsA therapy inhibits intestinal barrier function in BMT mice. Thus we propose that intestinal damage which occurs during the induction of AOM/DSS also will be prolonged by CsA therapy. Aim 2 will test the hypothesis that CsA-induced alterations in intestinal epithelium will lead to increased permeability and decreased barrier function via inhibition of inflammasome function which may contribute to increased colitis and development of CAC. As patients with IBD have reduced inflammasome activity the potential exists that the use of CsA to treat refractory IBD may enhance development of the disease by further reducing inflammasome function leading to and enhanced risk of CAC. It is imperative to analyze the effects of immunosuppressive therapy on intestinal damage induction of colitis and CAC in model animal systems to understand the risk of CsA therapy in the treatment of IBD.

project_terms:
Acute;Affect;Allogenic;Animal Diseases;Animal Model;Animals;Azoxymethane;Biological Models;Bone Marrow Transplantation;Calcineurin;Characteristics;Chronic;Clinical;Colitis;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Crohn's disease;Cyclosporine;Development;Disease;Dose;Epithelial Physiology;Exhibits;Experimental Models;Frequencies (time pattern);General Population;Health;Immune;Immunosuppressive Agents;Inflammation;Inflammatory Bowel Diseases;Inflammatory disease of the intestine;Intestinal Neoplasms;Intestines;Large Intestine;Lead;Malignant Neoplasms;Modeling;Mus;Neoplasm Metastasis;Patients;Permeability;Pharmaceutical Preparations;Population;Refractory;Risk;Role;Severities;Small Intestines;Sodium Dextran Sulfate;Steroids;Syndrome;System;Testing;Therapeutic;Therapeutic immunosuppression;Toxic effect;Ulcerative Colitis;cancer cell;cancer risk;colitis associated cancer;effective therapy;feeding;gut microbiota;intestinal epithelium;intestinal homeostasis;member;microbiome;mouse model;pre-clinical;response;tumor;tumor growth;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The murine AOM/DSS model exhibits many of the characteristics of IBD-associated colon cancer and is useful as a proof of concept model to examine the role of calcineurin inhibition in the integrity of the intestinal epithelium during chronic inflammation. This project will determine the effect of CsA/immunosuppressive therapy on the development of inducible colon cancer.


application_id: 8785871
project_number: 1R13ES024661-01
project_title: Tamburro Symposium on Environmental Chemicals and Liver Disease
administering_ic: NIEHS
award_notice_date: 2014-06-12
opportunity_number: PA-13-347
application_type: 1
activity_code: R13
ic: ES
serial_number: 024661
program_official: SHREFFLER, CAROL A
project_start_date: 2014-07-01
project_end_date: 2015-06-30
study_section: Special Emphasis Panel[ZES1 LKB-D (C)]
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
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:
DESCRIPTION (provided by applicant)   
   
The liver is the largest internal organ and also the most complex as it regulates xenobiotic and energy metabolism.  However liver disease is increasingly common and current population-based studies indicate that greater than 1/3 of adults and greater than 10% of children have chronic liver disease. Presumably due to its role in xenobiotic metabolism the liver is the target
organ most commonly affected by environmental chemicals.  However the role of environmental exposures in the current liver disease epidemic is simultaneously under-recognized by clinicians and understudied by the scientific research community. The primary objective of this application is to hold a two-day symposium on "Environmental Chemicals and Liver Disease". There have been no comprehensive conferences in the last five years (if ever) on the emerging field of environmental hepatology. An expert panel of faculty participants has been recruited and 26 lectures and a poster session are planned. Notably faculty participants with diverse professional backgrounds (ranging from clinical hepatologists to environmental health basic scientists) have been recruited. Female and minority investigators are also well-represented. In order to develop a comprehensive strategy to move the field of environmental hepatology forward it is necessary to first assemble experts who would otherwise not interact with each other to discuss current mechanistic data and identify knowledge gaps. To this end greater than 100 attendees from industry academics (including students and early stage investigators) and government are expected. Conference proceedings will be published in a scientific journal. This symposium is relevant to all physicians or scientists who either care for patients with liver disease or perform research in liver disease or environmental health science.

project_terms:
Adult;Affect;Chemical Industry;Chemicals;Child;Cirrhosis;Clinical;Clinical Sciences;Communities;Complex;Data;Discipline;Energy Metabolism;Environmental Exposure;Environmental Health;Environmental Pollutants;Epidemic;Extramural Activities;Faculty;Female;Fibrosis;Fostering;Geographic Locations;Goals;Government;Hepatic;Hepatitis;Hepatology;Hepatotoxicity;Individual;Industry;Journals;Knowledge;Lesion;Liver;Liver diseases;Malignant - descriptor;Malignant neoplasm of liver;Medical;Medical Education;Medical Students;Metabolism;Minority;National Institute of Environmental Health Sciences;Non-Malignant;Nutritional;Occupational;Organ;Outcome;Participant;Pathologic;Patient Care;Peer Review;Physicians;Play;Prevalence;Publishing;Recording of previous events;Recruitment Activity;Research;Research Personnel;Resources;Role;Scientist;Site;Staging;Students;Toxic Environmental Substances;Toxicity Tests;Translational Research;Universities;Veterinarians;Woman;Workplace;Xenobiotic Metabolism;chronic liver disease;design;environmental chemical;environmental chemical exposure;experience;graduate student;interest;lectures;liver injury;meetings;new technology;nutrition;population based;posters;professor;public health relevance;response;symposium;toxicant

public_health_relevance:
Public Health Relevance: Environmental chemical exposures may result in a variety of liver diseases ranging from hepatitis to cirrhosis and even liver cancer. This project proposes to host a scientific meeting to bring together experts in liver disease metabolism and environmental health for the purpose of focusing future research in the emerging field of environmental hepatology effecting change and curbing the current liver disease epidemic.


application_id: 8785678
project_number: 5R01DK090460-05
project_title: Maternal Exercise Protects Offspring from Obesity and Insulin Resistance
administering_ic: NIDDK
award_notice_date: 2015-01-15
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: DK
serial_number: 090460
program_official: SILVA, CORINNE M
project_start_date: 2011-01-01
project_end_date: 2016-12-31
study_section: Integrative Physiology of Obesity and Diabetes Study Section[IPOD]
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
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
project_abstract:
DESCRIPTION (provided by applicant):  The intrauterine environment affects the development of the growing embryo and an unsuitable environment can lead to termination of pregnancy. However emerging research has shown that more subtle factors can potentially influence long-term health in the offspring. For instance malnourished pregnant mothers produce smaller offspring that have a higher incidence of obesity diabetes and heart disease during adulthood. To this point most published studies have focused on negative changes in offspring caused by detrimental diets or stressful behavior. However in the Western world maternal obesity is an ever-increasing problem and epidemiology studies are now pointing to metabolic derangements in their offspring. In an attempt to be pro-active maternal voluntary exercise during pregnancy was chosen as a potential short-term intervention to improve health outcomes in offspring. Fasting circulating glucose and insulin levels were lower in offspring born to exercised dams compared to those born to non-exercised dams and glucose disposal and insulin sensitivity were significantly improved. As a result our hypothesis for this proposal is that maternal voluntary exercise during pregnancy and nursing will improve glucose regulation and decrease obesity and hypertension in offspring. The first aim is designed to determine whether maternal voluntary exercise can improve insulin sensitivity in offspring fed a normal standard diet and protect against obesity insulin resistance and hypertension progression in high calorie diet-fed offspring. The second aim hopes to elucidate the mechanism for long-lasting insulin sensitivity in offspring born to exercised dams which is likely through enhanced insulin signaling. The third aim will determine whether maternal exercise can be used as an intervention to improve pathology outcomes in offspring resulting from maternal consumption of a high calorie diet or gestational diabetes mellitus. To explore these aims female mice will be placed into sedentary or voluntary exercise groups. The exercise dams will have 24 hour access to running wheels before mating and throughout pregnancy and nursing. The maturing offspring will not have access to running wheels for any portion of the study. Obesity glucose and insulin tolerance and hypertension will be monitored in the offspring fed either standard or high calorie diet. These studies will provide important information on the potential positive impact maternal exercise can have on offspring health. Obesity diabetes and cardiovascular disease are at epidemic levels and interventions targeting gestation might be an efficient way to stem the tide.

project_terms:
Acetylation;Adult;Adult Children;Affect;Age;Behavior;Biological Assay;Blood Pressure;Body Composition;Cardiovascular Diseases;Consumption;CpG Islands;Development;Diabetes Mellitus;Diet;Discipline of Nursing;Disease;Embryo;Environment;Epidemic;Epigenetic Process;Exercise;Fasting;Female;Genes;Gestational Diabetes;Glucokinase;Glucose;Glucose Transporter;Health;Heart Diseases;Histone Acetylation;Home environment;Hour;Human;Hypertension;Incidence;Injection of therapeutic agent;Insulin;Insulin Receptor;Insulin Resistance;Insulin Signaling Pathway;Intervention;Laboratories;Lead;Liver;Longevity;Measures;Metabolic;Methylation;Modeling;Monitor;Mothers;Motor;Mus;Obese Mice;Obesity;Outcome;Parents;Partner in relationship;Pathology;Pathway interactions;Performance;Phenotype;Phosphorylation;Pilot Projects;Population;Pregnancy;Probability;Promoter Regions (Genetics);Proteins;Publishing;Research;Role;Running;Skeletal muscle structure;Termination of pregnancy;Testing;Tissues;Ursidae Family;Very Light Exercise;Western World;blood glucose regulation;design;epidemiology study;fasting glucose;feeding;glucose disposal;glucose tolerance;glucose-6-phosphatase;improved;insulin sensitivity;insulin signaling;insulin tolerance;leptin receptor;next generation;novel;offspring;pregnant;programs;protein expression;response;sedentary;stem;trend;unborn child

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Exercise is currently used as a treatment for gestational diabetes but the long-term influence of this intervention on offspring health has been ignored. The proposed studies will provide novel information on whether maternal exercise can be used as an intervention to decrease obesity diabetes and hypertension development in offspring. Maternal exercise during pregnancy is a very realistic intervention that may provide a lifetime of benefits for the next generation.


application_id: 8785110
project_number: 5R01DA033364-03
project_title: Medications Development for Cocaine: A Translational Approach in Monkey and Human
administering_ic: NIDA
award_notice_date: 2015-01-19
opportunity_number: PA-10-268
application_type: 5
activity_code: R01
ic: DA
serial_number: 033364
program_official: WANG, JIA BEI
project_start_date: 2013-02-01
project_end_date: 2015-12-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
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): Cocaine-use disorders continue to be a significant public health concern yet no effective pharmacological treatments have been identified. This application is founded on the proposition that translational research on development of cocaine pharmacotherapies will benefit from the use of coordinated and homologous procedures in animals and humans to study effects of Candidate medications on choice between cocaine and a non-drug reinforcer. Self-administration procedures will be used in this project because the reinforcing effects of drugs are central to their abuse and the development of dependence. An alternative reinforcer to cocaine will be offered because the choice to use cocaine to the exclusion of other behaviors is a hallmark of dependence and an effective medication should assist patients in reducing drug use and reallocating behavior from drug use to more responsible and productive activities. Advantages of including preclinical research in the medications development process include strict control over environment and subject history and testing novel compounds and/or extensive dose ranges not feasible in humans. Rhesus monkeys were selected as the animal subjects because they are phylogenetically more closely related to humans than rodents and can be instrumented with chronically indwelling IV catheters which facilitates implementation of drug vs. food choice procedures. Human laboratory research permits the testing of putative pharmacotherapy effects on challenges with the abused drug in a clinically relevant subject population. Another advantage of pairing rhesus monkey and human laboratory models is that powerful within-subjects designs can be used with both species. Despite the relative strengths of human and non-human primate approaches translational research has been hampered by the use of widely different self-administration procedures and medication treatment regimens. The proposed project seeks to harmonize rhesus monkey and human procedures used to screen medications by first establishing parallel self-administration methods that will employ the same cocaine doses route of cocaine administration and schedule of reinforcement as well as a species-specific alternative reinforcer that effectively reduces drug taking. Cocaine doses schedule parameters and alternative reinforcer magnitude will then be adjusted to obtain equivalent functional effects prior to d-amphetamine maintenance testing. The use of d-amphetamine will permit equilibration of cross-species sensitivity and provide a comparator for effects of other non-dopaminergic Candidate medications examined in future studies. Achieving the aims of this project will exert a sustained and powerful impact by establishing a research platform for cocaine medication screening that will tightly link animal and human approaches thereby accelerating translational research on medications development. The proposed project is highly innovative in that it will develop coordinated and homologous procedures in nonhuman primates and humans using sophisticated cocaine choice procedures aimed towards medications development for cocaine-use disorders.

project_terms:
Address;Animals;Behavior;Catheters;Clinical;Clinical Research;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Dependence;Development;Dextroamphetamine;Disease;Dopamine;Dopamine Agonists;Dose;Drug Use Disorder;Drug usage;Effectiveness;Ensure;Environment;Evaluation;Exclusion;Food;Future;Goals;Gold;Health;Human;Intravenous;Laboratories;Laboratory Research;Laboratory Study;Link;Macaca mulatta;Maintenance;Methods;Modeling;Monkeys;Patients;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacotherapy;Population;Prevalence;Prevention;Procedures;Process;Recording of previous events;Reinforcement Schedule;Relative (related person);Research;Rodent;Route;Safety;Schedule;Self Administration;Standardization;Testing;Translational Research;Treatment Protocols;base;clinically relevant;cocaine use;design;innovation;instrument;non-drug;nonhuman primate;novel;pre-clinical research;public health medicine (field);reinforcer;research study;screening;stimulant abuse;translational approach;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cocaine-use disorders continue to be a significant public health concern yet no effective medications have been identified. This application is founded on the proposition that research to develop medications for cocaine addiction will benefit from the use of highly coordinated and homologous animal and human procedures to study effects of promising drugs on choice between cocaine and a non-drug alternative. The ultimate goal of this project is to establish a research platform that facilitates animal-to-human translational research on the development of medications for treatment of cocaine abuse and dependence.


application_id: 8784433
project_number: 2R01AA017226-07
project_title: Alcohol and Breast Cancer
administering_ic: NIAAA
award_notice_date: 2014-09-04
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: AA
serial_number: 017226
program_official: JUNG, KATHY
project_start_date: 2008-03-05
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1 DKUS-C (90)]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
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_terms:
Alcohol consumption;Alcohols;Amino Acid Sequence;Animal Model;Animals;Attention;Breast Cancer Cell;Breast Cancer Treatment;Cancer Etiology;Cancer Patient;Cancer stem cell;Cell Culture System;Cell Polarity;Cells;Cellular biology;Characteristics;DLG1 gene;Data;Development;Diet;Environmental Risk Factor;Epidemiologic Studies;Epidermal Growth Factor Receptor;Etiology;Family;Funding;Genes;Heavy Drinking;Human;Human Development;In Vitro;Knockout Mice;Liquid substance;MAP Kinase Kinase 6;MAPK14 gene;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mediating;Mediator of activation protein;Mitogen-Activated Protein Kinase Kinases;Mitogen-Activated Protein Kinases;Molecular;Mus;Neoplasm Metastasis;Outcome;Patients;Phosphorylation;Phosphotransferases;Physiological;Play;Production;Protein Tyrosine Kinase;Reactive Oxygen Species;Recruitment Activity;Risk;Role;Signal Pathway;Signal Transduction;Stream;Testing;Time;Transgenic Organisms;Tumor Promoters;Tumor Promotion;Xenograft Model;alcohol effect;alcohol exposure;alcohol sensitivity;anticancer research;cancer cell;cancer risk;cancer therapy;epithelial to mesenchymal transition;feeding;human MAPK14 protein;in vivo;indexing;malignant breast neoplasm;member;mitogen-activated protein kinase p38;novel;novel therapeutics;outcome forecast;public health relevance;research study;stem;stem cell population;stress-activated protein kinase 1;therapeutic target;tumor;tumor initiation;tumor progression;tumor xenograft


application_id: 8784426
project_number: 1F32HL123215-01A1
project_title: Aortic Wall Distensibility in the Growth and Rupture of Abdominal Aortic Aneurysm
administering_ic: NHLBI
award_notice_date: 2014-08-11
opportunity_number: PA-11-113
application_type: 1
activity_code: F32
ic: HL
serial_number: 123215
suffix: A1
program_official: MEADOWS, TAWANNA
project_start_date: 2014-09-01
project_end_date: 2015-04-15
study_section: Special Emphasis Panel[ZRG1 F15-P (20)]
contact_pi_person_id: 11723394
contact_pi: HAGGERTY, CHRISTOPHER M
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
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
project_abstract:
DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) rupture is the 13th leading cause of death in the US. While prophylactic surgical repair is an effective treatment there is significant mortality risks associated with the procedure. Since most aneurysms do not rupture these surgical risks may outweigh the benefits of repair in many cases. However there are currently no means to accurately identify an aneurysm that will rupture to effectively evaluate the relative risk of rupture versus repair. The big-picture goal of this research program is to improve clinical care for patients with AAA by establishing sensitive non-invasive markers for aneurysm rupture that can be used to better identify patients who should undergo surgical repair. Aneurysm size as determined by medical imaging is currently the most common method used to evaluate AAA rupture risk. However recent advances in magnetic resonance imaging (MRI) allow for more sophisticated high resolution assessments of aortic mechanics which are known to be more sensitive. For example quantifying the dynamic changes in aortic size and shape with systolic pressure pulses can be used to assess the distensibility of the aortic wall. These images can also be used to create computer models of the aneurysm to calculate areas of high wall stress. Since AAA rupture occurs when aneurysm stress exceeds mechanical strength we hypothesize that non-invasive quantification of these mechanical and structural properties will lead to better rupture predictions. The first step in evaluating our hypothesis is to demonstrate proof of concept for this imaging-based paradigm in an animal disease model. The most widely used model of AAA is the ApoE-/-/angiotensin-II mouse model which was developed and has been extensively studied our institution over the past 15 years. This expertise coupled with our cardiovascular imaging abilities in both mice and humans uniquely qualifies us to successfully carry out this research. To develop mechanical rupture markers we propose a two-pronged approach. We first seek to relate the macroscopic mechanics measured via MRI to the microscopic function of cells and enzymes such a matrix metalloproteinases (MMPs) which are important deterministic factors in aneurysm grown and remodeling. Serial assessment of these mechanical measures in mouse AAA will then be related to rupture outcomes to evaluate their predictive value. The long-term objective of this proposal is to take these sensitive imaging markers and translate them to human studies to improve clinical decision-making.

project_terms:
Abdomen;Abdominal Aortic Aneurysm;Affect;Aneurysm;Angiotensin II;Animal Disease Models;Animals;Aorta;Aortic Diseases;Apolipoprotein E;Area;Attenuated;Biomedical Engineering;Caliber;Cause of Death;Cell physiology;Clinical;Computer Simulation;Coupled;Data;Development;Diagnosis;Doxycycline;Elements;Enzymes;Extracellular Matrix;Extracellular Matrix Degradation;Future;Goals;Gold;Growth;Growth and Development function;Heterogeneity;Human;Image;Incidence;Inhibition of Matrix Metalloproteinases Pathway;Institution;Kentucky;Knowledge;Lead;Left;Luminal region;Magnetic Resonance Imaging;Matrix Metalloproteinases;Measurement;Measures;Mechanics;Medial;Mediating;Medical Imaging;Methods;Metric;Microscopic;Modeling;Mortality Vital Statistics;Mus;Natural History;Operative Surgical Procedures;Outcome;Patients;Physiologic pulse;Play;Predictive Value;Procedures;Property;Qualifying;Relative Risks;Reliance;Research;Resolution;Risk;Role;Rupture;Ruptured Abdominal Aortic Aneurysm;Ruptured Aneurysm;Sensitivity and Specificity;Shapes;Stress;Systolic Pressure;Testing;Therapeutic;Time;Translating;Ultrasonography;Universities;abdominal aorta;base;cardiovascular imaging;clinical care;clinical decision-making;clinical practice;effective therapy;improved;insight;mouse model;outcome forecast;programs;prophylactic;public health relevance;reconstruction;repaired;response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Abdominal aortic aneurysm (AAA) rupture is the 13th leading cause of death in the US. Only a small percentage of diagnosed AAAs will rupture yet there are no known discriminating factors to identify patients at risk. This big picture goal of this projectis to develop non-invasive methods to clinically evaluate AAAs and accurately identify those at risk for rupture and in need of surgical repair.


application_id: 8784235
project_number: 5R01HL108621-05
project_title: Mitophagic and anti-angiogenic mechanism of heart failure
administering_ic: NHLBI
award_notice_date: 2014-12-11
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 108621
program_official: ADHIKARI, BISHOW B
project_start_date: 2011-04-15
project_end_date: 2016-12-31
study_section: Special Emphasis Panel[ZRG1-VH-B(02)M]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
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:
DESCRIPTION (provided by applicant): Although heart failure is inevitable disease its management depends on the understanding of the mechanism of ailing to failing myocardium. During heart failure the heart undergoes compensatory remodeling (i.e. left ventricle hypertrophy (LVH) and vascular angiogenesis. Unfortunately during end-stage heart failure there is dis-coordination between the LVH and angiogenesis (i.e. LVH persists but angiogenesis declines). This leads to continue increase in LV wall stress leading to failure. Remodeling by its very nature implies synthesis degradation and re-arrangement of intra and inter cellular matrix. Matrix metalloproteinases (MMPs) are designer architecture and tailor. The long-term goal of this project is to understand the differential role of MMPs in structural and functional heterogeneity in myocardial remodeling. The selective MMP-2 gene ablation reduces survival and exacerbates cardiac failure-induced by myocardial inflammation. MMP-9 gene ablation is cardioprotective. In human heart end-stage failure MMP-9 activation supersedes the MMP-2 activation. The hypothesis of this proposal is that MMP-2 is constitutive and during compensatory phase activates proteinase activated receptor-1 (PAR-1 a GPCR) and releases growth factors via the activation of anti-stress (PKB/AKT). Chronic stress leads to mitochondrial mitophagy and activation of MMP-9 and MMP-13 (an interstitial collagenase in rodent and MMP-1 in human). TIMP-3 (an apoptotic/autophagic factor) and anti-angiogenic statins are released The hypothesis will be tested by following three specific aims: Specific Aim #1: To determine whether the induction of MMP-2 PAR-1 G1s and AKT causes compensatory hypertrophy and mitochondrial mitophagy causes MMP-9 activation and decreases G1s and AKT in de-compensatory heart failure. Specific Aim #2: To determine whether the MMP-2 releases angiogenic growth factors during compensatory remodeling and MMP-9 releases anti-angiogenic statins in de-compensatory heart failure. Specific Aim #3: To determine whether the mitochondrial mitophagy attenuates angiogenesis in part by activating MMP-9 releasing TIMP-3 and generating statins during de-compensatory heart failure. These studies will delineate the causative role of PAR-1 MMP TIMP G1s and mitophagy in switch from compensatory LVH and angiogenesis to de-compensatory LVH and anti-angiogenesis and will have therapeutic ramifications for chronic heart failure.

project_terms:
Ablation;Address;Angiography;Angiostatins;Antibodies;Apoptotic;Architecture;Attenuated;Autophagocytosis;Barium;Biological Assay;Blood Vessels;Blood flow;Cardiac;Chronic stress;Congestive Heart Failure;Cytoskeleton;DNA;Disease;Endostatins;Enzyme-Linked Immunosorbent Assay;Failure (biologic function);Fibroblast Growth Factor;G-Protein-Coupled Receptors;Gelatinase A;Gelatinase B;Genes;Goals;Growth Factor;Health;Heart;Heart failure;Heterogeneity;Human;Hypertrophy;In Situ Nick-End Labeling;Inflammation;Interstitial Collagenase;Lasers;Left Ventricular Hypertrophy;Left ventricular structure;Matrix Metalloproteinases;Measures;Mitochondria;Mus;Myocardial;Myocardium;Nature;Outcome;Oxygen Consumption;PAR-1 Receptor;Pathogenesis;Pathway interactions;Phase;Protein Array;Proto-Oncogene Proteins c-akt;Rodent;Role;Small Interfering RNA;Staging;Stress;Testing;Therapeutic;Tissue Inhibitor of Metalloproteinase-1;Tissue Inhibitor of Metalloproteinase-3;Tissue Inhibitor of Metalloproteinases;Transforming Growth Factor beta;Vascular Endothelial Growth Factors;Ventricular Remodeling;angiogenesis;antiangiogenesis therapy;collagenase 3;constriction;density;in vivo;inhibitor/antagonist;matrigel;tissue inhibitor of metalloproteinase 4

public_health_relevance:
PUBLIC HEALTH RELEVANCE: These studies will delineate the differential role of mitochondrial mitophagy and anti- angiogenesis mechanisms in end-stage heart failure. The differential role of different MMPs in angiogenesis and anti-angiogenesis in transition from compensatory hypertrophy to de-compensatory heart failure will be determined. The positive outcome of this project will have therapeutic ramifications for chronic heart failure.


application_id: 8784056
project_number: 5R01CA143428-05
project_title: Rel B mediated-redox regulation of radiation therapy
administering_ic: NCI
award_notice_date: 2014-12-02
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: CA
serial_number: 143428
program_official: BERNHARD, ERIC J
project_start_date: 2011-01-01
project_end_date: 2016-12-31
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: ST CLAIR, WILLIAM H
congressional_district: 06
department: PHARMACOLOGY
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): Accumulating data suggest that prostate cancers exist in an elevated state of oxidative stress and that reactive oxygen species (ROS) contribute importantly to the cytotoxic effect of ionizing radiation (IR). However ROS also participate in cellular signaling processes leading to adaptive responses that reduce the effectiveness of radiation therapy. Thus despite rapid advances in treatment techniques the outcome of radiation therapy especially for patients with tumors with unfavorable prognoses remains to be improved. The goal of this project is to identify novel mechanisms that could lead to the development of specific measures for effective treatment of aggressive prostate cancers. We have identified the alternative pathway of the redox sensitive nuclear factor kappa beta (NF-B) as a major contributor to prostate cancer growth and progression. Preliminary data indicate that: 1) aggressive prostate cancers have high nuclear RelB a member of the alternative pathway of NF-:B and manganese superoxide dismutase (MnSOD) a critical antioxidant enzyme levels; 2) suppression of RelB in androgen independent-aggressive prostate cancer cells results in reduction of interleukin 8 (IL8) levels in tumor cells and reduced tumor growth in vivo; 3) overexpression of RelB in androgen responsive prostate cancer cells results in enhanced tumor growth and production of IL8 but reduced prostate specific androgen (PSA) production; and 4) suppression of RelB nuclear translocation enhances radiation sensitivity of prostate cancer. Based on these novel and important preliminary findings we hypothesize that RelB regulates prostate cancer response to radiation via a MnSOD dependent NF-B switch to activate expression of IL8 and suppress expression of PSA in prostate cancer cells. We propose that clinical testing for recurrent tumor growth should involve measuring levels of IL8 in addition to employing the standard PSA test. Combining these tests will enhance accurate cancer detection and prognosis. To test this hypothesis and validate the proof-of-concept for the combined use of IL8 and PSA as prognostic factors three interrelated specific aims will be addressed. Aim 1 will elucidate the mechanism by which MnSOD modulates the effect of RelB on the transcription of IL8 and PSA in prostate cancer cells using biochemical and molecular biology approaches. Aim 2 will examine the role of IL8 in the protection against the effects of radiation therapy of prostate cancer. Aim 3 will determine whether serum IL8 level is a predictive marker of prostate cancer response to radiation therapy using samples from cancer patients.  These mechanistic based bench to bedside approaches should provide novel insights into the mechanisms of prostate cancer resistant to radiation therapy and may provide practical predictive measures for prostate cancer diagnostic treatment planning and surveillance.

project_terms:
Address;Affinity Chromatography;Androgens;Animal Model;Basic Science;Binding (Molecular Function);Biochemical;Cancer Center;Cancer Detection;Cancer Diagnostics;Cancer Etiology;Cancer Patient;Cancer Prognosis;Cessation of life;Clinical;Clinical Research;Cultured Cells;Data;Development;Diagnosis;Diagnostic Neoplasm Staging;Effectiveness;Family;Gene Expression;Genes;Genetic Transcription;Goals;Growth;Health;Human;Immunoprecipitation;Interleukin-8;Ionizing radiation;Kentucky;Lead;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Manganese Superoxide Dismutase;Measures;Mediating;Modeling;Molecular Biology;NF-kappa B;Nuclear;Nuclear Translocation;Outcome;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Patients;Physicians;Play;Predictive Factor;Production;Prognostic Factor;Prostate;Prostate-Specific Antigen;Proteomics;Radiation;Radiation Tolerance;Radiation therapy;Reactive Oxygen Species;Recurrent tumor;Regulation;Risk;Role;Sampling;Serum;Site-Directed Mutagenesis;Small Interfering RNA;Techniques;Testing;Time;Transcriptional Regulation;Translating;Tumorigenicity;Universities;Visit;antioxidant enzyme;base;bench to bedside;cancer diagnosis;cancer type;chromatin immunoprecipitation;cytotoxic;cytotoxicity;effective therapy;follow-up;improved;in vivo;inflammatory marker;insight;member;men;neoplastic cell;novel;outcome forecast;overexpression;predictive marker;prostate cancer cell;radiation response;radioresistant;research clinical testing;research study;response;signal processing;treatment planning;treatment strategy;tumor;tumor growth

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Prostate cancer is the most frequently diagnosed cancer in men and the number of men who die from prostate cancer is unacceptably high. The results obtained from this study will provide insights into the novel mechanisms by which interleukin 8 (IL8) and prostate specific antigen (PSA) are differentially regulated and will test a proof-of-concept for using their relationship to predict the efficacy of radiation therapy for treating prostate cancer. Thus this study will enable physicians to tailor risk-adjusted strategies for treatment of prostate cancer.


application_id: 8784017
project_number: 1F31NS086395-01A1
project_title: Investigating the Role of Pioglitazone mitoNEET and Mitochondria following TBI
administering_ic: NINDS
award_notice_date: 2014-05-20
opportunity_number: PA-11-111
application_type: 1
activity_code: F31
ic: NS
serial_number: 086395
suffix: A1
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2014-07-01
project_end_date: 2017-09-30
study_section: Special Emphasis Panel[ZRG1 F01-F (20)]
contact_pi_person_id: 11272831
contact_pi: YONUTAS, HEATHER
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
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
project_abstract:
DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) causes severe complications to the estimated 1.7 million Americans who are injured annually. This has precipitated a major focus on the discovery and development of neuroprotective and pro-regenerative therapeutic agents. One potential neuroprotective target which has been well supported in the literature is mitochondrial dysfunction resulting from TBI induced excitotoxicity This excitotoxicity is caused by excessive synaptic glutamate and the consequent over-excitation of neurons at the site of injury leading to large increases in mitochondrial Ca2+ cycling/Ca2+ overload. Ca2+ overload precedes a notable decrease in mitochondrial respiration which has been documented in the first 3 to 48 hours post-injury. This decreased mitochondrial respiration which is an indication of decreased mitochondrial bioenergetics (ability to generate ATP) leads to the initiation of cell death pathways. As the injured neurons die the extent of tissue damage increases and functional (motor and cognitive) abilities decrease. We believe mitochondrial dysfunction to be a pivotal component to the neuropathological sequelae of brain injury and an important therapeutic target for drug discovery research in TBI. An overall goal of our laboratory is to determine whether amelioration of mitochondrial dysfunction will decrease the neuronal cell death associated with TBI. Findings from our lab and others show that pioglitazone a known PPAR-? agonist is neuroprotective and increases functional recovery following TBI. In support of this and the goals of our lab pioglitazone not only reduces mitochondrial dysfunction following TBI but also binds to mitoNEET a novel mitochondrial membrane protein. However the contribution of mitoNEET to pioglitazone- mediated neuroprotection is unknown. Preliminary results indicate that pioglitazone-mediated neuroprotection is absent in mitoNEET knockout mice and a specific mitoNEET ligand (NL-1) is neuroprotective following TBI. Taken together these data suggest that mitoNEET is an essential component of pioglitazone mediated neuroprotection. Therefore in order to understand the mechanisms of pioglitazone I will test the hypothesis that pioglitazone's ability to improve mitochondrial bioenergetics thereby decreasing tissue loss and improving functional recovery following TBI hinges on binding mitoNEET. I further hypothesize that the protective effects of pioglitazone can be reproduced by NL-1 an exogenous mitoNEET ligand.

project_terms:
Agonist;American;Behavior;Binding (Molecular Function);Bioenergetics;Brain Injuries;Cell Death;Clinical;Cognition;Cognitive;Data;Development;Diffusion Magnetic Resonance Imaging;Dose;FDA approved;Functional disorder;Glutamates;Goals;Healthcare;Hippocampus (Brain);Homeostasis;Hour;Ideal 1;Injury;Intervention;Investigation;Knockout Mice;Laboratories;Ligands;Literature;Magnetic Resonance;Maintenance;Measures;Mediating;Methods;Mitochondria;Mitochondrial Membrane Protein;Motor;Mus;Neurologic;Neurons;Outcome;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Pharmacological Treatment;Pioglitazone;Recovery of Function;Research;Respiration;Role;Science;Severities;Site;Synapses;Techniques;Testing;Therapeutic Agents;Therapeutic Effect;Tissues;Training;Traumatic Brain Injury;United States;Weight;Wild Type Mouse;cognitive change;cognitive recovery;controlled cortical impact;dosage;drug discovery;excitotoxicity;improved;in vivo;injured;mitochondrial dysfunction;morris water maze;neuron loss;neuropathology;neuroprotection;novel;protective effect;public health relevance;regenerative;response;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a devastating healthcare problem in the United States with no pharmacological treatments currently approved for clinical intervention following injury. Improved TBI treatment options are urgently needed. This proposal examines the potential of pioglitazone an FDA approved drug in limiting the brain damage and dysfunction resulting from TBI via maintenance of mitochondrial function.


application_id: 8783514
project_number: 1F32DA036291-01A1
project_title: Social isolation: effects on the stress axis and stimulant self-administration
administering_ic: NIDA
award_notice_date: 2014-06-11
opportunity_number: PA-11-113
application_type: 1
activity_code: F32
ic: DA
serial_number: 036291
suffix: A1
program_official: BABECKI, BETH
project_start_date: 2014-12-10
project_end_date: 2015-09-03
study_section: Special Emphasis Panel[ZRG1 F02A-J (20)]
contact_pi_person_id: 10613442
contact_pi: HOFFORD, REBECCA
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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): People suffering from post-traumatic stress disorder (PTSD) are 3 times more likely to abuse psychostimulants than people in the general population. This is alarming since estimates indicate that 8% of adults have abused stimulants in their lifetime. Identifying common substrates of both PTSD and drug addiction can provide a useful perspective on drug abuse treatment in patients with PTSD. Early life stress contributes to the development of both PTSD and drug addiction and can be modeled in rodents by employing social isolation during the early post-weaning period. Isolation enhances susceptibility to stress-related pathologies as assessed by animal models of depression and anxiety as well as increasing vulnerability to stimulant self- administration. Conversely environmental enrichment during development buffers against both anxiety and stimulant self-administration. Although alterations in the stress axis are likely involved in the effect of isolaton on drug self-administration the distinct neurobehavioral mechanisms of stress in drug abuse vulnerability induced by social isolation are largely unknown. Acute stress has the ability to increase drug seeking as measured by enhanced acquisition of self-administration and also causes reinstatement of drug seeking. Therefore relative to enriched rats it is hypothesized that rats raised in isolation and subjected to an acute stressor will acquire cocaine self-administration more rapidly and will demonstrate greater stress-induced reinstatement due to a sensitized stress axis. Specific Aim 1 will measure the acquisition of cocaine self- administration
after an acute stressor and measure stress-induced reinstatement of self-administration in rats raised in an isolated condition (IC) standard condition (SC) or an enriched condition (EC). An adapted single prolonged stress model (SPS) considered a type of acute stressor will be used to model PTSD. Corticosterone the major stress hormone in rodents and its receptor the glucocorticoid receptor (GR) are implicated in stress-induced acquisition and reinstatement. Differences in levels of corticosterone or GR have the potential to underlie addiction and anxiety-related pathologies such as PTSD. Given the importance of GR and corticosterone in both stress and drug abuse Specific Aim 2 will determine if this hormone/receptor system is altered by acute stress in IC SC and EC rats. GR expression levels will be quantified in brain areas involved in drug abuse after SPS administration in IC SC and EC rats. These areas will include the amygdala medial prefrontal cortex orbitofrontal cortex nucleus accumbens and dorsal striatum. Additionally levels of free corticosterone will be measured in response to SPS in rats raised in these different housing conditions. These experiments are important because co-morbidity of PTSD and stimulant addiction is a serious social and health problem. Understanding the neurobiological basis of a common risk factor early life stress can aid in the development of addiction treatment strategies targeting this at-risk group and can help design both psychosocial and pharmaceutical interventions that ameliorate an overly sensitive stress axis.

project_terms:
Acute;Adolescence;Adult;Amygdaloid structure;Animal Housing;Animal Model;Animals;Anxiety;Area;Behavior Therapy;Behavioral;Brain;Brain region;Buffers;Childhood;Cocaine;Comorbidity;Corpus striatum structure;Corticosterone;Development;Disease;Dorsal;Drug Addiction;Drug abuse;Early-life trauma;Environment;Event;Extinction (Psychology);General Population;Glucocorticoid Receptor;Goals;Health;Hormone Receptor;Hormones;Housing;Human;Individual;Intervention;Laboratories;Life Stress;Measures;Medial;Mental Depression;Mental disorders;Modeling;Neurobiology;Nucleus Accumbens;Organism;Pathology;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Physiological;Plasma;Post-Traumatic Stress Disorders;Predisposition;Prefrontal Cortex;Protein Hormone Receptor;Psychostimulant dependence;Rattus;Relative (related person);Research;Risk;Risk Factors;Rodent;Role;Self Administration;Social isolation;Staging;Stress;Substance Use Disorder;Syndrome;System;Testing;Time;Weaning;acute stress;addiction;base;design;drug reward;environmental enrichment for laboratory animals;experience;neurobehavioral;post-traumatic stress;preclinical study;psychosocial;public health relevance;receptor;receptor expression;research study;response;social;stimulant abuse;stressor;treatment strategy;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Post-traumatic stress and substance use disorders frequently co-occur in the same individuals and evidence suggests that both disorders are more likely to develop in patients experiencing stress during childhood or adolescence. The proposed preclinical studies seek to understand the addiction vulnerability of individuals exposed to both prolonged early life stress and an acute intense stressor that models PTSD. Mechanistic studies will determine if these events will change drug taking after stress in rats or change stress hormone and receptor protein levels in brain regions known to be involved in drug reward.


application_id: 8782945
project_number: 1F31AG046950-01A1
project_title: TRAF6 Signaling in Skeletal Muscle Regeneration during Aging
administering_ic: NIA
award_notice_date: 2014-06-20
opportunity_number: PA-11-111
application_type: 1
activity_code: F31
ic: AG
serial_number: 046950
suffix: A1
program_official: WILLIAMS, JOHN
project_start_date: 2014-07-01
project_end_date: 2014-12-31
study_section: Special Emphasis Panel[ZRG1 F10B-B (20)]
contact_pi_person_id: 11651573
contact_pi: HINDI, SAJEDAH M
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
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
project_abstract:
DESCRIPTION (provided by applicant): Impairment in regeneration process has been suggested as one of the most important contributors for age- related loss of skeletal muscle mass. However the molecular mechanisms leading to loss of muscle regenerative capacity during aging remain less understood. We have recently reported that levels of TNF receptor associated factor 6 (TRAF6) an adaptor protein involved in context-dependent activation of multiple pathways are upregulated in injured skeletal muscle. Deletion of TRAF6 in mature differentiated muscle of mice (TRAF6mko) improves regeneration in part by increasing the activation of Notch signaling pathway which promotes satellite cell activation to participate in the regeneration program. However whether the inhibition of TRAF6 will also improve muscle regeneration in aged animals remain unknown. We will test the hypothesis that muscle-specific inhibition of TRAF6 will augment skeletal muscle regeneration in aged mice through modulating the activity of Notch and Wnt signaling. AIM 1: Investigate whether TRAF6 regulates the activity of Wnt and Notch signaling pathways in injured skeletal muscle in adult (3 months) and aged (18 months) mice  A decline in Notch signaling activity in combination with accumulation of proinflammatory cellular infiltrates has been shown to account in part to the poor regenerative capacity of aged muscle. Environmental theories of stem cell aging propose that functional impairments that occur in stem cells as they age are potentially reversible when exposed to a young environment as been proven by the parabiotic experiments. We will determine whether the pro-regeneration environment brought about by TRAF6 deletion will carry through in aged muscle and overcome the age-related loss in regenerative capacity. AIM 2: Investigate satellite cells versus myofiber role of TRAF6 signaling during skeletal muscle regeneration in adult and aged mice.  While the improved regeneration phenotype observed in TRAF6-depleted muscle persisted in vitro we observed conflicting results when TRAF6 was deleted in satellite cells early during development under a Myf5 promoter (TRAF6dmko). Primary myoblast from TRAF6dmko mice displayed reduced proliferative and differentiation capacities in vitro. By contrast muscle regeneration is enhanced in response to injury in TRAF6dmko mice. Through generation of tamoxifen-inducible satellite cell-specific TRAF6-knockout mice and an established model of muscle injury we will delineate the role TRAF6 signaling in satellite cells o both adult and aged mice. Understanding the mechanisms that underlie such debilitation during aging can pave the way to developing novel therapeutics to preventing the loss of muscle mass.

project_terms:
1-Phosphatidylinositol 3-Kinase;A Mouse;Accounting;Adaptor Signaling Protein;Adult;Age;Age-Months;Aging;Animals;Atrophic;Back;Cell Aging;Cell Cycle;Cells;Commit;Conflict (Psychology);Development;Direct Lytic Factors;Elderly;Embryonic Development;Environment;Event;Exercise;Family;Fibrosis;Generations;Genetic;Growth;Human;Impairment;In Vitro;Inflammation;Injury;Integrins;Interleukin-1 Receptors;Knock-out;Knockout Mice;Laboratories;Lead;Leucocytic infiltrate;Link;Mediating;Modeling;Molecular;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle Weakness;Myoblasts;Myogenic Regulatory Factors;Myopathy;NF-kappa B;Natural regeneration;Neonatal;Notch Signaling Pathway;Notch and Wnt Signaling Pathway;Organ;Pathway interactions;Phenotype;Population;Process;Proliferating;Promotor (Genetics);Proteins;Published Comment;Publishing;Reporting;Resolution;Role;Signal Pathway;Signal Transduction;Skeletal muscle structure;Stem cells;Stimulus;TNF Receptor-Associated Factors;TNF receptor-associated factor 6;TRAF2 gene;Tamoxifen;Testing;Time;Toll-like receptors;Training;Tumor Necrosis Factor Receptor;Ubiquitination;Undifferentiated;age related;aged;cell age;functional disability;human MAPK14 protein;improved;inhibitor/antagonist;injured;member;mouse model;muscle aging;muscle form;muscle regeneration;myogenesis;notch protein;novel therapeutics;prevent;programs;public health relevance;receptor-mediated signaling;regenerative;repaired;research study;response;response to injury;sarcopenia;satellite cell;self-renewal;skeletal muscle wasting;theories;ubiquitin-protein ligase

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Skeletal muscle damage is a frequent occurrence in normal human population. Regeneration of skeletal muscle is impaired in aged population. Skeletal muscles have an evolutionarily conserved mechanism to repair this damage. However why muscle regeneration fails in aged subjects remains enigmatic. This proposal will define signaling mechanisms involved in muscle repair with focus on TRAF6 a recently identified regulator of muscle mass. This will lead to a greater understanding of skeletal muscle regeneration associated with defective repair and age- associated loss in muscle mass and regenerative capacity.


application_id: 8782801
project_number: 1F31AG048692-01
project_title: Maintenance of Positive Affect Following Pain in Older Adults
administering_ic: NIA
award_notice_date: 2014-07-01
opportunity_number: PA-11-112
application_type: 1
activity_code: F31
ic: AG
serial_number: 048692
program_official: NIELSEN, LISBETH
project_start_date: 2014-07-27
project_end_date: 2016-07-26
study_section: Special Emphasis Panel[ZRG1 F16-L (20)]
contact_pi_person_id: 11936065
contact_pi: BOGGERO, IAN ANDRES
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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Up to 80% of those over age 65 report experiencing some degree of physical pain yet older adults appear remarkably adept at maintaining positive emotionality in the face of pain. Whereas studies find that older adults are at least as good at managing pain as their younger counterparts the strategies they use to do so remain largely unknown. Guided by a socio-emotional selectivity framework which posits that older adults strategically use positivity-enhancing mechanisms the proposed research has a primary aim of investigating whether older and younger adults differ in their use of positivity mechanisms to maintain positive affect in the face of pain. Additionally little is known about the factors that make some older adults better able to cope with pain than others. Previous research has shown that high levels of executive functioning (EF) and heart rate variability (HRV) predict positive physical health outcomes for those experiencing pain but no research to date has examined how individual differences in these factors interact with pain to influence positive affect. Thus the proposed project has a second aim of testing whether EF or HRV moderate the relationship between pain and maintenance of positive affect in older adults. Both of the aims of the project contribute to a larger goal of expanding theoretical knowledge of factors contributing to health and psychological wellbeing in older age. The proposed project will allow the PI to gain invaluable skills and expand on his previous research experiences by using experimental laboratory and archival data to test hypotheses pertaining to both aims. In the laboratory study older and younger adults will be asked to provide affect EF and HRV data. They will be randomly assigned to a painful or non-painful task. After the pain task participants will undergo tasks assessing positivity mechanisms and will then be asked to provide a final affect rating. An archival longitudinal dataset of community-dwelling older adults will be used to test whether pain levels interact with EF within people to predict positive affect. It is hypothesized that 1) when i pain older adults will use positivity-enhancing mechanisms with greater success than younger adults; 2) older adults will maintain positive affect following pain better than younger adults; an 3) those with better EF and HRV will be most effective at maintaining positive affect in the face of pain. In addition to providing theoretical insight into how positive affect is maintained after pain the project will contribute to a larger objective of promoting diversity in health research b providing the PI - a Hispanic first generation college student - a training opportunity to develop the skills necessary to become an independent researcher. To this end the project includes a detailed plan designed to build on and expand the PI's ability to disseminate cutting-edge research learn novel statistical and methodological techniques and expand his research program on the psychological and physiological consequences of the pain experience.

project_terms:
Acute;Adult;Affect;Affective;Age;Aging;Communities;Data;Data Set;Elderly;Emotional;Environment;Frequencies (time pattern);Generations;Goals;Health;Hispanics;Individual Differences;Knowledge;Laboratories;Laboratory Study;Learning;Life;Literature;Longevity;Maintenance;Masks;Mental Health;Motivation;Outcome;Pain;Painless;Participant;Patients;Peat;Persons;Physiological;Randomized;Relative (related person);Reporting;Research;Research Personnel;Sampling;Techniques;Testing;Time;Training;Translating;coping;design;executive function;experience;heart rate variability;indexing;insight;novel;older women;physical conditioning;programs;psychologic;public health relevance;response;satisfaction;skills;social;success;theories;university student;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Older adults are able to maintain positive affect despite physical pain as well as or better than younger adults but little is known how such affect is maintained. This project aims to test whether older adults use positivity- enhancing mechanisms differently than younger adults after experiencing acute physical pain and test the factors that allow some adults to manage pain better than others. The project will support the PI a Hispanic first-generation college student in his goal to develop a research program on the psychological and physiological consequences of the pain experience.


application_id: 8782513
project_number: 5P30NS051220-10
project_title: MOLECULAR MECHANISMS
administering_ic: NINDS
award_notice_date: 2014-12-03
opportunity_number: PAR-08-116
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
subproject_number: 7623
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
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: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-12-01
budget_end_date: 2015-11-30
project_abstract:
CORE E. Molecular Mechanisms Core Plans: This core represents an expansion of the role of the previous Pharmacokinetics & Biomarker Core into what we now will call a Molecular Mechanisms Core in order to better meet the needs of the SCoBIRC faculty and other neuroscience investigators who use the SCoBIRC Core Facilities. In its former role the core managed by Core Director Dr. Edward D. Hall and Assistant Core Director and Supervisor Dr. Jeff Bosken primarily employed GC-MS and HPLC technologies for bioanalytical measurements of drugs and potential injury-related biomarker compounds in biofluids (e.g blood urine cerebrospinal fluid). However the core's scope was expanded very eariy during the current funding period to include equipment (LiCor Odyssey Infrared Image Analyzer) and expertise for highly sensitive analysis of immunoblots using infrared-emitting secondary anfibodies. This technology has been heavily employed by several SCoBIRC and other BBSRB neuroscience investigators. More recently the core has added an Applied Biosystem StepOnePlus quantitative RT-PCR capability for gene expression analysis studies which is growing in use. However going forward we intend to add another functional component to the Core to support the large number of SCoBIRC and other neuroscience faculty who are studying changes in mitochondrial bioenergetics in in vitro and in vivo models of acute and chronic neurodegenerative disease models. The growing interest in mitochondrial functional studies across several funded and pilot projects has made it desirable to centralize this capability into the core to insure methodological consistency and quality control and comparability of data across laboratories. We plan to provide this centralized capability by first of all shifting existing equipment used for mitochondrial preparation and bioenergetic analyses of ex vivo mitochondrial isolates into the core and secondly to add new Seahorse technology for highly sensitive imaging of mitochondrial bioenergetics and dysfunction and whole cells in culture models. Requested Molecular Mechanisms Core Equipment and Supplies: We are specifically requesting funding for purchase of the following. Note: all equipment quotes are listed in Appendix I  Seahorse Bioscience XF96 Dual Analyte Extracellular Analyzer- Justification: This state of art technology is capable of detecting real time changes in up to 3 analytes of cellular metabolism in a non-destructive manner in both energy producing pathways. $171636 Molecular Mechanisms Core Usage: The following SCoBIRC and other neuroscience invesfigators who have and will continue to use the core include: Cambi Geddes Gerhardt Gash Guttman Hall Rabchevsky Saatman Smith Snow Springer Sullivan Zhang and Zhu. Molecular Mechanisms Core Staffing: The Center Core Grant PI Dr. Edward D. Hall (5% effort) will confinue to serve as Core Director for the Molecular Mechanisms Core. Dr. Jeff Bosken (100% effort) will also continue to serve as Core Supervisor. He will also be specifically responsible for conduct and training in regards to the bioanalytical instrumentation (GC-MS HPLC) functional component. Dr. Indrapal Singh (25% effort) a Research Assistant Professor who is highly expert in mitochondrial bioenergetic studies will be responsible for the mitochondrial bioenergetics component of the core in regards to equipment maintenance training and pilot study conduct. . He will be responsible for maintenance pilot studies and training of laboratory personnel in regards to the immunoblotting (western slot infra-red imaging) and quantitative RT-PCR gene expression functions of the core.

project_terms:
Acute;Bioenergetics;Biological Markers;Blood;Cells;Center Core Grants;Cerebrospinal Fluid;Chronic;Core Facility;Data;Disease model;Drug Kinetics;Energy Metabolism;Equipment;Equipment and Supplies;Faculty;Functional disorder;Funding;Gases;Gene Expression;Gene Expression Profiling;Genus Hippocampus;High Pressure Liquid Chromatography;Image;Immunoblot Analysis;In Vitro;Injury;Laboratories;Laboratory Personnel;Life;Liquid substance;Maintenance;Measurement;Metabolism;Mitochondria;Modeling;Molecular;Nervous System Trauma;Neurodegenerative Disorders;Neurosciences;Pathway interactions;Performance;Pharmaceutical Preparations;Pilot Projects;Preparation;Quality Control;Research;Research Personnel;Reverse Transcriptase Polymerase Chain Reaction;Role;Snow;Technology;Testing;Time;Training;Urine;Western Blotting;extracellular;in vivo Model;instrumentation;interest;meetings;method development;professor;quantitative imaging;spinal cord and brain injury


application_id: 8782512
project_number: 5P30NS051220-10
project_title: MICROSCOPY CORE
administering_ic: NINDS
award_notice_date: 2014-12-03
opportunity_number: PAR-08-116
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
subproject_number: 7622
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
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: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-12-01
budget_end_date: 2015-11-30
project_abstract:
The Microscopy Image Analysis and Stereology Core located on the BBSRB fourth floor provides advanced instrumentation required for neurotrauma and other neuroscience research including two Olympus Provis AX70 Fluorescence Microscopes (Image Pro interfaced via MagnaFire Digital Camera) an Olympus BX 41 with Video Camera an Olympus BX 50 Epifluorescent Microscope (Bioquant Stereology package + 3D topographer interfaced with MagnaFire Digital Camera and Optronics Video Camera) a Zeiss Axiovert 200 M microscope and a Nikon E400 teaching microscope with DAGE Video Camera. In addition to this existing equipment SCoBIRC recently invested in three new specialized microscopes with funding from the NIH. The first an Olympus FluoViewTM 300 point-scanning point-detection confocal laser scanning microscope designed for biology research applications has excellent resolution efficiency of excitation and an intuitive user-friendly interface including preset parameters for individual users. The FluoViewTM 300 is also capable of 3D rendering and time-lapse observation and TTL I/O signals can be generated to coordinate experiments timed with external instrumentation. Additionally two high-sensitivity photomultiplier tubes (PMTs) are located directly within the FV300 confocal fluorescence emission light path for high sensitivity detection of the fluorescence signal. The second stereology microscope is an inverted Olympus IX 81 outfitted with motorized stage encoders and the BioQuant Nova Prime software particulariy well suited for quantification using modern stereological tools. The core is staffed by a Core Director Patrick Sullivan Ph.D. SCoBIRC Associate Director and Associate Professor of Anatomy & Neurobiology and an Assistant Director Alexander Rabchevsky Ph.D. Associate Professor of Physiology both of whom are well versed in the use of multiple image analysis endpoint measures and confocal imaging as endpoints in theirresearch. Both have expertise in developing protocols used to assess tissue sparing and cell loss in neurotrauma research.

project_terms:
Anatomy;Biology;Cell Count;Cells;Center Core Grants;Computer software;Computers and Advanced Instrumentation;Detection;Doctor of Philosophy;Educational process of instructing;Electrons;Equipment;Floor;Fluorescence;Funding;Housing;Human Resources;Image;Image Analysis;Individual;Lasers;Light;Measurement;Measures;Microscope;Microscopic;Microscopy;Nervous System Trauma;Neurobiology;Neurosciences Research;Physiology;Protocols documentation;Research;Resolution;Scanning;Signal Transduction;Staging;Time;Tissues;Tube;United States National Institutes of Health;design;digital;digital imaging;fluorescence microscope;instrumentation;light emission;method development;photomultiplier;professor;research study;spinal cord and brain injury;tool;transmission process;user-friendly


application_id: 8782511
project_number: 5P30NS051220-10
project_title: BEHAVIORAL TESTING
administering_ic: NINDS
award_notice_date: 2014-12-03
opportunity_number: PAR-08-116
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
subproject_number: 7621
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
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: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-12-01
budget_end_date: 2015-11-30
project_abstract:
The Behavioral Testing Core is housed within two rooms in the basement of BBSRB. B028 is a dedicated room for behavioral assessment of rats in which the Core has the capability of performing a) cognitive testing of learning and memory using a Morris water maze system b) sensory testing using a whisker nuisance task c) nociceptive testing using a Hargreaves plantar device and d) locomotor function testing using the Basso Beattie Bresnahan (BBB) scale and the foot misplacement apparatus (horizontal ladder). B030 is a dedicated room for behavioral assessment of mice in which the Core has the capability of performing cognitive testing of learning and memory using a white Morris water maze (for black mice) or a black maze (for white mice) in conjunction with an updated digital tracking system. Mice can also be evaluated for sensorimotor function using a corner turn test vestibulomotor ability using the rotarod apparatus and simple and complex motor function using the composite neuroscore neurological severity score. Basso mouse scale (BMS) grip strength meter and string test. Specific instruments purchased with P30 funds include 2 AccuScan Instruments EzVideoDV Automated Tracking System Digital Systems a Columbus Instruments Rotamex-5 and Foot Misplacement Apparatus 2 analgesia meters and a wading pool for open field locomotor assessment. Kathryn Saatman Ph.D. directs the Behavioral Testing Core along with Assistant Core Director Alexander Rabchevsky. Stephen Onifer Ph.D provide day-to-day management of core operations and overseeing training data storage and dissemination and core usage. Two senior technicians who are trained in behavioral testing in rodent TBI models (Ms. Jennifer Pleasant 25% effort) and SCI models (Mr. Travis Lyttle 25% effort) assist and instruct new core users with the behavioral assessments.

project_terms:
Absence of pain sensation;Behavior assessment;Center Core Grants;Cognitive;Complex;Data Storage and Retrieval;Devices;Doctor of Philosophy;Equipment;Evaluation Methodology;Funding;Housing;Learning;Memory;Modeling;Motor;Mus;Nervous System Trauma;Neurologic;Nociception;Rattus;Research;Rodent;Sensorimotor functions;Sensory;Severities;System;Testing;Training;Update;Vibrissae;behavior test;cognitive testing;digital;foot;grasp;improved;instrument;meter;morris water maze;operation;ranpirnase;spinal cord and brain injury


application_id: 8782510
project_number: 5P30NS051220-10
project_title: ANIMAL MODELING
administering_ic: NINDS
award_notice_date: 2014-12-03
opportunity_number: PAR-08-116
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
subproject_number: 7620
contact_pi_person_id: 1884283
contact_pi: SCHEFF, STEPHEN W
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
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: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-12-01
budget_end_date: 2015-11-30
project_abstract:
CORE B. Animal Modeling Core Plans: This core previously named the Animal Surgery & TBI/SCI Model Core will be renamed Animal Modeling Core to reflect the expansion of the capabilities of this widely used facility beyond its previous use as an animal surgery and neurotrauma modeling resource. While these functions will continue to constitute the central component of the core which will be the Surgery and In Vivo Models Component we request funding to add physiological (blood pressure heart rate arterial oxygenation body temperature and electrophysiological (e.g. somatosensory evoked potentials magnetically-evoled inter-enlargement recordings) monitoring capability during the acute recovery period after experimental neurotrauma. In addition we request support to establish a Viral Vectors Component and a Genetically-Modified Mice Component. These latter two capabilities currently exist within individual SCoBIRC laboratories (Dr. George Smith's lab in the former instance and Dr. Geddes' in the latter case). However the increasing need for the application of these across multiple laboratories has made it sensible to now expand and incorporate them under the umbrella of our Animal Modeling Core in order to improve access to them and to insure technical standardization across user laboratories.

project_terms:
Acute;Animal Model;Animals;Blood Pressure;Body Temperature;Breeding;Center Core Grants;Funding;Genes;Genotype;Heart Rate;Improve Access;Individual;Knock-out;Laboratories;Microinjections;Modeling;Monitor;Mus;Names;Nervous System Trauma;Operative Surgical Procedures;Physiologic Monitoring;Physiological;Recovery;Research;Resources;Rodent;Somatosensory Evoked Potentials;Standardization;Transgenic Organisms;Viral Vector;in vivo;in vivo Model;spinal cord and brain injury


application_id: 8782508
project_number: 5P30NS051220-10
project_title: ADMINISTRATIVE & BIOINFORMATICS
administering_ic: NINDS
award_notice_date: 2014-12-03
opportunity_number: PAR-08-116
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
subproject_number: 7619
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
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: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-12-01
budget_end_date: 2015-11-30
project_abstract:
The core which is located in SCoBIRC-controlled space on the 4th floor ofthe BBSRB will continue to provide an administrative and organizational framework to support monitor and coordinate the usage of each of the research cores and related activities and achieve increased collaboration among investigators. Ongoing scheduling of the research cores is done and monitored via our existing OfficeTracker system. Administrative functions will also include financial oversight (including maintenance contracts) and core facility staff management. In addition the core will continue to maintain a secure server to store and archive scientific data from each of the cores and and individual investigators. The core will also continue to maintain and further develop the existing Spinal Cord Injury-Related Gene Database or SCIgenes database which is accessible via the internet(httD://scigenes.ukv.edu). The goal of the database is to serve the spinal cord injury research community by compiling information at a single site about genes and gene products relevant to spinal cord injury such that gene sequence can be linked with protein function so that data mining algorithms will be able to determine patterns in the gene products affected by spinal cord injury. These patterns help predict relationships between proteins and therefore biochemical pathways affected by spinal cord injury.

project_terms:
Accounting;Affect;Algorithms;Archives;Biochemical Pathway;Bioinformatics;Budgets;Center Core Grants;Collaborations;Communities;Computers;Contracts;Core Facility;Data;Data Storage and Retrieval;Databases;Equipment;Floor;Funding;Genes;Goals;Grant;Human Resources;Individual;Internet;Link;Maintenance;Monitor;Pattern;Printing;Proteins;Research;Research Personnel;Schedule;Secure;Site;Spinal cord injury;System;data mining;posters;protein function;spinal cord and brain injury


application_id: 8782507
project_number: 5P30NS051220-10
project_title: UK Spinal Cord & Brain Injury Research Center Core Grant
administering_ic: NINDS
award_notice_date: 2014-12-03
opportunity_number: PAR-08-116
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
program_official: STEWART, RANDALL R
project_start_date: 2005-05-01
project_end_date: 2015-11-30
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
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:
This application is in response to the NINDS Program Announcement requesting institutional center core grants to support neuroscience research. Accordingly the current application seeks to create the UK Spinal Cord & Brain Injury Research Center (SCoBIRC) Core Grant to accelerate the research projects of 10 NINDS-funded investigators who are currently Pis on 12 NINDS R01s and to enhance . The application asks for support for five core facilities: an Administrative and Bioinformatics Core an Animal Surgery & TBI/SCI Model Core a Behavioral Testing Core a Microscopy Image Analysis & Stereology Core and a Pharmacokinetics and Biomarker Core. Although some of the proposed technologies are currently in place in the laboratories of individual investigators none of the cores currently exists. The proposal is for these resources to be centralized in some cases upgraded and added to with additional equipment. Dedicated technical support is requested for each of the cores to insure that they will be run efficiently with minimal downtime and equipment failure and serve to enhance the productivity of SCoBIRC and other NINDSsupported investigators. It is also expected that these cores will promote communication of data and foster overall collaboration. All of the participating investigators have documented needs for the use of most of the core facilities: 6 of 10 will use all 5 cores 3 will use 4 of the cores and only 1 will use 3 of them. Use of the cores will be shared with other non-qualifying neurological investigators. The PI has had considerable administrative experience and each of the Core Directors is fully qualified to direct the use of the proposed technologies. They will be backed up in 4 of the 5 cases with equally experienced Assistant Directors and dedicated technical staff who will perform pilot studies train new investigators handle scheduling maintain supplies and equipment maintenance. The performance of the cores will be reviewed quarterly by a Steering Committee consisting of all of the qualifying investigators. It is anticipated that the existence of these cores will greatly enhance the accomplishment of the SCoBIRC mission which is directed at the discovery and clinical translation of therapeutic approaches for spinal cord and brain injury. In addition these facilities will make available centralized technologies which will benefit UK neurological research in general and improve the ability of both experienced and young investigators to compete for extramural funding.

project_terms:
Animals;Back;Bioinformatics;Biological Markers;Center Core Grants;Clinical;Collaborations;Communication;Core Facility;Data;Drug Kinetics;Equipment;Equipment Failure;Equipment and Supplies;Extramural Activities;Fostering;Funding;Image Analysis;Individual;Laboratories;Maintenance;Microscopy;Mission;Modeling;NIH Program Announcements;National Institute of Neurological Disorders and Stroke;Neurologic;Neurosciences Research;Operative Surgical Procedures;Performance;Pilot Projects;Productivity;Qualifying;Research;Research Personnel;Research Project Grants;Resources;Running;Schedule;Technology;Therapeutic;Training;Translations;behavior test;experience;improved;response;spinal cord and brain injury


application_id: 8782475
project_number: 5R01DA032254-03
project_title: A Novel Anti Obesity Drug Combination as a Pharmacotherapy for Cocaine Dependence
administering_ic: NIDA
award_notice_date: 2015-02-10
opportunity_number: PA-10-268
application_type: 5
activity_code: R01
ic: DA
serial_number: 032254
program_official: HAMPSON, AIDAN
project_start_date: 2012-09-15
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)F]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
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): Cocaine (COC) dependence is a significant public health concern. A widely effective pharmacotherapy has not yet been identified for COC dependence. Innovative strategies are needed to identify an effective pharmacotherapy for COC dependence. Testing medications effective for disorders that share neurobiological substrates with drug dependence for example could yield treatments for managing COC dependence.  Obesity is also a significant public health concern. Although obesity and COC dependence are typically considered distinct clinical entities both diseases involve perturbations of central biogenic amine and/or hypothalamic-melanocortin systems. The obesity epidemic has spurred development of medications to promote weight loss. A combination of bupropion (BUP) and naltrexone (NTX) is effective for obesity. The overarching goal of this application is to demonstrate the initial efficacy safety and tolerability of BUP-NTX combinations for COC dependence. A mixed-model experiment will be conducted in which separate cohorts of non-treatment-seeking COC-dependent participants will be randomized to different maintenance doses of BUP (i.e. BUP is a between-subject factor). Participants (N=12) in each BUP cohort will be maintained concurrently on NTX (i.e. NTX is a within-subject factor). The reinforcing effects of intranasal COC will be determined after participants in each BUP cohort are maintained for 4-7 days on each of the NTX doses (i.e. COC is a within-subject factor). COC (0 25 50 100 mg) will be tested with multiple dose combinations of BUP (0 100 200 300 mg/day) and NTX (0 25 50 mg/day). The proposed study will also identify the optimal dose combination of BUP and NTX that most effectively attenuates the reinforcing effects of COC.  This research will provide critical information regarding the initial efficacy and optimal doses ofa novel drug combination BUP and NTX for COC dependence which will enhance the probability of success when advanced to a clinical trial. Innovations of the proposed research include: 1) testing a combination of marketed drugs that demonstrated modest efficacy when tested as mono-therapies; 2) the use of a sophisticated drug self-administration procedure; 3) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of BUP-NTX combinations for COC dependence; and 4) demonstrating the initial efficacy and optimal doses of a combination of commercially available drugs as opposed to waiting for novel molecules to be available for testing in humans thereby impacting clinical research and practice more quickly. In these ways the proposed project will shift the current clinical research paradigm in pharmacotherapy development and have a significant impact on the treatment of COC dependence.

project_terms:
Abstinence;Accounting;Admission activity;Adult;Adverse effects;Age Reporting;American;Anti-Obesity Agents;Attenuated;Behavior Therapy;Behavioral;Biogenic Amines;Body Weight;Body Weight decreased;Bupropion;Clinical;Clinical Research;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Combination Drug Therapy;Development;Disease;Dopamine Uptake Inhibitors;Dose;Drug Addiction;Drug Combinations;Enrollment;Epidemic;Evaluation;Food;Goals;Health;Human;Hypothalamic structure;Inpatients;Investigation;Laboratory Study;Maintenance;Modeling;Mono-S;Naltrexone;Narcotic Antagonists;Neurobiology;Obesity;Outcome Measure;Participant;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase II Clinical Trials;Physiological;Preventive Intervention;Probability;Procedures;Questionnaires;Randomized;Relative (related person);Research;Safety;Self Administration;System;Testing;United States;clinical practice;cocaine use;cohort;double-blind placebo controlled trial;drug market;indexing;innovation;interest;novel;programs;public health medicine (field);reinforcer;research study;secondary outcome;success

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The research proposed in this application will determine the initial efficacy safety and tolerability of a novel drug combination bupropion and naltrexone asa pharmacotherapy for cocaine dependence. A rigorous inpatient human laboratory study will be conducted. The proposed study is innovative and important because it will provide the impetus for the conduct of double blind placebo-controlled trials to further demonstrate the efficacy of bupropion-naltrexone combinations for managing cocaine dependence.


application_id: 8782337
project_number: 1R43DC012741-01A1
project_title: Microfabricated Cochlear Electrode Arrays
administering_ic: NIDCD
award_notice_date: 2014-08-15
opportunity_number: PA-13-234
application_type: 1
activity_code: R43
ic: DC
serial_number: 012741
suffix: A1
program_official: MILLER, ROGER
project_start_date: 2014-09-01
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1 ETTN-G (12)]
contact_pi_person_id: 11208190
contact_pi: JOHNSON, ANGELIQUE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 969965800
primary_uei: NPHRMGVU99E8
duns_number: 969965800
uei: NPHRMGVU99E8
fips: US
organization_id: 10030414
organization_name: MEMSTIM, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402022654
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): In the USA about 36 million adults suffer from hearing loss and three out of every 1000 children are born deaf or hard-of-hearing. When conventional hearing aids provide no appreciable benefit implantable electronic devices using electrode arrays inside the cochlea are a viable solution. With these cochlear implants the profoundly deaf achieve reasonable word recognition in quiet environments. However current technology has limited capabilities and little room for innovation due to the use of hand assembly for the implanted electrode arrays. This tedious manufacturing method is very costly extremely labor-intensive and inadequate in implementing new technologies for improving speech recognition and music appreciation. A superior alternative to hand assembly is MEMS fabrication which is a fully automated low cost and high yield manufacturing process that is capable of implementing a variety of innovations including smaller array size for residual hearing preservation drug delivery channels for inner ear health and cell regeneration and strain gauges for improved performance during surgical insertion. MEMS fabrication is a very promising alternative to hand-assembly but until now no MEMS-based electrode array has achieved all requirements for commercialization: (1) substrates composed of proven long-term implantable materials; (2) compatibility with standard surgical insertion techniques; and (3) robust substrate and stimulation sites capable of withstanding long-term use. Our novel MEMS manufacturing process meets all these requirements and will be the first to utilize robust medical-grade materials silicone and electroplated platinum. Surgical compatibility is accomplished through a patented array-on-channel process providing a guide for a stylet-wire in the advanced- off-stylet surgical insertion method and setting the array stiffness for direct forceps placement. We will use industry standard test methods critical for FDA approval to demonstrate the excellent capabilities of our manufacturing approach by evaluating electrical characteristics mechanical durability and biocompatibility of the fabricated cochlear electrode arrays. The outcome is a MEMS-fabricated electrode array that complies with important requirements for clinical use and commercialization.

project_terms:
Adoption;Adult;Benchmarking;Biological Preservation;Bionics;Cells;Characteristics;Charge;Child;Clinical;Cochlear Implants;Cochlear structure;Data;Deposition;Devices;Drug Delivery Systems;Elasticity;Electrodes;Electronics;Electroplating;Environment;Forcep;Goals;Growth;Hand;Hand functions;Health;Hearing;Hearing Aids;Hearing Impaired Persons;Human;Implanted Electrodes;Industry;Labyrinth;Legal patent;Manufacturer Name;Marketing;Mechanics;Medical;Methods;Microscope;Molds;Music;Natural regeneration;Operative Surgical Procedures;Otolaryngology;Outcome;Performance;Pharmaceutical Preparations;Phase;Platinum;Positioning Attribute;Prevention;Process;Prosthesis;Research;Residual state;Safety;Shapes;Silicones;Site;Solutions;Speech;Stress;System;Techniques;Technology;Temporal bone structure;Testing;Time;base;biomaterial compatibility;clinical application;clinically relevant;commercialization;cost;design;hearing impairment;implantation;improved;innovation;manufacturing process;meetings;millimeter;nanometer;new technology;novel;public health relevance;speech recognition;technological innovation;visual feedback

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cochlear implants allow the profoundly deaf to achieve reasonable word recognition in quiet environments but technological innovations to achieve fuller appreciation of music and speech are severely limited by the shortcomings of current hand assembly manufacturing methods for cochlear electrode arrays. MEMS fabrication is a fully automated low cost and high yield manufacturing process capable of implementing technological innovations that provide benefits such as small electrode array size for residual hearing prevention drug delivery channels for inner ear health and cell regeneration and strain gauges for improved surgical safety outcomes. We will design and validate a disruptive MEMS-based manufacturing process for cochlear electrode arrays complying with important requirements for clinical use and commercialization.


application_id: 8781214
project_number: 2U18IP000847-01
project_title: Anti-Influenza Therapy in Hospitalized Patients with Community-Acquired Pneumonia
administering_ic: NCIRD
award_notice_date: 2014-02-27
opportunity_number: RFA-IP-14-001
application_type: 2
activity_code: U18
ic: IP
serial_number: 000847
program_official: O'NEILL, EDUARDO
project_start_date: 2014-03-01
project_end_date: 2015-02-28
study_section: Special Emphasis Panel[ZIP1 GCA (24)]
contact_pi_person_id: 8816315
contact_pi: RAMIREZ, JULIO ALBERTO
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
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:
DESCRIPTION (provided by applicant): Lung infections such as pneumonia may be caused by bacteria or viruses and the current standard-of-care is to treat hospitalized patients with lung
infections with antibacterials (antibiotics). In a three-year study we treated over 1280 hospitalized patients with lung infections with drugs against both bacteria (antibacterials) and viruses (antivirals). We are requesting funding to see how patients are doing after one year of treatment and to analyze all of the study data.

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Pneumonia and influenza combined is the leading cause of infectious disease-related death in the world. The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) have developed guidelines for the management of community-acquired pneumonia (CAP). These guidelines recommend early initiation of empiric antibiotic therapy to cover the most likely typical and atypical bacteria tha may cause CAP. Several studies have indicated associations between delayed time to administration of empiric antibiotic therapy with increased clinical failure and mortality. This wel-documented association of a delay in appropriate antibacterial therapy and worse clinical outcomes in patients with bacterial CAP has not been evaluated in patients with influenza CAP. Since results of current diagnostic tests for influenza may be delayed and several tests have low sensitivity anti-influenza treatment for patients with influenza CAP is frequently initiated lte or not at all. We hypothesize that as happens with bacterial CAP hospitalized patients with influenza CAP will benefit from early initiation of empiric antiviral therapy soon after hospitalization. To test our hypothesis we conducted a prospective randomized multicenter clinical trial of hospitalized patients with lower respiratory tract infections (LRTIs) including AP. Patients were randomized to empiric antibacterial therapy as recommended by IDSA/ATS guidelines (Group A) versus a combination approach of empiric antibacterial plus anti-influenza therapy (Group B). The primary study outcome is development of clinical failure during 30 days after enrollment. The secondary study outcome is the cost-effectiveness of the intervention. Other clinical outcomes to be compared between study groups include: time to clinical stability duration of hospitalization development of cardiovascular events re-hospitalization short-term mortality (30 days) and long-term mortality (1 year). The primary aim of this study was to compare in hospitalized patients with influenza CAP the rate of clinical failure between Group A versus Group B. We hypothesized that patients in Group B (empiric anti-influenza therapy) will have a statistically significant decrease in the rate of clinical failure when compared with patients in Group A (guideline-recommended approach). We enrolled over 1280 patients with LRTIs from nine adult hospitals in Jefferson County Kentucky over the past three influenza seasons. Since the study protocol requires a full year follow-up on all enrolled patients the current study is to obtain funding to complete the data collection ensure the data is of the highest quality to perform necessary statistical analyses and to disseminate the study results.


application_id: 8780989
project_number: 1R41CA189517-01
project_title: Exosomal drug formulations
administering_ic: NCI
award_notice_date: 2014-09-03
opportunity_number: PA-13-235
application_type: 1
activity_code: R41
ic: CA
serial_number: 189517
program_official: ZHAO, MING
project_start_date: 2014-09-05
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1 OTC-T (10)]
contact_pi_person_id: 8240457
contact_pi: GUPTA, RAMESH C
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 831172668
primary_uei: HSCNW2K7VN97
duns_number: 831172668
uei: HSCNW2K7VN97
fips: US
organization_id: 10023330
organization_name: 3P BIOTECHNOLOGIES, INC.
organization_city: PROSPECT
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400598574
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): More people in the U.S. (160340 per year) die of lung cancer than of prostate breast and colon cancer combined. The most common type of lung cancer non-small-cell lung cancer (NSCLC) accounts for 75% of all lung cancers. Regrettably 85% of all patients diagnosed with NSCLC eventually die of the disease within 5 years due to micro-metastasis and relapse. Currently over 12 million cancer survivors reside in the U.S. of which only 3.3% (about 400000) are lung cancer survivors. Improved methods in effective cancer treatment are urgently needed and could greatly benefit not only lung cancer survivors but also those of other cancer types.  This project will develop a "platform technology"
for exosome formulations using bovine-milk-derived exosomes of both lipophilic and hydrophilic drugs. Specifically we will prepare exosome formulations of a standard chemotherapeutic (chemo) drug paclitaxel (PAC) and a natural compound with chemopreventive and therapeutic potential withaferin A (WFA) and examine their ability to prevent and treat cancer. We will focus on lung cancer and will seek to enhance the oral bioavailability of these drugs and reduce their required doses. Natural compounds often suffer from oral bioavailability issues despite high doses. On the other hand chemotherapeutic (chemo) drugs given intravenously are accompanied by undesirable large spikes in blood levels. Decades of work with liposomal and polymeric nanoparticle formulations have rendered only a handful of effective drugs for use in the clinics due to inherent limitations. In this application e will optimize exosome isolation and exosome formulations with potent therapeutic activity and determine their therapeutic efficacy and potential toxicity. Production of the bovine milk-derived exosomes will be scalable economically feasible and highly cost effective. The exosomal drug delivery approach has the potential to change the current practice of cancer treatment by challenging the existing paradigm involving high doses of toxic chemo drugs.  We hypothesize that exosome formulations of PAC and WFA administered orally will be more effective than respective free drugs (without exosome formulation) and that the formulation will reduce the required effective dose thus minimizing or eliminating toxicity. The specific aims are to (1) optimize exosome isolation/purification from bovine milk maximize drug loading of PAC and WFA and determine stability of the exosome formulations; and (2) determine the efficacy of exosome formulations of PAC and WFA in cell culture and in a nude mouse xenograft model against human lung cancer cells and also determine potential toxicities in a mouse model. Future efforts will optimize and determine the efficacy of nano spray-dried exosome formulations of PAC and WFA and other compounds including siRNAs determine their long-term stability test formulations of PAC and WFA both individually and in combination against drug-sensitive drug-resistant and metastatic lung cancer cells using orthotopic tumor xenograft nude mouse models.

project_terms:
Accounting;Alzheimer's Disease;Animal Model;Biodistribution;Biological Availability;Biotechnology;Blood;Cancer Survivor;Cattle;Cell Culture Techniques;Chemopreventive Agent;Chronic;Clinic;Colon Carcinoma;Cosmetics;Data;Data Analyses;Data Reporting;Diagnosis;Disease;Dose;Drug Delivery Systems;Drug Formulations;Drug resistance;Drug usage;Drug-sensitive;Excision;Exhibits;Future;Goals;Human;Immunologist;Immunotherapy;In Vitro;Individual;Inflammation;Liposomes;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Marketing;Methods;Milk;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Nude Mice;Oral;Paclitaxel;Pathologist;Patients;Pharmaceutical Preparations;Phase;Preparation;Prevention;Primary Cancer Prevention;Problem Formulations;Production;Recurrence;Relapse;Research Project Grants;Sampling;Small Business Technology Transfer Research;Source;Staging;Technology;Testing;Therapeutic;Therapeutic Uses;Tissues;Toxic effect;Treatment Efficacy;Vision;Work;Xenograft Model;anticancer activity;cancer cell;cancer therapy;cancer type;commercial application;cost effective;disorder later incidence prevention;high risk;improved;innovation;macromolecule;malignant breast neoplasm;mouse model;nano;nanoparticle;prevent;prophylactic;public health relevance;response;stability testing;stem;tumor;tumor xenograft

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The overall goal of this research project is to develop a "platform technology" for the prevention and treatment of cancer using milk-derived nanoparticles (exosomes) as a carrier for standard chemotherapeutic drugs and natural compounds. These formulations are intended to enhance the oral bioavailability of these drugs and reduce their required doses thus reducing their toxicities. This scalable cost-effective technology has the potential to change the current practice of treating cancers by challenging the existing paradigm involving high doses of toxic chemotherapeutic drugs. In this project we will optimize oral exosome formulations of a first-line chemotherapeutic drug and a naturally occurring compound with anticancer activity and determine their efficacy and potential toxicity against human lung cancer using both cell culture and animal models. The scope of this work has far reaching potential not only for lung cancer but for other cancer types such as ovarian cancer and other diseases.


