# projects

application_id: 9412623
project_number: 1R01AG057290-01
project_title: Programming amylin secretion to slow brain aging - an animal model
administering_ic: NIA
award_notice_date: 2017-09-12
opportunity_number: RFA-AG-17-050
application_type: 1
activity_code: R01
ic: AG
serial_number: 057290
program_official: VELAZQUEZ, JOSE M
project_start_date: 2017-09-15
project_end_date: 2022-04-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-6 (A1)]
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
other_pis: THINAKARAN, GOPAL
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:
APP-PS1;Affect;Age;Aging;Alzheimer's Disease;Alzheimer's Disease Pathway;Alzheimer's disease model;Amyloid;Amyloid beta-Protein;Amyloidosis;Animal Model;Behavior;Biological;Biological Neural Networks;Blood;Blood - brain barrier anatomy;Blood Vessels;Brain;Brain Diseases;Cerebrum;Data;Deposition;Development;Diabetes Mellitus;Disease Progression;Early Onset Familial Alzheimer's Disease;Feasibility Studies;Functional disorder;Genes;Goals;Heart failure;Hormones;Human;Impaired cognition;Individual;Injury;Insulin;Intravenous;Intravenous infusion procedures;Investigation;Islets of Langerhans;Late Onset Alzheimer Disease;Link;Longevity;Mediating;Microglia;Molecular;Mus;Neuraxis;Neuronal Dysfunction;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Pancreas;Pathogenesis;Pathology;Peripheral;Pre-Clinical Model;Protein Isoforms;Rattus;Structure of beta Cell of islet;Synapses;Testing;Time;Transgenes;Transgenic Mice;aging brain;amyloid peptide;apolipoprotein E-4;behavior change;beta amyloid pathology;cognitive performance;design;diabetic patient;early onset;in vivo;islet amyloid polypeptide;mouse model;non-diabetic;novel;overexpression;proteostasis;transgene expression;transgenic model of alzheimer disease;uptake


application_id: 9412505
project_number: 5R01HL074185-14
project_title: Reversing diabetic muscle myopathy by exercise and exosomes
administering_ic: NHLBI
award_notice_date: 2018-01-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 074185
program_official: SCHWARTZ, LISA
project_start_date: 2003-09-05
project_end_date: 2020-01-31
study_section: Special Emphasis Panel[ZRG1-MOSS-C(02)S]
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 exercise mitigates diabetic complications and myopathy the mechanism is unclear. The long-term goal of this project is to understand the mechanism of diabetic myopathy. Studies from previous funding period revealed causative role of endothelial-myocyte (E-M) uncoupling in cardiomyopathy. The connexin -37 and -43 are associated with endothelial and myocyte coupling; and mitochondria contains connexin-43. Matrix metalloproteinase-9 (MMP-9) disrupts connexins and is activated in diabetes unequivocally. Interestingly the exercise decreases MMP-9 activity. Exosomes 50-100 nm nanovesicles contain mir-RNAs and are released from myocytes. In this renewal application we will determine the role of exercise-mediated release in exosome containing mir-RNAs that mitigates the endothelium-myocyte myocyte-myocyte and mitochondrial-myocyte uncoupling by down regulating the MMP-9. The central hypothesis of this proposal is that MMP-9 degrades connexins and causes endothelial-myocyte myocyte-myocyte and mitochondria-myocyte uncoupling in diabetes. Exercise releases exosomes containing mir-RNAs that decreases MMP-9 and mitigates uncoupling. We will test the central hypothesis by following three specific aims. Specific aim #1: To determine whether the exercise releases exosomes that contain mir-29b mir-323 mir-455 and mir-466 which negatively regulate MMP-9 and mitigate fibrosis and uncoupling. Specific aim #2: To determine whether endothelial-myocyte uncoupling is caused by perivascular/pericapillary fibrosis and myocyte-myocyte uncoupling is caused by interstitial fibrosis in diabetes and exercise mitigates these conditions. Specific aim #3: To determine whether the dys-synchronization of mitochondrial fusion-fission causes mitochondria-myocyte uncoupling (mitochondrial remodeling) in diabetes and exercise alleviate. To evaluate the release of exosomes and their effect on MMP-9 and consequently Cx-37 and Cx-43 adult male db/db and controls db/+ wild type (WT-C57 and FVB) mice MMP-9 KO db/db/MMP-9 DKO Cx-37-Tg db/db/Cx-37-Tg; Cx-43-Tg and db/db/Cx-43-Tg mice with and without exercise will be used. Plasma and cardiac tissue exosomes will be isolated by ultracentrifugation/exoquick and characterized by electron microscopy/FACS/MACS. The levels of mir466 mir455 mir29b mir323 will be determined by RT-PCR and in situ hybridization. These studies will determine the mechanism of muscular structural functional and mitochondrial remodeling and exosomal therapeutic ramifications for diabetic myopathy.

project_terms:
3' Untranslated Regions;Acetylcholine;Adult;Adverse effects;Binding;Blood capillaries;Cardiac;Cardiomyopathies;Chimeric Proteins;Clinical Trials;Collagen;Complications of Diabetes Mellitus;Connexin 43;Connexins;Consumption;Coupling;Cytosol;Diabetes Mellitus;Electron Microscopy;Endothelium;Exercise;Extravasation;FVB Mouse;Fibrosis;Funding;Gelatinase B;Goals;In Situ Hybridization;Label;Laboratories;Matrix Metalloproteinases;Measures;Mediating;MicroRNAs;Mitochondria;Mitochondrial Matrix;Mus;Muscle;Muscle Cells;Myocardial Infarction;Myopathy;Nitroprusside;PECAM1 gene;Perivascular Fibrosis;Plasma;Preparation;Proteins;Reverse Transcriptase Polymerase Chain Reaction;Role;Sirius Red F3B;Swelling;Techniques;Testing;Therapeutic;Tissues;Ultracentrifugation;connexin 37;cytochrome c;diabetic;exosome;inhibitor/antagonist;innovation;interstitial;male;nanovesicle;public health relevance;response;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Because cardiac matrix is unique general matrix metalloproteinase-9 (MMP-9) inhibitors may not mitigate the cardiac remodeling (Clinical trial- PREMIER-Pevention of Myocardial Infarction Early Remodeling using the MMP-9 inhibitor PG-116800). Exosomes that carry microRNAs can provide alternate treatment strategy to inhibit MMP-9 since exosomes are non-immunogenic and have no side effects. Myocyte releases exosomes and exosomes contains miRNA. The miRNA inhibits MMP- 9 by binding to the 3'UTR region. These studies will determine the mechanism of muscular structural functional and mitochondrial remodeling and exosomal therapeutic ramifications for diabetic myopathy.


application_id: 9412400
project_number: 5R01AA021978-05
project_title: Role of ECM and inflammatory remodeling in alcohol-induced liver and lung damage
administering_ic: NIAAA
award_notice_date: 2018-01-18
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AA
serial_number: 021978
program_official: RADAEVA, SVETLANA
project_start_date: 2014-02-01
project_end_date: 2018-05-31
study_section: Special Emphasis Panel[ZRG1-DKUS-D(03)M]
contact_pi_person_id: 2047731
contact_pi: ARTEEL, GAVIN E
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): The overarching theme of this project is to study the role of nutrition and gut flora/intestinal dysfunction on alcohol-induced organ injury. We will focus on two organs that are the most common victims of chronic alcohol abuse: liver and lung. Specifically we will examine how alcohol activates tissue remodeling in liver and lung through the induction of plasminogen activator inhibitor-1 (PAI-1) and the consequences of these events. Novel in vitro and in vivo approaches will be used to address mechanisms of action with the goal of identifying new targets for intervention. We propose that liver and lung share similar mechanisms of organ damage in response to alcohol. We specifically propose that PAI-1 induction and subsequent extracellular matrix (ECM) remodeling are key to the early inflammatory changes in both organs. Considering observations linking the effects of alcohol on tissue remodeling in both organs we further propose that liver and lung not only share mechanisms of injury in response to alcohol but that these mechanisms are linked and represent interdependent events. Based on these observations and other preliminary data this proposal will test the hypothesis that alcohol through the activation of nicotinic acetylcholine receptors (nAChRs) induces the expression of PAI-1 in both liver (e.g. Kupffer cells) and lung (Type II epithelial cells). This in turn triggers a series of downstream events that promote live and lung injury in response to endotoxemia derived from the GI tract. Moreover we propose that liver-derived mediators further exacerbate lung injury through the induction of inflammation and tissue remodeling enhanced by inhibition of fibrinolysis. These hypotheses will be tested in the following Specific Aims: Aim 1: To explore the role of PAI-1 and nAChRs in the susceptibility of liver and lung to acute injury observed in the setting of chronic alcohol exposure. We hypothesize that alcohol stimulates the expression of PAI-1 in both liver and lung cells through effects on specific nAChRs. This in turn sensitizes both organs to acute injury (e.g. LPS). Aim 2: To test the hypothesis that liver-derived mediators are involved in pulmonary changes caused by chronic alcohol exposure and LPS- related organ damage. We propose that alcohol-induced damage to the liver sensitizes the host to acute lung injury in at-risk individuals. To test this e plan to evaluate the effects of alcohol on lung injury in animals with reduced hepatotoxicity usinggenetically engineered and chimeric mice. Aim 3: To determine the role of gut- derived products on alcohol-induced lung damage. Gut changes/injury caused by alcohol consumption could directly or indirectly damage liver and lung tissue. However how gut:lung or gut:liver:lung interactions are influenced by alcohol remains unknown. We propose to test these concepts and to explore the effect of novel therapeutic interventions that target the GI tract to protect th lung.

project_terms:
Acute;Acute Lung Injury;Address;Alcohol abuse;Alcohol consumption;Alcohol-Induced Disorders;Alcoholic Liver Diseases;Alcoholic liver damage;Alcohols;Animals;Cells;Chronic;Clinical;Comorbidity;Data;Deposition;Disease;Endotoxemia;Epithelial Cells;Ethanol;Event;Extracellular Matrix;Fibrin;Fibrinolysis;Functional disorder;Gastrointestinal tract structure;Genetic Engineering;Goals;Health;Hepatic;Hepatotoxicity;Hypoxemia;In Situ;In Vitro;Incidence;Individual;Inflammation;Inflammatory;Inflammatory Response;Injury;Intervention;Investigation;Kupffer Cells;Laboratories;Lead;Link;Liver;Lung;Lung Inflammation;Mediating;Mediator of activation protein;Modeling;Morbidity - disease rate;Mus;Nicotinic Receptors;Organ;Peptide Hydrolases;Plasminogen Activator Inhibitor 1;Predisposition;Preparation;Pulmonary Edema;Risk;Role;Series;Structure of parenchyma of lung;Testing;Tissues;Translating;Up-Regulation;Work;alcohol effect;alcohol exposure;alcohol response;base;gut microbiota;in vivo;liver inflammation;liver injury;lung injury;mortality;new therapeutic target;novel;novel therapeutic intervention;nutrition;problem drinker;public health relevance;response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Alcohol-induced organ damage is a major health concern. The liver and lungs are major target organs of alcohol damage but the mechanisms of injury remain unclear and there are no therapies for these diseases. This project test the overall hypothesis that liver and lung inflammation caused by ethanol is mediated by fibrin ECM deposition. Taken together these studies will establish new models of alcoholic injury explore multiple overlapping mechanisms and provide novel targets for therapies.


application_id: 9411724
project_number: 5K01DA031961-05
project_title: Glutamate Receptor Modulation of Calcium Signaling in Neuropathic Pain
administering_ic: NIDA
award_notice_date: 2018-02-01
opportunity_number: PA-11-190
application_type: 5
activity_code: K01
ic: DA
serial_number: 031961
program_official: RAPAKA, RAO
project_start_date: 2014-02-01
project_end_date: 2018-03-31
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 10670168
contact_pi: DOOLEN, SUZANNE
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): The long term goal of this K01 career award is to understand the mechanisms that lead to injury-induced central sensitization and to establish ameliorative therapeutic targets for chronic pain. My preliminary data suggests that AMPA receptors drive glutamate-evoked Ca2+ transients in spinal cord neurons and that glutamate-evoked Ca2+ transients are potentiated following nerve injury. The central hypothesis is that nerve injury potentiates neuronal activity and Ca2+ mobilization (Aim 1) via increased GluR2 AMPA receptor phosphorylation and trafficking in the dorsal horn (Aim 2) and that this mechanism of neuropathic pain is tonically inhibited by endogenous opioids (Aim 3). This hypothesis will be tested using innovative simultaneous Ca2+ imaging and whole-cell electrophysiology to evaluate dorsal root stimulated (DRS) Ca2+ transients and neuronal activity in dorsal horn of adult spinal cord slices. Aim 1. Experiment 1a will evaluate the effect f sham or spared nerve injury (SNI) on isolated AMPA receptor Ca2+ signals and membrane currents. Experiment 1b will evaluate Ca2+ mobilization and membrane currents DRS at A A and c-fiber activation strength. Aim 2 While AMPA GluR2 phosphorylation and trafficking have been implicated in inflammatory pain the mechanisms that mediate nerve injury-induced potentiation of Ca2+ levels are not known. To address this question Experiment 2a will determine levels and subcellular localization of total and phosphorylated GluR2 in dorsal horn. Based on studies indicating inflammation-induced GluR2 internalization is NMDA receptor-dependent Experiment 2b will test the hypothesis that intrathecal administration of NMDA receptor antagonists will reduce nerve-injury induced phosphorylation and internalization of GluR2. Aim 3. My new data suggest that opioids tonically inhibit glutamate receptor function after inflammation and thus mask neuropathic pain. Aim 3 seeks to extend this discovery to our model of peripheral neuropathic pain. Experiment 3a will attempt to correlate Ca2+ mobilization with pain-like behavior following traditional SNI and a modified nerve injury model that resolves over 4 weeks. Establishing a decrease in Ca2+ mobilization in association with behavioral resolution will allow us to test our hypothesis in Experiment 3b. Experiment 3b will evaluate the effects of opioid receptor antagonists on: DRS-stimulated Ca2+ transients and neuronal activity and GluR2 phosphorylation and subcellular localization. We expect that opioid receptor antagonists will increase Ca2+ mobilization neuronal activity GluR2 phosphorylation and shift Ca2+-impermeable GluR2 expression away from the cell surface.

project_terms:
AMPA Receptors;Address;Adult;Adverse effects;Analgesics;Award;Behavior;Behavioral;C Fiber;CTOP;Calcium;Calcium Signaling;Cell Fractionation;Cell surface;Cells;Chemosensitization;Data;Electrophysiology (science);Glutamate Receptor;Glutamates;Goals;Healthcare;Hyperalgesia;Image;Inflammation;Inflammatory;Injury;Lead;Masks;Mediating;Membrane;Mentors;Mission;Modeling;Mus;N-Methyl-D-Aspartate Receptors;NMDA receptor antagonist;Naltrexone;National Institute of Drug Abuse;Neurons;Opioid;Opioid Antagonist;Pain;Pain management;Peripheral;Permeability;Phosphorylation;Receptor Activation;Receptor Signaling;Research;Research Technics;Resolution;Signal Transduction;Slice;Spinal Cord;Techniques;Testing;Western Blotting;base;career;central sensitization;chronic pain;clinically relevant;dorsal horn;endogenous opioids;experimental study;inflammatory pain;innovation;mu opioid receptors;nerve injury;neuronal excitability;painful neuropathy;postsynaptic;public health relevance;receptor function;response;sensory input;spared nerve;spinal nerve posterior root;therapeutic target;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Chronic pain management is a major scientific and health care challenge as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. This project is relevant to NIDA's mission because it will 1) determine mechanisms that lead to injury-induced central sensitization and 2) establish clinically relevant therapeutic targets for alleviating chronic pain and 3) target mechanisms of endogenous opioids on long-lasting pain vulnerability following injury. This Research Plan employs highly innovative wide-field calcium imaging from numerous cells in a single spinal cord slice from adult mice.


application_id: 9411057
project_number: 5R25AA022823-05
project_title: Basic and Applied Summer Training in Alcohol Research
administering_ic: NIAAA
award_notice_date: 2018-01-18
opportunity_number: PAR-13-104
application_type: 5
activity_code: R25
ic: AA
serial_number: 022823
program_official: POWELL, ELIZABETH
project_start_date: 2014-02-01
project_end_date: 2020-01-31
study_section: Epidemiology, Prevention and Behavior Research Study Section[AA-2]
contact_pi_person_id: 8535960
contact_pi: PRENDERGAST, MARK A
other_pis: NIXON, KIMBERLY
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): The University of Kentucky Summer Training in Alcohol Research (STAR) program provides 12 weeks of intensive hands-on alcohol research for 11 outstanding undergraduate students. A broad range of research opportunities exist that are truly bench to bedside because of the breadth of empirical approaches employed by our alcohol research faculty. Research topics available to the trainees range from the cell biology of alcohol neurodegeneration to applied survey research on the role that alcohol may have in moderating interpersonal domestic violence. This program will mesh well with the long-standing existing infrastructure of the Department of Pharmaceutical Science's summer undergraduate research program. Trainees will perform independent research under the supervision of alcohol research faculty participate in weekly educational and professional development seminars and be trained in responsible conduct of research. Hard work discovery and great science will culminate in a research presentation to faculty laboratory personnel and peers at our annual Summer Alcohol Research Symposium. Aggressive advertising of the program through scientific organizations networking websites and directly to regional liberal arts colleges undergraduate institutions and especially those schools serving underrepresented groups in STEM fields will allow for the recruitment of a diverse pool of summer undergraduate trainees. In concert with the main goals of providing hands on experience in basic and applied alcohol research we will be promoting the biomedical and behavioral sciences as career choices for these students. Evaluations of short-term and long-term successes of the STAR program on our primary objective of increasing the pool of diverse applicants to graduate programs and biomedical research careers will be conducted and followed throughout the years of the program.

project_terms:
Advertising;Alcohol consumption;Alcohols;Arts;Behavioral Sciences;Biomedical Research;Brain Injuries;Career Choice;Cellular biology;Development;Domestic Violence;Engineering;Evaluation;Faculty;Goals;Institution;Kentucky;Laboratories;Laboratory Personnel;Mathematics;Nerve Degeneration;Pharmacologic Substance;Play;Research;Research Infrastructure;Role;STEM field;Schools;Science;Students;Supervision;Surveys;Technology;Training;Underrepresented Groups;Universities;Work;addiction;alcohol research;bench to bedside;career;college;experience;faculty research;peer;programs;public health relevance;recruit;responsible research conduct;scientific organization;success;summer research;symposium;undergraduate research;undergraduate student;web site

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The University of Kentucky Basic and Applied Summer Training in Alcohol Research (STAR) is a 12 week summer research program for 11 undergraduates to work hands on in the laboratory of faculty pursuing a broad spectrum of alcohol and addiction-related research questions. These research experiences range in focus from the cell biology of alcohol-induced brain damage to role that alcohol use/abuse plays in interpersonal domestic violence. This program aims to attract and develop a diverse pool of qualified experienced applicants for graduate study and/or careers in science technology engineering or math fields.


application_id: 9410948
project_number: 1UG3DA044798-01
project_title: Kentucky Communities and Researchers Engaging to Halt the Opioid Epidemic (CARE2HOPE)
administering_ic: NIDA
award_notice_date: 2017-08-14
opportunity_number: RFA-DA-17-014
application_type: 1
activity_code: UG3
ic: DA
serial_number: 044798
program_official: CRUMP, ARIA
project_start_date: 2017-08-15
project_end_date: 2019-07-31
study_section: Special Emphasis Panel[ZDA1 HXO-H (18)]
contact_pi_person_id: 11085214
contact_pi: YOUNG, APRIL MARIE
other_pis: COOPER, HANNAH LF
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_terms:
Address;Appalachian Region;Area;Behavioral;Caring;Centers for Disease Control and Prevention (U.S.);Cities;Coal;Collaborations;Communities;Community Trial;Country;County;Disease Outbreaks;Drug usage;Effectiveness;Elements;Ensure;Environment;Epidemic;Epidemiologic Methods;Epidemiology;Evidence based intervention;General Population;HIV;HIV/HCV;Harm Reduction;Health;Health Services;Hepatitis C;Heroin;Incidence;Injectable;Injecting drug user;Injection of therapeutic agent;Intervention;Kentucky;Knowledge;Laws;Letters;Methods;Modeling;Naloxone;National Institute of Drug Abuse;Opioid;Outcome;Overdose;Pathway Analysis;Pharmaceutical Preparations;Phylogenetic Analysis;Plant Roots;Policies;Provider;Public Health;Qualitative Research;Readiness;Research Infrastructure;Research Personnel;Resources;Risk;Risk Assessment;Rivers;Rural;Services;Site;Substance Use Disorder;Syringes;Testing;United States Substance Abuse and Mental Health Services Administration;Work;base;combat;community based participatory research;cost effectiveness;data exchange;design;evidence base;implementation science;improved;infectious disease treatment;injection drug use;innovation;mathematical model;member;prescription opioid;programs;randomized trial;response;rural counties;sex;social stigma;theories;virtual


application_id: 9410879
project_number: 1R21AI134323-01
project_title: Effector molecules for IFN-gamma-mediated prevention of Toxoplasma proliferation in the brain
administering_ic: NIAID
award_notice_date: 2017-07-13
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: AI
serial_number: 134323
program_official: PESCE, JOHN T
project_start_date: 2017-07-15
project_end_date: 2019-06-30
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 1882071
contact_pi: SUZUKI, YASUHIRO
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:
Reactivation of chronic infection with Toxoplasma gondii results in the development of life-threateningtoxoplasmic encephalitis (TE) in AIDS and other immunocompromised patients. To improve prevention andmanagement of TE it is critical to gain a better understanding of the immunopathogenesis of the disease. IFN- is required for preventing cerebral tachyzoite proliferation and TE. However the effector mechanisms bywhich the IFN--mediated immunity prevents tachyzoite growth within brain-resident cells are poorlyunderstood. Whereas in vitro studies previously showed an importance of inducible nitric oxide synthase andimmunity-related GTPase m3 in inhibition of tachyzoite growth within murine microglia and astrocytesrespectively more recent in vivo studies using bone marrow (BM) chimeric mice demonstrated that their rolesto control T. gondii within brain-resident cells (irradiation-resistant non-hematopoietic population in the brainsof the BM chimeras) are negligible or subordinate. Thus it is essential to employ in vivo models fordetermining IFN--mediated effector mechanisms to prevent tachyzoite growth within brain-resident cells anddevelopment of TE. Our recent study using a murine model revealed that an inhibition of cerebral tachyzoitegrowth by the IFN--dependent protective immunity is associated with marked increases in expression ofguanylate binding protein 1 (Gbp1) and indoleamine-2 3-dioxygenase 1 (IDO1) but not IDO2 in the brain. Invitro studies by others previously showed inhibitory activities of Gbp1 and IDO against intracellular T. gondiigrowth in multiple types of host cells activated by IFN-. However it is unknown whether Gbp1 preventstachyzoite growth in vivo. The role of IDO against cerebral tachyzoite growth also remains to be determined.Thus in order to elucidate the effector mechanisms required for prevention of TE it is important to examine theroles of Gbp1 and IDO especially IDO1 in inhibiting cerebral tachyzoite growth in vivo. Thus the goal of thisproject is to determine the roles of Gpb1 and IDO1 in IFN--mediated prevention of tachyzoite proliferationwithin the major glial cell populations in the brain microglia and astrocytes during reactivation of T. gondiiinfection using murine models. Whereas viral infections induce Gbp1 expression in both murine and humanmicroglia the induction of Gbp1 by infections in astrocytes has not been reported. In contrast both mouse andhuman primary astrocytes express IDO1. Thus we will determine the roles of Gpb1 in microglia (Aim 1) andthe roles of IDO1 in astrocytes (Aim 2) in their IFN--mediated protective activities to prevent intracellulartachyzoite proliferation and development of TE in vivo using murine models. We will employ a novel in vivomodel using BM chimeric mice deficient in Gbp1 or IDO1 only in brain-resident cells in the brain and infectingthe mice with a double reporter strain of T. gondii expressing red fluorescent protein in tachyzoites and greenfluorescent protein in bradyzoites. We will utilize an advanced system of purifying microglia from the brainsand flow cytometry to quantitatively visualize tachyzoite growth within the glial cell population.

project_terms:
Acquired Immunodeficiency Syndrome;Astrocytes;Binding Proteins;Bone Marrow;Brain;CD4 Positive T Lymphocytes;Cell Count;Cell physiology;Cells;Cerebrum;Chimera organism;Chronic;Cyst;Development;Dioxygenases;Disease;Encephalitis;Exhibits;Flow Cytometry;Goals;Green Fluorescent Proteins;Growth;Growth and Development function;Guanosine Triphosphate Phosphohydrolases;Human;Immunity;Immunocompromised Host;In Vitro;Individual;Infection;Interferon Type II;Knock-out;Knockout Mice;Lead;Life;Mediating;Methods;Microglia;Modeling;Mus;NOS2A gene;Neuroglia;Nitric Oxide;Nitric Oxide Synthase;Organ;Parasites;Patients;Play;Population;Prevention;Production;Reporter;Reporting;Resistance;Role;Rupture;T-Lymphocyte;Tissues;Toxoplasma;Toxoplasma gondii;Toxoplasmosis;Tumor stage;Virus Diseases;advanced system;base;brain parenchyma;guanylate;improved;in vivo;in vivo Model;indoleamine;inhibitor/antagonist;instrument;interest;irradiation;macrophage;mortality;mouse model;novel;pathogen;prevent;red fluorescent protein

public_health_relevance:
Reactivation of chronic infection with Toxoplasma gondii in the brain causes life-threatening toxoplasmic encephalitis (TE) in immunocompromised individuals. Theproposed studies are aimed to determine the effector molecules required for preventionof the pathogen growth within brain-resident cell populations. These studies will providethe information crucial for developing a novel method(s) to improve preventiontreatment and management of TE by directly amplifying the capability of the brain-resident cells to inhibit the pathogen growth.


application_id: 9409600
project_number: 1R43OD024887-01
project_title: Facilitation of vitrification in animal model systems using a cryovial insert device
administering_ic: OD
award_notice_date: 2017-07-27
opportunity_number: PAR-15-186
application_type: 1
activity_code: R43
ic: OD
serial_number: 024887
program_official: CONTRERAS, MIGUEL A
project_start_date: 2017-08-01
project_end_date: 2019-07-31
study_section: Special Emphasis Panel[ZRG1 IMST-B (12)]
contact_pi_person_id: 10138071
contact_pi: STONE, BARBARA JEAN
other_pis: MCLAUGHLIN, KENNETH J
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARYParaTechs Corporation aims to provide researchers with advanced technology and methods to simplifyprocedures for laboratory animal models. While actively supporting efforts to reduce replace and refine (3Rs)animal use ParaTechs provides safe and effective resources for assisted reproductive techniques. Byimplementing the Cryofork a novel tool for embryo and sperm preservation and recovery we intend to improvethe management of animal facilities and facilitate the use of cryopreserved material for experiments that useanimal models. One of the most important aspects of animal facility management is animal welfare.Cryopreservation of animal models is ubiquitously favored by the biomedical research community for its abilityto safeguard against catastrophic animal loss due to disease breeding problems disasters and genetic drift.Animal models not currently needed for experiments can also be cryopreserved. This provides substantialsavings; streamlining workloads and freeing vivarium resources for active projects. With the advent of highlyeffective genome editing approaches the number of animal models available for biomedical research is poisedto dramatically increase in the next 5-10 years with wide-sweeping implications for basic biologypharmacological studies generation of engineered animal models and human gene therapeutics. This explosionof potential animal models will require a convenient and inexpensive tool for rapid cryopreservation. The Cryoforkvitrification protocol provides a rapid and effective method for the cryopreservation of oocytes embryos andsperm for mouse and rat models. Cryoforks can easily be shipped reducing the need for transfer of live animals.The Cryofork will therefore help researchers and institutions meet the goal of continuous improvement in the useof research animals Use of the Cryofork will reduce the number of animals used and eliminate a potentiallyhazardous shipping procedure meeting the requirements of the 3Rs of animal research. In addition to benefitsto facility management animal welfare and experimental flexibility the Cryofork is also a cost- and time-savingalternative to current cryopreservation providing substantial cost savings versus contracted cryopreservationservices. Therefore the goals of this project are to design manufacture and test the Cryofork for use withembryos and sperm from mice and rats. The Cryofork design will be optimized; critically evaluating the shapeand surface characteristics which impact vitrification performance. The best prototype design will be selectedand manufactured for feasibility testing. The manufactured Cryofork will then be evaluated for strain recoveryafter rodent embryo and sperm vitrification. Since a rat sperm vitrification protocol has not been previouslyreported for rat sperm vitrification a new protocol will be developed for use with the Cryofork. The Cryofork hasthe potential to decrease the financial burden of creating storing and retrieving model organisms for biomedicalresearch.

project_terms:
Address;Adherence;Animal Experimentation;Animal Model;Animal Welfare;Animals;Archives;Area;Assisted Reproductive Techniques;Biological Models;Biological Preservation;Biology;Biomedical Research;Breeding;CRISPR/Cas technology;Characteristics;Collaborations;Communities;Containment;Contracts;Core Facility;Cost Savings;Cryopreservation;Development;Devices;Disasters;Disease;Embryo;Engineering;Explosion;Freezing;Funding Opportunities;Generations;Genes;Genetic Drift;Goals;Health Status;Human;Individual;Institution;Laboratories;Laboratory Animal Models;Laboratory Animal Production and Facilities;Laboratory Animals;Laboratory Procedures;Laboratory Research;Livestock;Mediating;Methods;Modeling;Mouse Strains;Mus;Mutation;Oocytes;Outsourcing;Performance;Pharmacology Study;Procedures;Production;Protocols documentation;Rat Strains;Rattus;Recovery;Reporting;Research;Research Personnel;Research Support;Resources;Rodent;Savings;Services;Shapes;Shipping;Ships;Social Welfare;Sperm Preservation;Stress;Surface;System;Techniques;Technology;Testing;Time;Training;United States National Institutes of Health;Vial device;Workload;animal care;animal facility;cost;cost effective;design;embryo preservation;experimental study;flexibility;functional genomics;genome editing;improved;meetings;novel;precise genome editing;prototype;response;sperm cell;therapeutic gene;tool

public_health_relevance:
NARRATIVEBecause of the recent development of precise genome-editing techniques the number of animal modelsavailable for biomedical research is poised to dramatically increase in the next 5-10 years. Cryopreservation ofmouse and rat strains produced by these methods is an economical means for storage and recovery. ParaTechsproposes to design manufacture and test the Cryofork a novel tool for vitrification of embryos oocytes andsperm for rodents. The Cryofork will improve the management of animal facilities and simplify use ofcryopreserved material for experiments which use animal models.


application_id: 9408971
project_number: 1R44CA221487-01
project_title: Exosomal Drug Delivery
administering_ic: NCI
award_notice_date: 2017-09-26
opportunity_number: PAR-14-088
application_type: 1
activity_code: R44
ic: CA
serial_number: 221487
program_official: ZHAO, MING
project_start_date: 2017-09-26
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1 OTC-T (10)]
contact_pi_person_id: 2081643
contact_pi: SPENCER, WENDY A
other_pis: GUPTA, RAMESH C
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:
Technical Abstract As with many chemotherapeutic drugs taxanes exhibit poor oral bioavailability; hence they areadministered intravenously (i.v.). This regimen results in significant toxicities due to both the high drug dose andvehicle (Cremophore ELR) used. Attempts made to develop an oral chemotherapeutic using liposomes andpolymeric nanoparticles as carriers have not made it to the clinic due to their inherent limitations. In Phase I 3PBiotechnologies proposed to develop a platform technology for the oral delivery of chemo drugs and othertherapeutics via bovine milk-derived nanoparticles known as exosomes. The Phase I specific aims were to (1)isolate and characterize milk exosomes; (2) prepare exosomal (Exo) formulations of the chemo drug paclitaxel(PAC) and the plant therapeutic withaferin A (WFA); and (3) show that Exo formulations enhance therapeuticresponses while lacking toxicity. Phase I proved feasible based on the following findings: a) differentialcentrifugation of raw bovine milk provided exosomes; b) exosomes were taken up by cells in vitro and in vivo; c)Exo formulations of PAC (ExoPACTM) WFA (ExoWFATM) and other compounds were developed which showedhigher anti-proliferative anti-inflammatory and anti-cancer activities vs. the free drugs against lung cancer cellsboth in vitro and in vivo; and d) milk exosomes lacked cross-species reactivity in wild-type mice. Additional datagenerated preliminary to Phase II showed that bovine colostrum powder produces exosomes with a yield andpurity that are several-fold higher than can be obtained from fresh milk resulted in significantly higher drugloading than milk and that exosomes can be functionalized with folic acid for tumor targeting. In Phase II a teamof multidisciplinary researchers will advance this technology by pursuing the following specific aims: 1) Establishthe reproducibility of colostrum exosome yield maximize drug loading of the taxane PAC identify and optimizeloading of a tumor-targeting ligand and test the resulting formulations for antiproliferative and anti-inflammatoryactivities against human lung cancer cells in vitro. 2) Determine the efficacy of Exo formulation of PAC(ExoPACTM) and functionalized-ExoPACTM for tumor targetability minimizing off-target sites using orthotopicxenograft patient-derived tumor xenograft (PDX) and K-ras spontaneous tumors. 3) Determine toxicities of theExoPACTM and functionalized-ExoPACTM formulations analyze blood and tissue levels of PAC (PK/PD studies)and determine stability of the formulations. The innovation lies in the use of standardized colostrum-derivedfunctionalized exosomes for oral delivery for cancer therapeutics to circumvent bioavailability issues. The currenttaxane therapeutic market is dominated by a single product Abraxane an i.v. albumin-PAC product. A productthat performs similar to or better than Abraxane would potentially generate U.S. and worldwide markets of over$7 billion and $28 billion respectively. If we are successful in achieving our objectives we will apply for Phase IIbwhere we will establish large-scale production of ExoPACTM and will conduct Phase 1/2 clinical trials. Oncologistson the Advisory Board of 3P Biotechnologies will guide as we advance these drug formulations.

project_terms:
Abraxane;Accounting;Adverse effects;Albumins;Anti-Inflammatory Agents;Anti-inflammatory;Biological Availability;Biotechnology;Blood;Bone Marrow;Cancer Cell Growth;Cancer Survivor;Capital;Cattle;Cell Culture Techniques;Cells;Centrifugation;Clinic;Clinical Trials;Colon Carcinoma;Colostrum;Data;Data Analyses;Diagnosis;Disease;Dose;Drug Delivery Systems;Drug Formulations;Drug usage;Excision;Exhibits;Folic Acid;Formulation;Funding;Goals;Harvest;Healthcare Systems;Human;Immune;Immune response;Immunologist;In Vitro;Intravenous;KRAS2 gene;Label;Ligands;Liposomes;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Milk;Modeling;Mus;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Nude Mice;Oncologist;Operative Surgical Procedures;Oral;Oral Administration;Paclitaxel;Pathologist;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Plants;Polymers;Powder dose form;Publishing;Radiation;Reaction;Recovery;Recurrence;Regimen;Relapse;Reporting;Reproducibility;Research;Research Personnel;Rodent Model;Site;Solvents;Source;Specificity;Spleen;Standardization;Technology;Test Result;Therapeutic;Tissues;Toxic effect;Tumor-Derived;Wild Type Mouse;Xenograft procedure;base;cancer cell;cancer therapy;chemotherapy;drug efficacy;drug testing;exosome;hydrophilicity;in vivo;innovation;large scale production;lipophilicity;malignant breast neoplasm;mouse model;multidisciplinary;nano;nanoparticle;neoplastic cell;public health relevance;taxane;treatment response;tripterine;tumor;tumor xenograft

public_health_relevance:
Narrative (Public Health Relevance Statement) In this project we will develop oral formulations of the widely used chemotherapeutic drug paclitaxel. Thisformulation (ExoPACTM) will use nanoparticles (exosomes) isolated from standardized bovine colostrumpowder to treat lung cancer. The drug formulation will be tagged with a tumor-targeting ligand to increasetumor-cell specificity thus minimizing or eliminating adverse effects associated with the current practice of high-dose intravenous chemotherapy. The oral formulation of paclitaxel will be highly patient friendly and besidesreducing adverse effects it will also significantly reduce financial burden to both patients and the health caresystem. The exosomes per se (in the absence of any drug) will provide additional benefits due to their intrinsicanti-inflammatory activity and by inhibiting the growth of cancer cells.


application_id: 9408298
project_number: 1U01AA026225-01
project_title: 2/2 Alcohol associated Comorbidities and Microbiome Evaluation in HIV (ACME HIV)
administering_ic: NIAAA
award_notice_date: 2017-09-21
opportunity_number: RFA-AA-17-014
application_type: 1
activity_code: U01
ic: AA
serial_number: 026225
program_official: WANG, JOE
project_start_date: 2017-09-22
project_end_date: 2022-08-31
study_section: Special Emphasis Panel[ZAA1 DD (14)]
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: COOK, ROBERT L
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:
Address;Adverse effects;Alcohol abuse;Alcohol consumption;Alcoholic beverage heavy drinker;Alcohols;Automobile Driving;Bacteria;Bacterial Genes;Behavior assessment;Biodiversity;Biological Markers;Brain;Chronic;Clinical;Cognition;Cognitive;Cohort Analysis;Cohort Studies;Collection;Comorbidity;Data;Development;Endotoxemia;Enrollment;Evaluation;Evaluation Studies;Florida;Functional disorder;Funding;Goals;HIV;HIV Infections;HIV-1;Heavy Drinking;Immune;Impaired cognition;Impairment;Individual;Infection;Inflammation;Inflammatory;Intervention;Intestines;Link;Longitudinal Studies;Measures;Neurobiology;Neurocognitive;Neurocognitive Deficit;Outcome;Participant;Pathogenesis;Pathogenicity;Pathologic;Peripheral;Permeability;Phylogeny;Prospective cohort study;Recruitment Activity;Research;Resolution;Resources;Role;Sample Size;Shotguns;Structure;Taxonomy;Testing;Virulence Factors;alcohol effect;alcohol measurement;alcohol research;clinically relevant;cognitive function;cognitive performance;cognitive testing;combinatorial;contingency management;cooking;drinking;gut microbiome;gut microbiota;immune activation;improved;metagenomic sequencing;microbial;microbial community;microbiome;microbiota;motivational enhancement therapy;neuroimaging;neuroinflammation;outcome prediction;payment;preclinical study;prospective;rRNA Genes;relating to nervous system;response;targeted treatment;whole genome


application_id: 9408287
project_number: 1R43HL136220-01A1
project_title: A Non-invasive Assay for Obstructive Sleep Apnea
administering_ic: NHLBI
award_notice_date: 2017-07-09
opportunity_number: PA-16-302
application_type: 1
activity_code: R43
ic: HL
serial_number: 136220
suffix: A1
program_official: BROWN, MARISHKA
project_start_date: 2017-07-10
project_end_date: 2019-12-31
study_section: Special Emphasis Panel[ZRG1 CVRS-Q (11)]
contact_pi_person_id: 1885098
contact_pi: VALDES, ROLAND
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 012986391
primary_uei: ZFN5J433DCT1
duns_number: 012986391
uei: ZFN5J433DCT1
fips: US
organization_id: 10019586
organization_name: PGXL TECHNOLOGIES, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40206
organization_country: UNITED STATES
project_abstract:
Project AbstractPGXL Technologies is developing novel urine-based tests for detecting obstructive sleep apnea(OSA) in children. Obstructive sleep apnea (OSA) is a disorder giving rise to behavioral and learningproblems including misdiagnoses as attention deficit hyperactivity disorder (ADHD) in children. TheCDC estimates the prevalence of pediatric OSA in the US at 3% - around 2.3 million. An addedcomplication is that the prevalence of primary snoring (PS) in children approaches 20% thusphysicians are challenged in differentiating OSA from PS. The gold standard test for diagnosingOSA in children is polysomnography (PSG) but it is expensive (up to $1200 per test) involves anovernight stay in a sleep laboratory and requires the placement of numerous sensors. Parents areoften unwilling  and children too uncooperative  to endure a PSG test. Take-home sleep devicesallow patients to monitor their sleep patterns at home but are not available to children. Thus a simpleand inexpensive urine test would fill an important and significant clinical need. A preliminary studycomparing children diagnosed with OSA by polysomnography to children with PS revealed that thepeptide urocortin 3 (UCN3) a stress-related biomarker was significantly increased in the urine ofchildren with OSA. We have an issued US patent for the use of UCN3 as a biomarker for detectingOSA and have also developed a mass spectrometry-based assay and an immunoassay to measureUCN3. To complete definitive studies validating the clinical sensitivity and specificity of using thisbiomarker as a diagnostic for OSA it is necessary to have robust CLIA-validated and standardizedassays - not available today. Upon completion of this Phase I project we will have optimized a massspectrometry assay to CLIA-validated standards including establishing preliminary reference rangesfor UNC3 in urine. Successful completion of this project will position our company for a Phase IIproject to rigorously develop immunoassays and clinically validate the use of UCN3 as a biomarkerfor detection of OSA. This project is innovative in the application of a novel biomarker for detection ofOSA in children and in the use of novel extraction methods for measuring UCN3. Having robustassays for detection of OSA is anticipated to have sustainable high impact in a significant and muchneeded clinical problem of diagnosing sleep apnea in children. This will provide a sustainablecommercialization path for PGXL Technologies to develop simple and inexpensive assays for clinicallaboratories by way of assay kits as well as point-of-care and other vitro diagnostics applications.

project_terms:
Adult;Affect;Apnea;Attention deficit hyperactivity disorder;Behavioral;Biological Assay;Biological Markers;Centers for Disease Control and Prevention (U.S.);Child;Childhood;Clinical;Clinical Research;Clinical Sensitivity;Clinical Trials;Complication;Continuous Positive Airway Pressure;Detection;Development;Devices;Diagnosis;Diagnostic;Diagnostic tests;Disease;Disease Management;Ensure;Future;Gold;Healthcare;Home environment;Immunoassay;In Vitro;Insurance Carriers;Laboratories;Learning;Legal patent;Mass Spectrum Analysis;Measures;Methods;Monitor;Obstructive Sleep Apnea;Oral Surgical Procedures;Orthodontic;Parents;Patients;Pattern;Peptides;Phase;Physicians;Polysomnography;Population;Positioning Attribute;Prevalence;Problem Solving;Process;Protease Inhibitor;Reagent;Recovery;Recurrence;Reference Values;Sampling;Sensitivity and Specificity;Sleep;Sleep Apnea Syndromes;Small Business Innovation Research Grant;Snoring;Specimen;Standardization;Stress;Symptoms;Technology;Testing;Therapeutic;Time;Treatment Effectiveness;Urine;Validation;analytical tool;base;commercialization;cost;cost efficient;diagnosis standard;indexing;innovation;liquid chromatography mass spectrometry;novel;novel marker;point of care;screening;sensor;treatment effect;urocortin;validation studies

public_health_relevance:
Project narrativePGXL Technologies is developing a urine-based test for detecting obstructive sleep apnea (OSA) inchildren. Obstructive sleep apnea is a common disorder affecting an estimated 2.3 million children inthe USA. Children are underdiagnosed for OSA due to the high cost and low compliance ofpolysomnography tests which require an overnight stay at a sleep center. Our technology onceclinically validated will allow physicians for the first time to screen children for OSA with a simple andinexpensive urine test.


application_id: 9407428
project_number: 1R43ES029071-01A1
project_title: Protection against UV radiation-induced skin damage by methoxylated flavonoids
administering_ic: NIEHS
award_notice_date: 2017-09-06
opportunity_number: PA-16-302
application_type: 1
activity_code: R43
ic: ES
serial_number: 029071
suffix: A1
program_official: RAVICHANDRAN, LINGAMANAIDU V
project_start_date: 2017-09-15
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1 MOSS-C (12)]
contact_pi_person_id: 15328833
contact_pi: JORDAN, CAROLYN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078529087
primary_uei: M9JMGN342NR5
duns_number: 078529087
uei: M9JMGN342NR5
fips: US
organization_id: 10032361
organization_name: BLUEGRASS ADVANCED MATERIALS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
project_abstract:
Project SummaryIn eukaryotic cells ultra-violet radiation (UVR) induces the formation of free radicals whichdamage cellular lipids proteins and nucleic acids. In man this damage can lead to chronicinflammation and skin neoplasias so that compounds which protect cells from UVR are oftherapeutic interest. Flavonoids are candidates because they protect plant cells by absorbingUVR and acting as free radical scavengers (FRS). Bluegrass Advanced Materials (BAM) haslicensed a technology from Naprogenix Inc. which is based on the discovery that methoxylatedflavonoids purified from extracts of a native goldenrod (Solidago nemoralis) have agonist activityat human alpha7-nicotinic receptors (nicAChRs). These receptors inhibit release of inflammatorymediators from skin macrophages which contribute to UV-mediated inflammation andcarcinogenesis. In support collaborative research with the University of Kentucky showed that aflavonoid-enriched goldenrod extract potently protected transgenic humanized mice againstUVR-induced inflammation and damage in vivo. However the potential therapeutic andcommercial value of this activity is limited by the modest persistence and bioavailability of theseflavonoids when applied topically. To overcome this drawback BAM will utilize its proprietarytechnology to convert flavonoids into biodegradable polymer microparticles. These slowly releasethe original flavonoids from the polymer essentially providing an extended release topicalpreparation with improved bioavailability. This phase I application will apply this technology to themethoxylated anti-inflammatory flavonoids and evaluate their microparticle preparation for UV-protection when administered topically in a mouse model of the fair-skinned UV-sensitive human.The first specific aim is to prepare microparticle polymers of (a) the flavonoid-enriched extract ofgoldenrod and (b) pure rhamnetin the methoxylated flavonoid with greatest potency on alpha7-nicAChRs. The second specific aim is to test each of these preparations for their ability topenetrate and protect humanized mouse skin against UVR specifically measuring the tissuecontent of pro- and anti-inflammatory mediators and measuring effects on erythema andinflammation. The effects of the microparticle polymers will be compared with those of the freeflavonoids applied topically in ethanol /polyethylene glycol as used previously. If as predictedthe UVR-protectant effects of the flavonoids are enhanced then phase II will aim to (a) relateefficacy to alpha7-nicAChR activity using selective antagonists and alpha7-nicAChR knockoutmice (b) test the effects of chronic use of the preparations on UVR-induced changes in mouseskin (c) develop new ways of producing these flavonoids. The ultimate objectives of phase I andII are to develop these methoxylated flavonoid polymer preparations as therapeutic andcosmeceutical agents. The intention is to commercialize these products in phase III in partnershipwith major pharmaceutical and cosmetics companies.

project_terms:
Acids;Agonist;Anti-Inflammatory Agents;Anti-inflammatory;Binding;Biological Availability;Biopolymers;Cells;Chemicals;Chronic;Cosmetics;Data;Development;Dietary Flavonoid;Dose;Drug Kinetics;Erythema;Ethanol;Eukaryotic Cell;Evaluation;Flavonoids;Formulation;Free Radical Formation;Free Radical Scavengers;Free Radical Scavenging;Gray unit of radiation dose;High Pressure Liquid Chromatography;Human;Hypersensitivity;In Vitro;Inflammation;Inflammation Mediators;Intellectual Property;Intention;Investigation;Kentucky;Knockout Mice;Lead;Legal patent;Lipids;Measurement;Measures;Mediating;Mus;Neoplasms;Nicotinic Receptors;Nucleic Acids;Penetration;Pharmacologic Substance;Phase;Physiological;Plants;Poa plant;Polyethylene Glycols;Polymers;Preparation;Property;Proteins;Quercetin;Radiation;Radiation Protection;Radiation exposure;Radiation induced damage;Radiation-Induced Change;Radiation-Protective Agents;Research;Skin;Skin Cancer;Solidago;Sunscreening Agents;Technology;Test Result;Testing;Therapeutic;Therapeutic Agents;Tissues;Topical Preparation;Topical application;Transgenic Mice;Transgenic Organisms;UV induced;UV protection;UV sensitive;Ultraviolet Rays;Universities;Viola;absorption;alpha-bungarotoxin receptor;anti aging;base;biodegradable polymer;carcinogenesis;commercialization;humanized mouse;improved;in vivo;interest;macrophage;man;mouse model;novel;polymerization;product development;receptor

public_health_relevance:
Project narrativeNatural compounds from plants that protect the skin against damage caused by ultraviolet radiation are ofcommercial value as cosmetics and therapeutic agents. This proposal is to begin the development offlavonoids from a native goldenrod for this purpose. The main objective of phase I is to demonstrate that theapplicants can produce biopolymer formulations of the flavonoids with a greater ability to be absorbed into theskin and with consequently greater protective actions.!


application_id: 9406905
project_number: 3R01EY026180-02S1
project_title: Tear Film Lipid Compositional Structural Functional Relationships and Dry Eye
administering_ic: NEI
award_notice_date: 2017-02-28
opportunity_number: PA-13-302
application_type: 3
activity_code: R01
ic: EY
serial_number: 026180
suffix: S1
program_official: MCKIE, GEORGE ANN
project_start_date: 2015-12-01
project_end_date: 2020-11-30
study_section: Diseases and Pathophysiology of the Visual System Study Section[DPVS]
contact_pi_person_id: 1962526
contact_pi: BORCHMAN, DOUGLAS
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_abstract:
DESCRIPTION (provided by applicant): Dry eye affects over six million people in the United States alone and may be classified as aqueous production-deficient (AD) and evaporative which is associated with meibomian gland dysfunction (MGD). Both mechanisms of development of dry eye share the common feature of instability of the tear film (TF) with rapid tear break-up time suggesting there may be a shared structural abnormality of the TF that is responsible for the instability. Our spectroscopic studies have identified several potential abnormalities in the TF lipid composition that may contribute to TF instability including terpenoids saturation protein and cholesteryl esters. We also identified hydrocarbon conformational abnormalities with dry eye. For example when terpenoid levels in meibum are low as in MGD the TF is unstable and patients have the signs and symptoms of dry eye. When terpenoids are restored with azithromycin treatment TF stability is restored and patients no longer have the signs and symptoms of dry eye. We have the best chance of testing which moieties are important to TF stability by studying samples with a wide range of TF stabilities. We propose to study samples from patients with dry eye (both AD and MGD) and samples from Asians because they have an 80% higher incidence of dry eye compared to Caucasians. We will also compare compositional changes in meibum and TF lipid when the signs and symptoms of dry eye are ameliorated with treatment. TF lipid and meibum will be studied since their composition is slightly if not significantly different. We propose to use spectroscopy Raman IR and NMR to determine how TF composition relates to tear film stability measured in vitro and in vivo on the same sample. The TF stability parameters we propose to measure in vitro include: surface pressure-area isotherms isocycles surface rheology surface Raman and quantitative Brewster angle microscopy to assess the meibum's lateral elasticity and capability of compressing and spreading during dynamic area changes. We propose to measure in vivo several parameters including tear osmolarity break-up time and blink rate. Natural and experimental differences in TF lipid and meibum amount and composition (especially terpenoids saturation protein and levels of cholesteryl esters) hydrocarbon conformation and lipid-protein interactions will be correlated to TF stability using principle component analysis t determine if and which moieties in meibum are important to TF stability with the ultimate goal of developing therapies to enhance TF stability.

project_terms:
Affect;Age;Alpha Cell;Anti-Bacterial Agents;Area;Asians;Azithromycin;Back;Blinking;Caucasians;Cholesterol Esters;Chronic;Clinical;Contact Lenses;Development;Diet;Disease;Elasticity;Environment;Etiology;Film;Genetic;Goals;Hydrocarbons;In Vitro;Incidence;Knowledge;Lateral;Lead;Lipids;Measures;Microscopy;Modification;Molecular Conformation;Nuclear Magnetic Resonance;Osmolar Concentration;Patients;Production;Property;Proteins;Rheology;Sampling;Sampling Studies;Signs and Symptoms;Sjogren's Syndrome;Spectrum Analysis;Structural defect;Structure;Surface;Symptoms;Techniques;Technology;Terpenes;Testing;Time;United States;Variant;Visual;aqueous;evaporation;experience;eye dryness;in vivo;meibomian gland;meibomian gland dysfunction;pressure;public health relevance;spectroscopic survey;therapy development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Dry eye affects over seven million people in the United States alone and meibomian gland disease is the most frequent cause. Dry eye can cause chronic and severe symptoms as well as secondary changes that can lead to visual disturbance. Elucidating the mechanism of tear film instability in dry eye will enable development of therapies to ameliorate the ocular effects of deranged structure of the lipid layer and meibum.


application_id: 9406330
project_number: 5R01HL124015-03
project_title: Latexin function in the maintenance and regeneration of the hematopoietic system
administering_ic: NHLBI
award_notice_date: 2017-12-22
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 124015
program_official: BAI, C BRIAN
project_start_date: 2016-01-01
project_end_date: 2020-12-31
study_section: Molecular and Cellular Hematology Study Section[MCH]
contact_pi_person_id: 9839693
contact_pi: LIANG, YING
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_terms:
Ablation;Acute;Apoptosis;Attenuated;Binding;Binding Proteins;Biological Models;Blood;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;CD34 gene;Cancer Patient;Cell Count;Cell Death;Cell Survival;Cell model;Cell physiology;Cells;Complex;DNA Damage;Development;Exposure to;Genes;Genetic;Genetic Transcription;Genetic Variation;Genomics;Goals;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Transplantation;Hematopoietic System;Hematopoietic stem cells;Human;In Vitro;Injury;Knockout Mice;Late Effects;Lead;Liquid substance;Maintenance;Mediating;Modeling;Molecular;Mouse Strains;Myelosuppression;NF-kappa B;Natural regeneration;Nuclear Translocation;PC3.1 antigen;Pathologic;Pathway interactions;Patients;Pharmacology;Population Sizes;Process;Protein Subunits;Publishing;Quality of life;Radiation;Radiation Dosage;Radiation Injuries;Radiation Tolerance;Radiation Toxicity;Radiation therapy;Radioprotection;Reactive Oxygen Species;Regulation;Regulator Genes;Reporting;Research;Ribosomal Proteins;Role;Second Primary Cancers;Signal Transduction;Solid;Stem cells;Stress;Techniques;Therapeutic;Variant;Work;Xenograft procedure;base;cancer therapy;cell injury;cell transformation;chemotherapy;effective therapy;functional decline;genome integrity;human model;in vivo;knock-down;mortality;mouse model;novel;overexpression;p65;preconditioning;preservation;prevent;promoter;radiation response;radiation-induced injury;recruit;response;self-renewal;senescence;small hairpin RNA;stem cell population;tumor


application_id: 9406120
project_number: 5R01DK056132-15
project_title: Neural Circuitry in the Dorsal Vagal Complex
administering_ic: NIDDK
award_notice_date: 2018-03-02
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 056132
program_official: HYDE, JAMES F
project_start_date: 2001-06-01
project_end_date: 2020-01-31
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
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): Diabetes mellitus is a major health concern affecting nearly 26 million people in the United States. Serious complications resulting from diabetes including include heart disease stroke hypertension blindness nervous system damage and autonomic dysfunction. A major impediment to developing successful diabetes treatments (versus treating symptoms) is the relative knowledge gap regarding the multifaceted and redundant systems that contribute to control of metabolic homeostasis. This proposal investigates disease-related plasticity of central neural circuitry involved in autonomic control including control of blood glucose homeostasis. Experiments utilize murine models of type 1 and type 2 diabetes. Preautonomic neurons of the dorsal vagal complex which contains second-order viscerosensory neurons in the nucleus tractus solitarius (NTS) and preganglionic parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV) are glucosensors and also contribute significantly to autonomic regulation of glucose homeostasis. Vagal motor output is suppressed in diabetes leading to autonomic dysregulation including excess hepatic glucose production and gastric motility dysfunction. Preliminary results show that GABA neurons in the NTS in particular are responsive to elevated glucose. Paradoxically GABAA receptor-mediated responses in the DMV are persistently enhanced in a model of type 1 diabetes in a manner consistent with maintenance of prolonged hyperglycemia. Some but not all of these responses are preserved in a type 2 diabetes model suggesting a form of GABA receptor plasticity that mediates the decreased vagal output seen in diabetes. In addition modulation of GABA receptors in the dorsal vagal complex has a significant effect on blood glucose levels and this effect is hypothesized to be enhanced in diabetic mice versus controls. This proposal aims to determine the causes and underlying features of the recently-discovered diabetes-induced plasticity of the GABAergic system in the vagal complex. Electrophysiological recordings from vagal complex neurons in slices from control and diabetic mice will be used to obtain functional cellular data related to altered GABAergic inhibition changes associated with diabetes development in the streptozotocin-treated mouse a model of type 1 diabetes and the TallyHo mouse a model of type 2 diabetes. Aim 1 will determine insulin- and glucose- dependence of enhanced tonic GABA currents in diabetic mice aim 2 will identify cellular mechanisms contributing to diabetes-associated GABA receptor plasticity in the DMV and aim 3 will determine the effects of GABA receptor modulation in the dorsal vagal complex on systemic glucose homeostasis. Results will guide future studies aimed at disease-modifying therapies from a systemic standpoint based on modulating specific inhibitory neural functions in the brainstem to address diabetes-related autonomic dysregulation in patients.

project_terms:
Abdomen;Address;Affect;Animal Model;Area;Autonomic Dysfunction;Blindness;Blood Glucose;Brain;Brain Stem;Cell Nucleus;Chronic;Complex;Data;Dependence;Development;Diabetes Mellitus;Diabetic mouse;Disease;Dorsal;Electrophysiology (science);Functional disorder;Future;GABA Receptor;Gastrointestinal tract structure;Genetic Transcription;Glucose;Goals;Health;Heart Diseases;Hepatic;Homeostasis;Human;Hyperglycemia;Hyperinsulinism;Hypertension;Insulin;Insulin-Dependent Diabetes Mellitus;Knowledge;Liver;Maintenance;Mediating;Metabolic Control;Modeling;Modification;Molecular;Motor Neurons;Motor output;Mus;Nervous System Trauma;Neurons;Neurophysiology - biologic function;Non-Insulin-Dependent Diabetes Mellitus;Organ;Output;Pancreas;Pathology;Patients;Peripheral;Physiological;Play;Regulation;Role;Slice;Stomach;Streptozocin;Stroke;Symptoms;Synapses;System;Testing;United States;Viscera;Visceral;Whole Blood;base;blood glucose regulation;cell motility;diabetes mellitus therapy;diabetic;dorsal motor nucleus;experimental study;gamma-Aminobutyric Acid;gastrointestinal;glucose metabolism;glucose production;mouse model;nerve supply;neural circuit;public health relevance;receptor;response;symptom treatment;trafficking;type I diabetic

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Preganglionic parasympathetic neurons in the vagal complex innervate the abdominal organs and critically regulate whole blood glucose metabolism. These neurons are sensitive to elevated glucose and undergo long-lasting changes in synaptic excitability in animal models of diabetes. The proposed experiments will examine mechanisms underlying diabetes-associated inhibition changes in the vagal complex that represent reactive responses to chronic hyperglycemia and/or hyperinsulinemia which may contribute to disease pathology and symptoms. The eventual goal of informing future studies aimed at treating pathologies underlying diabetes.


application_id: 9405542
project_number: 5R01ES016893-11
project_title: Particulate Cr(VI) Toxicology in Human Lung Epithelial Cells and Fibroblasts
administering_ic: NIEHS
award_notice_date: 2017-12-20
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: ES
serial_number: 016893
program_official: TYSON, FREDERICK L
project_start_date: 2009-07-06
project_end_date: 2019-01-31
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)S]
contact_pi_person_id: 6094413
contact_pi: WISE, JOHN PIERCE
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): Hexavalent chromium (Cr(VI)) also known as chromate is a major public health concern. Chromates particularly the insoluble compounds are well-established human lung carcinogens. Our study focuses on investigating the mechanisms of Cr(VI)-induced carcinogenesis which are currently unknown. Recent studies indicate that particulate Cr(VI) induces chromosome instability which is a hallmark of human lung tumors. However how Cr(VI) induces chromosome instability is poorly understood. Our preliminary data show that chronic exposure to particulate Cr(VI) induces a DNA repair deficient phenotype that underlies the chromosome instability and thus the goal of this research is to characterize this repair deficiency and its impact and understand the mechanisms that cause it to occur. We will test the hypothesis that particulate Cr(VI) induces epigenetic changes inactivating homologous recombination repair of Cr(VI)-induced DNA double strand breaks resulting in increased chromosome instability and carcinogenesis. We will test this hypothesis through four interrelated specific aims. Aim 1 will characterize the homologous recombination repair defect and show that particulate Cr(VI) causes cells to inactivate Rad51-mediated response and switch to lower fidelity non-homologous end joining (NHEJ) repair using immunoblotting immunofluorescence and repair assays. Aim 2 will show that the cells with particulate Cr(VI)-inactivated Rad51 response acquire chromosome instability and undergo neoplastic transformation using cytogenetic techniques and assays for contact- uninhibited and anchorage independent growth. Aim 3 will identify an epigenetic change (increased acetylation) that causes the loss of Rad51 response by affecting E2F1 ATM Rad51C and Rad51 with assays for acetylation status gene expression and protein interactions and localization. FinallyAim 4 will characterize the mechanism for particulate Cr(VI)-induced acetylation changes studying Cr(VI) binding to acetyl groups using assays for acetylation and histone deacetylase activity. Each aim will focus on human lung cells and confirm key findings in human Cr(VI) tumors. Results will lead to the first reports of detailed information of the interactions of Cr(VI with DNA double strand break machinery acetylation status and the first characterizations of these aspects in tumors from Cr(VI)-exposed workers. This research is significant because it will provide: 1) An understanding of particulate Cr(VI)'s carcinogenic mechanism; 2) Essential information to better assess the risk of exposure to particulates; and 3) A mechanistic approach for further study of Cr(VI) other metals and lung cancer in general.

project_terms:
Acetylation;Affect;Anchorage-Independent Growth;Binding;Biological Assay;Cancer Etiology;Carcinogen exposure;Carcinogens;Cells;Chromates;Chromium Compounds;Chromosomal Instability;Chronic;Cytogenetic Analysis;Cytoplasm;DNA Double Strand Break;DNA Repair;Data;Defect;Double Strand Break Repair;E2F1 gene;Environmental and Occupational Exposure;Epigenetic Process;Epithelial Cells;Event;Exposure to;Fibroblasts;Frequencies;G-Banding;Gene Expression;Genomic Instability;Goals;Histone Deacetylase;Histone Deacetylation;Human;Immunoblotting;Immunofluorescence Immunologic;In Vitro;Ions;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Mediating;Metals;Modeling;Molecular;Mutation;Neoplastic Cell Transformation;Nonhomologous DNA End Joining;Nuclear;Particulate;Peptide Mapping;Phenotype;Proteins;Public Health;Publishing;Reporting;Research;Risk;Salts;Solubility;Spectral Karyotyping;System;Techniques;Testing;Toxicology;Zinc;carcinogenesis;carcinogenicity;chromium hexavalent ion;homologous recombination;interest;prevent;public health relevance;recombinational repair;repaired;response;tandem mass spectrometry;tumor;zinc chromate

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Hexavalent chromium (Cr(VI)) is a human lung carcinogen with widespread occupational and environmental exposure. How Cr(VI) causes human cancer is unknown. Our study advances our basic understanding of the cellular and molecular mechanisms underlying how Cr(VI) causes cancer and informs us about how cells protect against Cr(VI)-induced genomic instability. Our findings will help us identify new potential treatment targets and approaches to reduce or prevent Cr(VI)-induced lung cancer and to better assess the risk of exposure to this major public health concern. Finally we will have established a mechanistic model in a human lung cell system that will allow us to conduct studies for other factors important for preventing human lung cancer both generally and by Cr(VI) and other agents.


application_id: 9404956
project_number: 5R01AI051517-14
project_title: Paramyxovirus F protein mediated membrane fusion
administering_ic: NIAID
award_notice_date: 2017-11-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 051517
program_official: PARK, EUN-CHUNG
project_start_date: 2002-05-15
project_end_date: 2019-12-31
study_section: Virology - B Study Section[VIRB]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
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): Compelling work in the last decade has shown that transmembrane domains (TMDs) once thought to function solely as hydrophobic anchors are central players driving cellular protein oligomerization cell signaling and regulation of channelfunction. However the role of TMDs in viral glycoprotein stability and function remains poorly understood. During the previous funding period our studies of the Hendra virus (HeV) fusion (F) protein identified key roles for TMDs in regulation of F protein stability cellular trafficking ad fusion function. Our novel studies utilizing sedimentation equilibrium (SE) analysis established that F protein TMDs efficiently trimerize separate from the rest of the protein. Altered TM-TM association was found for multiple functionally important mutations implicating TM-TM interactions in regulation of F protein folding and function. The long-term goal of our research isto understand the molecular details and regulation of membrane fusion promoted by the paramyxovirus F proteins. The overall hypothesis of this proposal is that interactions of the TMD with itself and the lipid environment are critical for fusion protein stability and function makin these interactions potential targets for antiviral therapeutics. To test this important hypothesiswe will pursue three specific aims. First we will define key elements driving F protein TM-TM interactions including defining the role of a L/I heptad in TM-TM association and Hendra F protein stability. Second we will determine how the TMD affects fusion triggering and promotion of membrane fusion with a focus on the role of C-terminal -branched residues and a determination of the conformational changes that can occur when TM-TM interactions cannot be released. Third we will dissect the role of the lipid environment in prefusion F stability in the context of cellular and viral membranes. These important experiments will provide critical new insight into the role of TMDs in regulation of F protein stability and fusion promotion.

project_terms:
Address;Affect;Antiviral Agents;Automobile Driving;C-terminal;Ca(2+)-Transporting ATPase;Cells;Characteristics;Chimeric Proteins;Cholesterol;Cytoplasmic Tail;Data;Development;Dissociation;Elements;Environment;Family;Funding;Glycoproteins;Goals;Hendra Virus;Human;Human Metapneumovirus;Hydrophobicity;Individual;Infection;Kinetics;Lipids;Measles;Mediating;Membrane;Membrane Fusion;Membrane Fusion Activity;Membrane Lipids;Molecular;Molecular Conformation;Mutation;Neuropilins;Paramyxovirus;Paramyxovirus Fusion Protein;Peptides;Process;Proteins;Regulation;Research;Respiratory syncytial virus;Rest;Role;Sarcoplasmic Reticulum;Signal Transduction;Sphingolipids;Structure;System;Testing;Therapeutic;Time;Transmembrane Domain;Vaccines;Viral;Viral Fusion Proteins;Viral Proteins;Virus;Virus-like particle;Work;Zoonoses;disulfide bond;experimental study;insight;mutant;novel;particle;pathogen;prevent;protein folding;protein function;public health relevance;sedimentation equilibrium;trafficking;virus envelope

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Viral fusion proteins promote fusion between the viral membrane and a membrane of the target cell a critical first step in the infection of enveloped viruses. Studies to determine factors regulating the stability and function of these proteins are important to the development of novel antiviral approaches targeting these viral proteins. This proposal addresses the role of the paramyxovirus fusion protein transmembrane domain is control of fusion protein stability and membrane fusion activity potentially identifying a novel target for antivirals.


application_id: 9404332
project_number: 5R01AI119022-04
project_title: Structure and mechanism of the ESX secretion system from pathogenic mycobacteria
administering_ic: NIAID
award_notice_date: 2017-12-07
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 119022
program_official: MENDEZ, SUSANA
project_start_date: 2015-07-25
project_end_date: 2019-12-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 11365624
contact_pi: KOROTKOV, KONSTANTIN V
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): Tuberculosis (TB) is a devastating infectious disease caused by Mycobacterium tuberculosis that results in more than 8 million new cases and 1.4 million deaths every year. The efficacy of currently available anti-TB drugs has been compromised by the emergence of multidrug-resistant and extensively drug-resistant strains therefore there is an urgent need to develop novel therapeutic strategies against TB. In M. tuberculosis three paralogous protein secretion systems - ESX-1 ESX-3 and ESX-5 - secrete PE-PPE dimers during defined stages of the infection process. PE and PPE proteins represent two large families of highly polymorphic proteins that are especially abundant in pathogenic mycobacteria. PE/PPE proteins are either cell wall associated or secreted into the extracellular milieu. These protein families are targets for vaccine development and diagnostic reagents. Multiple PE/PPE proteins play a role in in virulence immune evasion and persistence in host. An outstanding question in the field is what the mechanisms of PE/PPE secretion and assembly in the cell wall of mycobacteria. This proposal is designed to help answer this important biological question by using a range of genetic biochemical and structural approaches including X-ray crystallography and mass-spectrometry. This study is significant because the protein secretion systems of M. tuberculosis the ESX system in particular are attractive targets for drug development. The results of our study will significantly advance our understanding of mycobacterial pathogenesis and will provide structural knowledge that will guide the development of novel therapeutic targets and the design of a better vaccine against TB.

project_terms:
Affect;Amino Acids;Antigens;Architecture;Binding;Biochemical;Biological;Biological Process;C-terminal;Carrier Proteins;Cell Wall;Cell surface;Cessation of life;Communicable Diseases;Complex;Data;Development;Diagnostic;Diagnostic Reagent;Drug Targeting;ELF3 gene;Environment;Enzymes;Essential Amino Acids;Family;Future;Genetic;Genus Mycobacterium;Goals;Growth;Homologous Gene;Human;Immune Evasion;Individual;Infection;Investigation;Knowledge;Macromolecular Complexes;Mass Spectrum Analysis;Membrane;Methods;Modeling;Molecular;Molecular Chaperones;Multi-Drug Resistance;Mutation;Mycobacterium tuberculosis;Pathogenesis;Pathogenicity;Pathway interactions;Peptide Hydrolases;Pilum;Play;Process;Protein Family;Protein Secretion;Proteins;Role;Specificity;Structure;Surface;System;Testing;Therapeutic;Tuberculosis;Vaccines;Virulence;Work;X-Ray Crystallography;design;dimer;drug development;drug discovery;experimental study;extensive drug resistance;extracellular;improved;inhibitor/antagonist;insight;mycobacterial;new therapeutic target;novel therapeutics;pathogen;protein aggregation;protein protein interaction;protein transport;public health relevance;resistant strain;tool;tuberculosis diagnostics;tuberculosis drugs;vaccine candidate;vaccine development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed studies are expected to uncover the architecture and mechanism of the ESX secretion system a pathway essential for virulence and involved in the transport of multiple proteins to the cell surface or extracellular milieu in humanpathogen M. tuberculosis. The generated data will provide a framework for developing novel therapeutics and improved vaccines against tuberculosis.


application_id: 9403837
project_number: 2R01AI090048-06
project_title: Novel aminoglycoside adjuvants and stand-alone agents to combat tuberculosis
administering_ic: NIAID
award_notice_date: 2017-06-20
opportunity_number: PA-16-160
application_type: 2
activity_code: R01
ic: AI
serial_number: 090048
program_official: PERDUE, SAMUEL S
project_start_date: 2011-08-01
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZRG1 IDM-S (02)]
contact_pi_person_id: 8970083
contact_pi: GARNEAU-TSODIKOVA, SYLVIE
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_terms:
AIDS/HIV problem;Acetyltransferase;Adjuvant;Adjuvant Therapy;Aminoglycosides;Anti-Bacterial Agents;Antibiotics;Antitubercular Agents;Area;Bacteria;Biochemical;Biological;Biological Assay;Cells;Cessation of life;Chemicals;Combined Modality Therapy;Complex;Consultations;Coupled;Crystallization;Development;Drug resistance;Drug resistance in tuberculosis;Drug-sensitive;Epidemic;Evaluation;Exhibits;Extreme drug resistant tuberculosis;Funding;Future;Genotype;Genus Mycobacterium;Human;In Vitro;Infection;Kanamycin;Kanamycin A;Killings;Knock-out;Laboratories;Lead;Measurement;Mediating;Modeling;Multidrug-Resistant Tuberculosis;Mutation;Mycobacterium tuberculosis;Mycobacterium tuberculosis H37Rv;Pathogenicity;Permeability;Pharmaceutical Chemistry;Pharmaceutical Preparations;Property;Reporting;Resistance;Resort;Safety;Solubility;Structure;Testing;Therapeutic;Toxic effect;Tuberculosis;Up-Regulation;analog;clinical development;combat;cytotoxicity;design;experience;extensive drug resistance;genome sequencing;inhibitor/antagonist;innovation;interest;macrophage;mouse model;mutant;novel;novel strategies;pre-clinical;preclinical development;preclinical study;prevent;promoter;research clinical testing;resistance mechanism;scaffold;structural biology;success;synergism


application_id: 9403830
project_number: 1R01AA025591-01A1
project_title: Microglia and Adolescent Susceptibility to Developing an Alcohol Use Disorder
administering_ic: NIAAA
award_notice_date: 2017-09-12
opportunity_number: PA-14-139
application_type: 1
activity_code: R01
ic: AA
serial_number: 025591
suffix: A1
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2017-09-15
project_end_date: 2018-08-17
study_section: Special Emphasis Panel[ZRG1 IFCN-C (02)]
contact_pi_person_id: 1869834
contact_pi: NIXON, KIMBERLY
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
project_abstract:
Alcohol use and abuse often begins in adolescence where many factors collide to promoteexcessive intake. Most striking though is that those who drink during adolescence - specificallybefore age 15 - are four times more likely to develop an alcohol use disorder in adulthood. Thissuggests that alcohol impacts the adolescent brain in such a way to make it more susceptible todeveloping an alcohol use disorder. Indeed the adolescent brain is more susceptible to braindamage due to alcohol which has led several groups to examine subsequent neuroinflammatorysignaling in alcohol use disorders. A hallmark of neuroinflammation is microglial activation.Microglia are one of the three types of non-neuronal glia cells in the brain that act as the brainsimmune system but their role in alcohol use disorders is poorly understood. Microglia display afull spectrum of phenotypes from beneficial to cytotoxic and the phenotype of these microglia afteralcohol exposure has not been defined. Further microglia may become primed by an eventthen upon subsequent challenge they aggressively over-respond a phenomenon intertwined withtheir phenotype. Microglia priming appears to be more evident in development where early lifeexposure to immune insult has long-term consequences on a variety of adult outcomes. Thusthe priming or activation of microglia by alcohol during adolescent development may result in longterm consequences. Therefore the overarching hypothesis of this proposal is that youngadolescents are more to susceptible to microglia priming by alcohol versus adults and that alcoholpriming produces long term effects on alcohol-induced neuropathology and addiction-relevantbehavior. We will test this hypothesis through three specific aims that (1) determine theadolescents susceptibility to alcohol-induced effects on microglia (2) examine whetheradolescents have a greater susceptibility to alcohol priming microglia and (3) elucidate the role ofmicroglia priming in addiction-relevant behavior. By understanding the events that prime theadolescent brain to be susceptible to developing an alcohol use disorders better interventionsand treatments can be developed so that we can reduce the incidence of alcohol use disorders.

project_terms:
Adolescence;Adolescent;Adolescent Behavior;Adolescent Development;Adult;Age;Alcohol abuse;Alcohol consumption;Alcohol-Induced Disorders;Alcohols;Attention;Behavior;Behavior Control;Behavioral;Biological Assay;Brain;Brain Injuries;Brain region;Cells;Coupled;Data;Development;Disease;Dose;Employee Strikes;Event;Exposure to;Flow Cytometry;Grant;Growth Factor;HMGB1 gene;Heavy Drinking;Histology;Hypersensitivity;Immune;Immune system;Impulsivity;Incidence;Intake;Intervention;Long-Term Effects;Microglia;Morphology;Motivation;Nerve Degeneration;Neuroglia;Neuroimmune;Outcome;Pathology;Phenotype;Predisposition;Process;Publishing;Rattus;Reverse Transcriptase Polymerase Chain Reaction;Role;Sampling;Signal Transduction;Surface Antigens;System;Testing;Therapeutic Intervention;Time;addiction;adolescent alcohol;adolescent alcohol exposure;alcohol effect;alcohol exposure;alcohol response;alcohol use disorder;behavioral impairment;brain behavior;cytokine;cytotoxic;cytotoxicity;discount;discounting;drug of abuse;early life exposure;immune activation;immune function;in vivo;inflammatory marker;interest;macrophage;neuroinflammation;neuropathology;neuroprotection;neurotoxic;new therapeutic target;preference;protein expression;response;underage drinking

public_health_relevance:
Project NarrativeAlcohol use and abuse often begins in adolescence despite the adolescent brains susceptibility to thedamaging effects of alcohol. This grant explores a potential mechanism of that susceptibility: developmentalvulnerability to the effect of alcohol on microglia one of three types of non-neuronal glial cells and how thatvulnerability contributes to the brain and behavioral pathologies associated with the development of alcoholuse disorders.


application_id: 9403722
project_number: 3R01DA040694-02S1
administering_ic: NIDA
award_notice_date: 2017-02-08
opportunity_number: PA-16-287
application_type: 3
activity_code: R01
ic: DA
serial_number: 040694
suffix: S1
program_official: WALTON, KEVIN
project_start_date: 2017-02-01
project_end_date: 2019-07-31
contact_pi_person_id: 9641889
contact_pi: ASHFORD, KRISTIN H.
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
budget_start_date: 2017-02-01
project_title:
Supplement-The impact of electronic cigarettes (e-cigs) on perinatal immune responsiveness and birth outcomes in Appalachia

project_abstract:
DESCRIPTION (provided by applicant): The United States has the largest and fastest growing market for electronic cigarettes (e-cigs) and adult women of childbearing age are the most common users. However no data exist regarding the health effects of e-cigs on pregnant women or their babies. It is well known that tobacco use during pregnancy is the most modifiable risk associated with adverse birth outcome yet nearly one in four women in Kentucky continue to use tobacco products during pregnancy. E-cigs also contain varied (unregulated) concentrations of nicotine despite nicotine being classified as a pregnancy class-D drug (exhibiting teratogenic effects on the fetus). The addictive nature of nicotine may explain continued use during this vulnerable time. E-cigs have been the center of recent controversy regarding novel smoking cessation or harm reduction products. There is also concern that marketing strategies promoting harm reduction may increase the appeal and obfuscate the known adverse effects of nicotine on fetal development. In addition to the adverse effects of prenatal nicotine maternal tobacco use alters immune response during pregnancy placing women at increased risk for preterm birth. We plan to build on previous work to determine the impact (better same or worse) that e-cigs and dual use (conventional + e-cig) have on prenatal immune response and birth outcomes compared to conventional use and dual use. Our overall goal is to determine the effects of e-cigs (and dual use) on perinatal biomarkers and birth outcomes. Three hundred and sixty pregnant women will be recruited. Participants will complete a survey to measure tobacco related behaviors and provide perinatal biomarkers at four time points (each trimester and postpartum). Data analysis will include a series of repeated ANCOVAs to determine the association of perinatal cigarette smoking (conventional e-cigarettes-only and dual use) with perinatal biomarkers. A one- way ANCOVA will be used to determine the association with birth outcomes. Primary biomarker measures include: expired air carbon monoxide urine and serum cotinine serum immune markers and urinary NNAL. Gestational age at birth and birth weight are the primary birth outcomes. Until more data about the effects of e-cigs and dual use on perinatal immune response and birth outcomes are available promotion of e-cigs during pregnancy would be premature. There is an urgent need to investigate the impact of e-cigs and dual use on perinatal biomarkers and birth outcomes. The lack of research may unnecessarily place women-and their babies -at risk for lifelong adverse health outcomes.

project_terms:
1-Butanol;Adult;Adverse effects;Air;Analysis of Covariance;Appalachian Region;Awareness;Behavior;Biological;Biological Markers;Birth;Birth Weight;Bone Density;Butanones;Carbon Monoxide;Cigarette;Cotinine;Data;Data Analyses;Electronic cigarette;Exhibits;Female of child bearing age;Fetal Development;Fetus;Gestational Age;Goals;Harm Reduction;Health;Heart Diseases;Immune;Immune response;Immunologic Markers;Immunologics;Infant;Interleukin-1 beta;Interleukin-10;Interleukin-6;Interleukin-8;Interleukins;Kentucky;Liquid substance;Literature;Malignant neoplasm of lung;Marketing;Measures;Methods;National Institute of Drug Abuse;Nature;Neutrophil Collagenase;Nicotine;Nitrosamines;Outcome;Participant;Perception;Perinatal;Pharmaceutical Preparations;Postpartum Period;Postpartum Women;Pregnancy;Pregnant Women;Premature Birth;Recruitment Activity;Relapse;Research;Risk;Safety;Series;Serum;Serum Immunologic;Smoke;Smoking;Smoking Behavior;Smoking Status;Spontaneous abortion;Surveys;TNF gene;Teratogenic effects;Time;Tobacco;Tobacco use;United States;United States Food and Drug Administration;Urine;Vulnerable Populations;Woman;Work;adverse pregnancy outcome;authority;burden of illness;carcinogenicity;cigarette smoking;cytokine;design;experience;maternal tobacco use;modifiable risk;mortality;nicotine use in pregnancy;novel;premature;prenatal;prenatal smoking;prospective;public health relevance;smoking cessation;urinary;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: There has been a dramatic escalation of electronic cigarette (e-cig) use among women of childbearing age including pregnant women. Our overall goal is to determine the effects of e-cigs on prenatal biomarkers and birth outcomes. It is imperative that more data about these effects be available to better inform this vulnerable population. We believe our goals will generate the necessary data to guide regulatory authorities.


application_id: 9403627
project_number: 1R01AI127970-01A1
project_title: Mechanisms of successful vaccine adjuvants
administering_ic: NIAID
award_notice_date: 2017-06-26
opportunity_number: PAS-15-055
application_type: 1
activity_code: R01
ic: AI
serial_number: 127970
suffix: A1
program_official: LAPHAM, CHERYL K
project_start_date: 2017-06-26
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZRG1 IMM-U (90)]
contact_pi_person_id: 1941645
contact_pi: MITCHELL, THOMAS C.
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
project_terms:
Adjuvant;Agonist;CD8-Positive T-Lymphocytes;Cell Culture Techniques;Cells;Cervarix;Chemicals;Clinical;Clinical Trials;Communicable Diseases;Dendritic Cells;Development;Dose;Epitopes;Goals;HLA A*0201 antigen;Human;Immune;Immune response;Immune system;Immunization;Individual;Inflammatory;Knowledge;Learning;Lipid A;Malaria;Modeling;Mus;Oryctolagus cuniculus;Outcome;Pathway interactions;Pattern;Peripheral Blood Mononuclear Cell;Persons;Preparation;Property;Public Health;Research;Research Personnel;Safety;Signal Pathway;Signal Transduction;Squalene;Structure;Subunit Vaccines;System;TLR4 gene;Testing;Therapeutic;Tissues;Tonsil;Toxic effect;Transgenic Organisms;Vaccinated;Vaccine Adjuvant;Vaccine Design;Vaccines;Work;aluminum sulfate;analog;clinical development;cytokine;immunoregulation;improved;inhibitor/antagonist;mimetics;neutrophil;next generation;novel;novel vaccines;pathogen;peripheral blood;preclinical study;predictive modeling;prevent;prophylactic;research study;response;success;vaccine safety


application_id: 9403237
project_number: 5R01HL134731-02
project_title: Serum Amyloid A Inflammasome Activation and Abdominal Aortic Aneurysms
administering_ic: NHLBI
award_notice_date: 2017-12-29
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 134731
program_official: MCDONALD, CHERYL
project_start_date: 2017-01-01
project_end_date: 2020-12-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
other_pis: DE BEER, FREDERICK C.
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:
Recent estimates indicate that 5-10% of men and 1-2% of women 65-79 years of age in the United States areliving with an abdominal aortic aneurysm (AAA). Approximately 15000 will die each year due to AAA rupture.The treatment for AAA is limited to surgical intervention due to lack of other therapies with proven benefit.Although most patients with AAAs are asymptomatic the risk of death due to rupture increases greatly asAAAs expand. Insights into mechanisms contributing to AAA progression would have a major impact on theclinical management of AAA by providing new biomarkers that predict AAA expansion and thus the risk foraortic rupture as well as novel strategies for intervention. Recent published findings from our laboratoryprovide the impetus for a detailed evaluation of serum amyloid A (SAA) in AAA progression: 1) SAA deficiencyattenuates AAA in a mouse model; 2) in mice SAA is present in AAA in regions with substantial elastindegradation macrophage infiltration and matrix metalloproteinase (MMP) activity; and 3) SAA can be detectedin human AAA. In unpublished work we also determined that SAA induces IL-1 and NLRP3 expression aswell as IL-1 secretion in macrophages consistent with priming and activation of the NLRP3 inflammasome.These findings are notable given the recent recognition that NLRP3 inflammasome activation is a critical eventin AAA development in mice. Thus our central hypothesis is that SAA activates the NLRP3 inflammasomethereby amplifying local inflammatory responses that enhance pathological tissue remodeling and promoteAAA progression. AIM 1: Investigate the role of the NLRP3 inflammasome in SAA's ability to promote AAA inmice. Aim 1a. Using mice deficient in various inflammasome components (NLRP3-/- ASC-/- caspase-1-/- mice)or IL-1 signaling (IL-1R-/- mice) we will determine whether SAA-mediated AAA is dependent on the NLRP3inflammasome. We will also investigate whether small-molecule anionic sulphonates a treatment that blocksthe deposition of SAA in tissues is effective in reducing AAA in mice. Aim 1b. Using macrophage cell cultureswe will investigate whether any of the known biological activities attributed to SAA including reactive oxygenspecies generation or association with HDL are involved in SAA-mediated NLRP3 inflammasome activation.AIM 2: To test the hypothesis that systemic SAA promotes the progression of an established AAA. Aim 2a.Our approach will be to transiently increase SAA expression in livers of mice at specific intervals during thecourse of AngII infusion through the use of viral vectors and an inducible transgene. As a complementaryapproach SAA expression will be suppressed using antisense oligonucleotides. The impact of SAA on indicesof AAA progression and aortic inflammation and remodeling will be determined. Aim 2b. To investigate thepotential role of SAA and inflammasome activation in human AAA the relationship between plasma SAA IL-1and the rate of AAA expansion in humans will be determined in the prospective N-TA3CT trial. These studieshold the potential for identifying new strategies for the clinical management of AAA.

project_terms:
Abdominal Aortic Aneurysm;Acute;Age-Years;Angiotensin II;Antisense Oligonucleotides;Aortic Rupture;Aortitis;Apolipoprotein E;Attenuated;Biological;Biological Markers;Blood Vessels;CASP1 gene;CCL2 gene;Caring;Cell Culture Techniques;Cells;Cessation of life;Chronic;Clinical Management;Data;Deposition;Development;Elastin;Evaluation;Event;Generations;High Density Lipoproteins;Human;Infection;Infiltration;Inflammasome;Inflammation;Inflammation Mediators;Inflammatory Response;Infusion procedures;Injury;Interleukin-1 beta;Intervention;Laboratories;Liver;Matrix Metalloproteinases;Medial;Mediating;Mus;Operative Surgical Procedures;Pathologic;Patients;Plasma;Proteins;Publications;Publishing;Reactive Oxygen Species;Risk;Role;Rupture;Ruptured Abdominal Aortic Aneurysm;Serum amyloid A protein;Signal Transduction;Smooth Muscle Myocytes;Stains;Symptoms;TNF gene;Testing;Tissues;Transgenes;United States;Viral Vector;Woman;adeno-associated viral vector;base;effective therapy;human old age (65+);indexing;innovation;insight;macrophage;men;mouse model;novel;novel strategies;predictive marker;prospective;response;small molecule;therapeutic target;translational study;unpublished works;vascular inflammation

public_health_relevance:
Approximately 15000 people in the United States alone die every year due to rupture of an abdominal aorticaneurysm (AAA). The clinical management of patients with AAA is challenged by the lack of effectivetreatments and the fact that most patients with AAA do not exhibit symptoms. This project investigateswhether serum amyloid A a protein known to be involved in the normal response to infection and injury maybe useful for developing new approaches for the identification care and management of patients with AAA.


application_id: 9402536
project_number: 5R01DE017921-08
project_title: Role of JAKs in innate responses to P. gingivalis
administering_ic: NIDCR
award_notice_date: 2017-12-12
opportunity_number: PA-13-302
application_type: 5
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 activationin 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;Autocrine Communication;Bacteria;Bacterial Infections;Bone Marrow;Cells;Chronic;Data;Disease;Equilibrium;Event;Family;Genetic Transcription;Gingiva;Goals;Health;Homeostasis;Human;Immune;Immune response;Impairment;Inflammation;Inflammatory;Inflammatory Response;Innate Immune Response;Interleukin-10;Interleukin-4;JAK3 gene;Janus kinase;Knock-in;Knockout Mice;Mass Spectrum Analysis;Mediating;Microbe;Modeling;Modification;Mus;Natural Immunity;Neutrophil Infiltration;Organism;Pathway interactions;Pattern;Periodontal Diseases;Periodontitis;Periodontium;Phosphorylation;Porphyromonas gingivalis;Process;Production;Protein Tyrosine Kinase;Proto-Oncogene Proteins c-akt;Regulation;Role;Signal Pathway;Signal Transduction;Signaling Protein;Site-Directed Mutagenesis;Testing;Time;Tissues;Translating;Work;bone loss;cytokine;design;immunoreaction;in vivo;knock-down;macrophage;member;microbial;microbial community;monocyte;new therapeutic target;novel;oral infection;pathogen;pathogenic bacteria;prevent;public health relevance;response;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: To protect against bacterial infection our bodies mount an inflammatory response; however this response must be regulated to prevent excessive inflammation and associated tissue damage. We have identified a host signaling protein called JAK3 that can dampen inflammatory responses to a gum disease causing organism. In this study we will characterize the role of JAK3 with the ultimate goal of designing means to stimulate this molecule and curtail inflammatory destruction in gum disease.


application_id: 9402503
project_number: 7R01ES026151-02
project_title: The epigenetic mechanism of hexavalent chromium carcinogenesis
administering_ic: NIEHS
award_notice_date: 2017-03-24
opportunity_number: PA-16-285
application_type: 7
activity_code: R01
ic: ES
serial_number: 026151
program_official: TYSON, FREDERICK L
project_start_date: 2016-09-01
project_end_date: 2021-08-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 9719630
contact_pi: YANG, CHENGFENG
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): Hexavalent chromium [Cr(VI)] is one of the most common environmental pollutants causing lung and other cancer. The mechanism of Cr(VI) carcinogenesis has not been elucidated. The long-term goal of this study is to determine the mechanism of Cr(VI) carcinogenicity and identify targets for better treatment and prevention of lung cancer resulting from Cr(VI) exposure. Epigenetics refers to heritable changes in the pattern of gene expression that are not caused by changes in DNA sequence but are mediated by DNA methylation histone posttranslational modifications microRNAs and long noncoding RNAs. Cancer stem cells (CSCs) are cancer cells possessing characteristics of normal stem cells. CSCs or CSC-like cells are considered as cancer initiating cells. Genomic imprinting refers to an epigenetic mechanism by which certain genes are expressed in a parent- of-origin-specific manner restricting their expression from only one of the two parental chromosomes. Many studies demonstrated that deregulation of epigenetics and genomic imprinting plays key roles in carcinogenesis. Accumulating evidence shows that Cr(VI) also causes epigenetic effects such as changing DNA methylation and histone posttranslational modifications. However the mechanisms by which Cr(VI) triggers these epigenetic modifications remain largely unknown and whether these epigenetic modifications play a causal role in Cr(VI) carcinogenesis are not clear. Our preliminary studies found: (i) Chronic Cr(VI) exposure induces CSC-like property and cell malignant transformation; (ii) Chronic Cr(VI) exposure increases the levels of several HMTases which play a causal role in Cr(VI)-induced CSC-like property and cell transformation; (iii) Higher levels of H3 repressive methylation marks and their related HMTases are also detected in lung cancer tissues of mice and humans exposed to chromium; (iv) Up-regulation of HMTases plays a crucial role in chronic Cr(VI) exposure- caused deregulation of Dlk1-Dio3 genomic imprinting cluster; (v) miR-494 down-regulation plays a causal role in Cr(VI)-induced cell transformation; and (vi) Oxidative stress increases the levels of HMTases. Based on literature and our preliminary data we hypothesize: (i) Cr(VI) exposure generates oxidative stress which increases the levels of HMTases; (ii) Up-regulation of HMTases deregulates the Dlk1-Dio3 genomic imprinting cluster which decreases the level of miR-494; and (iii) Down-regulation of miR-494 increases the levels of its targets and key CSC factors c-Myc and BMI1 which produce CSC-like property promoting Cr(VI)-induced cell transformation and tumorigenesis. This proposed study not only fills the knowledge gap of epigenetics and Cr(VI) carcinogenesis but also provides novel mechanistic insights for the crucial role of oxidative stress in Cr(VI) carcinogenesis. Three aims are proposed: Aim 1: Induction of CSC-like property by down-regulating miR-494 of Dlk1-Dio3 imprinting cluster and its role in Cr(VI)-induced cell transformation and tumorigenesis. Aim 2: Down-regulation of miR-494 by chronic Cr(VI) exposure-induced HMTases through deregulating Dlk1-Dio3 genomic imprinting cluster. Aim 3: Up-regulation of HMTases by chronic Cr(VI) exposure through oxidative stress.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Hexavalent chromium [Cr(VI)] is one of the most common environmental and occupational pollutants and exposure to Cr(VI) is a major environmental health concern affecting millions of people in the United States as well many other countries. The goal of this study is to determine the mechanism by which Cr(VI) exposure causes cancer and identify molecular targets for better treatment and prevention of cancers resulting from Cr(VI) exposure.


application_id: 9401767
project_number: 1F31MH114551-01
project_title: Do Bulimic Behaviors Increase Shame? Toward an Understanding of Transdiagnostic Risk
administering_ic: NIMH
award_notice_date: 2017-08-02
opportunity_number: PA-16-308
application_type: 1
activity_code: F31
ic: MH
serial_number: 114551
program_official: CHAVEZ, MARK RAY
project_start_date: 2017-08-06
project_end_date: 2019-08-05
study_section: Special Emphasis Panel[ZRG1 F16-M (09)]
contact_pi_person_id: 14505464
contact_pi: DAVIS BORCHETTA, HEATHER A.
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: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
There is abundant evidence documenting the comorbidity of bulimia nervosa (BN) internalizing disorders suchas anxiety and depression and externalizing disorders such as substance misuse. One important line ofresearch is to move beyond descriptions of comorbidity to determine underlying mechanisms that may accountfor it. The intent of the proposed research is to begin to test the possibility that engagement in one behavior ina specified set of comorbid dysfunctional behaviors increases the experience of shame and that theincreased shame contributes to risk for others of the comorbid behaviors. The scientific basis for investigatingthis possibility is that (a) estimates of comorbidity between BN internalizing and externalizing disorders are ashigh as 74.4% (Ulfvebrand et al 2015); (b) prior research on comorbidity has often been descriptivehighlighting the need to investigate mechanisms to explain it; (c) the experience of shame is associated witheach of these disorders; and (d) in recent longitudinal work my colleagues and I demonstrated that bingeeating in elementary school predicts increased levels of depression alcohol use and tobacco smoking fouryears later in high school. The research component of this proposal is a study designed to begin to test thisidea using bulimic behaviors by women with BN as an entry point for studying this comorbidity model.Specifically I propose to test in the laboratory whether eating while in a negative mood increases stateshame in women with BN as compared to healthy controls. After an ad lib eating session following negativemood induction women with BN will experience an increase in state shame that is greater than any increase instate shame for the healthy control group and these increases will predict subsequent increases in stateanxiety and depression as well as increased urges to use substances. Demonstration of increased stateshame and transdiagnostic risk following a distress-based eating session for women with BN is a crucial stepin a program of research I hope to conduct using both experimental and longitudinal designs. The trainingcomponent of this proposal includes the following: (1) training in the design and execution of laboratoryexperimental studies; (2) training in the construct of shame its distinction from related constructs such as guiltthe role of shame transdiagnostically methods of measuring shame and the possibility of reducing shame; (3)training in multilevel modeling: my planned program of research will involve studies of observations nestedwithin people nested within groups; (4) further advanced training in research ethics including a secondgraduate course on ethical research with clinical populations attendance at the University's clinical ethicsgrand rounds and research ethics lecture series; (5) preparation of research reports for publication includinglearning how to respond effectively to revise and resubmit decisions; (6) presenting original research atleading international scientific meetings; and (7) training in the mentoring of junior graduate students andundergraduate research assistants including those assisting with the proposed research.

project_terms:
Alcohol abuse;Alcohol consumption;Alcohol or Other Drugs use;Alcohols;American Indians;Anxiety;Behavior;Binge Eating;Bulimia;Clinical;Clinical Ethics;Comorbidity;Conscious;Control Groups;Disease;Distress;Eating;Emotions;Ethics;Experimental Designs;First Generation College Students;Functional disorder;Future;Goals;Guilt;Hyperphagia;Impulsive Behavior;Individual;International;Intervention;Laboratories;Laboratory Study;Lead;Learning;Measures;Mental Depression;Mentors;Methods;Modeling;Negative Valence;Observational Study;Pharmaceutical Preparations;Population;Preparation;Process;Proxy;Public Health;Publications;Reporting;Research;Research Assistant;Research Design;Research Ethics;Risk;Role;Series;Shame;Specific qualifier value;Symptoms;Testing;Tobacco smoking;Training;Universities;Woman;Work;anxiety states;anxiety symptoms;base;binge type behavior;cigarette smoking;depressive symptoms;design;elementary school;experience;experimental study;graduate student;high school;lectures;longitudinal design;meetings;multilevel analysis;negative affect;negative mood;programs;purge;response;substance misuse;therapy design;undergraduate research

public_health_relevance:
Bulimia nervosa (BN) internalizing disorders such as depression and anxiety and externalizing disorders suchas substance use tend to co-occur in people. The proposed project is part of a program of research designedto test the experience of shame as one mechanism explaining this co-occurrence. The project will support thePI a first generation college student of American Indian background in her goal to develop a cutting edgeresearch program to understand risk processes that contribute to multiple forms of dysfunction.


application_id: 9398898
project_number: 5R37DE011111-25
project_title: P.gingivalis interactions with gingival epithelial cells
administering_ic: NIDCR
award_notice_date: 2017-12-13
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: 2019-06-30
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;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;Infection;Instruction;Interferons;Knowledge;LIM Domain Kinase 1;LIMK1 gene;Label;Lead;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;Protein Dephosphorylation;Proteins;ROCK1 gene;Regulation;Reporter;Role;Serine;Signal Transduction;Signal Transduction Pathway;Signaling Molecule;Small Interfering RNA;Structure;T-Lymphocyte;TNF gene;Testing;Therapeutic Agents;Variant;actin depolymerizing proteins;cell motility;chemokine;cofilin;design;druggable target;dysbiosis;in vivo;live cell imaging;mutant;new therapeutic target;novel therapeutics;overexpression;p65;pathogen;prevent;promoter;response;transcription factor

public_health_relevance:
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.


application_id: 9397865
project_number: 1R13DC016547-01
project_title: Third International Meeting on Internet and Audiology
administering_ic: NIDCD
award_notice_date: 2017-06-16
opportunity_number: PA-16-294
application_type: 1
activity_code: R13
ic: DC
serial_number: 016547
program_official: KING, KELLY ANNE
project_start_date: 2017-07-01
project_end_date: 2018-06-30
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 1920229
contact_pi: PREMINGER, JILL E
other_pis: Not Applicable
congressional_district: 03
department: MISCELLANEOUS
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:
AbstractSince the 1990s internet-based applications have rapidly become an essential pillar of modern healthcare.Internet-based research and internet-based health applications are ideal mechanisms for promoting public andpersonalized hearing health and internet applications are essential for the advancement and improvement ofaudiology care for children and adults. Following a successful 1st International Meeting on Internet & Audiologyheld in October 2014 at Linkping University Sweden and a 2nd fruitful meeting in September 2015 at theEriksholm Research Centre Snekkersten Denmark the 3rd International Meeting on Internet & Audiology will beheld at the University of Louisville (Louisville KY) July 27-28 2017. This 2-day conference will focus on fourmajor themes; each theme will be introduced by a keynote speaker: 1) Barriers and facilitators to theimplementation of telepractice 2) Methodology of internet-based research and service delivery 3) Big data and4) Ethical issues related to internet-based research and service delivery. These topics will be covered in four half-day sessions composed of keynote talks podium presentations poster presentations panel discussions anddemonstration sessions. This small meeting (up to 100 attendees) will allow for interaction and networking. Thespecific aims of the conference are to: 1) Bring together researchers and clinicians (both in-person and online)from around the world to discuss research activities (past present and future) in terms of needs design andimplementation in the areas of internet-based audiology research and internet-based clinical care; 2) Promotefuture research in the area of internet and audiology via podium and poster presentations panel discussionshands-on activities networking opportunities and through the provision of early-career investigator and graduatestudent travel awards; and 3) Disseminate findings from the conference in a special issue of the American Journalof Audiology as an additional method to promote further research. There are several important aspects of themeeting. First the keynote speakers will be diverse in experience in hearing healthcare (two keynotes) and fromother healthcare fields (two keynotes). Second the scientific and planning committee members have a broadrange of internet-based research experience related to pediatric and adult audiology. Third travel awards will beprovided for early-career investigators and PhD students; a subset of awards will be dedicated to applicants fromunderrepresented groups. Recipients will be selected in order to promote high quality research and create adiverse representation of attendees and presenters. Fourth a portion of the meeting will be available by livestreamto100 remote attendees in order to promote research and collaboration with a wider audience who are unable toattend in person.

project_terms:
Adult;American;Area;Audiology;Auditory;Award;Big Data;Caring;Child Care;Childhood;Cochlear Implants;Collaborations;Committee Members;Data;Data Analyses;Databases;Denmark;Development;Doctor of Philosophy;Ethical Issues;Family;Funding;Future;Goals;Grant;Health;Health Sciences;Health Services;Healthcare;Hearing;Hearing Aids;International;Internet;Journals;Link;Manufacturer Name;Methodology;Methods;Modernization;Participant;Patients;Persons;Publishing;Research;Research Activity;Research Personnel;Self Management;Services;Students;Sum;Sweden;Technology;Training;Travel;Underrepresented Groups;Universities;base;career;clinical care;design;eHealth;experience;graduate student;health application;innovation;interoperability;meetings;posters;programs;public health relevance;shared decision making;symposium;tool

public_health_relevance:
Public Health Relevance StatementInternet-based research and internet-based health applications are ideal mechanisms for promoting public andpersonalized hearing health and internet applications are essential for the advancement and improvement ofaudiology care for children and adults. This conference grant proposes funding for the 3rd International Meetingon Internet & Audiology; the goals of the conference are to promote research in and development of internetbased audiology applications.


application_id: 9397734
project_number: 2R01DK074720-10
project_title: Novel mechanisms involving complement cascade in stem cell trafficking
administering_ic: NIDDK
award_notice_date: 2017-07-15
opportunity_number: PA-16-160
application_type: 2
activity_code: R01
ic: DK
serial_number: 074720
program_official: ROY, CINDY
project_start_date: 2007-03-01
project_end_date: 2021-06-30
study_section: Molecular and Cellular Hematology Study Section[MCH]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
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:
Address;Alternative Complement Pathway;Animal Model;Antibodies;Blood Circulation;Blood Vessels;Bone Marrow;Bone Marrow Transplantation;CXCR4 Receptors;CXCR4 gene;Cell Adhesion Molecules;Cell physiology;Cells;Chemotactic Factors;Circadian Rhythms;Coagulation Process;Complement;Complement 1q;Complement 3 Convertase;Complement Activation;Complement Factor H;Data;Defect;Development;Distal;Elements;Engraftment;Enzymes;Generations;Growth Factor;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Mobilization;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Homing;Immunoglobulin M;Integrin alpha4beta1;Integrins;Ligands;Mannose Binding Lectin;Mediating;Molecular;Mus;Natural Immunity;Nitric Oxide;Nitric Oxide Synthase;Pathway interactions;Patients;Pattern;Pattern recognition receptor;Pharmacology;Phase;Physiological;Play;Process;Properdin;Protocols documentation;Reporting;Research;Role;Stem cells;Stress;Testing;Thrombin;Translating;Transplantation;Vascular Cell Adhesion Molecule-1;antigen binding;base;cell motility;conditioning;granulocyte;heme oxygenase-1;leukemia;mannose-binding protein-associated serine proteases;monocyte;novel;novel therapeutics;peripheral blood;pre-clinical;public health relevance;reconstitution;small molecule inhibitor;trafficking


application_id: 9397621
project_number: 1R01GM122994-01A1
project_title: Talin2-mediated traction force drives MMP secretion and cell invasion
administering_ic: NIGMS
award_notice_date: 2017-09-21
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: GM
serial_number: 122994
suffix: A1
program_official: XU, JIANHUA
project_start_date: 2017-09-30
project_end_date: 2019-06-30
study_section: Intercellular Interactions Study Section[ICI]
contact_pi_person_id: 11099256
contact_pi: HUANG, CAI
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
project_abstract:
ABSTRACT Talin is a key component in the intracellular complex of proteins linking the extracellular martrix to the actincytoskeleton via integrins at the plasma membrane. Talin interacts with -integrin tails and actin to control integrinactivation and force generation. It also binds to phosphatidylinositol 4 phosphate 5-kinase type I  90 (PIPKI90)an enzyme that catalyzes the production of phosphatidylinositol 45-bisphosphate (PIP2) and regulates vesicletrafficking. In this capacity talin regulates focal adhesion dynamics force generation and invadopodium stabilitythus governing cell migration and invasion. There are two talin genes Tln1 and Tln2 which encode talin1 andtalin2; talin1 has been well studied and it is generally believed that talin2 functions redundantly with talin1.However our preliminary data reveal some important differences between talin 1 and 2. Specifically talin2 hasstronger binding to  integrin tails than talin1 and Ser339 of talin2 is largely responsible for this affinity difference.Intriguingly a new study shows that Fifth Finger Camptodactyly a human genetic disease is caused by a Leumutation at talin2 Ser339 suggesting that the talin2-integrin interaction may be important for development.Talin2 is localized at invadopodia and is indispensable for traction force generation and invadopodiummaturation. And ablation of talin2 but not talin1 abolished the secretion of matrix metalloproteinase (MMP) 1and 9. In this regard talin2 promotes PIPKI90 binding to Exo84 (a component of the exocyst involved in vesiclesecretion) and interacts with non-muscle myosin IIA (NMMIIA) a major myosin involved in traction forcegeneration. Based on these data our central hypothesis is that talin2 interacts with NMMIIA to mediate tractionforce generation and promotes PIPKI90-Exo84 complex formation thus driving MMP1 and MMP9 secretioninvadopodium maturation and cell invasion. We will test this hypothesis by addressing the following SPECIFICAIMS: 1) define how talin2 regulates MMP secretion invadopodium maturation and cell invasion; 2) dissect howtalin2 modulates PIPKI90-Exo84 interaction to regulate MMP secretion invadopodium maturation and cellinvasion; 3) determine how talin2 interacts with NMMIIA to regulate traction force generation MMP secretioninvadopodium maturation and cell invasion. Our proposed studies are designed to uncover a novel fundamentalrole for talin2 in regulating MMP secretion invadopodium maturation and cancer cell invasion and the underlyingmechanisms. Support for this connection is provided by the fact that talin2 was found to be down-regulated byTrastuzumab a HER2-targeting antibody drug for breast cancers and our findings indicate that talin2 is essentialto the traction force development required for invadopodium maturation and cell invasion. Thus talin2 could bea target for therapies designed to inhibit the first steps of metastasis.

project_terms:
Ablation;Actins;Address;Affinity;Antibodies;Automobile Driving;Binding;Biochemical;Cell Count;Cell membrane;Cell physiology;Cells;Cellular biology;Complex;Computational Technique;Confocal Microscopy;Congenital Camptodactyly;Cytoskeleton;Data;Development;ERBB2 gene;Enzymes;Fingers;Focal Adhesions;Generations;Genes;Goals;Golgi Apparatus;Hereditary Disease;Human Genetics;Imaging Techniques;Integrin beta Chains;Integrins;Interstitial Collagenase;Leucine;MMP9 gene;Matrix Metalloproteinases;Mediating;Methodology;Microscopy;Modeling;Molecular;Mutation;Myosin ATPase;Neoplasm Metastasis;Nonmuscle Myosin Type IIA;Pharmaceutical Preparations;Phosphatidylinositol 45-Diphosphate;Phosphatidylinositols;Phosphotransferases;Positioning Attribute;Production;Proteins;Research;Resolution;Role;Tail;Talin;Testing;Traction;Trastuzumab;Vesicle;Work;base;cancer cell;cancer therapy;cell motility;design;experience;extracellular;genome editing;link protein;malignant breast neoplasm;non-muscle myosin;novel;phosphatidylinositol 4-phosphate;protein complex;targeted treatment;therapy design;trafficking

public_health_relevance:
Cell invasion is prerequisites for cancer metastasis. Thus the elucidation of the molecularmechanisms of cell invasion is a compelling goal in cell biology. The work proposed here willelucidate the role of talin2 in regulating invadopodium maturation and cell invasion and theunderlying regulatory mechanisms providing potential strategy for cancer therapy.


application_id: 9397586
project_number: 5R01NS091146-04
project_title: Anti-Oxidant Promoting Cytokine LIF Enhances Neural Cell Survival During Ischemia
administering_ic: NINDS
award_notice_date: 2017-12-05
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 091146
program_official: BOSETTI, FRANCESCA
project_start_date: 2016-05-01
project_end_date: 2019-12-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 1879898
contact_pi: PENNYPACKER, KEITH R
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): Leukemia inhibitory factor (LIF) is an anti-inflammatory cytokine that activates the expression of endogenous antioxidants in neural cells. Our laboratory has been examining the efficacy of LIF in the rodent stroke model of middle cerebral artery occlusion (MCAO) which reflects the most commonly occluded vessel in humans. We have found that LIF administered at 6 h after MCAO improves anatomical and functional outcomes in rats. Of interest this treatment reflects a 33% extension of the therapeutic window when extrapolated to the current clinical stroke window for therapy. LIF increased the expression of antioxidant proteins via Akt in cultured neurons and oligodendrocytes. Aim 1: Is the efficacy of LIF dependent on SOD? We have found total superoxide dismutase (SOD) levels are significantly elevated and protein levels of one isoform SOD3 are increased several-fold at 3 days following MCAO. In this Aim we will determine if specific SOD subtype(s) are responsible for the LIF-induced effects and determine cell-specific expression of these SOD isoforms. MCAO studies will first use knockout mice to examine the SOD subtypes and these results will then be confirmed in rats. Aim 2: Does this LIF dosing regimen translate into long-term behavioral recovery? This Aim will determine whether this treatment regimen has lasting effects. These data will be used to devise a treatment regimen to extend the short-term efficacy to long-term histological and functional recovery at 90 days post-MCAO in rats. Aim 3: Which signals are transduced following LIF activation? The efficacy of LIF is dependent on the protein kinase Akt. From analysis of antioxidant promoters the transcription factor MZF-1 is the putative transcription factor that activates their gene expression via Akt. We will use immunohistochemistry and gel shift assays to quantify their expression and promoter binding respectively in the infarct regions of rats treated with LIF after MCAO. siRNA techniques with neuronal cultures will be employed to knock down expression of this factor to validate previous findings. Aim 4: Will LIF administration be effective in elderly rats after MCAO?In this Aim we will treat elderly male and female rats in short-term studies. These studies will b used to determine if there are any age- or sex- dependent differences in LIF efficacy after MCAO. Both histological and functional recovery will be examined. This proposal is aimed to further elucidate the mechanism(s) of LIF treatment and optimize the treatment regimen for long-term efficacy. While treatment with exogenous antioxidants has failed we believe that the systemic activation of endogenous antioxidants is a better approach and could have substantial implications for treating clinical stroke.

project_terms:
Address;Age;Anatomy;Anti-inflammatory;Antioxidants;Behavioral;Binding;Cell Survival;Cells;Clinic;Clinical;Data;Dose;Elderly;Electrophoretic Mobility Shift Assay;Exploratory/Developmental Grant for Diagnostic Cancer Imaging;FDA approved;Female;Gene Expression;Histologic;Human;Immunohistochemistry;Infarction;Intravenous;Ischemia;Knockout Mice;LIF gene;Laboratories;Measures;Middle Cerebral Artery Occlusion;Motor Skills;Neurologic;Neurons;Occlusion injury;Oligodendroglia;Performance;Protein Isoforms;Protein Kinase;Proteins;Public Health;Rattus;Records;Recovery;Recovery of Function;Regimen;Rodent;Safety;Signal Transduction;Small Interfering RNA;Stroke;Superoxide Dismutase;Techniques;Therapeutic;Translating;Treatment Protocols;activating transcription factor;base;combat;cytokine;enhancing factor;experimental study;functional outcomes;gray matter;improved;individualized medicine;interest;knock-down;male;pre-clinical;promoter;public health relevance;response;sex;stroke model;transcription factor;treatment optimization;treatment strategy;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Stroke is a major public health problem in the USA with only one FDA-approved treatment that has a limited treatment window. We have found that leukemia inhibitory factor (LIF) protects neural cells from stroke. The proposed experiments will identify how LIF increases the cells own antioxidants to protect it from stroke induced damage.


application_id: 9397465
project_number: 1U44AA026126-01
administering_ic: NIAAA
award_notice_date: 2017-08-24
opportunity_number: PAR-15-154
application_type: 1
activity_code: U44
ic: AA
serial_number: 026126
program_official: FERTIG, JOANNE
project_start_date: 2017-08-25
project_end_date: 2022-07-31
study_section: Special Emphasis Panel[ZAA1 DD (44)]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-08-25
project_abstract:
Abstract Alcohol dependence affects at least 4% of the US population with a financial cost in excess of $100Bn. Prevention of relapse in patients attempting to reduce alcohol consumption is a major therapeutic target but current treatments are ineffective and there is an urgent need for new medications. Major factors in causing relapse include the protracted symptoms of withdrawal from alcohol which are relieved by returning to drinking. Alcohol withdrawal is also implicated in the neurodegeneration that is associated with dependence. There is abundant evidence that the glutamate/NMDA receptor (NMDAR) is a molecular target in alcohol withdrawal and that inhibitory modulators of the NMDAR are potentially valuable as anti-relapse pharmacotherapy. Target validation identified polyamine enhancement of NMDAR function via the NR2B subunit as a specific target in alcohol withdrawal and molecular screening identified several lead compounds. JR220 was the most active novel compound from an aryliminoguanidine series and its cellular effects on neuronal cultures were consistent with NMDAR inhibition via this site. JR220 was then tested in a variety of rodent screens relevant to alcohol dependence withdrawal and neurotoxicity including several screens in other laboratories. The drug was highly active in all of these screens with a potency 5-200x that of acamprosate which is FDA-approved for the prevention of relapse. JR220 caused mild sedation at higher doses but there was no overt toxicity even on repeated administration. Pharmacokinetic studies in the rat showed dose dependent elevations of concentrations in plasma after intraperitoneal subcutaneous and oral administration (oral bioavailability >70%). Concentrations obtained in brain were ~10x higher than plasma suggesting an active uptake system at the blood/brain barrier. On repeated once daily dosing for 7 days JR220 did not accumulate in plasma or brain and no overt toxicity was observed. The only concern is that the plasma half-life following oral administration may be too short for once-a-day dosing in relapse prevention. This can be addressed by formulation as an oral extended release formulation or by a transdermal patch (which would also have other advantages for treatment of alcohol use disorders). Intellectual property in JR220 as a treatment for aspects of alcohol withdrawal and the transdermal patch formulation of JR220 are covered by provisional applications to the USPTO. The preliminary data indicates that JR220 is an excellent candidate as an anti-relapse medication and the current proposal is to develop the drug further for this use. The aim is now to complete the studies required prior to submission of the drug to the FDA for consideration as an investigational new drug (IND). Thus in the proposed studies we will complete investigation of metabolism and metabolite identification in vitro and Absorption Distribution Metabolism and Excretion in vivo. The studies will also include a screen for off target actions and studies on safety and toxicology in two species. These studies will include escalating acute dose studies and sub-chronic studies (to reflect the maintenance of patients on anti-relapse medication). JR220 will be produced under GMP conditions and production scaled up to meet requirements for future human trials. If an IND designation is obtained the objective will then be to partner with a major pharmaceutical company in testing the drug in a human safety trial and then in clinical trials in alcohol dependent volunteers. The objective is to develop JR220 for relapse prevention and neuroprotection to provide a pharmacotherapy that is more effective for these therapeutic targets than others currently available.

project_terms:
Acute;Address;Adverse effects;Affect;Alcohol consumption;Alcohol dependence;Alcohol withdrawal syndrome;Alcohols;Autopsy;Binding;Biological Availability;Blood - brain barrier anatomy;Brain;Canis familiaris;Cardiovascular system;Chemicals;Chronic;Clinical;Clinical Trials;Complex;Data;Dependence;Development;Dose;Drug Kinetics;Enzymes;Equilibrium;Evaluation;Excretory function;FDA approved;Financial cost;Formulation;Future;Gastritis;Glutamates;Guanidines;Half-Life;Hepatic;Hepatocyte;Human;In Vitro;Intellectual Property;Investigation;Investigational Drugs;Kilogram;Label;Laboratories;Lead;Liver Microsomes;Lung;Macaca fascicularis;Maintenance;Maximum Tolerated Dose;Medical;Metabolism;Methods;Modeling;Molecular;Molecular Target;N-Methyl-D-Aspartate Receptors;NMDA receptor antagonist;Nerve Degeneration;Neurons;Oral;Oral Administration;Pathologic;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Pharmacotherapy;Phase;Physiological;Plasma;Plasma Proteins;Play;Polyamines;Population;Production;Rattus;Receptor Inhibition;Recovery;Relapse;Research;Rodent;Role;Route;Safety;Schedule;Sedation procedure;Series;Site;Symptoms;System;Testing;Therapeutic Uses;Toxic effect;Toxicokinetics;Toxicology;Treatment Efficacy;Up-Regulation;Validation;Withdrawal;Withdrawal Symptom;absorption;acamprosate;alcohol abuse therapy;alcohol exposure;alcohol use disorder;aminoguanidine;chemical synthesis;design;disorder later incidence prevention;drinking;drug testing;genotoxicity;high throughput screening;human subject;in vivo;ineffective therapies;intraperitoneal;meetings;neuroprotection;neurotoxicity;nonhuman primate;novel;novel therapeutics;phase 1 study;preclinical development;preclinical study;receptor;receptor function;reduce symptoms;scale up;screening;subcutaneous;therapeutic target;uptake;volunteer


application_id: 9396482
project_number: 1F31AA026175-01
project_title: Intentional personality change: Towards preventing problem drinking
administering_ic: NIAAA
award_notice_date: 2017-09-14
opportunity_number: PA-16-309
application_type: 1
activity_code: F31
ic: AA
serial_number: 026175
program_official: RUFFIN, BEVERLY
project_start_date: 2017-09-17
project_end_date: 2019-09-16
study_section: Special Emphasis Panel[ZAA1 GG (32)]
contact_pi_person_id: 14181742
contact_pi: RILEY, ELIZABETH
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:
I have begun a program of research on the precipitants of change in personality traits that confer high risk foryoung adult problem drinking. This work has focused on the trait of negative urgency the tendency to actrashly when distressed; negative urgency has been shown in meta-analytic research to relate more stronglythan other impulsigenic traits to problem drinking (Berg et al. 2015; Stautz & Cooper 2013) and inprospective work to predict the onset of and increases in drinking behavior (Riley et al. 2016). Usinglongitudinal designs my colleagues and I have demonstrated that (1) very early onset drinking predictedsubsequent increases in negative urgency which in turn predicted yet further drinking suggesting a positivefeedback loop of prospective increases in both negative urgency and drinking (Riley et al. 2016); and (2)increases in negative urgency following early drinking behavior mediated the predictive impact of elementaryschool drinking on multiple negative high school outcomes including increased drinking smoking and bingeeating (Riley & Smith in press). Recently a co-sponsor of this proposed traineeship published evidence that atraining program produced reductions in negative urgency in a small sample of women suffering from PTSD(Weiss et al. 2015). The scientific premise of this proposal is to test whether this training program produces (a)reductions in drinking behavior (b) reductions in negative urgency among heavy drinking young adults and (c)evidence that reduced negative urgency mediates the impact of the training on drinking behavior. I propose totest these hypotheses using a within-subjects laboratory design within a sample of heavy drinking youngadults. A successful test will have direct implications for the prevention of heavy drinking behavior. Becausenegative urgency has been shown to increase risk transdiagnostically findings may have implications forcomorbid disorders and reducing other risky impulsive behaviors as well. A key component of the training planof this proposal is for me to receive training in conducting laboratory experimental studies because my workthus far has primarily involved longitudinal studies. Thus the training plan includes: (1) training in the designand execution of laboratory experimental studies; (2) training in how to conduct the negative urgencyreduction training which focuses on emotion modulation; (3) training in multilevel modeling: my plannedprogram of research will involve studies of observations nested within people nested within groups; (4) furtheradvanced training in research ethics including a second graduate course on ethical research with clinicalpopulations and attendance at the University's clinical ethics grand rounds and research ethics lecture series;(5) preparation of research reports for publication including learning how to respond effectively to revise andresubmit decisions; (6) presenting original research at leading international scientific meetings; and (7) trainingin the mentoring of junior graduate students and undergraduate research assistants including those assistingwith the proposed research.

project_terms:
Alcohol abuse;Alcohol consumption;Behavior;Binge Eating;Clinical;Clinical Ethics;Comorbidity;Disease;Distress;Drug Use Disorder;Drug usage;Eating Disorders;Emotions;Environment;Ethics;Exanthema;Exposure to;Feedback;Functional disorder;Future;Heavy Drinking;Impulsive Behavior;Impulsivity;International;Laboratories;Laboratory Study;Learning;Literature;Longitudinal Studies;Measures;Mediating;Mediation;Mentors;Minority;Modeling;Negative Reinforcements;Observational Study;Outcome;Participant;Personality;Personality Traits;Persons;Population;Post-Traumatic Stress Disorders;Preparation;Prevention;Process;Public Health;Publications;Publishing;Reporting;Research;Research Assistant;Research Ethics;Research Personnel;Rewards;Risk;Risk Factors;Risk Reduction;Sampling;Series;Smoking;Students;Testing;Time;Traineeship;Training;Training Programs;Trauma;Universities;Woman;Work;Youth;base;design;distraction;drinking;drinking behavior;drinking onset;early adolescence;early drinking;early onset;elementary school;experimental study;fifth grade;graduate student;heavy drinking young adult;high risk;high school;lectures;longitudinal design;meetings;multilevel analysis;negative affect;non-suicidal self injury;prevent;programs;prospective;reinforced behavior;response;sexual assault;success;therapy design;trait;undergraduate research;young adult

public_health_relevance:
Negative urgency is a personality trait that reflects the tendency to act impulsively when distressed and thatpredicts alcohol consumption in young adults. If researchers can reduce negative urgency they might well beable to reduce risk for problem drinking and thus advance the public health. The proposed project constitutesthe first test of the possibility that an emotion modulation training program could reduce drinking behavior byreducing negative urgency


application_id: 9395947
project_number: 5R01NS045954-12
project_title: Neuropeptidergic Inhibition of Spinal Pain Transmission
administering_ic: NINDS
award_notice_date: 2017-11-24
opportunity_number: PA-13-118
application_type: 5
activity_code: R01
ic: NS
serial_number: 045954
program_official: OSHINSKY, MICHAEL L
project_start_date: 2002-09-10
project_end_date: 2018-03-31
study_section: Special Emphasis Panel[ZRG1-IFCN-B(03)]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
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:
Nerve injury dramatically increases NPY expression in sensory neurons and NPY receptor-mediatedanalgesia yet this is underappreciated as a potential pain relief mechanism that might prevent the transitionfrom acute to chronic pain. Among 35 original research articles reviews and a book published during theprevious funding cycle (28 as first or senior authors) our work published in PNAS discovered that intrathecalNPY receptor antagonists or conditional genetic NPY depletion reinstated hyperalgesia even when appliedmonths after nerve injury or inflammation. Our overall hypothesis is that injury induces a sustained release ofNPY and activation of NPY Y1 receptor signaling that opposes the transition to a chronic state of lasting painvulnerability. However whether tissue- or nerve-injury induced increases in spinal NPY Y1 receptor (Y1R)signaling is associated with a tonic increase in the releasable pool of NPY has been difficult to determine. Toaddress this gap we developed a new in situ assay of functional NPY release (Y1R internalization). Our newdata indicate that Y1R internalization is greater with nerve injury after high frequency electrical stimulation ofdorsal horn slices or after in vivo non-noxious stimulation of the hindpaw. Specific Aim 1 will use this novelmethod to test the hypothesis that non-noxious stimulus-evoked release of NPY from A-fibers will remainprimed for weeks and even months after nerve injury. We now report that NPY produces an outward currentand inhibits action potentials evoked by dorsal root stimulation (DRS) in Y1-EGFP labeled neurons. To test thehypothesis that injury increases synaptic inhibition by NPY Specific Aim 2A will patch-clamp lamina IIneurons and conduct Fura-2 [Ca2+]i imaging at peak of hyperalgesia after injury. We predict that Y1R agonistswill inhibit stimulus-evoked responses and their concentration-response curves will be left-shifted by injury. Ourprogress with NPY saporin-conjugated neurotoxin indicates that Y1R-expressing dorsal horn neuronscontribute to neuropathic pain and new double-label immunohistochemistry and patch-clampelectrophysiology data in Y1R-EGFP mice support the concept that Y1R-positive neurons are excitatory. Totest the hypothesis that Y1R-expressing neurons maintain LS after inflammation or nerve injury but are held incheck by NPY Specific Aim 2B will evaluate the effects of Y1 receptor antagonists on [Ca2+]i mobilization andNMDA or AMPA receptor currents in Y1R-expressing neurons upon dorsal root stimulation or laser-directedNMDA/AMPA uncaging. Specific Aim 3 will then use an intrathecal pharmacology approach to determinewhether NPY silences pronociceptive GluN AC1 Epac signaling on Y1R-expressing dorsal horn neuronsand TRPA1 TRPV1 signaling on central afferents terminals. Completion of this project will bring us closer toour long-term goal of alleviating chronic pain by either: a) facilitating endogenous NPY analgesia thusrestricting pain within a state of remission; or b) extinguishing spinal neuron sensitization altogether forexample with a selective AC1 or Epac1 inhibitor.

project_terms:
AMPA Receptors;Absence of pain sensation;Action Potentials;Acute;Address;Adenylate Cyclase;Affect;Afferent Neurons;Agonist;American;Analgesics;Biological Assay;Books;Chronic;Confocal Microscopy;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Data;Disease remission;Electric Stimulation;Electrophysiology (science);Evoked Potentials;Failure;Fiber;Frequencies;Funding;Fura-2;Genetic;Goals;Hyperalgesia;Image;Immunohistochemistry;In Situ;Inflammation;Injury;Interneurons;Intrathecal Injections;Label;Lasers;Left;Mediating;Methods;Molecular;Mus;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;Neurons;Neuropeptide Y Receptor;Neurotoxins;Nociceptors;Pain;Peripheral nerve injury;Pharmacology;Physical Function;Physiologic pulse;Posterior Horn Cells;Productivity;Proteins;Public Health;Publishing;Quality of life;Receptor Activation;Receptor Signaling;Reporting;Research;Signal Transduction;Site;Slice;Spinal;Spinal Cord;Spine pain;Stimulus;Synapses;TRPV1 gene;Testing;Tissues;Traumatic injury;Work;central sensitization;chronic pain;cost;dorsal horn;excitatory neuron;in vivo;inflammatory neuropathic pain;inhibitor/antagonist;knock-down;mental function;nerve injury;neuropeptide Y;neuropeptide Y-Y1 receptor;novel;pain relief;painful neuropathy;patch clamp;prevent;public health relevance;receptor;receptor internalization;response;small molecule inhibitor;somatosensory;spinal nerve posterior root;synaptic inhibition;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE STATEMENTChronic pain is a public health problem which affects the physical and mental functioning quality oflife and productivity of over 100 million Americans costing $600 billion dollars annually. Our recentwork suggests that our body's own natural pain killers (namely neuropeptide Y) exert an extremelypowerful and very long-lasting ability to put chronic pain in remission. This project seeks to elucidatenot only the molecular mechanisms that cause painful suffering following chronic inflammation or atraumatic injury but also the compensatory mechanisms in the spinal cord that prevent the transition tochronic pain.


application_id: 9394764
project_number: 5R01AI128862-02
project_title: Biosynthesis and medicinal chemistry of the capuramycin antimycobacterial antibiotics
administering_ic: NIAID
award_notice_date: 2017-11-15
opportunity_number: RFA-AI-16-006
application_type: 5
activity_code: R01
ic: AI
serial_number: 128862
program_official: BOYCE, JIM P
project_start_date: 2017-01-01
project_end_date: 2021-12-31
study_section: Special Emphasis Panel[ZRG1-IDM-W(50)R]
contact_pi_person_id: 9509796
contact_pi: VAN LANEN, STEVEN GARY
other_pis: THORSON, JON SCOTT
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:
Achievement;Address;Anabolism;Antibiotics;Antimycobacterial Agents;Antitubercular Agents;Applied Research;Biological;Biological Availability;Cell Wall;Cessation of life;Chemicals;China;Clinical;Collaborations;Communicable Diseases;Country;Development;Disease;Drug resistance;Drug resistance in tuberculosis;Engineering;Enzymes;Family;Fostering;Funding Mechanisms;Future;Goals;Health;Hexuronic Acids;Human;In Vitro;Incidence;India;Individual;Lead;Libraries;Modification;Multi-Drug Resistance;Multidrug-Resistant Tuberculosis;Mus;Mycobacterium tuberculosis;Natural Products;Nucleosides;Open Reading Frames;Peptidoglycan;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Phosphotransferases;Population;Preparation;Production;Property;Reaction;Recovery;Reporting;Research;Resistance;Rifampin;Series;Source;Structure;Substrate Specificity;Sugar Substitute;System;Technology;Therapeutic;Toxic effect;Treatment Protocols;Tuberculosis;United States;Uridine;World Health Organization;analog;bactericide;chemical function;clinical development;drug development;drug discovery;extensive drug resistance;fighting;fundamental research;glycosyltransferase;improved;in vitro activity;in vivo;inhibitor/antagonist;innovation;isoniazid;nanomolar;novel;pathogen;pharmacophore;resistance mechanism;resistant strain;scaffold;sugar;tool;translocase;tuberculosis drugs;tuberculosis treatment;virtual


application_id: 9393956
project_number: 5R01AG049806-03
project_title: The effects of exercise on satellite cell dynamics during aging
administering_ic: NIA
award_notice_date: 2017-11-17
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AG
serial_number: 049806
program_official: WILLIAMS, JOHN
project_start_date: 2016-01-01
project_end_date: 2020-11-30
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
other_pis: PETERSON, CHARLOTTE A.
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: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Ablation;Address;Adult;Affect;Age;Age-Months;Aging;Biological Assay;CD34 gene;Cell Nucleus;Cell physiology;Cells;Coculture Techniques;Collagen;Data;Development;Disease;Elderly;Environment;Etiology;Exercise;Expression Profiling;Fiber;Fibroblasts;Fibrosis;Functional disorder;Gastrocnemius Muscle;Gene Targeting;Genetic;Goals;Growth;Homeostasis;Human;Hypertrophy;Immunohistochemistry;Individual;Integrins;Intervention;Knock-out;Knowledge;Label;Life;Longevity;MAPK14 gene;Maintenance;Measures;Mediating;Methods;MicroRNAs;Modeling;Mouse Strains;Mus;Muscle;Muscle Fibers;Nucleosomes;Outcome;Phase;Phenotype;Physical activity;Production;Proteins;Publishing;Quality of life;Regulation;Reporter;Reporting;Research;Rodent;Role;Running;Skeletal Muscle;Skeletal Muscle Satellite Cells;Stem cells;Stimulus;Testing;Therapeutic;Time;Untranslated Regions;base;exosome;experimental study;extracellular;falls;frailty;improved;loss of function;muscle aging;muscle form;muscle hypertrophy;muscle strength;normal aging;novel;progenitor;regenerative;response;sarcopenia;satellite cell;sedentary;senescence;skeletal muscle growth;skeletal muscle wasting;tool


application_id: 9392879
project_number: 5R21AG051945-02
project_title: Astrocytic connexin 43 modulation in AD
administering_ic: NIA
award_notice_date: 2017-12-02
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AG
serial_number: 051945
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2016-12-15
project_end_date: 2019-11-30
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
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_abstract:
7. Project Summary/AbstractAstrocytes are vital to brain metabolism and help to optimize synaptic function and promote neuronal health.Direct coupling of astrocytes to the extracellular milieu via unapposed hemichannels (uHCs)made up ofconnexin 43 (Cx43) proteinsappears to be increased under a variety of pathological conditions. Elevatedlevels of amyloid- (A) peptides and pro-inflammatory cytokines characteristic of Alzheimers disease (AD)lead to greater uHC permeabilitywhich in turn impairs neuronal function and viability. In this project we willtest the novel hypothesis that A-dependent changes in uHCs are mediated in part by aberrant activation ofthe protein phosphatase calcineurin (CN) shown by our lab and others to drive several critical components ofthe activated astrocyte phenotype. Aim 1 will use a combination of adenoviral vectors and pharmacologicalagents in addition to Western blot ethidium bromide uptake patch-clamp electrophysiology and a variety ofbiochemical assays to determine whether CN and Cx43 are necessary and sufficient for the effects of A onthe functional status of HCs in primary astrocytes. In addition this aim will determine the feasibility of using anovel peptide-based reagent 43Gap52 to selectively disrupt CN/Cx43 interactions without inhibiting CN activityper se. This aim will establish whether aberrant CN/Cx43 interactions in astrocytes are a direct outcome of Apathology. Aim 2 will use adeno-associated virus (AAV) bearing astrocyte-specific promoters and CNactivators (active CN fragment) or CN inhibitors (CN-autoinhibitory peptide or 43Gap52) to selectively modulateastrocytic CN/Cx43 interactions in an intact mouse model of AD. The functional status of astrocytic uHCs willbe investigated in acutely prepared brain slices using an EtBr uptake assay as described for Aim 1. Inaddition slice electrophysiology will be used to assess the impact of CN/Cx43 interactions on hippocampalsynaptic strength and plasticity. This Aim will validate Aim 1 results in a commonly used animal model of ADen route to determining the extent to which CN/Cx43 interactions in astrocytes disrupt synaptic function duringthe progression of A pathology. These studies will shed light on the role of astrocytic HCs in ADpathophysiology and determine whether disruption of the CN/Cx43 interaction is a feasible strategy forameliorating neurologic dysfunction due to AD and other types of neurodegenerative disease.

project_terms:
APP-PS1;Acute;Adenovirus Vector;Adenoviruses;Age-Months;Aging;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Animal Model;Astrocytes;Award;Biochemical;Biochemical Pathway;Biological Assay;Brain;Calcineurin;Calcineurin inhibitor;Cell membrane;Cells;Characteristics;Cognitive;Connexin 43;Coupling;Custom;Data;Dependovirus;Deposition;Development;Disease;Drug Targeting;Electrophysiology (science);Excitatory Neurotoxins;Functional disorder;Generations;Glutamates;Health;Hippocampus (Brain);Homidium Bromide;Human;Impairment;Inflammatory;Injections;Injury;Ion Channel;Lead;Light;Mediating;Mediator of activation protein;Membrane;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurologic Dysfunctions;Neurons;Neurophysiology - biologic function;Outcome;PPP3CA gene;Pathologic;Peptides;Permeability;Pharmacology;Phenotype;Phosphorylation Site;Process;Property;Protein Dephosphorylation;Protein phosphatase;Proteins;Radial;Reagent;Role;Route;Signal Transduction;Site;Slice;Surface;Synapses;Tail;Testing;Vascular Diseases;Water;Western Blotting;Wild Type Mouse;adeno-associated viral vector;arm;base;beta amyloid pathology;brain metabolism;calcineurin phosphatase;cytokine;design;experimental study;extracellular;fluorescence imaging;functional outcomes;functional status;glial activation;hydrophilicity;mild cognitive impairment;mouse model;neuroinflammation;novel;overexpression;patch clamp;prevent;promoter;protein activation;protein protein interaction;pup;relating to nervous system;solute;synaptic function;transcription factor;transgene expression;uptake

public_health_relevance:
8. Project NarrativeThis project will investigate novel interactions between intracellular mediators of glial activation (i.e. calcineurin)and specialized membrane channels (hemichannels) used for coordinating astrocyte network activity. Novelreagents will be used to validate a new astrocyte-based drug target for disrupting Alzheimers pathophysiology.


application_id: 9391002
project_number: 5U01AI123832-03
project_title: Role of TRPV1 in asthma exacerbation
administering_ic: NIAID
award_notice_date: 2017-11-15
opportunity_number: PA-13-302
application_type: 5
activity_code: U01
ic: AI
serial_number: 123832
program_official: MINNICOZZI, MICHAEL
project_start_date: 2016-01-15
project_end_date: 2020-12-31
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 1857989
contact_pi: LEE, LU-YUAN
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): Inflammatory reaction is known to lead to an increase in tissue temperature but whether airway tissue temperature increases during asthma exacerbation is not yet known. Transient receptor potential vanilloid type 1 receptor (TRPV1) a ligand gated non-selective cation channel with a distinct sensitivity to heat is selectively and abundantly expressed in vagal bronchopulmonary C-fiber sensory nerves. A series of studies carried out in our lab have established the first evidence that an increase in temperature within the normal physiological range can activate and sensitize these TRPV1-expressing sensory neurons innervating the lung and airways; activation of these C-fiber afferents can elicit reflex bronchoconstriction cough and other airway defense responses. Indeed our recent study has demonstrated that an increase in airway temperature by hyperventilating humidified hot air triggered cough and bronchoconstriction in patients with mild and stable asthma but not in healthy subjects. The airway constriction was mediated through cholinergic reflex because it was completely prevented by pretreatment with ipratropium. The accompanying airway irritation and coughing further suggested an involvement of airway sensory nerves presumable TRPV1-expressing C-fiber afferents. In the light of these novel findings this proposed study aims to tes the following hypotheses: 1) in patients with allergic asthma the airway tissue temperature is elevated locally in the region when the inflammatory reaction is evoked by a segmental bronco-provocation with allergen. 2) Both the thermal sensitivity of these neurons and the expression of TRPV1 at the sensory nerve terminals are enhanced by chronic airway allergic inflammation. Thus a slight increase in local tissue temperature can lower the activation thresholds and enhance the sensitivity of TRPV1-expressing C-fiber sensory nerves in the airways of asthmatics. The synergistic effects of these factors may play a major part in the development of the airway hypersensitivity during chronic inflammation. This translational study will be performed in both asthmatic patients and in an animal model of allergic asthma. Results obtained from these studies should provide novel insights into the involvement of TRPV1 in the pathogenic mechanisms of airway hypersensitivity and help to uncover the mechanisms underlying the debilitating symptoms associated with airway inflammatory diseases.

project_terms:
Advanced Development;Afferent Neurons;Air;Allergens;Allergic inflammation;Animal Model;Asthma;Bronchial Provocation Tests;Bronchial Spasm;Bronchoconstriction;C Fiber;Cations;Chronic;Coughing;Data;Development;Devices;Disease;Exhibits;Exposure to;Extrinsic asthma;Humidifier;Hyperventilation;Inflammation;Inflammation Mediators;Inflammatory;Inhalation;Institutional Review Boards;Ion Channel;Ipratropium;Irritants;Kentucky;Laboratories;Lead;Ligands;Lung;Measures;Mediating;Membrane;Mucous Membrane;Names;Neurons;Pathogenicity;Patients;Persons;Physiological;Pilot Projects;Play;Property;Protocols documentation;Rattus;Reaction;Reflex action;Reporting;Research;Research Personnel;Respiratory Signs and Symptoms;Respiratory System;Risk;Role;Sensory;Sensory Nerve Endings;Series;Technology;Teleconferences;Temperature;Testing;Tissues;Training;Universities;Vanilloid;Wisconsin;afferent nerve;airway hyperresponsiveness;allergic airway inflammation;associated symptom;asthmatic;asthmatic airway;asthmatic patient;cholinergic;clinically relevant;constriction;defense response;design;disabling symptom;experience;human subject;insight;irritation;novel;novel therapeutic intervention;prevent;public health relevance;receptor;response;sensor;translational study

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Airway hypersensitivity characterized by symptoms of airway irritation cough and bronchospasm is a hallmark feature of airway inflammatory diseases. This study is designed to test a novel hypothesis that a specific ion channel named TRPV1 present in the airway sensory nerves plays an important role in the airway hypersensitivity found in patients with allergic asthma. Results of this translational study to be conducted in both asthmatic patients and pulmonary sensory neurons isolated from an animal model of asthma will help to advance the development of new therapeutic strategies for alleviating these debilitating symptoms.


application_id: 9390488
project_number: 5R01HL125228-04
project_title: Mineralocorticoid receptor and abdominal aortic aneurysm
administering_ic: NHLBI
award_notice_date: 2018-01-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 125228
program_official: OH, YOUNGSUK
project_start_date: 2014-11-15
project_end_date: 2019-10-31
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. Interestinglydenuding 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:
Abdomen;Abdominal Aortic Aneurysm;Acetates;Affect;Age;Agonist;Aldosterone;Animal Genetics;Animal Model;Aorta;Aortic Aneurysm;Attenuated;Basic Science;Biochemical;Cardiovascular Diseases;Cardiovascular system;Cell Membrane Permeability;Cessation of life;Clinic;Clinical;Country;Deoxycorticosterone;Diagnosis;Disease;Elastin;Endothelial Cells;Etiology;Free Radical Scavengers;Genetic Transcription;Goals;Heart failure;Hospitalization;Human;Hypertension;Intake;Kidney;Knockout Mice;Left Ventricular Hypertrophy;Link;MMP2 gene;MMP9 gene;Medial;Messenger RNA;Metalloproteases;Mineralocorticoid Receptor;Molecular;Mus;Myocardial Infarction;NADPH Oxidase;Operative Surgical Procedures;Oxidative Stress;Pathologic;Patients;Pharmaceutical Preparations;Plasma;Prevalence;Procedures;Role;Rupture;Ruptured Abdominal Aortic Aneurysm;Scheme;Smooth Muscle Myocytes;Sodium;Sodium Chloride;Spironolactone;Stress;Stroke;Tamoxifen;Testing;Time;Vascular Diseases;Withdrawal;Woman;abdominal aorta;age related;alpha Actin;clinical practice;diagnosis evaluation;effective therapy;eplerenone;insight;loss of function;male;men;mortality;mouse model;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;prevent;promoter;public health relevance;salt intake;tempol;vascular inflammation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Abdominal aortic aneurysm (AAA) is defined as a permanent localized dilations of aorta affect 4 to 8% of men and 0.5 to 1.5% of women over the age of 60 and account for about 2% of all deaths in Western countries. AAA is a vascular disease with rising prevalence and a high mortality rate (65% to 85%) related to AAA rupture. Currently surgery is the only option for treatment of AAA and no drug has been approved for the treatment of this devastating disease. The goals of this application are to elucidate the mechanisms responsible for AAA and thereby identify new therapeutic targets to develop new drugs to treat AAA.


application_id: 9390034
project_number: 5R01AT008617-03
project_title: Plant exosomes non-coding RNA-mediated anti-inflammatory mechanisms
administering_ic: NCCIH
award_notice_date: 2017-12-07
opportunity_number: PAR-13-375
application_type: 5
activity_code: R01
ic: AT
serial_number: 008617
program_official: WANG, YISONG
project_start_date: 2015-12-01
project_end_date: 2020-11-30
study_section: Special Emphasis Panel[ZRG1-EMNR-V(55)R]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
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): The overall goal of this proposal is to define the role of edible plant exosomal non-coding small RNA (nc-sRNA) in the prevention of gut inflammation using the dextran sulfate sodium (DSS) induced colitis and three other gut inflammatory related mouse models. Although evidence is supportive of the beneficial effects for most edible plants taken as part of the diet the evidence that specific plant-based supplements are beneficial is controversial and the underlying mechanisms are not clear. The challenge is to isolate and characterize the biological activities of the essential functional unit contained in specific naturl products to determine if and how it's cellular and molecular effects on the host can be used in a beneficial manner. Our recently published data (1-5) indicates that exosome-like nanoparticles (ELNs) present in a number of edible plants including grapefruit and ginger have anti-inflammatory properties. Mice fed grapefruit ELNs (FELNs) are protected against DSS induced mouse colitis. Up take of FELNs by intestinal macrophages inhibits the release of IL-1 and IL-6 and the induction of HO-1 and IL-10 expression. Our preliminary data further indicate that FELNs carry high levels of specific nc-sRNA that inhibit the induction of proinflammatory cytokines by targeting intestinal macrophages. The nc-sRNA is associated with inactivation of macrophage miR155. A specific FELN nc-sRNA complexed with naringin binds to miR155 and subsequently prevents miR155 binding to 3-UTRs of certain anti-inflammatory genes thus inhibiting the induction of proinflammatory cytokines. We have also demonstrated that ginger ELN nc-sRNAs promotes the production of IL-10 in lamina propria macrophages under steady-state as well as inflammatory conditions. Therefore we hypothesize that plant ELNs carrying the nc-sRNA bioactive complex are taken up by intestinal macrophages and subsequently bind to inflammatory microRNAs resulting in inhibition of induction of chronic inflammation cytokines thereby preventing chronic intestinal inflammation. Our hypothesis will be tested in vitro and in vivo to determine: (1) whether FELN taken up by intestinal macrophages leads to induction of tolerant dendritic cells (DCs) through nc-sRNA-155 mediated anti-inflammatory effects since DCs are critical for gut immune tolerance and homeostasis through cross-talk with intestinal macrophages; (2) the factors that regulate sorting of anti-inflammatory nc-sRNA-155 into macrophage exosomes; and (3) which ginger ELNs nc-sRNA(s) are required for induction of anti- inflammatory IL-10 expressed in macrophages. Demonstration of the ELNs complex targeting to gut inflammatory cells would be a significant step forward in the understanding of how the plant kingdom interacts with the mammalian species to regulate anti-inflammatory responses through ELNs. The data generated should provide a foundation for selecting specific ELNs from different types of plants for personalized complementary medicine for patients and determine whether oral administration of a customized exosome isolated from different plants will have a synergistic/additive effect on prevention or treatment of disease.

project_terms:
Anti-inflammatory;Antigens;Antiinflammatory Effect;Bacteria;Binding;Biological;Cells;Chronic;Colitis;Communication;Complementary Medicine;Complex;Crohn's disease;Custom;Data;Dendritic Cells;Diet;Disease;Edible Plants;Encapsulated;Escherichia;Escherichia coli;Exposure to;Food;Foundations;Genes;Ginger;Goals;Grapefruit;Gut Mucosa;Health;Homeostasis;Immune;Immune Tolerance;Immune response;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Inflammatory disease of the intestine;Interleukin-1;Interleukin-1 beta;Interleukin-10;Interleukin-6;Intestines;Investigation;Lamina Propria;Lipids;Literature;Macrophage Activation;Mediating;MicroRNAs;Modeling;Molecular;Mononuclear;Mus;Myeloid Cell Activation;Natural Products;Oral Administration;Pathway interactions;Patients;Phagocytes;Plant Extracts;Plants;Play;Prevention;Production;Property;Proteins;Publishing;RNA Binding;Role;Sampling;Signal Transduction;Small RNA;Sodium Dextran Sulfate;Sorting - Cell Movement;Study models;TNF gene;Testing;Untranslated RNA;Untranslated Regions;base;bioactive natural products;cytokine;exosome;experimental study;fruits and vegetables;gut bacteria;in vitro testing;in vivo;interspecies communication;lymph nodes;macrophage;mouse model;nanoparticle;prevent;public health relevance;transcription factor;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Although evidence is supportive of the beneficial effects for most edible plants taken as part of the diet molecule mechanisms underlying beneficial of edible plants and extracts for sustaining health is not clear. The studies that we have accomplished to date suggest that edible plant exosome-like nanoparticles encapsulated with non-coding small RNAs that binds to miRNAs prevent mouse colitis- standard mouse models for studying Crohn's disease. The focus of this application is to further characterize these mechanisms and then to determine whether targeting of these mechanisms is through communication with different subsets of miRNAs expressed in the intestinal macrophages and this will also allow for further investigations as to how interspecies communication takes place via plant derived exosomes.


application_id: 9388995
project_number: 5R01EY024051-04
project_title: The danger signals in autoimmune uveitis
administering_ic: NEI
award_notice_date: 2017-11-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: EY
serial_number: 024051
program_official: MCKIE, GEORGE ANN
project_start_date: 2014-12-01
project_end_date: 2020-11-30
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Autoimmune uveitis mediated by T cells is a major cause of blindness in the USA and worldwide particularly among relative young and working populations. Proposed studies will focus on the danger signals in pathogenesis of chronic autoimmune uveitis using a murine model induced by the adoptive transfer of interphotoreceptor retinoid-binding protein (IRBP)-specific T cells. Aims described in this proposal will examine the release of danger signals initiated by uveitogenic IRBP-specific T cells and the role of them in ocular inflammation. Aim 1 will determine the Fas/FasL signaling in rapid release of HMGB1 from viable retinal cells after interaction with IRBP-specific T cells. Aim 2 will examine the roleof HMGB1 in sustaining and promoting IRBP-specific T cell function during chronic intraocular inflammation. Results of these studies will further our understanding of the molecular pathogenesis of autoimmune uveitis and identify novel targets for anti-inflammatory intervention to limit visual loss.

project_terms:
Adoptive Transfer;Affect;Anti-inflammatory;Antigen-Presenting Cells;Antigens;Apoptotic;Astrocytes;Blindness;CD95 Antigens;Caspase;Cell Death;Cell physiology;Cells;Chronic;Disease;Eye;Frequencies;Functional disorder;Generations;Goals;HMGB1 gene;Human;Immunity;Inflammation;Inflammatory;Intervention;Local Therapy;MAPK14 gene;MAPK8 gene;Maintenance;Mediating;Memory;Molecular;Pathogenesis;Pathogenicity;Phenotype;Population;Proteins;Regulatory T-Lymphocyte;Resistance;Retinal;Role;Signal Transduction;Systemic Therapy;T memory cell;T-Lymphocyte;Testing;Th1 Cells;Therapeutic Intervention;Uveitis;Western World;autoimmune uveitis;autoreactive T cell;cell mediated immune response;chemokine;cytokine;experimental study;inhibitor/antagonist;interstitial retinol-binding protein;mouse model;novel;novel therapeutic intervention;public health relevance

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Autoimmune uveitis is a common ocular inflammation mediated by auto-reactive T cells. Despite a wide range of local and systemic therapies to treat this disease uveitis is still one of the leading causes of blindness in the Western world. Experiments described in this proposal will examine danger signals in the progress of T cell immunity in the eye. The long-term goal of proposed studies is to identify targets for interventional therapy for the disease.


application_id: 9388971
project_number: 5R00CA181500-05
project_title: The Role of Protein Tyrosine Phosphate PRL3 in Leukemia Development
administering_ic: NCI
award_notice_date: 2017-12-25
opportunity_number: PA-11-197
application_type: 5
activity_code: R00
ic: CA
serial_number: 181500
program_official: JHAPPAN, CHAMELLI
project_start_date: 2015-12-15
project_end_date: 2018-11-30
study_section: NSS
contact_pi_person_id: 10310607
contact_pi: BLACKBURN, JESSICA S.
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): The aggressive and unpredictable nature of relapsed T-cell acute lymphoblastic leukemia (T-ALL) represents a major clinical challenge in large part due to highly toxic and ineffective chemotherapies. Further advances in therapy will require a detailed understanding of the molecular underpinnings of T- ALL development and relapse. To this end I have completed a highly innovative screen in zebrafish to identify genes associated with T-ALL progression and have found that the protein tyrosine phosphotase PRL-3 was commonly amplified in single T-ALL cells as they developed increased ability to form relapse over time. In transgenic animals PRL-3 over-expression significantly enhanced primary T-ALL development and relapse formation. I have found that PRL-3 amplified in a subset of human T-ALL and is highly expressed by a majority of T-ALL patient samples. These cells are also sensitive to PRL-3 knock-down through the induction of apoptosis. These results imply that PRL-3 activity has an important role in T-ALL malignancy and that PRL-3 and its substrates may represent novel therapeutic targets for the treatment of T-ALL. The objectives of this proposal are to 1) define the contribution of PRL-3 to T- ALL progression and relapse and 2) identify the mechanism by which PRL-3 drives T-ALL malignancy. This objective will be achieved through two specific aims. During the K99 phase of this award I will complete Aim 1 where I will examine the effect of PRL-3 gain-of-function and loss-of-function in various stages of T-ALL development in zebrafish including invasion from the thymus intravasation proliferation and relapse and I will also test the effects of PRL-3 knock-down on human cells in a murine xenograft model. During this phase I will learn techniques to directly image cancer progression in live animals and to develop orthotopic leukemia xenografts in mice. With this knowledge in hand during the R00 phase I will complete Aim 2 where I will identify the target substrates of PRL-3 in T-ALL cells and test the contribution of these genes and pathways to T-ALL malignancy using in vivo and in vitro epistasis experiments. In total this work will lay the foundation for the development of small molecule PRL-3 and pathway inhibitors for potential therapeutic use in T-ALL. The mentored phase of this award will occur under the guidance of Dr. David Langenau an expert in zebrafish models of cancer and Dr. Thomas Look an internationally recognized leader in the field of leukemia research. Their proven track record of mentorship coupled with an intensive didactic component and the rigorous and nurturing academic environment offered by the research community of Massachusetts General Hospital and Harvard Medical School offer the best opportunity for my success as I transition to becoming an independent investigator.

project_terms:
Acute;Acute T Cell Leukemia;Adult;Adverse effects;Animals;Award;B-Cell Acute Leukemia;Behavior;Cancer Model;Cell Line;Cells;Chemotherapy-Oncologic Procedure;Child;Childhood;Chronic Myeloid Leukemia;Clinical;Clinical Treatment;Communities;Coupled;Data;Development;Drug Targeting;Environment;Foundations;General Hospitals;Genes;Genetic Epistasis;Goals;Hand;Human;In Vitro;Induction of Apoptosis;International;Knowledge;Learning;Malignant Neoplasms;Massachusetts;Mentors;Mentorship;Modeling;Molecular;Molecular Target;Multiple Myeloma;Mus;Nature;Oncogenes;Outcome;Pathway interactions;Patients;Phase;Phosphorylation;Play;Protein Tyrosine Phosphatase;Proteins;Relapse;Research;Research Personnel;Role;Sampling;Solid Neoplasm;Survival Rate;Techniques;Testing;Therapeutic;Therapeutic Uses;Thymus Gland;Time;Transgenic Animals;Tumor stage;Tyrosine;Work;Xenograft Model;Xenograft procedure;Zebrafish;base;cancer imaging;cancer type;chemotherapy;defined contribution;experimental study;gain of function;improved;in vivo;inhibitor/antagonist;innovation;inorganic phosphate;knock-down;leukemia;loss of function;medical schools;molecular targeted therapies;mortality;mouse model;new therapeutic target;novel;outcome forecast;overexpression;phosphoproteomics;preclinical trial;public health relevance;small molecule;small molecule inhibitor;success;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Relapse in the major cause of mortality in patients with T-cell acute lymphoblastic leukemia due to ineffective therapeutics. The protein tyrosine phosphotase PRL-3 is emerging as an important contributing oncogene in cancer progression. This proposal will define the mechanism by which PRL-3 drives T-ALL malignancy to identify novel molecular targets for the treatment of T-ALL.


application_id: 9386854
project_number: 1R21AI130756-01A1
project_title: Innate immune mechanisms regulating silicosis
administering_ic: NIAID
award_notice_date: 2017-06-02
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: AI
serial_number: 130756
suffix: A1
program_official: MINNICOZZI, MICHAEL
project_start_date: 2017-06-05
project_end_date: 2019-05-31
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 6074575
contact_pi: BODDULURI, HARIBABU
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
project_abstract:
ABSTRACT Exposure to irritant crystals such as crystalline silica (CS) induces inflammation of lungs leading tochronic irreversible disease-silicosis. Silicosis is incurable due to impaired particle clearance resulting in chroniclung inflammation and may eventually lead to many inflammatory diseases such as arthritis and lung cancer. CSexposure leads to recruitment of inflammatory cells to lungs of which neutrophils are key mediators of thepathophysiology of silicosis. Our results in mouse models showed that CS-induced pulmonary inflammation isattenuated in leukotriene B4 receptor1 (BLT1-/-) deficient. Extensive in vivo studies in CS exposed mice and exvivo studies in isolated bone marrow derived mast cells and macrophages suggested an intricate interplay ofmediators such as LTB4 IL-1 and neutrophil active chemokines regulate silicosis. Moreover our results suggestthat CS-induced LTB4 production by mast cells sets the pace of sterile neutrophilic inflammation in the lung. Suchinflammation is further perpetuated by IL-1 and CXC and CC neutrophil chemokines. The hypothesis of thisproposal is that CS-induced lipidosome and inflammasome pathways function in consort with chemokinesto coordinate sustained chronic sterile inflammation in silicosis. In the proposed research plan in twospecific aims we will perform studies to 1) delineate the molecular links between phagosome lipidosome andinflammasome pathways in regulating the CS-induced production of neutrophil chemoattractants (LTB4 IL-1 andCXCL1). Signaling intermediates unique to each of these pathways will be identified as they can serve as potentialdrug targets to block neutrophil recruitment into silicotic lungs. In aim2 we will identify the cellular mechanismsthat integrate the lipid/cytokine/chemokine (LTB4 IL-1 and CXCL1) responses into chronic inflammation in vivo.Select inhibitors of the leukotriene pathway will be tested for their efficacy in controlling CS-induced neutrophilicinflammation in preclinical mouse models. This knowledge will facilitate development of immunotherapeuticstrategies to fight silicosis.

project_terms:
Actins;Acute;Arthritis;Attenuated;Bone Marrow;Breathing;CCR;CXC Chemokines;CXCL1 gene;CXCR;Cells;Chemotactic Factors;Chronic;Chronic Disease;Chronic lung disease;Clinical Trials;Complex;Crystallization;Cytoskeleton;Data;Development;Disease;Dominant-Negative Mutation;Drug Targeting;Epithelial Cells;Exposure to;Fibrosis;Functional disorder;G-Protein-Coupled Receptors;Glass;Health;Immune;Immunotherapeutic agent;Impairment;Inflammasome;Inflammation;Inflammation Mediators;Inflammatory;Interleukin-1;Interleukin-1 beta;Irritants;Knockout Mice;Knowledge;LTB4R gene;Lead;Leukotriene B4;Leukotriene Production;Leukotrienes;Leukotrienes A;Link;Lipids;Lung;Lung Inflammation;Lung diseases;MAPK8 gene;Malignant neoplasm of lung;Mediating;Mediator of activation protein;Methods;Microscopy;Mining;Modeling;Molecular;Mus;Neutrophil Infiltration;Occupational;Pathway interactions;Phagocytosis;Phagosomes;Pharmacology;Phase;Production;Pulmonary Inflammation;Recruitment Activity;Research;Risk;Role;Signal Transduction;Silicon Dioxide;Silicosis;Small Interfering RNA;Sterility;Testing;base;beta-Chemokines;cell type;chemokine;chemokine receptor;crystallinity;cytokine;experimental study;fighting;in vivo;inhibitor/antagonist;knock-down;macrophage;mast cell;mouse model;neutrophil;novel strategies;novel therapeutic intervention;overexpression;particle;pre-clinical;rab GTP-Binding Proteins;response;treatment choice;uptake

public_health_relevance:
PROJECT NARRATIVE Chronic exposure of crystalline silica (CS) often encountered in occupational settings such asconstruction mining glass and concrete production is a worldwide problem with tens of millions of people at risk.Such exposure is well known to induce lung inflammation and eventually causes an incurable irreversibledisease of lung-silicosis. Silicosis has now been shown to promote many inflammatory diseases includingarthritis and lung cancer. The research proposed in this project will identify the molecular and cellular basis forCS-mediated lung inflammation in mouse models. These studies will lead to new approaches to treat silicosis.


application_id: 9385122
project_number: 3R01GM113087-02S3
project_title: Deciphering the molecular mechanisms underlying active scaffolding
administering_ic: NIGMS
award_notice_date: 2017-01-13
opportunity_number: PA-16-289
application_type: 3
activity_code: R01
ic: GM
serial_number: 113087
suffix: S3
program_official: DUNSMORE, SARAH
project_start_date: 2015-08-01
project_end_date: 2020-05-31
contact_pi_person_id: 8586925
contact_pi: GALPERIN, EMILIA
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): The extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway plays an essential role in several critical steps of embryonic development and tumor progression. It also controls critical cellular functions such as apoptosis motility and differentiation. Kinases and phosphatases of this pathway have been extensively studied and targeted therapeutically. However the mechanisms that determine the signal specificity and orchestrate the diverse biological outcomes of ERK1/2 signaling are still poorly understood. Scaffold proteins are key players in the ERK1/2 signaling pathway that are thought to integrate incoming signals and deliver signaling specificity and yet their role in signal propagation and the mechanisms of their action are still unknown. The long-term goal of our research is to reveal how scaffold proteins are involved in the biological processes regulated by the ERK1/2 cascade. In this way new therapeutic strategies can be developed to more specifically target this cascade without affecting other essential biological functions.  The objective of this proposal is to determine the mechanisms underlying the ability of the key scaffold protein Shoc2 to regulate ERK1/2-mediated cell motility. Shoc2 is essential for embryonic development and a critical regulator of ERK1/2 activity. We have shown that depletion of Shoc2 in zebrafish results in defects in hematopoiesis. We also found that Shoc2 integrates endocytic and ubiquitin machineries to regulate ERK1/2 signaling. Based on this preliminary data the central hypothesis of this proposal is that Shoc2 creates a signaling hub that regulates ERK's developmental signals in a spatio-temporal manner.  Our hypothesis will be tested by pursuing three specific aims: Aim 1 will determine the spatio-temporal organization and dynamics of Shoc2 scaffold complexes. Aim 2 will reveal the molecular mechanism by which the E3 ligase HUWE1 controls Shoc2 function and assembly of the Shoc2 scaffold complexes. Aim 3 will determine the signaling events mediated through the Shoc2 scaffold complexes that control embryonic development. The proposed Aims therefore are expected to provide a detailed understanding of how Shoc2 is involved in determining the specificity of ERK1/2 signaling outcomes. These studies will employ state-of-the-art innovative microscopy genetic molecular and cellular techniques and will provide critical insights into our understanding of the spatial-temporal control of signaling by scaffold proteins. This research has significance for contributing to the advancement of novel therapeutic strategies and biomarker innovations for developmental disorders and cancer progression. Thus the proposed studies are relevant to the NIH's mission to increase understanding of biological processes and to lay the foundation for advances in disease diagnosis treatment and prevention.

project_terms:
Address;Affect;Apoptosis;Biochemical;Biological;Biological Markers;Biological Process;Blood;Cell Adhesion;Cell membrane;Cell model;Cell physiology;Cells;Cognitive deficits;Complex;Cultured Cells;Data;Defect;Development;Disease;Effectiveness;Embryo;Embryonic Development;Endocytosis;Endosomes;Ensure;Event;Face;Fluorescence Resonance Energy Transfer;Foundations;Genetic;Genetic Models;Goals;Growth;Heart Abnormalities;Hematopoiesis;Hematopoietic;Income;Lead;Link;MAP Kinase Gene;MAPK3 gene;MEKs;Mediating;Microscopy;Mission;Modeling;Molecular;Mus;Mutation;Outcome;Pathology;Pathway interactions;Phosphoric Monoester Hydrolases;Phosphotransferases;Physiological;Play;Prevention;Prognostic Marker;Protein Biochemistry;Proto-Oncogene Proteins c-raf;Ras/Raf;Regulation;Research;Role;Scaffolding Protein;Signal Pathway;Signal Transduction;Spatial Distribution;Specificity;Study models;System;Techniques;Testing;Ubiquitin;Ubiquitination;United States National Institutes of Health;Work;Zebrafish;base;cell motility;cellular transduction;chromophore;developmental disease/disorder;disease diagnosis;imaging approach;imaging study;in vivo;innovation;insight;novel;novel therapeutic intervention;novel therapeutics;public health relevance;scaffold;spatiotemporal;targeted treatment;therapeutic development;transmission process;tumor;tumor progression;ubiquitin-protein ligase;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Deregulation of the MAPK signaling cascade is found in 30% of all tumors and multiple cardiac abnormalities and virtually every component of the cascade is target for therapeutic development. The effective targeting of this pathway in disease relies upon a clear understanding of all the intricacies in modulating numerous signaling components. Understanding the molecular mechanisms underlying the role of Shoc2 in MAPK signaling propagation potentially may lead to the development of specific prognostic markers and will enhance the effectiveness of targeted treatment.


application_id: 9385034
project_number: 1R21AI128206-01A1
project_title: Intestinal epithelial cells-derived exosomal miRNAs regulate liver inflammation in obesity
administering_ic: NIAID
award_notice_date: 2017-07-03
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: AI
serial_number: 128206
suffix: A1
program_official: ROTHERMEL, ANNETTE L
project_start_date: 2017-07-14
project_end_date: 2019-06-30
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 11629370
contact_pi: DENG, ZHONG-BIN
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
project_abstract:
The overarching theme of this project is to explore the mechanisms that lead to liver inflammation/injury in obesity.We will focus on extracellular miRNAs of intestinal epithelial cells (IECs) and macrophages. Specifically we willexamine how polyunsaturated fatty acids mediated-intestinal inflammation stimulates the production ofextracellular miRNAs from IECs and the consequences of these events. Novel in vitro and in vivo approacheswill be used to address mechanisms of action with the goal of identifying new targets for intervention. Wepropose that dietary n-6 polyunsaturated fatty acids (n-6 PUFAs) promote liver inflammation and injuryvia IEC-derived exosomes. We specifically propose that Stat3-activated extracellular miRNAs are the keyto the accumulation/polarization of macrophages in liver in obese mice. Based on our published work andother preliminary data this proposal will test the hypothesis that the n-6 PUFAs regulate the production ofextracellular miRNAs from intestinal epithelial cells through Stat3 signaling which initiates a crosstalk amongmacrophages NK cells and hepatocytes in liver. Moreover we will determine whether diet fat-associatednanoparticles carrying miR-155 inhibitor have potential therapeutic implications in obesity. These hypotheseswill be tested in the following Specific Aims: Aim 1: Determine whether IEC-derived extracellular miRNAsregulated by the n-6 PUFAs/Stat3 pathway are specific mediators of NFALD development andprogression. Aim 2: Determine whether alteration of IEC miRNAs via STAT3 modulation affects theseverity of HFD-induced liver inflammation and injury in obesity. Following the successful completion of theabove Specific Aims our novel studies will (i) validate Stat3-activated extracellular miRNAs is directly relevantto the accumulation/polarization of hepatic macrophages in obesity and (ii) provide a foundation for futuremechanistic investigation of the regulation of diet fat and extracellular miRNA in obesity therapy.

project_terms:
Address;Affect;Automobile Driving;Cell physiology;Cells;Chronic;Colitis;Colon Carcinoma;Consumption;Data;Development;Diet;Dietary Supplementation;Distant;Eicosapentaenoic Acid;Encapsulated;Epithelial;Epithelial Cells;Event;Fatty acid glycerol esters;Foundations;Future;Goals;Hepatic;Hepatocyte;High Fat Diet;Hypoxia;Immune;Immune signaling;Impairment;In Vitro;Infiltration;Inflammation;Inflammatory;Inflammatory disease of the intestine;Injury;Intervention;Intestines;Investigation;Lead;Link;Linoleic Acids;Liver;Mediating;Mediator of activation protein;MicroRNAs;Modeling;Molecular;Mucins;Mucous Membrane;N-3 polyunsaturated fatty acid;Natural Killer Cells;Nonesterified Fatty Acids;Obese Mice;Obesity;Pathogenicity;Pathway interactions;Patients;Permeability;Play;Polyunsaturated Fatty Acids;Production;Property;Proteins;Publishing;Recruitment Activity;Regulation;Role;STAT3 gene;Severities;Signal Transduction;Testing;Therapeutic;Therapeutic Intervention;Tumor Angiogenesis;Ulcer;Ulcerative Colitis;Up-Regulation;Work;antimicrobial;base;exosome;extracellular;gastrointestinal epithelium;in vivo;inhibitor/antagonist;interest;liver development;liver inflammation;liver injury;macrophage;migration;nanoparticle;nanovesicle;non-alcoholic fatty liver;novel;nutrition;octadecadienoic acid;overexpression;prevent;translational study

public_health_relevance:
Project NarrativeThis proposal underscores the importance of investigating Stat3-activated extracellular miRNAs as a criticalIECs-derived factor for the development of nonalcoholic fatty liver diseases by regulating the function of hepaticmacrophages. We anticipate that we can abrogate their local and/or distant activities by targeting gutextracellular miRNAs.


application_id: 9383979
project_number: 2R01AG026307-11
project_title: Self-Regulation and Brain and Cognitive Health in Older Adults
administering_ic: NIA
award_notice_date: 2017-08-17
opportunity_number: PA-16-160
application_type: 2
activity_code: R01
ic: AG
serial_number: 026307
program_official: NIELSEN, LISBETH
project_start_date: 2006-07-15
project_end_date: 2022-03-31
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
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:
SummaryThe typical older adult experiences declines in brain structure and cognitive function but these mean declinesoccur in the context of what can be very different individual trajectories. The purpose of this project is tomeasure individual differences and changes in self-regulation (control of thoughts emotions behaviors andimpulses) over time in older adults and to link self-regulation to physical activity inflammation and trajectoriesof neurocognitive health. This is a competing renewal of this longitudinal study which began in 2001 andreceived R01 funding in 2006 submitted by a research team with expertise in aging self-regulation exercisescience neuropsychology neuroimaging and longitudinal design and analysis. The previous renewal periodfocused on relationships among facets of self-regulation and their relationship to immunological andcardiovascular health. The renewal continues assessment of these measures to provide continuity in thislongitudinal dataset and adds innovation in the inclusion of repeated neuroimaging and assessment ofinfectious disease burden. Specifically the aims of the study are: (1) to test the effects of facets of self-regulation (conscientiousness self-regulation executive cognitive function and heart rate variability) onmeasures of neurocognitive health associated with aging and risk for neurological disease; (2) to test thedegree to which the relationship between self-regulation and neurocognitive health is mediated by physicalactivity and inflammation; (3) to test whether neurocognitive health associated with executive cognitivefunctions (e.g. dorsolateral frontal lobe volume) contributes to better self-regulation higher physical activityand lower inflammation; and (4) to test effects of infectious disease burden (latent viruses Toxoplasma gondii)on self-regulation inflammation and neurocognitive health. At 6-month intervals older adults (N = 175) willcomplete measures of self-reported self-regulation; executive cognitive functions including inhibition shiftingand working memory; and resting HRV. Physical activity BMI and waist circumference will be measured ateach visit. Blood draws will be synchronized with these visits and assays performed on these samples willcapture serum proinflammatory cytokines and antibodies against latent infections. The sample has follow-backdata on many of these measures from 1-15 years and an eligible subset (N = 90) will already have baselineneuroimaging. Neuroimaging will be repeated twice at 2-year intervals. This renewal will be innovative in itslongitudinal assessment of a dynamic system that includes brain behavior and immunity; integration ofneuroimaging measures with other domains of healthy and unhealthy aging; and multimodal assessment ofneurocognitive health including subjective cognitive health cognitive function volumetric imaging measuresconnectivity fractional anisotropy and resting cerebral blood flow.

project_terms:
Adult;Affect;Age;Aging;Alzheimer's disease risk;Anisotropy;Antibodies;Back;Behavior;Biological Assay;Blood;Brain;Cerebrovascular Circulation;Cognition;Cognitive;Communicable Diseases;Cytomegalovirus;Data;Dementia;Elderly;Eligibility Determination;Emotions;Episodic memory;Exercise;Failure;Funding;Goals;Health;Hippocampus (Brain);Image;Immunity;Immunologic Factors;Impaired cognition;Individual;Individual Differences;Infection;Inflammation;Informal Social Control;Knowledge;Latent Virus;Link;Longevity;Longitudinal Studies;Longitudinal cohort;Maintenance;Measures;Mediating;Mental Health;Motivation;Neurocognitive;Neuropsychology;Outcome;Parasites;Pathway interactions;Patient Self-Report;Physical activity;Prefrontal Cortex;Psychological Factors;Psychoneuroimmunology;Research;Rest;Risk;Risk Factors;Role;Sampling;Science;Serum;Short-Term Memory;Structure;Testing;Time;Toxoplasma gondii;Virus Latency;Visit;brain behavior;brain health;burden of illness;cardiovascular health;cognitive function;cohort;cytokine;dynamic system;executive function;experience;frontal lobe;heart rate variability;immune health;inflammatory marker;innovation;interest;latent infection;longitudinal analysis;longitudinal dataset;longitudinal design;multimodality;nervous system disorder;neuroimaging;physical conditioning;prospective;success;thought control;waist circumference


application_id: 9383876
project_number: 1R01AG054459-01A1
project_title: Multi-Modal MRI to Assess Alzheimer's Disease Prevention in an APOE4 Mouse Model
administering_ic: NIA
award_notice_date: 2017-06-30
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: AG
serial_number: 054459
suffix: A1
program_official: WAGSTER, MOLLY V
project_start_date: 2017-07-01
project_end_date: 2022-04-30
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 10518078
contact_pi: LIN, AI-LING
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
project_terms:
Aftercare;Alleles;Alzheimer disease prevention;Alzheimer's Disease;Amyloid beta-Protein;Animal Model;Animals;Apolipoproteins;Biochemical;Biological Assay;Blood - brain barrier anatomy;Blood Vessels;Brain;Cerebrovascular Circulation;Clinical Trials;Cognitive;Dementia;Development;Diet;Dietary Intervention;Disease Progression;Early Intervention;Effectiveness;FDA approved;FRAP1 gene;Functional disorder;Future;Genes;Goals;Human;Impaired cognition;Impairment;Inflammation;Intervention;Magnetic Resonance Imaging;Measurement;Memory;Metabolic;Methods;Mitochondria;Modality;Modeling;Molecular;Mus;Mutation;Myelin;Neurodegenerative Disorders;Neurons;Oligodendroglia;Pathology;Pharmacology;Public Health;Radial;Reporting;Research;Sirolimus;Surrogate Markers;Synapses;Technology;Testing;Therapeutic Uses;Transgenic Mice;Translating;Treatment Efficacy;Validation;Water;abeta accumulation;age related;arm;base;behavior test;behavioral outcome;brain tissue;cerebrovascular;cognitive function;cohort;density;familial Alzheimer disease;feeding;flexibility;genetic risk factor;glucose metabolism;gray matter;imaging study;improved;in vivo;inhibitor/antagonist;innovation;mouse development;mouse model;multidisciplinary;multimodality;nanoparticle;neuroimaging;neuroinflammation;neuropathology;neurovascular;new technology;novel;object recognition;outcome prediction;overexpression;prevent;tau aggregation;time use;tool;white matter


application_id: 9383524
project_number: 1R01HL135000-01A1
project_title: Role of myocyte Na+ dysregulation in diabetic heart disease
administering_ic: NHLBI
award_notice_date: 2017-07-19
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: HL
serial_number: 135000
suffix: A1
program_official: BUXTON, DENIS B
project_start_date: 2017-08-01
project_end_date: 2021-07-31
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 9983033
contact_pi: DESPA, SANDA
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
project_terms:
5'-AMP-activated protein kinase;Animal Model;Animals;Arrhythmia;Automobile Driving;Biochemistry;Blood Vessels;Cardiac;Cardiomyopathies;Death Sudden Cardiac;Diabetes Mellitus;Electric Stimulation;Electrophysiology (science);Event;Genes;Glucose;Heart;Heart Diseases;Heart failure;Homeostasis;Human;Hyperglycemia;Hypertrophy;Impairment;Individual;Insulin;Insulin Resistance;Kidney;Left Ventricular Dysfunction;Link;Maintenance;Mediating;Messenger RNA;Mitochondria;Modeling;Mus;Muscle Cells;Mutation;Myocardial;Myocardial dysfunction;Myocardium;Na(+)-K(+)-Exchanging ATPase;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oxidative Stress;Pathology;Patients;Pharmacology;Phase;Physiological;Prediabetes syndrome;Protein Isoforms;Proteins;Rattus;Regulation;Rest;Risk;Role;Sarcoplasmic Reticulum;Structure;Testing;Thinness;Tissues;Transgenic Animals;Transgenic Mice;Translating;Up-Regulation;Work;base;db/db mouse;diabetic;diabetic cardiomyopathy;experimental study;fluorescence imaging;glucose uptake;heart function;improved;in vivo;injured;insulin sensitizing drugs;insulin signaling;new therapeutic target;non-diabetic;overexpression;prevent;tool


application_id: 9383428
project_number: 1R01DK112136-01A1
project_title: Community to Clinic Navigation to Improve Diabetes Outcomes
administering_ic: NIDDK
award_notice_date: 2017-07-04
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: DK
serial_number: 112136
suffix: A1
program_official: THORNTON, PAMELA L
project_start_date: 2017-08-01
project_end_date: 2022-07-31
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
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
project_terms:
Address;Affect;American;Appalachian Region;Area;Biometry;Blood Pressure;Church;Clinic;Clinical;Communities;Community Health Aides;Complications of Diabetes Mellitus;Data;Diabetes Mellitus;Diagnosis;Education;Environment;Epidemic;Evidence based intervention;Focus Groups;Future;Glycosylated hemoglobin A;Goals;Health;Health Professional;Health care facility;Healthcare;Individual;Influentials;Intervention;Interview;Kentucky;Lipids;Low income;Mediator of activation protein;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Participant;Patients;Persons;Pilot Projects;Population;Positioning Attribute;Protocols documentation;Randomized;Randomized Controlled Trials;Recruitment Activity;Research;Research Activity;Rural;Rural Population;Self Management;Social support;Talents;Testing;Training;Vulnerable Populations;Work;adverse outcome;arm;base;behavioral outcome;clinical care;community center;community setting;cost effectiveness;design;diabetes control;evidence base;glycemic control;health care quality;health care service organization;health disparity;improved;improved outcome;innovation;low socioeconomic status;meetings;member;outreach;primary outcome;programs;randomized trial;relative cost;satisfaction;social;theories;waist circumference


application_id: 9382846
project_number: 5R01AI065530-13
project_title: Type III exported effectors of Chlamydia trachomatis
administering_ic: NIAID
award_notice_date: 2017-10-24
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 065530
program_official: VINCENT, LEAH REBECCA
project_start_date: 2005-06-01
project_end_date: 2021-10-31
study_section: Special Emphasis Panel[ZRG1-IDM-R(02)M]
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_terms:
Acute Disease;Address;Alleles;Animal Model;Animals;Attenuated;Biochemical;Biological Assay;Cell physiology;Cells;Cellular biology;Chlamydia;Chlamydia Infections;Chlamydia trachomatis;Chronic Disease;Communities;Data;Defect;Development;Disease;Epithelial Cells;Event;Fluorescence;Funding;Genes;Genetic;Goals;Grant;Health;Human;Individual;Infection;Infection prevention;Integration Host Factors;Lead;Maintenance;Mediating;Membrane;Methods;Microbiology;Modeling;Molecular;Mus;Mutagenesis;Pathogenesis;Pathology;Pathway interactions;Phenotype;Physiological;Prevalence;Process;Proteins;Proteome;Reporting;Role;Science;Sexually Transmitted Agents;Sexually Transmitted Diseases;Techniques;Testing;Time;Type III Secretion System Pathway;United States;Vacuole;Virulence;Work;base;comparative;design;genetic manipulation;member;mutant;novel;novel therapeutic intervention;null mutation;obligate intracellular parasite;pathogen;recruit;socioeconomics;success;suicide vector;tissue culture


application_id: 9382500
project_number: 1R35GM124977-01
project_title: Probing cellular intracellular calcium signaling and sensing through computation
administering_ic: NIGMS
award_notice_date: 2017-07-24
opportunity_number: RFA-GM-17-004
application_type: 1
activity_code: R35
ic: GM
serial_number: 124977
program_official: RESAT, HALUK
project_start_date: 2017-08-01
project_end_date: 2022-07-31
study_section: Special Emphasis Panel[ZRG1 CB-M (50)]
contact_pi_person_id: 10445272
contact_pi: KEKENES-HUSKEY, PETER MICHAEL
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
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:
2+Intracellular Ca signaling Kekenes-Huskey PM. University of KentuckyProbing cellular intracellular calcium signaling and sensing throughcomputation Calcium signaling regulates biological function across a broad range of tissue types and species2+but several factors known to control Ca -dependent signaling efciency have challenged both compu-tational and experimental inquiry. There are signicant gaps in our understanding of how nuances inprotein structure and dynamics as well as their intracellular distribution affect fundamentally important2+processes including how 1) Ca accumulates within localized intracellular regions 2) proteins bind2+ 2+Ca with high afnity 3) Ca 'sensor' proteins regulate signaling cascades. Detailed knowledge aboutthese topics and their inter-dependencies would yield new paradigms in how we view biology physiologyand health. Computer simulations are attractive in this regard both for describing phenomena that aredifcult to directly resolve experimentally as well as forming integrative conceptual models spanningthese underlying topics. However several prominent hurdles render such transformative simulationscost-prohibitive. Among these reducing the intractable computational expense involved with model-ing ne detail processes like transport governed by sub-nanometer to micron scales atomistic-scalethermodynamic factors shaping ion/protein binding and long-range forces that promote protein/proteinsignaling pathways is likely the foremost challenge in biophysics today. In this proposal we outline sev-eral multi-scale algorithmic advances that will ease this challenge while providing insight into important2+Ca -driven processes that orchestrate life: Theme 1 Tuning Ca2+ sensing and response at the molecular level. In this theme we will develop new paradigms for understanding nature's tricks for controlling specicity and kinetics in2+ Ca sensing functions. Theme 2 Automated detection of disease-associated morphological changes in cardiac2+ cells and their inuence on Ca homeostasis. In this theme our lab will leverage troves of underutilized microscopy data to answer questions regarding the role of intracellular organization2+ in shaping Ca signaling. Theme 3 Molecular mechanisms of cellular-scale control via the P2X4 receptor. In thistheme we will establish strong links between molecular scale protein structure/function and theircontrol of cellular-scale signaling outcomes.1

project_terms:
Affect;Affinity;Algorithms;Binding Proteins;Biological Process;Biology;Biophysics;Calcium Signaling;Cardiac;Cell physiology;Cells;Computer Simulation;Data;Dependency;Detection;Disease;Functional disorder;Health;Homeostasis;Immune response;Ions;Kentucky;Kinetics;Knowledge;Lead;Life;Link;Malignant Neoplasms;Microscopy;Modeling;Molecular;Morphology;Motivation;Muscle Contraction;Nature;Nervous System Physiology;Outcome;Physiology;Process;Protein Dynamics;Proteins;Role;Shapes;Signal Pathway;Signal Transduction;Signaling Protein;Specificity;Thermodynamics;Tissues;Universities;combat;computerized tools;cost;hormone regulation;human disease;innovation;insight;molecular scale;nanometer;novel;novel strategies;protein structure;protein structure function;receptor;response;sensor;simulation

public_health_relevance:
2+Intracellular Ca signaling Kekenes-Huskey PM. University of KentuckyThe key innovation in this proposal are novel computational tools to integrate molecular details of2+Ca handling into whole-cell cellular physiology as well as specic hypotheses examining aspects2+of molecular through cellular control of Ca -dependent function. These innovations are directly2+relevant to human disease given the pervasive role of Ca in orchestrating cellular physiology andpathophysiology including muscle contraction neurological function immune responses hormoneregulation and cancer. Successful completion of these studies would lead to new insight into how2+Ca signaling is modulated at the subcellular level which affords new insight and motivation to novelstrategies to combat human disease.2


application_id: 9382367
project_number: 1R01NS092680-01A1
project_title: ER Ca2+ store mediated white matter injury
administering_ic: NINDS
award_notice_date: 2017-05-01
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: NS
serial_number: 092680
suffix: A1
program_official: JAKEMAN, LYN B
project_start_date: 2017-05-01
project_end_date: 2022-01-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 11601659
contact_pi: STIRLING, DAVID PAUL
other_pis: Not Applicable
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
project_terms:
AVIL gene;Area;Atrophic;Axon;Behavioral;Binding Proteins;Calcium;Data;Degenerative Disorder;Distal;Dyes;Electron Microscopy;Elements;Event;FDA approved;Fiber;Gait;Generations;Goals;Human;ITPR1 gene;Image;Imagery;Imaging Techniques;Injury;Inositol;Intervention;Kainic Acid Receptors;Knockout Mice;Mediating;Microscopy;Modeling;Molecular;Morphology;Multiple Sclerosis;Mus;Myelin;Nature;Neurologic Deficit;Pathologic;Pathology;Patients;Pharmacology;Process;Recovery;Recovery of Function;Reproducibility;Research;Reticulum;Role;Ryanodine Receptors;Secondary to;Signal Pathway;Signal Transduction;Site;Spinal;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Swelling;System;Technology;Testing;Therapeutic;Time;Transgenic Mice;Wallerian Degeneration;Work;axonal degeneration;carvedilol;clinically relevant;effective therapy;functional outcomes;genetic approach;improved;in vivo;injured;innovation;kinematics;lipophilicity;loss of function;nervous system disorder;neurological recovery;new therapeutic target;novel;novel therapeutics;oxidation;prevent;receptor;spinal tract;stroke;two-photon;white matter;white matter injury


application_id: 9381114
project_number: 1R01GM121796-01A1
project_title: Mechanism of adrenal insufficiency as a risk factor for sepsis
administering_ic: NIGMS
award_notice_date: 2017-08-08
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: GM
serial_number: 121796
suffix: A1
program_official: DUNSMORE, SARAH
project_start_date: 2017-09-01
project_end_date: 2021-08-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
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_terms:
Address;Adrenal Cortex;Adrenal Glands;Adrenal gland hypofunction;Animal Model;Binding;Cessation of life;Corticotropin;Data;Effector Cell;Glucocorticoids;Goals;Grant;Health;High Density Lipoprotein Cholesterol;Immune;Individual;Infection;Inflammatory;Inflammatory Response;Knockout Mice;Knowledge;Laboratories;Ligation;Mediating;Mitogen-Activated Protein Kinases;Modeling;Molecular;Mus;Pathogenesis;Pathway interactions;Patients;Positioning Attribute;Production;Puncture procedure;Regulation;Reporting;Risk Factors;SR-BI receptor;Sepsis;Septic Shock;Signal Transduction;Stress;Subgroup;Supplementation;TIS11 protein;Testing;Time;Toll-like receptors;Translations;Up-Regulation;base;clinical translation;cytokine;high density lipoprotein receptor;improved;in vivo;insight;mortality;multidisciplinary;novel;phosphatase-1 kinase;preclinical study;response;septic;uptake


application_id: 9380331
project_number: 5R01DC014468-03
project_title: In vivo patterns of receptor activation by odorants
administering_ic: NIDCD
award_notice_date: 2017-11-13
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DC
serial_number: 014468
program_official: SULLIVAN, SUSAN L
project_start_date: 2015-12-01
project_end_date: 2020-11-30
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
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 uses a new in vivo assay that allows the identification of the odorant receptors activated in live mice by any odor making it possible to identify in one experiment many receptors activated by the odor. This accelerates the identification of receptors sensitive to any odor and when combined with in vitro assays for the function of individual odorant receptors allows testing of hypotheses about the sets of receptors activated by odorants and odor mixtures. The first aim targets a specific region of the broad universe of odorants testing whether the overlap in sets of receptors responsive to these odorants depends on their structural similarity. The second aim tests hypotheses about the possible interactions between odorants at odorant receptors. It begins with pairs of odorants that are known or suspected of interacting mostly by the ability of one odorant to block activation of one or more receptors by another odorant. It then moves on to testing more complex mixtures seeking to identify interactive effects between odorants at receptors - effects that are fundamental to the characteristic sensation of the odor and the discrimination of one odor from another. In addition to improving our understanding of the mechanisms of odor perception these experiments provide knowledge expected to facilitate the development of more sophisticated ways of manipulating odor environments to benefit the quality of human life.

project_terms:
Alcohols;Biological Assay;Breathing;Carboxylic Acids;Characteristics;Chemicals;Code;Color;Complex;Complex Mixtures;Data;Detection;Development;Discrimination;Environment;Esthesia;Face;Hearing;Human;Individual;Ketones;Knowledge;Lead;Learning;Life;Ligands;Mammals;Mus;Nature;Odorant Receptors;Odors;Pattern;Perception;Pest Control;Pharmacology;Prevalence;Problem Solving;Receptor Activation;Receptor Cell;Smell Perception;Testing;Time;Vision;experimental study;improved;in vitro Assay;in vivo;novel strategies;public health relevance;receptor;sensor;stem;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE  The array of sensors for odors is composed of hundreds of distinct odorant receptors in most mammals but which of these receptors respond to the thousands of odor chemicals is virtually unknown making it difficult to understand how we detect and discriminate odors. This project uses a newly developed novel strategy to identify the sets of receptors responsive to any odor we choose to test. This information will help us understand how we discriminate odors as well as lay the groundwork for developing pharmacological agents for altering odor detection a direction that should lead to improved flavors and fragrances blockers of noxious smells and even improved pest control.


application_id: 9379841
project_number: 5R13AI129382-02
project_title: Autumn Immunology Conference
administering_ic: NIAID
award_notice_date: 2017-10-25
opportunity_number: PA-13-347
application_type: 5
activity_code: R13
ic: AI
serial_number: 129382
program_official: MILLER, LARA R
project_start_date: 2016-11-01
project_end_date: 2018-10-31
study_section: ZAI1-TC-M(S2)
contact_pi_person_id: 1864845
contact_pi: SNOW, ERNEST CHARLES
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:
This proposal requests funds to support the annual Autumn ImmunologyConference (AIC). The AIC was established in 1972 to promote Immunologyresearch in the upper Midwest region of the United States. The conferenceprovides a forum for the exchange of scientific data and ideas fosterscollaboration between scientists at different institutions and provides careerdevelopment and education opportunities to a diverse group of individuals withan interest in Immunology. The scientific focus of the meeting is intentionally broad; itincludes basic Immunology and related biomedical fields such as cancer biologypathogenesis vaccine development inflammation and autoimmunity. Special emphasisis given to providing pre- and post-doctoral trainees with an opportunity to sharetheir data participate in scientific and career discussions and to meet andexchange ideas with established investigators. The organizers also seek to attractinvolve and promote the careers of women and racial/ethnic minorities that areunderrepresented in science. These objectives are met by inviting a group ofoutstanding Immunology researchers (12-13 each year) from around the world to speakat the meeting. All presenters present both an oral and poster presentation in sessionsthat are designed to provide the greatest opportunity for feedback to the trainees.Finally scholarship programs career development workshops and mentoringluncheons promote the inclusion of minority scientists and seek to recruitundergraduates into the discipline of Immunology.

project_terms:
Address;Allergic Disease;Applied Research;Autoimmunity;Award;Basic Science;Cancer Biology;Collaborations;Communicable Diseases;Data;Discipline;Education;Educational workshop;Equilibrium;Feedback;Fostering;Funding;Gender;Goals;Grant;Immune System Diseases;Immunology;Individual;Inflammation;Institution;Mentors;Midwestern United States;National Institute of Allergy and Infectious Disease;Oral;Participant;Pathogenesis;Postdoctoral Fellow;Preparation;Request for Applications;Request for Proposals;Research;Research Personnel;Scholarship;Science;Scientist;Travel;Underrepresented Minority;United States;United States National Institutes of Health;Vendor;Woman;career;career development;design;interest;meetings;minority scientist;posters;pre-doctoral;prevent;programs;racial and ethnic;recruit;symposium;undergraduate student;vaccine development

public_health_relevance:
Project NarrativeThis application requests funding for an annual scientific conference called theAutumn Immunology Conference. The purpose of this meeting is to exchangeand disseminate information and to explore contemporary problems in the fieldof Immunology. Thus it is consistent with the fiscal and programmatic priorities ofthe National Institutes of Allergy and Infectious Diseases (NIAID) which is toconduct and support basic and applied research to better understand treat andultimately prevent infectious immunologic and allergic diseases.


application_id: 9378531
project_number: 1R01AG056998-01
project_title: Preclinical evaluation of tacrolimus in a canine model of Alzheimer's disease
administering_ic: NIA
award_notice_date: 2017-09-05
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: AG
serial_number: 056998
program_official: REFOLO, LORENZO
project_start_date: 2017-09-15
project_end_date: 2022-05-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 8662513
contact_pi: HEAD, ELIZABETH
other_pis: NORRIS, CHRISTOPHER MARK
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_abstract:
7. Project Summary/AbstractThis project uses aging beagles and a longitudinal treatment design to test the potential of a calcineurin (CN)inhibiting strategy in Alzheimer's disease (AD). Beagles are metabolically similar to humans and spontaneouslydevelop amyloid- (A) deposition with advanced age. Consequently the aging beagle model has shownexceptional predictive validity in regard to several high-profile anti-AD drug trials. The molecular target of ourtreatment strategy CN has recently emerged as a key mechanism for AD pathophysiology. Signs of CNhyperactivity are found during early stages of cognitive decline in humans and in mouse models of AD. Studiesacross numerous laboratories using a variety of experimental models suggest that CN activity is bothnecessary and sufficient for the progression of key AD biobehavioral markers including A depositionneurodegeneration neuroinflammation/glial activation synapse dysfunction and cognitive loss. To inhibit CNwe will use tacrolimus an FDA-approved drug for the prophylaxis of allograft rejection and a second linetreatment for numerous immune/inflammatory disorders. In animal models tacrolimus exhibits potent anti-inflammatory neuroprotective and perhaps lifespan extending properties. Moreover a recent epidemiologicalstudy found that the incidence of dementia was strikingly reduced in human kidney transplant patients takingtacrolimus relative to age-matched subjects in the general population. In this project 5-6 month old beagles will undergo 1 year of behavioral/cognitive screening. At 6-7months-of age (prior to the development of significant amyloid pathology) dogs will be sorted into two groupsmatched for cognitive status. One group will received tacrolimus (.075mg/kg/day orally) continuously for thenext two years while the other group will receive placebo. Aim 1 will assess multidomain cognition andmeasure blood and CSF biomarkers (e.g. A and cytokines) at multiple time points across the tacrolimustreatment period. Aim 2 will use MRI/MRS to measure longitudinal changes in cerebral perfusion brainmetabolism and structural integrity. Aim 3 will use immunohistochemistry and a variety of biochemical assaysto assess AD biomarkers (e.g. A deposition glial activation synapse loss and neurodegeneration) and CN-related signaling parameters (e.g. cell-type specific expression CN proteolysis and NFAT activation) inpostmortem brain tissue. These studies will provide a rigorous test of the CN hypothesis of AD and possiblypave the way for investigating CN inhibition has a primary or complimentary treatment strategy in human ADclinical trials.

project_terms:
7 year old;9 year old;Adverse effects;Age;Age-Months;Aging;Alzheimer's Disease;Alzheimer's disease model;Amyloid;Amyloid beta-Protein;Amyloid deposition;Animal Model;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Atrophic;Attenuated;Autopsy;Behavioral;Biochemical;Biological Assay;Biological Markers;Blood;Brain;Calcineurin;Calcineurin inhibitor;Canis familiaris;Cerebrospinal Fluid;Cerebrovascular Disorders;Cerebrum;Clinical Trials;Cognition;Cognitive;Dementia;Development;Diffusion Magnetic Resonance Imaging;Disease;Dose;Elderly;Exhibits;Experimental Models;FDA approved;FK506;Freezing;Functional disorder;General Population;Genes;Genetic;Gold;Human;Hyperactive behavior;Image;Immune;Immunohistochemistry;Impaired cognition;Incidence;Individual;Inflammatory;Investigation;Kidney Transplantation;Label;Laboratories;Liquid substance;Literature;Longevity;Longitudinal Studies;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Maintenance;Matched Group;Measures;Metabolic;Metabolism;Modeling;Molecular;Molecular Target;Mus;Nerve Degeneration;Neurons;Oral;Oral Administration;Organ Transplantation;PPP3CA gene;Pathologic;Pathology;Pathway interactions;Perfusion;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Placebos;Plant Roots;Pre-Clinical Model;Preclinical Testing;Predisposition;Property;Prophylactic treatment;Protein phosphatase;Proteolysis;Recovery;Rodent;Role;Safety;Sampling;Signal Transduction;Solid;Spin Labels;Synapses;Tacrolimus;Testing;Therapeutic;Time;Transgenic Mice;Transgenic Organisms;Translations;Transplant Recipients;Work;abeta deposition;allograft rejection;amyloid pathology;biobehavior;brain metabolism;brain tissue;calcineurin phosphatase;cell type;cerebrovascular;cerebrovascular imaging;cognitive function;cytokine;epidemiology study;familial Alzheimer disease;glial activation;improved;middle age;mouse model;mutant;neurogenesis;neuroimaging;neuroinflammation;neuron loss;neuropathology;neurotoxicity;overexpression;preclinical evaluation;prevent;relating to nervous system;screening;synaptic function;therapy design;treatment duration;treatment strategy;white matter

public_health_relevance:
8. Project NarrativeThis study will use an FDA approved drug (tacrolimus) to inhibit the protein phosphatase calcineurin in a highermammalian model of Alzheimer's disease (i.e. aging beagles). Studies will determine the mechanistic role ofcalcineurin in AD and lay the groundwork for the use of calcineurin inhibitors in anti-AD drug trials.


application_id: 9377800
project_number: 2R15GM085722-03A1
project_title: Mechanisms of Action of UmuD in Regulating DNA Damage-Induced Genes in a umuC-Deficient Bacterium
administering_ic: NIGMS
award_notice_date: 2017-08-18
opportunity_number: PA-16-200
application_type: 2
activity_code: R15
ic: GM
serial_number: 085722
suffix: A1
program_official: REDDY, MICHAEL K
project_start_date: 2009-08-01
project_end_date: 2021-08-31
study_section: Special Emphasis Panel[ZRG1 GGG-D (80)]
contact_pi_person_id: 9257147
contact_pi: HARE, JANELLE M
other_pis: Not Applicable
congressional_district: 05
department: BIOLOGY
primary_duns: 041957010
primary_uei: MRGUP99ZAZ59
duns_number: 041957010
uei: MRGUP99ZAZ59
fips: US
organization_id: 569601
organization_name: MOREHEAD STATE UNIVERSITY
organization_city: MOREHEAD
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 403511684
organization_country: UNITED STATES
project_abstract:
This AREA R15 grant will (i) support meritorious research (ii) strengthen the research environmentof a non-research intensive university and (iii) engage undergraduate students in biomedical research. Theoverall goal of this research is to understand the mechanisms used by cells to respond to DNA damage whichis important because defects in DNA repair processes are linked to various cancers in humans but their use cancause antibiotic resistance in bacteria. Control of DNA damage repair processes thus must allow DNA repairprocesses to be induced appropriately while confining their use to needed situations. Specifically this researchwill identify how the mechanism of a error-prone polymerase manager (UmuD) homolog which has evolved torepress DNA damage response (SOS) genes is affected by the DdrR protein in the Acinetobacter bacterial genus.Mechanisms of this novel regulator UmuDAb will be dissected in the opportunistic pathogen Acinetobacterbaumannii. DNA damage causes antibiotic resistance in this bacterium via the induction and SOS mutagenesisaction of its numerous umuDC genes which are normally repressed by UmuDAb. The UmuDAb regulonincludes all six error-prone polymerase umuDC genes umuDAb itself and the ddrR gene transcribed divergentlyfrom umuDAb. Our preliminary data indicate that like UmuDAb DdrR also regulates the DNA damage-induced umuDC genes as well as umuDAb and ddrR. We hypothesize that UmuDAb regulatory actions (repression and self-cleavage) require cooperationwith DdrR action. The specific Aims of this project are to: 1) Detect UmuDAb and DdrR co-regulation of DNAdamage-induced genes using transcriptome analyses of a ddrR mutant; 2) Identify how UmuDAb regulatoryactions of DNA binding and self-cleavage are impacted by DdrR measuring the expression and SOSmutagenesis phenotypes of error-prone polymerase target genes in ddrR and umuDAb mutant strains; and 3)Determine if UmuDAb and DdrR physically interact to achieve co-regulation of DNA damage responsesusing ChIP-Seq two-hybrid analyses cross-linking and biochemical approaches. This project will create newknowledge about the regulatory mechanisms and proteins that bacteria use to respond to DNA damage byinvestigating both the novel UmuDAb repressor and the DdrR co-repressor. We will identify how the bacteriaintegrate UmuDAb and DdrR co-regulation of the mutagenic polymerases which could reveal methods forpreventing drug resistance in pathogens. Experiments will be completed with undergraduate and graduatestudents mentored and trained by the PI to perform authentic biomedical research help write scientificmanuscripts and communicate their findings to the campus community and larger scientific networks. Theenhanced research infrastructure and the expectation of and opportunities for student engagement in researchwill be beneficial to the entire Biology and Chemistry department at Morehead State University.

project_terms:
Acinetobacter;Acinetobacter baumannii;Affect;Antibiotic Resistance;Antibiotic Therapy;Antibiotics;Bacteria;Bacterial DNA;Base Pairing;Binding;Biochemical;Biological Assay;Biology;Biomedical Research;C-terminal;Cancer Etiology;Cell physiology;Cells;ChIP-seq;Chemical Exposure;Chemistry;Cleaved cell;Clinical;Communities;Complex;DNA;DNA Binding;DNA Damage;DNA Repair;DNA Replication Damage;DNA biosynthesis;DNA-Directed DNA Polymerase;Data;Defect;Dimerization;Drug resistance;Environment;Exposure to;Family;Gammaproteobacteria;Gene Expression;Gene Expression Regulation;Gene Targeting;Genes;Goals;Grant;Helix-Turn-Helix Motifs;Homodimerization;Homologous Gene;Hospitals;Human;Knowledge;Lead;Link;Malignant Neoplasms;Manuscripts;Measures;Methods;Molecular Conformation;Mutagenesis;Mutation;N-terminal;Operon;Phenotype;Polymerase;Process;Proteins;Radiation exposure;Regulation;Regulon;Repression;Research;Research Infrastructure;Resistance development;Site;Skin Cancer;Son of Sevenless Proteins;Specificity;Structure;Surface;System;Technology;Testing;Ultraviolet Rays;Universities;Virulence;Writing;alpha helix;clinically significant;crosslink;design;dimer;drug development;expectation;experimental study;graduate student;mutant;novel;pathogen;prevent;promoter;quinolone resistance;recombinational repair;repair enzyme;response;student mentoring;student participation;student training;transcriptome;transcriptome sequencing;undergraduate student;yeast two hybrid system

public_health_relevance:
Both humans and bacteria respond to DNA damage using similar error-prone (mutagenic) DNApolymerases where polymerase defects can cause cancer after exposure to DNA damage and polymeraseaction can cause mutations in bacterial pathogens that lead to antibiotic resistance and their increasedvirulence. This project will identify the mechanism of action of a novel bacterial regulator which closelyresembles a human error-prone DNA polymerase and its co-repressor. These experiments will help identifyhow pathogens control mutagenic responses to DNA damage that is present in a clinical setting (e.g. the UVlight used to disinfect hospital surfaces or antibiotic treatment).


application_id: 9377764
project_number: 1R15ES028440-01
project_title: Developmental CSE: Impact on Intestinal Bacterial Community Development
administering_ic: NIEHS
award_notice_date: 2017-07-28
opportunity_number: PA-16-200
application_type: 1
activity_code: R15
ic: ES
serial_number: 028440
program_official: DZIERLENGA, ANIKA LIN
project_start_date: 2017-08-01
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZRG1 DKUS-J (82)]
contact_pi_person_id: 8531285
contact_pi: NEAL, RACHEL ELIZABETH
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV 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 PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT:Cigarette smoke is one of the most prevalent developmental toxins. The World Health Organization estimatesthat ~700 million children worldwide are exposed either pre- and/or postnatally to cigarette smoke. Theoverarching theme of this proposal is to study the role of developmental cigarette smoke exposure on thecolonization maintenance and function of the gut microbiome. Since neonatal gut colonization is initiated byexposure to maternal bacteria during birth and tobacco smoke exposure alters cecal bacterial content inadults we propose that maternal tobacco smoke exposure during pregnancy results in aberrant bacterialcolonization of the neonatal gut such that pathogenic bacterial overgrowth occurs and that continued cigarettesmoke exposure during postnatal development entrenches this phenotype. Utilizing a unique and wellcharacterized murine inhalation model simulating maternal cigarette smoking during pregnancy and newbornsmoke exposure - established in our laboratory - we will: 1) Examine the impact of developmental cigarettesmoke exposure on offspring gut microbial community colonization and the persistence of the microbiomephenotype; 2) Examine the impact of developmental cigarette smoke exposure on offspring gut microbialcommunity function; and 3) Compare the outcomes within our murine model of developmental tobaccocigarette smoke exposure with findings from very low birth weight human infants of mothers who smokedduring pregnancy. Central Hypothesis: Developmental cigarette smoke exposure induces pathogenicintestinal bacterial colonization with persistent alterations in carbohydrate metabolism in mice with asimilar impact in very low birth weight infants of mothers who smoked during pregnancy.

project_terms:
Adult;Age;Animal Husbandry;Animal Model;Archives;Bacteria;Bile Acids;Birth;Breathing;Butyrates;Carbohydrates;Child;Cigarette;Classification;Coenzyme A-Transferases;Communities;Community Developments;Consumption;Cotinine;DNA;Data Set;Development;Exposure to;Fatty Acids;Fermentation;Formate-Tetrahydrofolate Ligase;Gene Expression;Growth;Hour;Human;Human Microbiome;Impairment;Individual;Infant;Inhalation Exposure;Intestines;Isotope Labeling;Label;Laboratories;Libraries;Life;Low Birth Weight Infant;Maintenance;Measures;Metabolic;Metabolism;Modeling;Mothers;Mus;Neonatal;Newborn Infant;Outcome;Pathogenicity;Phenotype;Population;Pregnancy;Preparation;Production;RNA;Resistance;Role;Sampling;Smoke;Smoking;Stable Isotope Labeling;Starch;Statistical Data Interpretation;Structure;Supervision;Testing;Tissue Banks;Tobacco;Tobacco smoke;Toxin;Training;Very Low Birth Weight Infant;Volatile Fatty Acids;Weight;World Health Organization;analog;carbohydrate metabolism;cigarette smoke;environmental tobacco smoke exposure;graduate student;gut microbiome;maternal cigarette smoking;metabolome;metabolomics;microbial community;microbiome;mouse model;offspring;postnatal;prenatal;tributyrin;undergraduate student

public_health_relevance:
PROJECT NARRATIVECigarette smoke is one of the most prevalent developmental toxins. Developmental cigarette smoke exposureresults in low birth weight and persistent decrements in infant growth. Studies proposed in the currentapplication will: 1) examine the impact of developmental cigarette smoke exposure on the establishment of theintestinal bacterial community in a well established animal model simulating maternal smoking duringpregnancy and neonatal smoke exposure and 2) examine the impact of maternal smoking during pregnancy onthe establishment of the intestinal microbial community in very low birth weight human infants.


application_id: 9377237
project_number: 1R35ES028373-01
project_title: Environmental Liver Disease
administering_ic: NIEHS
award_notice_date: 2017-09-12
opportunity_number: RFA-ES-16-008
application_type: 1
activity_code: R35
ic: ES
serial_number: 028373
program_official: SCHUG, THADDEUS
project_start_date: 2017-09-15
project_end_date: 2025-08-31
study_section: Special Emphasis Panel[ZES1 LWJ-K (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_terms:
Academia;Address;Adolescent;Adult;Affect;Animal Model;Area;Cardiovascular Diseases;Cessation of life;Chemical Exposure;Chemicals;Child;Cirrhosis;Collaborations;Data;Development;Diabetes Mellitus;Endocrine;Environment;Environmental Health;Epidemiologist;Exposure to;Fatty Liver;Goals;Government Agencies;Health;Hepatocyte;Industry;Lipids;Liver;Liver diseases;Malignant neoplasm of liver;Medical Societies;Metabolism;Methods;Mission;National Institute of Environmental Health Sciences;Nutrient;Obesity;Physicians;Poisons;Policies;Polychlorinated Biphenyls;Population;Practice Guidelines;Reproducibility;Research;Resources;Scientist;Strategic Planning;Time;Training and Education;Transplantation;Vinyl Chloride;Vision;Work;chronic liver disease;diagnostic biomarker;disease registry;environmental chemical;global health;human subject;innovation;next generation;programs;sex


application_id: 9376981
project_number: 2R01GM077422-08A1
project_title: Targeting Nucleic Acids with an Integrated Virtual and Actual Screen
administering_ic: NIGMS
award_notice_date: 2017-08-22
opportunity_number: PA-16-160
application_type: 2
activity_code: R01
ic: GM
serial_number: 077422
suffix: A1
program_official: PREUSCH, PETER
project_start_date: 2007-02-01
project_end_date: 2021-04-30
study_section: Macromolecular Structure and Function B Study Section[MSFB]
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
other_pis: TRENT, JOHN O
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
project_terms:
Binding;Binding Proteins;Biological;Biological Assay;Biophysics;Characteristics;Computer Simulation;DNA;DNA Binding;DNA Sequence;DNA Structure;DNA biosynthesis;Development;Drug Design;Elements;Face;Funding;G-Quartets;Gene Expression;Genome;Grant;Human;Kinetics;Laboratories;Lead;Measures;Methods;Modeling;Molecular Conformation;Nucleic Acids;Nucleotides;Oligonucleotides;Pathway interactions;Pharmaceutical Preparations;Play;Positioning Attribute;Property;Proteins;Recombinants;Role;Series;Single-Stranded DNA;Source;Structural Models;Structure;Telomerase;Telomerase inhibition;Therapeutic Agents;Thermodynamics;Validation;base;biophysical properties;biophysical techniques;design;innovation;new therapeutic target;novel;novel strategies;novel therapeutics;nucleic acid structure;programs;protein complex;quadruplex DNA;screening;small molecule;small molecule inhibitor;small molecule therapeutics;structural biology;telomere;virtual


application_id: 9376638
project_number: 1U01AI132817-01
administering_ic: NIAID
award_notice_date: 2017-06-20
opportunity_number: RFA-AI-16-042
application_type: 1
activity_code: U01
ic: AI
serial_number: 132817
program_official: KULKARNI, SHILPA S
project_start_date: 2017-06-20
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZAI1 TC-I (M1)]
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
other_pis: GARCIA, ANDRES J;YOLCU, ESMA S
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-06-20
project_title:
Targeted delivery of immunomodulatory biologics for induction of immune privilege to allogeneic pancreatic islet grafts

project_abstract:
PROJECT SUMMARY Type 1 diabetes (T1D) is a chronic autoimmune disorder that affects ~1% of population worldwide.Exogenous insulin treatment is the standard of care for T1D but often negatively affects the quality of life andis ineffective in preventing recurrent hyperglycemia episodes and chronic complications. Recent studies showthat human islet allografts can restore long-term normoglycemia and insulin independence protect from severehypoglycemia and slow progression of microvascular lesions in immunosuppressed T1D patients. Howeverimmune rejection and continuous use of immunosuppression to control rejection are two major limitationsof clinical islet transplantation. Standard immunosuppression is ineffective in achieving long-term graft survivaland also has significant adverse effects on the graft and graft recipients. Therefore the development of novelapproaches to prevent rejection of islet grafts without chronic immunosuppression is a significant goal. Allogeneic islets are subject to rejection by both alloreactive and autoreactive T effector (Teff) cells. Animbalance in the frequency of pathogenic Teff and protective T regulatory (Treg) cells is the underlying causeof T1D and allogeneic islet graft rejection. Restoring the physiological Teff and Treg balance has significanttherapeutic potential. Approaches attempting to tilt the balance in favor of Treg cells have so far targeted eitherTeff or Treg cells individually for modulation with limited success. The primary goal of this application is totarget both cell types simultaneously for modulation for an outcome in favor of Treg cell expansion. This willbe achieved using innovative polyethylene glycol hydrogel particle platforms for graft-targeted deliveryand controlled presentation of two novel biologics serving as agonists of Fas and IL-2R receptors. Teffcells activated by antigens express Fas receptor and become sensitive to FasL-mediated apoptosis. IL-2Rsignaling preferentially sensitizes Teff cells to Fas-induced apoptosis and is also required for Treg cells(CD4+CD25+FoxP3+) generation expansion and survival. Therefore we hypothesize that the combined useof agonists of Fas and IL-2R will preferentially eliminate Teff cells and generate/expand Treg cells withinthe graft microenvironment resulting in induced-immune privilege and sustained survival and function of isletallograft in the absence of any immunosuppression. A set of preliminary data support this hypothesis andprovide strong scientific premise and feasibility for this application. This concept will be tested in threedifferent allogeneic islet transplantation settings for efficacy and mechanisms; chemically diabetic BALB/c-to-C57BL/6 mice spontaneously diabetic C57BL/6-to-NOD mice and human islets into humanized mice. Thesemodels will generate critical data relevant to the human setting. Furthermore proof-of-efficacy and theelucidation of the immune mechanisms regulating effective outcomes will expedite further refinement of thisimmunomodulatory concept and its eventual translation to nonhuman primates as a prelude to clinical trials forthe treatment of type 1 diabetes.

project_terms:
Acute;Adverse effects;Affect;Agonist;Allogenic;Antigens;Apoptosis;Apoptotic;Autoantigens;Autoimmune Diseases;Binding;Biocompatible Materials;Biological Process;C57BL/6 Mouse;CD8B1 gene;CD95 Antigens;Cell Death;Cell membrane;Cells;Chemicals;Chronic;Clinical;Clinical Treatment;Clinical Trials;Cloning;Complex;Data;Development;Engineering;Equilibrium;Eragrostis;FOXP3 gene;Failure;Formulation;Frequencies;Generations;Goals;Graft Rejection;Graft Survival;Homeostasis;Human;Hydrogels;Hyperglycemia;Hypoglycemia;IL2 gene;IL2RA gene;Immune;Immune response;Immunosuppressive Agents;Inbred BALB C Mice;Inbred NOD Mice;Individual;Insulin;Insulin-Dependent Diabetes Mellitus;Interleukin-2;Islets of Langerhans;Islets of Langerhans Transplantation;Lead;Lesion;Life;Mediating;Membrane;Memory;Metabolic Control;Modeling;Natural immunosuppression;Outcome;Pathogenicity;Pathway interactions;Patients;Peripheral;Pharmaceutical Preparations;Physiological;Play;Polyethylene Glycols;Population;Pre-Clinical Model;Prevention Protocols;Protocols documentation;Quality of life;Rattus;Recurrence;Regulatory T-Lymphocyte;Research;Rodent;Signal Pathway;Signal Transduction;Skin;Streptavidin;Surface;T memory cell;T-Lymphocyte;Testing;Therapeutic;Time;Translations;Tumor Necrosis Factor Ligand Superfamily Member 6;Work;alternative treatment;autoreactivity;base;cell type;chronic autoimmune disease;controlled release;design;diabetic;effective therapy;efficacy testing;extracellular;graft function;humanized mouse;immunoregulation;immunosuppressed;improved;innovation;islet;islet allograft;mouse model;negative affect;nonhuman primate;novel;novel strategies;particle;prevent;receptor;response;standard of care;success;synergism;targeted delivery;therapeutic target;translation to humans

public_health_relevance:
PROJECT NARRATIVEType 1 diabetes (T1D) is a chronic autoimmune disorder that affects more than 1% of the populationworldwide. Transplantation of pancreatic islets producing insulin has been shown to be an effective treatment.However graft recipients are required to take immunosuppressive drugs which has significant adverse effectsduring their life to control rejection. The primary objective of this proposal is to establish and test a graft-targeted immunomodulatory protocol delivered using advanced biomaterials that sustains long-term islet graftsurvival and function in the absence of any immunosuppression in various relevant pre-clinical modelsincluding a humanized mouse model. If effective this approach will have immediate and important implicationsfor the use of allogeneic islets for the treatment of T1D in humans.


application_id: 9374989
project_number: 1R03AI133056-01
project_title: Borrelia burgdorferi responses to antibiotic stresses
administering_ic: NIAID
award_notice_date: 2017-06-06
opportunity_number: PA-16-162
application_type: 1
activity_code: R03
ic: AI
serial_number: 133056
program_official: ILIAS, MALIHA R
project_start_date: 2017-06-06
project_end_date: 2019-05-31
study_section: Special Emphasis Panel[ZRG1 IDM-B (80)]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTLyme disease which is caused by the spirochete Borrelia burgdorferi is generally treatable by a 2-4 weekcourse of antibiotics. However there is strong evidence from studies of human patients and experimentalanimals that antibiotics do not always clear B. burgdorferi infections. Studies of other bacterial species haverevealed genetically-encoded physiological adaptations to antibiotic stresses such as altering expressionlevels of target proteins or metabolic enzymes. To gain insight on whether the Lyme spirochete also adapts toantibiotic stresses we will examine the transcriptomes and proteomes of B. burgdorferi that are exposed tosub-lethal and lethal concentrations of antibiotics that are commonly used to treat human Lyme diseaseinfections. Results of these studies will reveal whether B. burgdorferi possesses genetically-encoded adaptivemechanisms which can then be targeted for development of improved therapeutics.

project_terms:
Address;Animals;Antibiotics;Bacteria;Borrelia burgdorferi;Development;Enzymes;Escherichia coli;Exhibits;Gene Expression;Genes;Genetic Transcription;Human;Individual;Infection;Killings;Laboratory Animals;Laboratory Study;Lyme Disease;Metabolic;Molecular;Order Spirochaetales;Patients;Physiological Adaptation;Production;Proteins;Proteome;Research Personnel;Residual state;Staphylococcus aureus;Stress;Symptoms;Therapeutic;Ticks;Tissues;base;improved;insight;pathogen;pathogenic bacteria;response;transcriptome

public_health_relevance:
PROJECT NARRATIVEEvidence exists that the spirochete bacterium Borrelia burgdorferi the agent of Lyme disease may possessmechanisms to avoid killing by antibiotics during human infection. Some other pathogenic bacteria undergogenetically-encoded physiological adaptations to antibiotic stresses such as altering expression levels oftarget proteins or metabolic enzymes. We hypothesize that the Lyme disease spirochete also adapts toantibiotic stresses which we will address by comparing the transcriptomes and proteomes of B. burgdorferithat are exposed to antibiotics which are commonly used to treat human Lyme disease.


application_id: 9371922
project_number: 1R34MH111783-01A1
project_title: Validation of an Implementation Strategy of COMPASS for School Trainers of Children with Autism
administering_ic: NIMH
award_notice_date: 2017-08-14
opportunity_number: RFA-MH-16-410
application_type: 1
activity_code: R34
ic: MH
serial_number: 111783
suffix: A1
program_official: PINTELLO, DENISE
project_start_date: 2017-08-15
project_end_date: 2020-05-31
study_section: Special Emphasis Panel[ZMH1 ERB-K (03)]
contact_pi_person_id: 1960113
contact_pi: RUBLE, LISA A
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 EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project Summary/AbstractWe seek to conduct a pilot effectiveness trial within an implementation trial for improving educational outcomesof children with autism spectrum disorder (ASD). Modeled after a Hybrid Trial Type 2 design [1] our study aimsto (a) to create a valid and locally adapted implementation training strategy leveraging the mechanismsunderlying the intervention effects and delivered in priority educational settings located in urban andunderserved rural contexts while also (b) considering implementation and maintenance factors impactingtraining sensitivity to mechanisms and adoption/uptake of COMPASS. The study addresses a significantresearch-to-practice gap that less than 10% of educational strategies for children with ASD are based onevidence [2 3]. Importantly consultation methods have a multiplier effect in the efficient and broaddissemination of best practices. This proposal responds to recommendations from the Interagency AutismCoordinating Committee for studies that utilize implementation science to test methods to improveimplementation of evidence-based treatments (p.41) and develop and evaluate quality measures to helpmonitor progress in improving care and outcomes for people with ASD (p.41) [4]. Our approach aligns withrecommendations from the Institute of Medicine framework for establishing evidence based standards [5] andthe goals of this RFA for effectiveness research on therapeutic interventions with previously demonstratedefficacy for use in community settings. The proposed study builds on two completed NIH funded randomizedcontrolled studies (RCTs) [6 7] a recently published treatment manual [8] and a monograph-length scientificreview [9]. The RCTs provided strong support for the efficacy of consulting delivered by the research team toassist public school special educators and parents via face-to-face interactions and through videoconferencingtechnology [10]. High quality ecological assessments research-informed goal development and guideddecision-making for individualizing evidence-based interventions for children with ASD are accomplished usingthe consultation intervention the Collaborative Model for Promoting Competence and Success (COMPASS)[8]. COMPASS consists of an initial parent-teacher session (3 hours) occurring near the start of the schoolyear followed by four 1-hour teacher coaching sessions evenly spaced through the rest of the school year.COMPASS assists in creating (1) individualized educationally appropriate well-constructed psychometrically-sensitive goals and (2) effective educational plans to meet the goals. Goals and teaching plans take intoaccount the personalized context within which the evidence based interventions will be delivered. Theobjectives of the current proposal are to evaluate the effectiveness of training local consultants/trainersincluding how well the training engages the mechanisms of change (e.g. fidelity) that have been identified andreplicated in two RCTs [67]. The long-term goal is to improve the quality of services and overall functional andsocial outcomes of children with ASD when COMPASS is delivered by practitioners. Our aims are framed withthe Replicating Effective Programs (REP) [11] Framework for implementation in community settings.

project_terms:
Address;Adherence;Administrator;Adoption;Assessment tool;Autistic Disorder;Behavior;Caring;Child;Competence;Consult;Consultations;Decision Making;Development;Educational process of instructing;Effectiveness;Evidence based intervention;Evidence based treatment;Feedback;Fibrinogen;Funding;Goals;Grant;Hour;Hybrids;Institute of Medicine (U.S.);Intervention;Knowledge;Length;Maintenance;Manuals;Measures;Methods;Modeling;Monitor;Monograph;Outcome;Parents;Protocols documentation;Psychometrics;Publishing;Randomized Controlled Trials;Recommendation;Research;Rest;Rural;Schools;Services;Technology;Testing;Therapeutic Intervention;Time;Training;Translations;United States National Institutes of Health;Use Effectiveness;Validation;Videoconferencing;autism spectrum disorder;base;combat;community setting;design;effectiveness research;effectiveness trial;evidence base;implementation science;implementation trial;improved;intervention effect;programs;research to practice;rural underserved;satisfaction;social;success;teacher;uptake;urban underserved;usability

public_health_relevance:
NarrativeThis application is pilot research that responds to the Interagency Autism Coordinating Committee for studiesthat utilize implementation science to test methods to improve implementation of evidence-based treatments.High quality ecological assessments research-informed goal development and decision-making forindividualizing evidence-based interventions for children with ASD is accomplished using the consultationintervention called the Collaborative Model for Promoting Competence and Success (COMPASS). Specificallywe will create a valid and locally adapted COMPASS training package; pilot the trainer package; and identifyimplementation and maintenance factors impacting training ongoing quality (including mechanisms) andadoption/uptake of COMPASS when delivered by nonexperts.


application_id: 9370981
project_number: 1K99AG056635-01
project_title: Stress and Immunosenescence: Protective Effects of Emotion Regulation
administering_ic: NIA
award_notice_date: 2017-09-13
opportunity_number: PA-16-193
application_type: 1
activity_code: K99
ic: AG
serial_number: 056635
program_official: NIELSEN, LISBETH
project_start_date: 2017-09-15
project_end_date: 2019-05-31
study_section: Behavior and Social Science of Aging Study Section[NIA-S]
contact_pi_person_id: 11895122
contact_pi: REED, REBECCA G
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: ORGANIZED RESEARCH UNITS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYIdentifying factors that influence age-related immune dysfunction (immunosenescence) in older adults iscentral to promoting well-being and reducing morbidity  an increasing public health concern given the rapidlyexpanding aging population. Evidence from observational and experimental studies suggests that stress isassociated with poorer immune function in older adults. However less is known about the dynamic(intraindividual variability) emotional and physiological mechanisms by which stress influences older adults'immune function. In addition emotion regulation may be a protective factor that can buffer stress-relatedimmunosenescence in later life but there is a dearth of knowledge in this area. This K99/R00 proposal lays thefoundation for an independent research career focused on characterizing adaptive emotional andimmunological mechanisms that contribute to healthy aging during stress. The proposed career developmentplan will provide the candidate: (1) expertise in theories and methodologies of aging research (2) advancedknowledge in immunosenescence and age-related immune changes and (3) training in emotion and emotionregulation processes focused specifically on contexts of aging and stress. The mentored phase capitalizes onsubstantial research and professional development resources at the University of Kentucky (UK) and theexpertise of an inter-disciplinary mentoring team (UK: Dr. Segerstrom and Dr. Lutz; UC Berkeley: Dr. Mauss;Penn State University: Dr. Ram UCLA: Dr. Effros). These experiences will supplement the candidate's existingbackground in stress emotions health and quantitative methods. The present study has three aims to testdifferent components of a proposed model. Aim 1 (K99): To examine whether emotion regulation moderatesthe association between life stressors and immunosenescence. Aim 2 (K99): To explain how daily stressorsare associated with elevated stress biomarkers through intraindividual variability in negative emotion. Aim 3(R00): To test the moderated mediation pathways of the entire proposed biopsychosocial model. The researchincorporates a rigorous approach to test the proposed model by examining its interacting components acrossdifferent time domains (i.e. life stressors that occur over years and daily hassles that occur on a more microlevel) in various samples (community-dwelling older adults and a large nationally representative sample) andacross several markers of immunosenescence (lymphocyte senescence inflammation a chief proinflammatorytranscription factor and a latent virus that may drive senescence). Concurrent and prospective laggedmoderation and mediation models using multilevel modeling and regression will be used to test relationshipsamong stressors emotional and physiological responses to stress immunosenescence and emotionregulation. Ultimately this project will increase understanding of the dynamic mechanisms by which stressorsinfluence immunosenescence in older adults and the role of emotion regulation in promoting healthy aging.

project_terms:
Adult;Affective;Age;Aging;Antibody titer measurement;Area;Biological Markers;Buffers;Chronic Disease;Communicable Diseases;Communities;Cytomegalovirus;Data;Development Plans;Elderly;Emotional;Emotions;Event;Feeling;Fostering;Foundations;Goals;Health;Hydrocortisone;Immune;Immune System Diseases;Immune System and Related Disorders;Immunity;Immunologics;Incidence;Individual;Inflammation;Interleukin-6;Kentucky;Knowledge;Latent Virus;Life;Link;Lymphocyte;Mediation;Mediator of activation protein;Mentors;Methodology;Methods;Modeling;Morbidity - disease rate;NF-kappa B;Natural Killer Cells;Nature;Observational Study;Pathway interactions;Phase;Physiological;Process;Psychological Stress;Public Health;Research;Research Project Grants;Resource Development;Resources;Risk;Role;Sampling;Science;Severities;Stress;T-Lymphocyte;Testing;Time;Training;Universities;Virus Latency;age related;aging population;biopsychosocial;career;career development;diaries;emotion regulation;experience;experimental study;healthy aging;immune function;immunosenescence;mortality;multilevel analysis;physical conditioning;prospective;protective effect;resilience;response;senescence;stress management;stressor;theories;trait;transcription factor

public_health_relevance:
Psychological stress can accelerate age-related decline in immune function (immunosenescence) thatincreases risk of poor health. Greater understanding of how this happens and what may foster resilient healthin the face of stress is needed. This project examines emotional and physiological mechanisms by whichstressors influence immunosenescence and the potential protective role of emotion regulation in reducingnegative effects.


application_id: 9370511
project_number: 1R21CA218231-01
administering_ic: NCI
award_notice_date: 2017-08-10
opportunity_number: PAR-16-248
application_type: 1
activity_code: R21
ic: CA
serial_number: 218231
program_official: BLAKE, KELLY D
project_start_date: 2017-08-10
project_end_date: 2019-07-31
study_section: Special Emphasis Panel[ZRG1 PSE-B (58)]
contact_pi_person_id: 11081240
contact_pi: KAVULURU, VENKATA NAGA RAMAKANTH
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
budget_start_date: 2017-08-10
project_title:
Toward fine-grained e-cigarette surveillance on social media: Evolving themes popularity predictors and demographic variations

project_abstract:
ABSTRACTElectronic cigarettes (or e-cigarettes) are currently a popular emerging tobacco product. Because e-cigarettes donot generate toxic tobacco combustion products produced when smoking regular cigarettes they are perceivedand sometimes promoted as a less harmful alternative to smoking and also as a means to quit smoking. Althoughthey may be less harmful the efcacy of using them for smoking cessation has not been demonstrated conclu-sively with studies indicating evidence both favoring and opposing such an application for them. Furthermoreowing to their recent introduction there are also safety concerns given reported adverse events. The US FederalDrug Administration (FDA) has introduced regulations that went into effect on 8/8/2016 requiring FDA review fore-cigarette products banning sales to minors and free samples and requiring warning labels on certain prod-ucts. In this context surveillance of evolving themes and factors contributing to message popularity for e-cigarettechatter on social media platforms is an important activity. Twitter has become the favorite network for teenagersand young adults owing to the short message size and associated ease of use on smart phones. For an emerg-ing product like e-cigarettes the asymmetric follower-friend connections and hashtag functionality in Twitter offera convenient way to propagate information and facilitate discussion. Among online forums Reddit allows forlonger messages from users inviting specic feedback from other users. Within Reddit the e-cigarette subredditfacilitates focused discussions on e-cigarette use and products. In this project we propose to computationallyanalyze the contents and user proles available in the dataset of all e-cigarette tweets generated during 7/20166/2017 and all e-cigarette subreddit posts/comments generated since 9/2016. We will continue such analyseswith data collected through free but rate limited API throughout the duration of the project. Our rst aim is to sur-face specic themes of interest directly from e-cigarette messages using phrase based online and binned topicmodels. We expect these themes to complement familiar broad themes that researchers currently consider whenanalyzing online messages. Next we will identify factors (involving message content and prole characteristics)that contribute to different notions of popularity (#retweets #replies #up-votes) of e-cigarette tweets/messages.We expect these results will help health agencies the FDA and researchers gain insights into observed viralnature of certain messages and designing effective strategies to maximize diffusion of their messages. Finallywe will conduct these analyses along the dimensions of gender race and age to grasp variations in themes andpopularity factors specic to different vulnerable demographic segments.

project_terms:
Adverse event;African American;Age;Cellular Phone;Centers for Disease Control and Prevention (U.S.);Cereals;Characteristics;Cigarette;Communication;Complement;Data;Data Set;Data Sources;Diffusion;Dimensions;Electronic Nicotine Delivery Systems;Electronic cigarette;Evolution;Feedback;Frequencies;Friends;Gender;Goals;Harm Reduction;Health;High School Student;Influentials;Informatics;Label;Light;Liquid substance;Long-Term Effects;Measures;Methods;Minor;Modeling;National Health Services;Nature;Nicotine Dependence;Outcome;Pharmaceutical Preparations;Psychometrics;Published Comment;Race;Regulation;Reporting;Research Personnel;Safety;Sales;Sampling;Site;Smoke;Smoker;Smoking;Social Network;Surface;Teenagers;Time;Tobacco;United States Food and Drug Administration;Vaporizer;Variant;Viral;Visual;Voting;Work;base;combustion product;computerized tools;design;exhaustion;grasp;insight;interest;junior high school;member;news;phrases;smoking cessation;social media;social networking website;young adult

public_health_relevance:
NARRATIVEElectronic cigarettes (e-cigarettes) have emerged as the main smoke-free alternative to regular cigarettes overthe past few years. While the ongoing healthy scientic debate about their long term health effects and theirsuitability for smoking cessation are important in this project we propose computational approaches towardne-grained surveillance of specic themes factors inuencing message popularity and demographic variations.The overarching goal is to create new affordances for researchers and health agencies to leverage online socialmedia platforms for knowing and reaching their audience in effective ways.


application_id: 9369401
project_number: 3R01HL123927-03S1
project_title: Crosstalk Between Membrane Traffic Proteins and Integrin Activation
administering_ic: NHLBI
award_notice_date: 2017-03-31
opportunity_number: PA-16-288
application_type: 3
activity_code: R01
ic: HL
serial_number: 123927
suffix: S1
program_official: CHANG, HENRY
project_start_date: 2014-09-25
project_end_date: 2018-06-30
contact_pi_person_id: 8558885
contact_pi: LI, ZHENYU
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): 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 sequellae. Platelet secretion is a multistep process involving centralization of cytoplasmic organelles that provides a contractile force membrane fusion controlled by membrane traffic proteins and release of granule contents. The platelet integrin llb3 interacts with adhesive ligands such as fibrinogen and fibrin and mediates platelet adhesion and aggregation and thus plays a critical role in the development of thrombotic diseases such as heart attack and stroke. The overall goal of this proposal is to establish a link between the membrane traffic proteins and integrins that involve the two key events to platelet function platelet cargo release and integrin activation. VPS33B is a member of the Sec1/Munc18 protein family that has multiple roles in exocytosis. VPS33B is defective in patients with arthrogryposis renal dysfunction cholestasis (ARC) syndrome. Platelets from these patients lack -granules. In an attempt to define the roles of -granules in platelet functio and thrombosis we produced a mouse model of -granule deficiency in which VPS33B was deleted only in megakaryocytes and platelets. In Specific Aim 1 we will determine the roles of VPS33B in llb3-dependnet endocytosis and llb3 outside-in signaling. -granule contents vWF and fibrinogen are significantly reduced in the platelets lacking VPS33B. Surprisingly VPS33B-/- platelets fail to retract a clot and are defective in spreading on fibrinogen. Using the CHO recombinant llb3 activation model we showed that overexpression of VPS33B markedly potentiates cell spreading on fibrinogen and actin polymerization. Thus we hypothesize that in platelets there exists a crosstalk between the membrane traffic proteins and integrin activation and that VPS33B is a key contributor to llb3 outside-in signaling. This hypothesis will be tested using the platelet- specific VPS33B conditional knockout mice and other VPS33B knockout mice such as whole-body knockout mice and a Chinese Hamster Ovary (CHO) integrin activation model. Our preliminary data demonstrated that VPS33B co-localizes with llb3 as detected by confocal microscopy and forms a complex with llb3 as detected by co-immunoprecipitation. In Specific Aim 2 we will use multiple approaches to characterize the binding determinants in VPS33B and the 3 cytoplasmic domains for each other. In Specific Aim 3 we will identify the molecular mechanisms of VPS33B-dependent llb3 outside-in signaling. Completion of these studies will not only identify a novel llb3 binding partner that plays an important role in llb3 outside-in signaling but also for the first time establish a lin between membrane traffic proteins and integrin activation in platelets.

project_terms:
Actins;Acute;Adhesions;Adhesives;Alpha Granule;Anabolism;Arthrogryposis;Atherosclerosis;Binding;Binding Proteins;Biochemical;Blood Platelets;Blood Vessels;Cause of Death;Cell Adhesion;Cell physiology;Cell surface;Cells;Chinese Hamster;Chinese Hamster Ovary Cell;Cholestasis;Co-Immunoprecipitations;Coagulation Process;Complex;Confocal Microscopy;Cytomegalovirus;Cytoplasmic Granules;Cytoplasmic Organelle;Cytoplasmic Tail;Data;Defect;Development;Disease;Endocytosis;Enterobacteria phage P1 Cre recombinase;Epitopes;Event;Exocytosis;Extracellular Matrix;Fibrin;Fibrinogen;Functional disorder;Goals;Hemostatic function;Host Defense;Human;Impairment;Inflammation;Integrin Binding;Integrin beta Chains;Integrins;Kidney;Knockout Mice;Ligands;Link;MAP Kinase Gene;Malignant Neoplasms;Maps;Mediating;Megakaryocytes;Membrane Fusion;Membrane Protein Traffic;Membrane Proteins;Modeling;Molecular;Mouse Strains;Mus;Myocardial Infarction;Ovary;P-Selectin;Pathway interactions;Patients;Phosphorylation;Plasma;Platelet Activation;Play;Process;Protein Family;Proteins;Recombinants;Research Project Grants;Role;SRC gene;Signal Pathway;Signal Transduction;Syndrome;Testing;Thrombosis;Time;United States;VWF gene;Work;Wound Healing;angiogenesis;antimicrobial;base;experimental study;extracellular;in vivo;insight;member;mouse model;mutant;novel;overexpression;polymerization;prevent;promoter;public health relevance;receptor;receptor mediated endocytosis;rho GTP-Binding Proteins;stem;stroke;syntaxin binding protein 1

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Blood platelets are essential for acute thrombotic events such as heart attacks and strokes and also contribute to local and systemic inflammation. This research project seeks to understand how the membrane traffic proteins such as VPS33B regulate platelet integrin activation and thrombosis. Completion of the work will provide new insights into pathways that could be targeted to prevent and treat arterial thrombosis a leading cause of death in the United States.


application_id: 9369007
project_number: 271201600028C-0-0-1
administering_ic: NIDA
project_start_date: 2016-09-18
project_end_date: 2021-09-17
contact_pi_person_id: 14759366
contact_pi: MURTY, RAM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 943117366
primary_uei: DNJBTJ3XBQM6
duns_number: 943117366
uei: DNJBTJ3XBQM6
fips: US
organization_id: 3514301
organization_name: MURTY PHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405091016
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_title:
IGF::OT::IGF Development & Manufacture of Pharmaceutical Products for the Treatment of Substance Abuse Disorcer. NIDA Ref. No. N01DA-16-8926; POP: 09/18/2016 - 09/17/2021.

project_abstract:
The purpose of this contract is to carry out the development and manufacture of pharmaceutical preparations to beused in the medications development program for addiction treatment at the National Institute on Drug Abuse (NIDA).

project_terms:
Clinical Trials;Contractor;Contracts;Data Reporting;Development;Documentation;Dosage Forms;Drug Compounding;Evaluation;Formulation;Generations;Investigational Drugs;Maintenance;National Institute of Drug Abuse;Pharmaceutical Preparations;Pharmacologic Substance;Placebos;Preparation;Program Development;Resources;Site;Validation;addiction;analytical method;method development;novel therapeutics;pre-clinical;substance abuse treatment


application_id: 9368930
project_number: 261201300013I-2-26100005-3
administering_ic: NCI
project_start_date: 2015-05-01
project_end_date: 2017-04-30
contact_pi_person_id: 14511283
contact_pi: TUCKER, THOMAS
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
funding_mechanism: R and D Contracts
project_title:
IGF::OT::IGF CORE INFRASTRUCTURE SUPPORT FOR SURVEILLANCE EPIDEMIOLOGY AND END RESULTS (SEER) PERIOD OF PERFORMANCE: 05/01/2015 TO 04/30/2017

project_abstract:
The aim of this Task Order modification is to support a pilot test to obtain medical claims data from Unlimited System a medical claims aggregator (also referred to as a clearinghouse). Medical claims aggregators receive edits and submit insurance claims from medical practices. Working through a medical claims aggregator will ensure that this pilot test is conducted in the most efficient and cost effective manner because the desired oncology practice will be able to be recruited directly through the aggregator and once recruited the aggregator will directly submit their claims data. Also since oncology practices are required to by law to submit data on newly diagnosed cases of cancer it is hoped that the option of claims aggregator submitted data will prove appealing. The goal of this pilot is to evaluate the feasibility of utilizing medical claims data to obtain longitudinal treatment data.

project_terms:
Data;Ensure;Goals;Insurance;Laws;Malignant Neoplasms;Medical;Medical Surveillance;Modification;Newly Diagnosed;Performance;Recruitment Activity;Research Infrastructure;System;Testing;Work;cost effective;oncology


application_id: 9367360
project_number: 1R01HL138488-01
project_title: Lysophosphatidic Acid Mediates Cardiac Inflammation After Acute Infarction
administering_ic: NHLBI
award_notice_date: 2017-07-28
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: HL
serial_number: 138488
program_official: SOPKO, GEORGE
project_start_date: 2017-08-01
project_end_date: 2022-07-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 11330155
contact_pi: ABDEL LATIF, AHMED
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_terms:
Acute;Acute myocardial infarction;Address;Adhesions;Affect;Animal Model;Atherosclerosis;Blood;Blood Vessels;Bone Marrow;Bone Marrow Cells;Cardiac;Cardiac Myocytes;Cells;Cessation of life;Chemotactic Factors;Clinical;Complement;Coupled;DNA Sequence Alteration;Data;Development;Endothelial Cells;Enzymes;Frequencies;G-substrate;GTP-Binding Proteins;Gap Junctions;Genetic;Goals;Healthcare;Heart;Heart failure;Heritability;Homing;Human;Impairment;Infarction;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Injury;Knowledge;Link;Lipids;Lysophosphatidic Acid Receptors;Lysophospholipids;Mass Spectrum Analysis;Mediating;Metabolism;Mission;Modeling;Molecular;Monocytosis;Morbidity - disease rate;Mus;Myelopoiesis;Myocardial;Myocardial Ischemia;Myocarditis;Outcome;Pathologic;Pathway interactions;Patients;Pharmacology;Phosphoric Monoester Hydrolases;Plasma;Play;Population;Process;Production;Proteins;Public Health;Recovery;Research;Role;Sampling;Signal Pathway;Signal Transduction;Site;Source;Spleen;System;Testing;Therapeutic;Tissues;Tracer;United States National Institutes of Health;Variant;base;cardiogenesis;chemokine;cytokine;experience;genetic manipulation;genetic variant;gustin;healing;improved;inhibitor/antagonist;innovation;lysophosphatidic acid;monocyte;mortality;mouse model;novel strategies;peripheral blood;progenitor;receptor;receptor expression;repaired;response;role model;stable isotope


application_id: 9367032
project_number: 1R01EY028188-01
project_title: Understanding signal processing in retinal bipolar cell pathways
administering_ic: NEI
award_notice_date: 2017-08-01
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: EY
serial_number: 028188
program_official: GREENWELL, THOMAS
project_start_date: 2017-09-01
project_end_date: 2022-05-31
study_section: Neurotransporters, Receptors, and Calcium Signaling Study Section[NTRC]
contact_pi_person_id: 11294714
contact_pi: BORGHUIS, BART GERARD
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_terms:
Address;Aging;Amacrine Cells;Area;Axon;Biosensor;Brain;Calcium;Cell physiology;Cells;Cone;Electrophysiology (science);Equilibrium;Feedback;Glutamate Receptor;Glutamates;Glycine;Goals;Image;Individual;Kainic Acid Receptors;Kinetics;Knowledge;Light;Light Adaptations;Lighting;Maps;Measures;Methods;Molecular;Natural regeneration;Neurons;Optic Nerve;Output;Pathway interactions;Photic Stimulation;Photoreceptors;Preparation;Process;Property;Retina;Retinal;Retinal Cone;Retinal Diseases;Retinal Ganglion Cells;Role;Route;Series;Shapes;Signal Pathway;Signal Transduction;Slice;Stimulus;Stratification;Structure;Synapses;Testing;Transgenic Mice;Vision;Visual;Visual system structure;Whole-Cell Recordings;base;cell type;developmental disease/disorder;experimental study;extrastriate visual cortex;feeding;fluorescence imaging;gamma-Aminobutyric Acid;ganglion cell;information processing;innovation;live cell imaging;loss of function mutation;luminance;mouse model;nervous system disorder;neural circuit;neuromechanism;parallel processing;postsynaptic;prevent;receptive field;receptor;response;retinal rods;signal processing;spatiotemporal;transmission process;two-photon;visual information;visual processing;voltage;voltage gated channel


application_id: 9363914
project_number: 1R01CA217934-01
project_title: (PQ9)A redox-mediated mechanism of chemotherapy-induced cognitive impairment
administering_ic: NCI
award_notice_date: 2017-09-15
opportunity_number: RFA-CA-15-008
application_type: 1
activity_code: R01
ic: CA
serial_number: 217934
program_official: CHEN, WEIWEI
project_start_date: 2017-09-15
project_end_date: 2022-07-31
study_section: Special Emphasis Panel[ZCA1 RTRB-E (M2)]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: BONDADA, SUBBARAO ;BUTTERFIELD, D. ALLAN
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:
4 hydroxynonenal;Address;Alpha Cell;Animal Model;Antibodies;Antineoplastic Agents;Antioxidants;Apoptotic;BCL2 gene;Biochemical;Blood - brain barrier anatomy;Blood Circulation;Brain;Brain Injuries;Cancer Patient;Cancer Survivor;Cells;Choline;Clinical;Clinical Trials;Cognition;Confusion;Cytotoxic Chemotherapy;Development;Doxorubicin;Drug Targeting;Drug usage;Etiology;Family;Functional disorder;Future;Generations;Goals;Immune;Impaired cognition;Impairment;In Vitro;Inflammatory;Injury;Intrathecal Chemotherapy;Knockout Mice;Link;Lymphoma;Magnetic Resonance Spectroscopy;Mediating;Mediator of activation protein;Memory;Mitochondria;Modeling;Molecular;Mus;Neuraxis;Neuronal Injury;Nitrates;Oxidation-Reduction;Oxidative Stress;Pathology;Patients;Peripheral;Permeability;Pharmaceutical Preparations;Plasma;Prevention;Production;Proteins;Proteomics;Publishing;Quality of life;Radiation;Reaction;Reactive Oxygen Species;Recommendation;Research;Respiration;Risk;Role;SOD2 gene;Symptoms;Syndrome;Systemic Therapy;TNF gene;Technology;Testing;Therapeutic Effect;Therapeutic Uses;Tissues;Toxic effect;Toxicity due to chemotherapy;Treatment Efficacy;United States;Vision;antioxidant enzyme;cancer cell;cancer therapy;chemobrain;chemotherapy;cytokine;cytotoxic;design;executive function;experience;extracellular vesicles;improved;in vivo;inhibitor/antagonist;insight;macrophage;mimetics;mitochondrial dysfunction;multitask;neuron loss;nitration;novel;prevent;prototype;specific biomarkers;targeted treatment;tumor


application_id: 9362971
project_number: 1R01HL138179-01
project_title: Platelet Endocytosis in Innate Immunity
administering_ic: NHLBI
award_notice_date: 2017-06-23
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: HL
serial_number: 138179
program_official: YANG, YU-CHUNG
project_start_date: 2017-07-01
project_end_date: 2021-03-31
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:
Surprisingly platelets are capable of many cellular processes (i.e. RNA splicing translationglycosylation endocytosis); however their effects on platelet function are often unclear. Ascirculating sentries platelets sample the vasculature via endocytosis. Some of theendocytosed cargo (i.e. fibrinogen) traffics to granules; however other material initiatesplatelet responses. In this proposal we show that pathogen endocytosis induces immuno-activation of platelets. This likely contributes to the increased cardiovascular risks associatedwith persistent infections (as seen in HIV-1/AIDS patients). In this application we build onour novel findings hypothesizing that platelet endocytosis is critical for innate immuneresponse to viral infections. To test this hypothesis we focus on how platelet endocytosisfacilitates Toll-like Receptor (TLR)-based signaling in an animal model that mimics chronicHIV-1/AIDS. Using novel genetically-altered mice (Arf6-/- VAMP-3-/- and Syntaxin-2/4-/-)which are defective at different endocytic steps we will address the roles routes andmechanisms of platelet endocytosis with specific focus on how platelets interact with HIV-1virus. We propose two specific aims: Aim 1. Determine the effects of defective plateletendocytosis on innate immune responses in a model of viremia. Aim 2. Determine themechanisms and routes of the platelet endocytosis system. Our proposal advances plateletsas active monitors of the vasculature continuously interacting with and interpreting theirenvironment while circulating. In this scenario platelets use endocytosis to continuouslysample their microenvironment and through endocytic trafficking process and evaluate cuesthat initiate responses to what the platelets have endocytosed. Our work will yield insights intoplatelet function during systemic infections thus reshaping the uses of anti-thrombotictherapies. Finally understanding platelet endocytosis will uncover novel strategies to increasethe efficiency of loading platelets with therapeutics that can be used to treat CVD.

project_terms:
AIDS/HIV problem;Acquired Immunodeficiency Syndrome;Address;Affect;Agonist;Albumins;Animal Model;Area;Binding;Biogenesis;Blood - brain barrier anatomy;Blood Platelets;Blood Tests;Blood-Borne Pathogens;Cardiovascular Diseases;Cell physiology;Cells;Cellular biology;Chronic;Clot retraction;Communicable Diseases;Cues;Cytoplasmic Granules;DNA;Data;Dextrans;Endocytosis;Environment;Fibrinogen;Goals;HIV-1;Hemorrhage;Hemostatic function;Image;Immune;Immune response;Immune system;Infection;Injection of therapeutic agent;Innate Immune Response;Innate Immune System;Integrins;Kinetics;Knockout Mice;LAMP-1;Label;Leukocytes;MPL gene;Maps;Measurement;Measures;Mediating;Modeling;Molecular;Monitor;Mus;Natural Immunity;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Phase;Physiological;Platelet Activation;Positioning Attribute;Preparation;Process;Proteins;Public Health;RNA Splicing;Recycling;Role;Route;Sampling;Sepsis;Signal Transduction;Stream;Surface;Surveys;System;Systemic infection;Testing;Therapeutic;Thrombocytopenia;Thrombosis;Thrombus;Toll-like receptors;Transgenic Mice;Translations;Viral;Viremia;Virion;Virus;Virus Diseases;Work;antiretroviral therapy;base;cardiovascular disorder risk;cardiovascular risk factor;detector;disorder risk;emergency service/first responder;experimental study;glycosylation;in vivo Model;insight;novel;novel strategies;particle;pathogen;receptor;response;syntaxin-2;trafficking;uptake

public_health_relevance:
NarrativeRelevance of the Project to Public Health:Cardiovascular disease (CVD) is the #1 killer in the US and the risk for CVD increases by 50% inHIV/AIDS patients. Platelets are circulating sentries that detect and respond to vessel damage and topathogens (e.g. viruses). This proposal seeks to understand how platelets actively test the bloodstream to determine how their sentry duty contributes to CVD during persistent viral infections.


application_id: 9361873
project_number: 1R01ES028321-01
project_title: ROS and Nrf2 in arsenic carcinogenesis
administering_ic: NIEHS
award_notice_date: 2017-08-16
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: ES
serial_number: 028321
program_official: REINLIB, LESLIE J
project_start_date: 2017-09-01
project_end_date: 2022-07-31
study_section: Special Emphasis Panel[ZRG1 DKUS-P (04)]
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
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:
PROJECT SUMMARY Arsenic-induced cancers of lung skin liver and bladder pose serious health threats given the global extentof environmental arsenic contamination. Although the mechanism by which arsenic drives carcinogenesis isstill poorly understood increasing evidence implicates reactive oxygen species (ROS) in transformation ofcells to a malignant phenotype. NF-E2-related factor-2 (Nrf2) is a key transcription factor that regulatesantioxidant proteins to neutralize ROS and restore cellular redox balance. Indeed many natural compoundswith anticancer properties exhibit protective effects by activating Nrf2. Conversely constitutive activation ofNrf2 which is prominent in several types of human cancer cell lines and tumors is known to be oncogenic asit protects cancer cells against oxidative stress and chemotherapeutics. Our preliminary studies have shownthat human lung bronchial epithelial (BEAS-2B) cells exposed to arsenic generate ROS leading to malignantcell transformation and a cascade of subsequent effects: sharply reduced level of ROS; increased levels ofantioxidants; constitutive activation of Nrf2; and resistance to apoptosis. These arsenic-transformed cells alsoexhibit autophagy impairment leading to accumulation of p62 protein and constitutive activation of Nrf2 highlevels of inflammatory agents COX-2 and TNF- and activation of transcription factor hypoxia-inducible factor(HIF)-1. Animals exposed to arsenic through drinking water showed both activated HIF-1 and Nrf2.Knockdown of Nrf2 down-regulates HIF-1 resulting in decreased angiogenesis of arsenic-transformed cells.The central hypothesis is that inducible Nrf2 is anti-oncogenic at the early stage of arsenic-inducedcarcinogenesis (cell transformation) via up-regulation of antioxidants to decrease ROS while constitutivelyexpressed Nrf2 is oncogenic in the later stages (tumorigenesis and metastasis) by inducing resistance toapoptosis creating an inflammatory microenvironment and activating angiogenesis. Aim 1 will elucidate aprotective role of inducible Nrf2 in arsenic-induced malignant cell transformation decrease of ROS by Nrf2induction of Nrf2 target antioxidant proteins by arsenic and protective role of Nrf2 in arsenic-induced oxidativedamage. Aim 2 will establish the oncogenic role of constitutively activated Nrf2 in development of resistance toapoptosis of arsenic-transformed cells. The study will determine whether p62 is a positive inducer of Nrf2establish a mechanism for Bcl-2 up-regulation and elucidate the roles of decreased ROS generation and Bcl-2up-regulation in apoptosis resistance. Aim 3 will establish the oncogenic role of constitutive Nrf2 intumorigenesis and metastasis of arsenic-transformed cells in vivo by deciphering the role of p62/Nrf2 increating an inflammatory microenvironment by studying activation of NF-B and expressions of COX-2 andTNF- in arsenic-transformed cells. The roles of p62 Nrf2 inflammatory proteins angiogenesis and apoptosisresistance in arsenic-induced tumorigenesis and metastasis will be investigated using animal models.

project_terms:
Animal Model;Animals;Antioxidants;Apoptosis;Apoptotic;Arsenic;Autophagocytosis;BCL2 gene;Biological;Cancer cell line;Carcinogens;Cells;Curcumin;Data;Development;Environmental Exposure;Environmental Health;Epithelial;Equilibrium;Exhibits;Exposure to;GTF2H1 gene;Generations;Health;Human;Hypoxia Inducible Factor;Impairment;Individual;Inflammation;Inflammatory;Link;Lung;Malignant - descriptor;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;NF-E2-related factor 2;Nature;Neoplasm Metastasis;Normal Cell;Oncogenic;Oxidation-Reduction;Oxidative Stress;PTGS2 gene;Phenethyl Isothiocyanate;Precancerous Conditions;Premalignant;Privatization;Property;Proteins;Public Health;Publishing;Reactive Oxygen Species;Reporting;Resistance;Resistance development;Resveratrol;Role;Skin Cancer;Stress;Sulforaphane;TNF gene;Time;Transcriptional Activation;United States;Up-Regulation;Water;angiogenesis;antioxidant enzyme;arsenic-induced carcinogenesis;cancer cell;carcinogenesis;cell transformation;chemotherapeutic agent;drinking water;epidemiology study;exposed human population;in vivo;inflammatory milieu;knock-down;malignant phenotype;oxidative damage;protective effect;protein activation;transcription factor;tumor;tumorigenesis

public_health_relevance:
PROJECT NARRATIVE Human environmental exposure to arsenic a Group 1 carcinogen is a world-wide public healthconcern. This proposal investigates the dual roles of Nrf2 in arsenic-induced carcinogenesis. Whileinduction of Nrf2 protects against arsenic-induced cell transformation by activating target antioxidantsagainst reactive oxygen species (ROS) in the early stage of carcinogenesis in the later stage(tumorigenesis and metastasis) constitutive activation of Nrf2 is oncogenic by causing apoptosis resistancein arsenic-transformed cells by creating an inflammatory environment and by activating angiogenesis.


application_id: 9361172
project_number: 261201300013I-2-26100005-2
administering_ic: NCI
project_start_date: 2015-05-01
project_end_date: 2017-04-30
contact_pi_person_id: 14511283
contact_pi: TUCKER, THOMAS
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
funding_mechanism: R and D Contracts
project_abstract:
The SEER Program was initiated in 1972 in response to requirements of the National Cancer Program for assessing the magnitude of the cancer burden in the United States and for identifying factors related to cancer risk and/or patient survival. The SEER Program has among its objectives: 1.         To assemble and report on a periodic basis estimates of cancer incidence. 2.         To monitor annual cancer incidence trends to identify unusual changes in specific forms of cancer occurring in population subgroups defined by geographic demographic and social characteristics. 3.         To provide continuing information on changes over time in extent of disease at diagnosis trends in therapy and changes in cancer patient survival. 4.         To identify the occurrence of possible iatrogenic cancers i.e. cancers that are caused by cancer therapy. 5.         To serve as a research resource to the National Cancer Institute and conduct studies dealing with current cancer control issues as well as problems related to the operation of the SEER Program.

project_terms:
Cancer Burden;Cancer Control;Cancer Etiology;Cancer Patient;Diagnosis;Disease;Incidence;Malignant Neoplasms;Medical Surveillance;Monitor;National Cancer Institute;National Cancer Program;Patients;Performance;Population;Reporting;Research Infrastructure;Resources;SEER Program;Social Characteristics;Subgroup;Time;Treatment-Related Cancer;United States;base;cancer risk;cancer therapy;operation;response;trend


application_id: 9360638
project_number: 5R01HG008988-02
project_title: Addressing Ethical Challenges in Networked Biorepositories
administering_ic: NHGRI
award_notice_date: 2017-07-26
opportunity_number: PA-14-276
application_type: 5
activity_code: R01
ic: HG
serial_number: 008988
program_official: LOCKHART, NICOLE C
project_start_date: 2016-09-28
project_end_date: 2020-07-31
study_section: Special Emphasis Panel[ZRG1-SEIR-R(01)Q]
contact_pi_person_id: 10692185
contact_pi: BROTHERS, KYLE BERTRAM
other_pis: GOLDENBERG, AARON J
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTIndividual institutions across the country have worked to support research in a wide variety of areas includingprecision medicine research by developing large biorepositories comprised of biospecimens and health datacollected from local patients and controls. However these local cohorts rarely provide the diversity and sizeneeded to identify and study subsets of patients who share biological mechanisms for their disease and arethus more likely to respond to the same targeted therapies. To address this need researchers have begun topromote the networking of multiple repositories within or across multiple institutions. This networkedbiorepository approach makes it possible for researchers to access larger more diverse sets of data andbiospecimens in a way that leverages the research relationships that local institutions have built with their owncommunities of donors. In order for this approach to be successful networked biorepositories need to addressimportant ethical legal and social challenges. Networked biorepositories are comprised of diverse sets ofspecimens and data from different institutions each with their own governance structures and donor needs.For these reasons they encounter complex issues related to consent and donor permission privacy and datasecurity and data access. These novel challenges have not previously been examined in detail and bestpractices for addressing these issues through governance and oversight processes are lacking. This study willaddress these important needs through a rigorous mixed-methods study of the perspectives and experiencesof stakeholders currently engaged in designing operating and governing networked biorepositories. It will alsoaim to develop approaches to consent and donor permission privacy and data security data accessgovernance and oversight that are most appropriate and effective for a variety of networked biorepositoryconfigurations.

project_terms:
Address;American;Area;Authorization documentation;Biological;Collection;Communities;Complex;Consent;Country;Data;Data Security;Data Set;Development;Disease;Elements;Ethics;Focus Groups;Future;Genetic Variation;Genomics;Health;Human Resources;Individual;Institution;Interview;Knowledge;Link;Literature;Medical;Methods;National Human Genome Research Institute;Participant;Patients;Persons;Policies;Precision Medicine Initiative;Privacy;Problem Solving;Process;Rare Diseases;Recommendation;Research;Research Personnel;Research Support;Resources;Sampling;Specimen;Structure;Time;Work;biobank;cohort;data access;design;ethical legal social implication;experience;health data;informant;interest;meetings;network models;novel;patient subsets;permissiveness;personalized health care;precision medicine;prospective;repository;sharing data;symposium;targeted treatment;tool

public_health_relevance:
PROJECT NARRATIVENetworked biorepositories make it possible for investigators in a wide variety of research domains to accesslarge diverse collections of biospecimens and health data across multiple institutions. At the same time theyalso raise complex issues related to consent and donor permission privacy and data security and dataaccess. Developing a detailed account of these challenges and identifying appropriate solutions includingeffective governance and oversight processes will enable new and developing networked biorepositories tosupport important health research while at the same time meeting the needs of donors and protecting theinterests of contributing institutions.


application_id: 9360425
project_number: 1U01HL133359-01A1
project_title: Multiscale modeling of inherited cardiomyopathies and therapeutic interventions
administering_ic: NHLBI
award_notice_date: 2017-08-03
opportunity_number: PAR-15-085
application_type: 1
activity_code: U01
ic: HL
serial_number: 133359
suffix: A1
program_official: ADHIKARI, BISHOW B
project_start_date: 2017-08-03
project_end_date: 2022-07-31
study_section: Special Emphasis Panel[ZEB1 OSR-C (M1)]
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH S
other_pis: WENK, JONATHAN F
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_terms:
Acute;Affect;Algorithms;American;Biological Assay;Biology;Cardiac;Cardiac Death;Cardiomyopathies;Cardiovascular Diseases;Cells;Chronic;Computer Simulation;Computer software;Congenital cardiomyopathy;Coupled;DNA Sequence Alteration;Data;Data Analyses;Depressed mood;Development;Drug usage;Elements;Engineering;Fiber;Future;Genetic;Geometry;Goals;Growth;Heart;Heart Abnormalities;Heart Diseases;Heart Hypertrophy;Heart failure;Histology;Hypertrophy;Inherited;Intervention;Kinetics;Laws;Magnetic Resonance Imaging;Mathematics;Measurement;Measures;Modeling;Molecular;Motor;Mutation;Myocardial;Myosin ATPase;Myosin Regulatory Light Chains;Organ;Patients;Pattern;Performance;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Proteins;Records;Research;Research Personnel;Sarcomeres;Scientist;Structure;Techniques;Testing;Therapeutic Intervention;Time;Tissues;Transgenic Animals;Transgenic Mice;Treatment Failure;Validation;Ventricular;Ventricular Remodeling;Wild Type Mouse;Work;cell motility;data modeling;drug testing;experience;experimental study;genetic regulatory protein;improved;innovation;interest;mathematical model;model development;molecular scale;multi-scale modeling;novel therapeutics;personalized medicine;predictive modeling;response;simulation;skills;software development;treatment planning


application_id: 9359613
project_number: 2P01HL078825-11
project_title: Project 4 - Metabolic Regulation of Myocardial Repair
administering_ic: NHLBI
award_notice_date: 2017-08-26
opportunity_number: PAR-16-402
application_type: 2
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2022-08-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP (JH)]
subproject_number: 6153
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
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
project_terms:
Affect;Autologous;Biological;Cardiac;Cause of Death;Cell Communication;Cell Proliferation;Cell Survival;Cell Therapy;Cell Transplantation;Cell secretion;Cells;Characteristics;Chronic;Clinical;Clinical Trials;Collaborations;Comorbidity;Competence;Data;Defect;Diabetes Mellitus;Diabetic mouse;Family suidae;Functional disorder;Glucose;Glycolysis;Heart;Heart Transplantation;Heart failure;Hyperglycemia;Immune;Impairment;In Vitro;Injectable;Insulin Resistance;Intervention;Knowledge;Mediating;Mediator of activation protein;Mesenchymal;Metabolic;Metabolic Diseases;Metabolic Pathway;Metabolism;Mitochondria;Modeling;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Nutrient;Outcome;Paracrine Communication;Patients;Pharmacology;Process;Property;Protocols documentation;Recovery of Function;Regulation;Role;SIRT1 gene;Stem cells;Stress;Testing;Tissues;Transplantation;Treatment Efficacy;Up-Regulation;Work;cardiac repair;clinical translation;cytokine;diabetic;diabetic patient;glucose metabolism;glucose transport;improved;improved functioning;improved outcome;in vivo;insight;ischemic cardiomyopathy;loss of function;negative affect;non-diabetic;novel;overexpression;paracrine;pre-clinical;preclinical study;repaired;response;senescence


application_id: 9359612
project_number: 2P01HL078825-11
project_title: Project 3 - Cell Therapy and Remodeling
administering_ic: NHLBI
award_notice_date: 2017-08-26
opportunity_number: PAR-16-402
application_type: 2
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2022-08-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP (JH)]
subproject_number: 6152
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
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
project_terms:
Acute;Address;Affect;Animals;Attenuated;Autologous;Binding;CD44 Antigens;CD44 gene;Cardiac;Cell Shape;Cell Therapy;Cell Transplants;Cells;Chronic;Clinical;Clinical Trials;Collaborations;Competence;Data;Defect;Environment;Enzymes;Equilibrium;Event;Extracellular Matrix;Extravasation;Family suidae;Fibroblasts;Fibrosis;Future;Goals;Heart;Heart failure;Hyaluronan;Hyaluronidase;Infarction;Inflammation;Inflammatory;Injection of therapeutic agent;Leukocytes;Ligands;Logic;Mediating;Mesenchymal;Metabolism;Modeling;Mus;Muscle;Muscle Cells;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myofibroblast;Pathology;Patients;Phenotype;Positioning Attribute;Process;Production;Recording of previous events;Reporting;Response Elements;Role;Severities;Signal Transduction;Source;Stromal Cells;Testing;Therapeutic;Time;Ventricular Function;Ventricular Remodeling;Work;Wound Healing;clinical translation;effective intervention;gain of function;improved;in vivo Model;innovation;insight;interest;lens;novel;paracrine;pre-clinical;preclinical study;programs;receptor;repaired;response;response to injury;stem;synergism;transdifferentiation


application_id: 9359611
project_number: 2P01HL078825-11
project_title: Project 2 - Role of Inflammation in CMC-Induced Myocardal Repair
administering_ic: NHLBI
award_notice_date: 2017-08-26
opportunity_number: PAR-16-402
application_type: 2
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2022-08-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP (JH)]
subproject_number: 6151
contact_pi_person_id: 11176762
contact_pi: WYSOCZYNSKI, MARCIN
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
project_terms:
Affect;Alpha Cell;Bone Marrow;Cardiac;Cardiac Myocytes;Cardiovascular system;Cell Therapy;Cells;Cessation of life;Clinical;Clinical Research;Coculture Techniques;Data;Diabetes Mellitus;Disease;Fibrosis;Gene Expression;Genetic;Heart;Heart failure;Homeostasis;Homo;Immune;Immune response;Immune system;In Vitro;Infiltration;Inflammation;Inflammatory;Injectable;Injection of therapeutic agent;Injury;Knowledge;Left;Left Ventricular Function;Left ventricular structure;Mediating;Mediator of activation protein;Mesenchymal;MicroRNAs;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Natural regeneration;Nature;Neonatal;Outcome;Patients;Phenotype;Play;Population;Process;Proliferating;Pump;Recruitment Activity;Role;Rupture;Signal Transduction;Spleen;Sterility;Surface;TNFRSF5 gene;Testing;Time;Tissues;Transgenic Organisms;Ventricular;angiogenesis;base;cardiac repair;cell type;extracellular vesicles;improved;in vivo;inhibitor/antagonist;insight;macrophage;monocyte;myocardial damage;novel;p65;preclinical study;programs;repaired;response;synergism


application_id: 9359610
project_number: 2P01HL078825-11
project_title: Project 1 - Repeated Cell Therapy for Heart Failure: A New Paradigm
administering_ic: NHLBI
award_notice_date: 2017-08-26
opportunity_number: PAR-16-402
application_type: 2
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2022-08-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP (JH)]
subproject_number: 6150
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
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
project_terms:
Ablation;Advocate;Animal Model;Cardiac;Cell Therapy;Cell Transplantation;Cell Transplants;Cells;Chronic;Clinical Research;Clinical Trials;Collaborations;Comorbidity;Data;Diabetes Mellitus;Diabetic mouse;Dose;Engraftment;Family suidae;Fibroblasts;Genetic;Goals;Heart;Heart failure;Human;Immune response;Infarction;Inflammatory;Left Ventricular Remodeling;Mesenchymal;Metabolic;Modeling;Mus;Myocardial Infarction;Myocardial Ischemia;Myocardium;Outcome;Patients;Phase I Clinical Trials;Population;Proteins;Protocols documentation;Research;Research Design;Route;Stem cells;Testing;Therapeutic;Therapeutic Effect;Time;Transplantation;Treatment Efficacy;Uncertainty;Vesicle;Work;base;cell type;clinical translation;clinically relevant;efficacy testing;extracellular vesicles;heme oxygenase-1;improved;in vivo;inflammatory modulation;ischemic cardiomyopathy;mouse model;novel;overexpression;pre-clinical;preclinical study;reparative medicine;response;therapeutic effectiveness;transcriptome;vesicular release


application_id: 9359609
project_number: 2P01HL078825-11
project_title: Core D - Pathology and Flow Cytometry Core
administering_ic: NHLBI
award_notice_date: 2017-08-26
opportunity_number: PAR-16-402
application_type: 2
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2022-08-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP (JH)]
subproject_number: 6149
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY 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
project_terms:
American Heart Association;Antibodies;Biochemistry;Biography;Biological;Blinded;Bone Marrow;Budgets;Calibration;Cardiac;Cell Culture Techniques;Cell Cycle;Cell Separation;Cell Therapy;Cell physiology;Cells;Centers of Research Excellence;Collaborations;Collection;Complex;Computer software;Confocal Microscopy;Core Facility;Cost Savings;Data Analyses;Diabetes Mellitus;Doctor of Medicine;Doctor of Philosophy;Ensure;Equipment;Experimental Designs;Financial compensation;Flow Cytometry;Funding;Goals;Heart;Heart failure;Histology;Histopathology;Human Resources;Immunofluorescence Microscopy;Immunohistochemistry;Inflammatory;Institutes;International;Investigation;Laboratories;Maintenance;Mesenchymal;Molecular Biology Techniques;Myocardial Ischemia;Myocardial tissue;Obesity;Pathologic;Pathology;Phenotype;Population;Population Heterogeneity;Procedures;Protocols documentation;Reagent;Regulation;Research Personnel;Rodent Model;Running;Sampling;Signal Transduction;Sorting - Cell Movement;Staining method;Stains;Standardization;Stem cells;Supervision;Techniques;Tissue Sample;Tissues;Tobacco;Training;United States National Institutes of Health;Universities;Work;addiction;analytical tool;base;cell type;experience;experimental study;extracellular vesicles;instrument;light microscopy;member;operation;programs;skills;stem;stem cell biology;tissue processing


application_id: 9359608
project_number: 2P01HL078825-11
project_title: Core C - Cell Biology Core
administering_ic: NHLBI
award_notice_date: 2017-08-26
opportunity_number: PAR-16-402
application_type: 2
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2022-08-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP (JH)]
subproject_number: 6148
contact_pi_person_id: 8307878
contact_pi: LI, QIANHONG
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
project_terms:
Area;Biochemical;Bioinformatics;Biological Assay;Biological Markers;Biology;Bone Marrow;Budgets;Cardiac;Cell Culture Techniques;Cell Cycle;Cell Survival;Cell Therapy;Cell physiology;Cells;Cellular biology;Collaborations;Core Facility;Data Analyses;Data Set;Databases;Disease;Doctor of Medicine;Doctor of Philosophy;Ensure;Equipment;Equipment and Supplies;Equipment and supply inventories;Experimental Designs;Family suidae;Foundations;Funding;Gene Expression;Gene Expression Regulation;Gene Transfer;Genes;Grant;Heart;Human;Human Resources;Immunology;In Vitro;Individual;Institutes;International;Leadership;Length;Maintenance;Mesenchymal;Methods;MicroRNAs;Molecular;Molecular Biology;Molecular and Cellular Biology;Mus;Myocardial Ischemia;Particle Size;Pathway Analysis;Phase;Population;Preparation;Procedures;Production;Proteins;Protocols documentation;Quality Control;RNA;Rattus;Reagent;Reproducibility;Research;Research Personnel;Resources;Role;Signal Transduction;Solid;Source;Span 20;Standardization;Stem cells;Structure of thyroid parafollicular cell;Supervision;Techniques;Time;Training;Transplantation;United States National Institutes of Health;Universities;Untranslated RNA;Validation;Work;cost;experience;experimental study;extracellular vesicles;progenitor;protein profiling;skills;stem;stem cell biology;success;vector;wasting


application_id: 9359607
project_number: 2P01HL078825-11
project_title: Core B - Mouse Surgery and Physiology
administering_ic: NHLBI
award_notice_date: 2017-08-26
opportunity_number: PAR-16-402
application_type: 2
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2022-08-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP (JH)]
subproject_number: 6147
contact_pi_person_id: 8251726
contact_pi: GUO, YIRU
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
project_terms:
Animal Disease Models;Animals;Biography;Biopsy;Blinded;Breeding;Bromodeoxyuridine;Budgets;Cardiac;Cardiac Catheterization Procedures;Cardiovascular Physiology;Cardiovascular system;Catheterization;Catheters;Cell Therapy;Cells;Chin;Collaborations;Complex;Coronary Occlusions;Data Analyses;Data Collection;Development;Doctor of Medicine;Doctor of Philosophy;Echocardiography;Equipment;Family suidae;Funding;Future;Genotype;Heart failure;Human Resources;Injection of therapeutic agent;Intraventricular Infusion;Knock-out;Knockout Mice;Laboratories;Left Ventricular Function;Left Ventricular Remodeling;Length;Magnetic Resonance Imaging;Maintenance;Measurement;Mesenchymal;Modeling;Mus;Myocardial Infarction;Myocardial Ischemia;Operative Surgical Procedures;Output;Paper;Physiological;Physiology;Pressure Transducers;Procedures;Protocols documentation;Quality Control;Radiology Specialty;Reperfusion Therapy;Research;Research Personnel;Scientist;Study of magnetics;Supervision;Techniques;Testing;Transgenic Mice;Transgenic Organisms;Translational Research;Universities;Work;cardiovascular visualization;cohesion;coronary artery occlusion;experience;experimental study;extracellular vesicles;hemodynamics;imaging program;imaging study;implantation;in vivo;molecular imaging;mortality;mouse model;pressure;programs


application_id: 9359606
project_number: 2P01HL078825-11
project_title: Administrative Core
administering_ic: NHLBI
award_notice_date: 2017-08-26
opportunity_number: PAR-16-402
application_type: 2
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2022-08-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP (JH)]
subproject_number: 6146
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
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
project_terms:
Animals;Basic Science;Biography;Biological Markers;Biometry;Biostatistics Core;Blinded;Budgets;Cardiac;Cardiology;Cardiotonic Agents;Cardiovascular system;Cell Therapy;Cells;Clinical Trials;Communication;Data;Data Analyses;Effectiveness;Ensure;Environment;Exclusion Criteria;Faculty;Family suidae;Funding;Future;Goals;Grant;Growth;Guidelines;Human Resources;Individual;Institutes;Institution;Knowledge;Laboratories;Laboratory mice;Leadership;Logistics;Medicine;Mesenchymal;Methods;Mission;Molecular;Monitor;Myocardial Ischemia;National Heart Lung and Blood Institute;Personality;Principal Investigator;Procedures;Productivity;Protocols documentation;Randomized;Reagent;Regulation;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Sample Size;Scientist;Services;Specimen;Standardization;Statistical Methods;Therapeutic Studies;Time;United States National Institutes of Health;Work;base;experience;experimental study;in vivo;meetings;member;multidisciplinary;next generation;power analysis;pre-clinical;preclinical study;programs;student training;tool;treatment group


application_id: 9359605
project_number: 2P01HL078825-11
project_title: Protection of Ischemic Myocardium
administering_ic: NHLBI
award_notice_date: 2017-08-26
opportunity_number: PAR-16-402
application_type: 2
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2022-08-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP (JH)]
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:
Address;Affect;Animal Model;Animals;Attenuated;Autologous;Cardiac;Catabolism;Cell Culture Techniques;Cell Separation;Cell Therapy;Cell Transplantation;Cell Transplants;Cells;Chronic;Clinical Trials;Collaborations;Comorbidity;Competence;Data;Defect;Diabetes Mellitus;Diabetic mouse;Dose;Employee Strikes;Engraftment;Event;Family suidae;Fibroblasts;Flow Cytometry;Funding;Glycolysis;Goals;Heart;Heart failure;Human;Hyaluronan;Immune;Immune response;Infarction;Inflammation;Injury;Intervention;Investigation;Knowledge;Left Ventricular Remodeling;Mediating;Mediator of activation protein;Mesenchymal;Metabolic;Metabolism;Mitochondria;Modeling;Molecular;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Operative Surgical Procedures;Paracrine Communication;Pathology;Patients;Phenotype;Population;Property;Recording of previous events;Recruitment Activity;Regulation;Research Design;Research Personnel;Role;SIRT1 gene;Stromal Cells;Testing;Therapeutic;Therapeutic Effect;Therapeutic Intervention;Time;Translations;Treatment Efficacy;Treatment Protocols;cardiac repair;cell type;clinical application;clinical translation;cohesion;diabetic;effective therapy;extracellular vesicles;immunoregulation;improved;improved outcome;inflammatory modulation;insight;macrophage;monocyte;non-diabetic;novel;novel therapeutics;paracrine;pre-clinical;preclinical study;programs;repaired;reparative medicine;response;stem;tool;translational study;vesicular release;virtual


application_id: 9358711
project_number: 5R03HS024633-02
project_title: Systematic evaluation of operating room scheduling across the perioperative process
administering_ic: AHRQ
award_notice_date: 2017-09-06
opportunity_number: PA-15-147
application_type: 5
activity_code: R03
ic: HS
serial_number: 024633
program_official: BURGESS, DENISE
project_start_date: 2016-09-30
project_end_date: 2019-05-31
study_section: Healthcare Effectiveness and Outcomes Research[HEOR]
contact_pi_person_id: 12233283
contact_pi: LI, WEI
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
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: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This study addresses research priority areas of patient-centered outcomes and health care efficiency in the Agency for Healthcare Research and Quality (AHRQ). Operating room (OR) scheduling is critical for OR management in any hospital setting and this project utilizes information systems and industrial engineering technologies to address a critical health service need. The perioperative (peri-op) process encompasses three stages: 1) preoperative (pre-op); 2) intraoperative (intra-op); and 3) postoperative (post-op). Solutions to improving OR performance in the intra-op stage can only have negative impact on other stages and impair the performance of the whole perioperative (peri-op) process. OR management is complicated involving two flows (information and patient) and three phases (OR planning scheduling and adaptive control). Because of this complexity in OR management the standard practice is to use simple rules in scheduling and key performance indicators to evaluate performance. Our recent studies in production scheduling theory identified inconsistencies between every two adjacent stages in the peri-op process which explains why the currently applied simple rules and key performance indicators (KPIs) are not suitable for OR scheduling. Solutions to OR management should be efficient at the unit level and effective at the hospital level. To achieve efficiency and effectiveness in OR scheduling we will establish a scheme to evaluate the performance of OR scheduling across the peri-op process from the perspectives of time and quality. Specific Aim 1 (effectiveness of OR scheduling at the hospital level) smoothes the information flow between units across the peri-op process and reconciles conflicting incentives of local management of different units by identifying the relationship among units from the quality perspective. Specific Aim 2 (efficiency at the unit level) smoothes the patient flow from the time perspective by simulation and revising our former heuristics for flow shop scheduling. This simulation model will enable University of Kentucky (UK) HealthCare to carry out OR scheduling for elective surgeries emergencies and coordination among its three hospitals. Moreover the application of multi- objective optimization to the findings while extending statistic process control (SPC) technologies in manufacturing and industrial engineering to healthcare systems.

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  This project "Systematic Evaluation of Operating Room (OR) Scheduling across the Perioperative (Peri-op) Process" addresses patient-centered outcomes and health care efficiency in the Agency for Healthcare Research and Quality (AHRQ). This study will examine the root causes to stagnant patient and information flows for surgery services in three hospitals at the University of Kentucky (UK) HealthCare and the performance inconsistencies in the peri-op process. Solutions to OR management generated by this project are efficient at the unit level and effective at the hospital level which is critical to improve te efficiency of surgery service.


application_id: 9358364
project_number: 5UH2NS100606-02
project_title: Small vessel disease biomarkers in a longitudinally-followed "stroke-belt" cohort
administering_ic: NINDS
award_notice_date: 2017-08-08
opportunity_number: RFA-NS-16-020
application_type: 5
activity_code: UH2
ic: NS
serial_number: 100606
program_official: MCGAVERN, LINDA
project_start_date: 2016-09-30
project_end_date: 2018-07-31
study_section: ZNS1-SRB-T(19)
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: JICHA, GREGORY A
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_terms:
ABCC9 gene;Address;Affect;Alzheimer's Disease;Amyloid beta-Protein;Angiogenic Proteins;Applications Grants;Basic Science;Biological Markers;Biometry;Brain;Brain Diseases;Brain Pathology;Cerebral small vessel disease;Cerebrovascular Disorders;Cerebrum;Clinical;Clinical Trials;Cognition;Comorbidity;Data;Dementia;Diagnosis;Diffusion;Disease;Disease Progression;Elderly;Ensure;Foundations;Genetic Polymorphism;Genotype;Goals;Image;Impaired cognition;Individual;Inflammatory;Injury;Interleukin-12;Kentucky;Liquid substance;Longitudinal Studies;Longitudinal cohort;Magnetic Resonance Imaging;Measures;Microvascular Dysfunction;Monitor;Neurofilament-M;Neuropsychology;Participant;Pathology;Patients;Perfusion;Phase;Plasma;Population;Process;Proteins;Public Health;Recording of previous events;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Resource Sharing;Risk;Sampling;Severities;Spatial Distribution;Spin Labels;Subcategory;TNF gene;Therapeutic Intervention;Time;Translational Research;United States National Institutes of Health;Universities;Vascular Diseases;White Matter Hyperintensity;Work;accurate diagnosis;biomarker development;candidate marker;cerebrovascular;cohort;effective intervention;experience;imaging biomarker;imaging modality;medical specialties;member;multidisciplinary;pre-clinical;predictive marker;prognostic;response;sharing data;stroke;success;targeted treatment;tau Proteins;therapeutic development;vascular cognitive impairment and dementia;vascular contributions


application_id: 9358347
project_number: 5R21NS096983-02
project_title: Molecular regulation of myelin development and repair by Ick kinase
administering_ic: NINDS
award_notice_date: 2017-08-02
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: NS
serial_number: 096983
program_official: MORRIS, JILL A
project_start_date: 2016-09-30
project_end_date: 2019-08-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 1906514
contact_pi: QIU, MENGSHENG
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:
Oligodendrocytes are myelin-forming macroglia found in all regions of the centralnervous system. The major function of myelin sheaths is to ensure the rapid andfaithful transmission of electrical signals. During development oligodendrocytesprecursor cells (OPCs) have to go through a series of morphological and molecularchanges before they become fully differentiated into mature myelinatingoligodendrocytes. The differentiation and myelination processes of oligodendrocytesare regulated by protein tyrosine phosphorylation. Recently we found that Ickcytoplasmic serine/threonine kinase is selectively up-regulated in differentiatingOPCs and disruption of Ick resulted a significant inhibition of OL differentiation. Inthis application we hypothesize that Ick enhances OPC differentiation and axonalmyelination by Ick during development and enhance myelin repair followingdemyelination insults. The first aim of this application is to examine whether Ickexpression is required for myelin development in Ick conditional mutant mice andinduced expression of Ick protein in OPCs promotes developmental myelination ininducible transgenic mice. In the second aim we will test the hypothesis that Ickexpression is also required for axonal remyelination in adult animals andoverexpression of Ick in inducible transgenic mice can promote myelin recoveryfollowing demyelination This line of study could help us understand molecular mechanisms thatcontrol axonal myelination process and provide insights into the development ofmolecular approaches to stimulate oligodendrocyte regeneration and remyelination indemyelinating diseases.

project_terms:
Address;Animal Model;Axon;Birth;Cell Communication;Cell Differentiation process;Cells;Cuprizone;Demyelinating Diseases;Demyelinations;Development;Developmental Process;Ensure;In Situ;Injury;Intestines;Knock-out;Knockout Mice;Knowledge;Ligands;Molecular;Morphology;Mutant Strains Mice;Myelin;Myelin Sheath;Natural regeneration;Nature;Neuraxis;Neurologic;Oligodendroglia;Patients;Pattern;Phenotype;Phosphorylation;Phosphotransferases;Play;Process;Protein Kinase;Protein-Serine-Threonine Kinases;Proteins;Recovery;Regulation;Role;SHH gene;Series;Signal Transduction;Spinal Cord;Spinal cord injury patients;Surface;Testing;Time;Transducers;Transgenic Mice;Tyrosine Phosphorylation;base;conditional mutant;insight;macroglia;mature animal;mutant;myelination;neonatal death;oligodendrocyte precursor;overexpression;postnatal;precursor cell;receptor;remyelination;repaired;screening;smoothened signaling pathway;transmission process

public_health_relevance:
The proposed studies will provide important information on the functional role of Ickcytoplasmic serine/threonine kinase in the control of oligodendrocyte differentiationmyelin development and repair in the developing central nervous system. Knowledgeobtained from this study will yield important insights into the development of molecularstrategies for promoting oligodendrocyte regeneration and axonal remyelination inneurological patients and spinal cord injury patients.


application_id: 9357731
project_number: 5R01NR016824-02
project_title: Rural Intervention for Caregivers' Heart Health (RICHH)
administering_ic: NINR
award_notice_date: 2017-06-28
opportunity_number: RFA-NR-16-003
application_type: 5
activity_code: R01
ic: NR
serial_number: 016824
program_official: HUSS, KAREN
project_start_date: 2016-09-26
project_end_date: 2021-06-30
study_section: ZNR1-REV-M(25)
contact_pi_person_id: 1906318
contact_pi: MOSER, DEBRA KAY
other_pis: CHUNG, MISOOK LEE
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:
Address;Adherence;Adult;American;Behavior;Blood Pressure;Body mass index;Cardiac health;Cardiovascular Diseases;Caregivers;Caring;Cessation of life;Chronic Disease;Chronically Ill;Communication;Computer software;Control Groups;Data;Development;Devices;Diagnostic;Diet;Distress;Economically Deprived Population;Enrollment;Environment;Epidemic;Family;Family Caregiver;Family member;Female;Fibrinogen;Gender;Goals;Health;Health Personnel;Health Policy;Health Promotion;Health Resources;Health behavior;Healthcare;Heart Diseases;High Prevalence;Individual;Intervention;Kentucky;Light;Lipids;Long-Term Effects;Maintenance;Major Depressive Disorder;Mental Depression;Mental Health;Methods;Modality;Multimedia;Outcome;Patient Care;Patient Self-Report;Patients;Persons;Physical activity;Physically Handicapped;Policy Maker;Population;Poverty;Prevention;Psyche structure;Quality of life;Randomized;Randomized Clinical Trials;Randomized Controlled Trials;Reporting;Research;Resources;Risk;Risk Factors;Risk Reduction;Rural;Rural Health;Self Care;Self Management;Skilled Nursing Facilities;Symptoms;Tablets;Technology;Testing;Time;United States Health Resources and Services Administration;Videoconferencing;Work;associated symptom;cardiogenesis;cardiovascular disorder risk;cardiovascular health;caregiver interventions;caregiving;clinically significant;depressive symptoms;design;digital;efficacy testing;evidence base;group intervention;health care availability;health disparity;high risk;improved;informal caregiver;innovation;intervention effect;intervention program;male;mortality;physical conditioning;prevent;primary caregiver;primary outcome;programs;psychological distress;rural America;rural area;rural environment;rural setting;social;socioeconomics;treatment as usual


application_id: 9357587
project_number: 5R21ES027391-02
project_title: Treatment of persistent chlorine-induced small airway disease
administering_ic: NIEHS
award_notice_date: 2017-08-02
opportunity_number: PAR-15-315
application_type: 5
activity_code: R21
ic: ES
serial_number: 027391
program_official: NADADUR, SRIKANTH
project_start_date: 2016-09-30
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1-MDCN-B(55)R]
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY W.
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV 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 PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent because of thepossibility that it could be released in industrial accidents or terrorist attacks. Acute effects of chlorineinhalation include dyspnea hypoxemia pneumonitis and pulmonary edema. Longer term consequences ofchlorine inhalation include both pulmonary function impairment and structural changes that have beenobserved in some exposed individuals. Our collaborator Dr. Erik Svendsen has documented pulmonaryfunction abnormalities in a population of individuals who were exposed to chlorine as a result of a largeaccidental release that occurred in Graniteville SC in 2005. The results point to a spectrum of respiratorydisease states but suggest that an important component involves small airway disease. An impediment todeveloping countermeasures for persistent chlorine-induced lung disease is the lack of a relevant animalmodel for efficacy testing. Our preliminary data indicate that rabbits exposed to chlorine and examined 7days later exhibit inflammation of the small airways and develop sporadic obliterative lesions characteristic ofbronchiolitis obliterans (BO). These animals exhibited normal baseline lung resistance but exhibitedhyperreactivity to inhaled methacholine. Based on these preliminary data we propose to expand on thesestudies to develop a model in which the obliterative changes to small airways are more widespread resultingin increased baseline lung resistance as has been observed in humans exposed to chlorine gas. We willthen assess the efficacy of a potential countermeasure when administered following chlorine exposure forthe prevention of small airway disease. The hypotheses to be tested are: 1) Increasing post-exposuremonitoring time and/or chlorine dose will produce widespread small airway BO lesions that result insignificant increases in baseline lung resistance; and 2) Treatment with inhaled corticosteroid plus -adrenergic agonist after chlorine exposure will inhibit the development of BO lesions and abnormal lungfunction. Specific Aim 1 will be to develop an animal model of persistent chlorine-induced lung disease thatreplicates the disease states observed in chlorine-exposed humans. Specific Aim 2 will be to evaluate acurrently available therapy (inhaled corticosteroid plus long-acting -adrenergic agonist) in a rabbit model ofpersistent chlorine-induced lung disease. These exploratory studies will generate valuable informationtoward development of an appropriate animal model for countermeasure testing and will generate initial dataregarding efficacy of a type of treatment currently used for irritant-induced asthma that could be readilyadopted as a countermeasure.

project_terms:
Acute;Acute Lung Injury;Adopted;Adrenal Cortex Hormones;Adrenergic beta-Agonists;Adverse effects;Affect;Airway Obstruction;Animal Model;Animals;Area;Asthma;Breathing;Bronchiolitis Obliterans;Characteristics;Chemicals;Chlorine;Chronic;Conscious;Data;Development;Disease;Dose;Dyspnea;Exhibits;Exposure to;Fibrosis;Genetic;Goals;Histologic;Hospitals;Human;Hypoxemia;Impairment;Individual;Industrial Accidents;Industrialization;Inflammation;Inflammatory;Investigation;Irritants;Length;Lesion;Lung;Lung diseases;Mechanics;Methods;Modeling;Molecular;Monitor;Morbidity - disease rate;Mus;Oryctolagus cuniculus;Pathology;Poisoning;Poisons;Population;Prevention;Pulmonary Edema;Pulmonary Inflammation;Pulmonary Pathology;Recording of previous events;Recovery;Research;Resistance;Respiratory physiology;Techniques;Terminal Bronchiole;Testing;Therapeutic;Time;Toxic effect;Trachea;Trees;Unconscious State;United States;Ventilator;acute symptom;base;chemical threat;chlorine gas;efficacy testing;experimental study;injury and repair;interest;lung injury;methacholine;morphometry;novel;prevent;pulmonary function;repaired;respiratory;respiratory health;small airways disease

public_health_relevance:
The goal of the proposed experiments is to develop novel ways to treat chronic airway disease caused byacute high level exposure to chlorine gas. This type of research is important because of concerns that U.S.civilians could be adversely affected by the accidental or intentional release of highly toxic chemicals suchas chlorine.


application_id: 9357568
project_number: 5U01DK074007-12
project_title: University of Louisvilles Clinical Center in Gastroparesis Clinical Research Consortium
administering_ic: NIDDK
award_notice_date: 2017-09-01
opportunity_number: RFA-DK-16-010
application_type: 5
activity_code: U01
ic: DK
serial_number: 074007
program_official: HAMILTON, FRANK A
project_start_date: 2006-04-15
project_end_date: 2021-08-31
study_section: ZDK1-GRB-8(O2)S
contact_pi_person_id: 8264660
contact_pi: ABELL, THOMAS LYMAN
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:
Abdominal Pain;Affect;Anatomy;Ancillary Study;Area;Brain;Chronic;Clinical;Clinical Research;Complex;Data;Databases;Devices;Digestive System Disorders;Disease;Effectiveness;Electric Stimulation;Electrolytes;Electrophysiology (science);Enteral;Etiology;Functional disorder;Gastric Emptying;Gastroparesis;Goals;Grant;Health;Homeostasis;Inflammatory;Insulin Infusion Systems;Knowledge;Life;Liquid substance;Malnutrition;Measures;Methods;Mission;Motor;Motor Activity;Multicenter Studies;Natural History;Nausea;Nausea and Vomiting;Nortriptyline;Nutritional Support;Nutritional status;Outcome;Pain;Pathogenesis;Patient-Focused Outcomes;Patients;Peripheral;Pharmacology Study;Physical Function;Physicians;Psychological Impact;Publications;Publishing;Quality of life;Recommendation;Recruitment Activity;Registries;Research;Safety;Sensory;Series;Severities;Signal Transduction;Stomach;Symptoms;Syndrome;Time;Tissue Sample;Treatment Efficacy;United States National Institutes of Health;Universities;Visceral;Vomiting;Work;aprepitant;base;disability;early satiety;effective therapy;glucose monitor;improved;motor disorder;novel strategies;response;social;treatment strategy;young woman


application_id: 9357488
project_number: 5R21AG052050-02
project_title: Optimal Vitamin D Status as a Strategy to Rescue Cognitive Aging
administering_ic: NIA
award_notice_date: 2017-04-07
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AG
serial_number: 052050
program_official: WAGSTER, MOLLY V
project_start_date: 2016-09-30
project_end_date: 2021-04-30
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 7875396
contact_pi: PORTER, NADA MICOVIC
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:
Optimal Vitamin D Status as a Strategy to Rescue Cognitive Aging NIA PA-13-303SUMMARY/ABSTRACTBecause the numbers of older adults are increasing dramatically there is an urgent need to identify interventionsthat may alleviate the personal/socioeconomic burdens associated with age-related memory impairment. Onesuch potential intervention is treatment with vitamin D. Lower serum vitamin D levels are linked to several age-related disorders including cognitive decline and aging individuals are especially susceptible to vitamin Ddeficiency. For these reasons and because we previously found that vitamin D can reduce severalneurophysiological markers of brain aging we recently undertook a major vitamin D intervention study in malerats. For 6 months we fed aging male rats different amounts of vitamin D in an attempt to model serum levelsof vitamin D found in humans ranging from deficient to sufficient. We found that rats with higher serum levelsof vitamin D considered in the optimal range for humans had superior long term memoryoutperforming rats with lower vitamin D on a complex memory task (spatial reversal in the water maze).Additional electrophysiological and gene expression analyses showed that hippocampal synaptic function andmultiple synaptic markers were altered with higher serum levels of vitamin D including gene expression forNr4a2 an immediate early gene and transcription factor that appears to selectively promote long-term memory.Interestingly our preliminary results from a separate study show that Nr4a2 is expressed in a sex-dependentmanner in the hippocampus. Because women are more than twice as likely to be vitamin D deficient and because the consequences ofcognitive aging are greater in women our goal is to determine whether vitamin D intervention in aging femalescan offset cognitive decline as it does in males. Therefore in Aim 1 we directly compare mid-aged male andfemale F344 rats treated with diets containing standard or higher vitamin D3 to test the hypothesis that higherserum levels of vitamin D will prevent declining memory function in females as in males. This Aim uses asystems-level approach that includes behavioral testing of multiple forms of memory in the Morris water mazeand molecular analyses (gene expression microarrays and immunohistochemistry) to assess processespertaining to memory. Aim 2 compares males and females on the high vitamin D3 diet to test the novelhypothesis that Nr4a2 is necessary for the cognition enhancing effects of vitamin D. F344 rats will receive intra-hippocampal injections of a viral vector containing shNr4a2 to knockdown Nr4a2 activity. Outcome measureswill be the same as in Aim 1. This proposal builds on recent NIH initiatives to investigate sex as a relevantbiological variable in order to appropriately tailor therapies/interventions. As the F344 rat is a relevant model ofhuman aging for both sexes our results also will provide pertinent mechanistic information regarding vitamin Daction in the brain. Further studies on Nr4a2 which selectively promotes long-term memory and appears to beboth vitamin D- and sex-dependent stand to significantly move the field of cognitive aging forward.

project_terms:
Address;Affect;Aging;Animals;Attention;Biological;Blood;Brain;Candidate Disease Gene;Canis familiaris;Cell Communication;Cholecalciferol;Cognition;Cognitive;Cognitive aging;Complex;Diet;Disease;Dose;Elderly;Electrophysiology (science);Female;Gene Chips;Gene Expression;Gene Expression Profiling;Genes;Goals;Hippocampus (Brain);Human;Immediate-Early Genes;Immunohistochemistry;Impaired cognition;Inbred F344 Rats;Individual;Injection of therapeutic agent;Intervention;Intervention Studies;Learning;Link;Longevity;Mediating;Mediator of activation protein;Memory;Memory Loss;Memory impairment;Modeling;Molecular Analysis;Mus;Nuclear Orphan Receptor;Outcome Measure;Pathway interactions;Pattern;Performance;Population Study;Predisposition;Process;Rattus;Serum;Sex Characteristics;Study models;Synapses;Synaptic Transmission;System;Technology;Testing;Therapeutic Intervention;Time;Treatment Efficacy;United States National Institutes of Health;Viral Vector;Vitamin D;Vitamin D Deficiency;Water;Woman;age related;aged;aging brain;base;behavior test;bone health;brain tissue;cerebral atrophy;cognitive function;cognitive performance;dosage;improved;knock-down;long term memory;male;middle age;morris water maze;neurophysiology;novel;precision medicine;prevent;sex;small hairpin RNA;socioeconomics;synaptic function;transcription factor

public_health_relevance:
Project Narrative:The goal of this proposal is to determine if the therapeutic efficacy of dietary vitamin D inpreserving cognitive function in aging is sex dependent. Animals will receive either a standardor high vitamin D diet beginning at middle-age for six months because this time period has thegreatest potential for preserving cognitive function. Aged rats 18 months old will be evaluatedon a learning and memory task and gene expression from brain tissue will be analyzed.


application_id: 9356678
project_number: 3P30AG028383-13S1
project_title: University of Kentucky Alzheimer's Disease Core Center - Biomarker Core
administering_ic: NIA
award_notice_date: 2018-09-14
opportunity_number: PAR-13-342
application_type: 3
activity_code: P30
ic: AG
serial_number: 028383
suffix: S1
study_section: Special Emphasis Panel[ZAG1 ZIJ-G (M2)]
subproject_number: 5033
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
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: 2017-08-15
project_abstract:
ABSTRACT The University of Kentucky Alzheimer's Disease Center (UK-ADC) was founded in 1985 prior to theadvent of biomarker initiatives that continue to grow in size and scope. We propose the development of aBiomarker Core to enrich the UK-ADC and provide an infrastructure that will allow us to contribute significantlyto the discovery of antemortem biomarkers. The UK-ADC has focused on the early transitions from normalcognitive aging to the development of cognitive impairment. The shift of focus in the AD field to earlier pre-clinical stages of disease ideally positions our center which has had a focus on subjects with normal cognitionand early detection and tracking of changes associated with degenerative disease states for the last 30 years.As a result our center has collected over 700 plasma samples 100 CSF samples and 250 MRI batteries fromcognitively intact individuals. Further we have over 350 plasma samples 150 CSF samples and 300 MRIbatteries from individuals with mild cognitive impairment. In establishing a biomarker core we will build aninfrastructure that allows us to analyze distribute and track these valuable current and future biomarkersamples. The infrastructure will also provide the means for us to support intramural extramural and nationalbiomarker initiatives such as NACC ADGC/NCRAD ADNI ADCS/ATRI and other NIH/NIA initiatives. We willalso establish a trial-ready biomarker-characterized subject cohort facilitating enrollment into intramural andextramural clinical translational studies to eliminate recruitment and screen fail bottlenecks. Finally our centerhas been at the forefront of research on AD-mimics including hippocampal sclerosis (HS-Aging) primary age-related tauopathies (PART) cerebral age-related TDP-43 and sclerosis (CARTS) and vascular contributions tocognitive impairment and dementia (VCID). As such the addition of a biomarker core will allow us to continueto contribute to these fields and the rapidly growing interest in biomarker development in these areas. Overallthe bolus of support for our new biomarker core will allow us the increased infrastructure needed to supportNIH/NIA initiatives and our researchers needs in the 21st century and beyond.

project_terms:
Aging;Algorithms;Alzheimer's Disease;Alzheimer's Disease Core Center;Amyloid;Amyloid beta-Protein;Area;Autopsy;Awareness;Biological;Biological Markers;Biometry;Blood;Bolus Infusion;Budgets;Cataloging;Catalogs;Cerebrum;Clinical;Cognition;Cognitive;Cognitive aging;Collection;Communities;Complex;Consensus;Consent;Data;Degenerative Disorder;Dementia;Development;Diagnosis;Disease;Early Diagnosis;Enrollment;Extramural Activities;Funding;Future;Image;Impaired cognition;Individual;Inflammatory;International;Intervention Studies;Investigation;Kentucky;Letters;Liquid substance;Longitudinal cohort;Magnetic Resonance Imaging;Modeling;Pathologic;Pathway interactions;Pharmaceutical Preparations;Plasma;Policies;Positioning Attribute;Positron-Emission Tomography;Procedures;Protocols documentation;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Risk;Sampling;Sclerosis;Stress;Tauopathies;Translational Research;United States National Institutes of Health;Universities;Validation;Work;age related;base;biomarker development;biomarker discovery;clinical development;clinical phenotype;cognitive development;cohort;comparative;cost;hippocampal sclerosis;interest;mild cognitive impairment;neuroimaging;neuropathology;novel;novel marker;pre-clinical;programs;protein TDP-43;recruit;sharing data;stem;translational study;vascular cognitive impairment and dementia


application_id: 9356677
project_number: 3P30AG028383-13S1
project_title: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2018-09-14
opportunity_number: PAR-13-342
application_type: 3
activity_code: P30
ic: AG
serial_number: 028383
suffix: S1
program_official: SILVERBERG, NINA B
project_start_date: 2006-07-01
project_end_date: 2021-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-G (M2)]
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
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:
PROJECT SUMMARY/ABSTRACT  OVERALL (Adapted from Abstract of parent grant UK-ADC)The University of Kentucky Alzheimer's Disease Core Center (UK-ADC) is an experienced and collaborativeADC originally funded in 1985. Our principal mission is to serve as the focal point for all AD-related activities atUK and this region of the United States by providing an environment and core resources that catalyzeinnovative research outreach education and clinical programs. Our signature resources include: 1) acognitively normal group of ~500 subjects followed longitudinally with all committed to brain autopsy upondeath; 2) a strong program in clinical-neuropathological correlations and short postmortem interval autopsies;3) a maturing program studying the early preclinical biological emergence of pathology that may lead todementia states with an increasing focus on antemortem imaging and CSF biomarker collection; 4) anintegrated centralized database and innovative biostatistical expertise to characterize clinical and biologicaltransitions; and 5) a successful and close partnership with the African-American community and increasedparticipation of underrepresented individuals in our longitudinal cohort and ADC-affiliated research studies andclinical trials. The overall scientific emphasis of the UK-ADC continues to be on our interrelated themes:Transitions & Translation. Our well-characterized longitudinal cohort and historically strong neuropathologyprogram focused on normal aging preclinical disease states and early cognitive transitions have been centralto our success in defining early pathogenic mechanisms underlying the transitions from normal cognitive agingto impairment. The depth of expertise and collaborative nature of our investigators have also resulted insubstantial progress on translation of that knowledge into new targets and novel therapeutic strategies. TheUK-ADC will continue to provide the infrastructure and resources to focus on these integrated themes andadvance innovative AD research through the pursuit of four overarching specific aims.Aim 1. Facilitate and enhance basic translational and clinical research in AD and related dementias.Aim 2. Provide the necessary resources and interactive environment to support and create new opportunitiesfor innovative research.Aim 3. Maintain and grow educational opportunities and community partnerships to promote awarenessincrease participation in research and provide an innovative and interdisciplinary training environment.Aim 4. Contribute to the national efforts to advance AD research education and care.The UK-ADC provides an infrastructure and environment that focuses on these integrated themes andadvances AD research education outreach and clinical programs through highly interactive and effectivecomponents: Administrative Core Clinical Core Data Management and Statistics Core Neuropathology CoreOutreach and Recruitment Core Research Education Component and proposed new Biomarker Core.

project_terms:
African American;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Autopsy;Awareness;Basic Science;Biological;Biological Markers;Biometry;Brain;Caring;Cessation of life;Clinical;Clinical Research;Clinical Trials;Cognitive;Cognitive aging;Collaborations;Collection;Communities;Community Outreach;Comorbidity;Databases;Dementia;Disease;Education;Education and Outreach;Environment;Funding;Goals;Health Professional;Image;Impaired cognition;Impairment;Individual;Industry;Intervention;Kentucky;Lead;Longitudinal cohort;Mission;Nature;Neurodegenerative Disorders;Outcome;Pathogenicity;Pathology;Pilot Projects;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Risk;Training;Translating;Translational Research;Translations;United States;Universities;Work;aging brain;biomarker development;clinical practice;cognitive development;cohesion;collaborative environment;community partnership;data management;education research;experience;healthcare community;innovation;knowledge translation;neuropathology;new therapeutic target;next generation;normal aging;novel therapeutics;outreach;parent grant;pre-clinical;prevent;programs;recruit;research study;statistics;success

public_health_relevance:
NARRATIVE  OVERALL (from parent grant UK-ADC)The University of Kentucky Alzheimer's Disease Center facilitates and supports research efforts to identify theearly manifestations of disease and the pathogenic mechanisms underlying the transitions from normal agingto the development of cognitive impairment with an overall goal of more rapid translation of that knowledgeinto new therapies to delay or prevent AD. We are also dedicated to training the next generation ofresearchers and to educating the lay and healthcare community to increase awareness of AD and relateddisorders and the importance of research and research participation.


application_id: 9356446
project_number: 5R44AA025804-02
project_title: Mutant transgenic plant cells as a novel source of drugs
administering_ic: NIAAA
award_notice_date: 2017-08-21
opportunity_number: PAR-14-088
application_type: 5
activity_code: R44
ic: AA
serial_number: 025804
program_official: FERTIG, JOANNE
project_start_date: 2016-09-22
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1-IMST-L(10)B]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractThe objective is further development of a biotechnology that evolves biosynthesis in a plant species towardbioactive metabolites with a specific molecular target. In wild-type plants bioactive metabolites have generallyevolved by mutation and natural selection over millennia [1] whereas here target-directed evolution canchange the active metabolite profile in mutant plant cells within months. Proof of concept has been obtained inLobelia cardinalis which contains the complex alkaloid lobinaline. This is a novel inhibitor of the dopaminetransporter (DAT) [2] a molecular target in Parkinson's Disease and drug dependence [34 ]. First hairy rootcultures of this species were transformed to express the human DAT. This made these transgenic (hDAT)plant cells highly susceptible to toxicity induced by the neurotoxin MPP+ which is accumulated intracellularlyby activity of the DAT. Gain of function mutants of these transgenic cells were then generated in aconcentration of MPP+ that is lethal to non-mutants. This selection procedure favors survival of mutants thatoverproduce metabolites that inhibit the DAT. As a result more than half the >100 MPP+-resistant mutantswere significantly overproducing DAT inhibitory activity relative to controls. In the majority of these mutantsenhanced DAT inhibition could be ascribed to lobinaline or other known active metabolites but 25 mutantscontain unknown DAT inhibitors. In these mutants there are 9 novel HPLC peaks that are not observed inwild-type and these all contain DAT inhibitory activity. The first specific aim is to separate sufficient quantitiesof these metabolites for chemical identification and pharmacological analysis (DAT inhibition in vitro and invivo). This will establish whether novel DAT inhibitory metabolites with therapeutic potential exist in thesemutants. Many of the remaining MPP+-resistant population (mutants that do not overproduce DAT inhibitors)appear to overproduce metabolites that inhibit the intracellular mechanism of MPP+. Extracts from thesemutants protect the dopaminergic cell line SH-SY5Y against MPP+ and so may contain novel neuroprotectivemetabolites. The second specific aim is to separate and analyze these also using the same approach basedon separation and analysis of novel HPLC peaks so that their potential therapeutic value can be ascertained.Successful completion of these aims will establish proof of application for the technology as a platform for plantdrug discovery. The same approach can also be used to generate overproducing mutants to becomebiosynthetic production systems and as a means of optimizing biosynthesis of therapeutic metabolites inmedicinal plants. In addition although this proposal uses the human DAT and L. cardinalis as examples thetechnology can be applied to many other targets and plant species. If adopted by the global pharmaceuticalindustry this could be a transformative technology. The applicants intend to pursue this in phase III by seekingpartnerships with major pharmaceutical and/or biotechnology companies. Thus the main purpose of theproposal is technology development to be achieved by demonstrating that this approach is capable ofdiscovering novel active metabolites with therapeutic potential in mutant transgenic plant cells.

project_terms:
1-Methyl-4-phenylpyridinium;Adopted;Alkaloids;Alpha Cell;Anabolism;Biotechnology;Carbon;Cell Line;Cells;Chemicals;Complex;Development;Directed Molecular Evolution;Dopaminergic Cell;Drug Addiction;Drug Industry;Evaluation;Freeze Drying;High Pressure Liquid Chromatography;Human;In Vitro;Industry;Lobelia;Mass Fragmentography;Mass Spectrum Analysis;Medicinal Plants;Methanol;Methodology;Molecular Target;Mutation;N-Methylaspartate;Natural Selections;Neurons;Neurotoxins;Nuclear Magnetic Resonance;Parkinson Disease;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phase;Plant Roots;Plants;Population;Preparation;Procedures;Production;Proteins;Protons;Resistance;Resolution;Source;Spectrometry;Spectrum Analysis;Structure;Synapses;System;Technology;Testing;Therapeutic;Toxic effect;Traditional Medicine;Transgenic Organisms;Transgenic Plants;Work;alpha Toxin;aqueous;base;chemical synthesis;commercialization;cytotoxicity;dopamine transporter;drug discovery;drug production;gain of function;gain of function mutation;in vitro activity;in vivo;inhibitor/antagonist;mutant;novel;novel therapeutics;technology development;therapeutic target;uptake;vibration

public_health_relevance:
Project narrativeThe company is developing a technology which enables us to tell mutant cells of a plant species what kind ofdrug we want them to make. This proposal applies the technology to drugs that may be of value in Parkinson'sDisease or drug dependence. The main objective is to show that the technology works so that it can beadopted by the industry as an alternative to chemical synthesis as a source of new drugs.


application_id: 9355554
project_number: 261201300013I-1-26100007-1
project_title: SEER LINKED VIRTUAL TISSUE REPOSITORY (VTR)
administering_ic: NCI
project_start_date: 2015-09-11
project_end_date: 2018-09-10
contact_pi_person_id: 14259412
contact_pi: TUCKER, THOMAS
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
funding_mechanism: R and D Contracts
project_abstract:
The National Cancer Institute Surveillance Epidemiology and End Results (SEER) Program is interested in developing a SEER-linked Virtual Tissue Repository (VTR). A SEER VTR with its population representativeness and large sampling frame would be a unique resource for assembling robust collections of biospecimens even for rare tumors and outcomes. SEER demographic and clinical data can be augmented with custom annotation of data including detailed chemotherapy time to recurrence and body mass index.The objectives of the VTR Pilot Study are to assess the ability of SEER RegistriesTo serve as a resource for biospecimen researchTo locate cases with biospecimens in pathology laboratories and determine the requirements to retrieve those biospecimensTo provide custom annotation of specified data itemsThe VTR Pilot will also capture costs to identify and annotate these biospecimens.

project_terms:
Body mass index;Clinical Data;Collection;Custom;Data;Laboratories;Link;Medical Surveillance;National Cancer Institute;Outcome;Pathology;Pilot Projects;Population;Recurrence;Registries;Research;Resources;SEER Program;Sampling;Specific qualifier value;Time;Tissues;chemotherapy;cost;interest;repository;tumor;virtual


application_id: 9355149
project_number: 5R21DE026280-02
project_title: Protease - protease inhibitor system of Tannerella forsythia
administering_ic: NIDCR
award_notice_date: 2017-08-23
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: DE
serial_number: 026280
program_official: LUNSFORD, DWAYNE
project_start_date: 2016-09-20
project_end_date: 2019-08-31
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: 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:
Tannerella forsythia belongs to the red complex of oral bacteria strongly associated with progression ofchronic periodontitis. However in contrast to Porphyromonas gingivalis and Treponema denticola (othermembers of the red complex) relatively little is known about virulence factors produced by T. forsythia. Afeature in common between these and other periodontal pathogens is the production of high levels ofproteolytic enzymes. In T. forsythia the majority of proteolytic activity is due to six secreted proteases ofunique subdomain structure (KLIKK proteases) belonging to five different families of serine and metallo-proteases. On the genomic level every gene of the KLIKK protease is directly preceded by a gene encoding aputative lipoprotein in a seemingly co-transcriptional unit. Based on preliminary data it is clear that at least twoof these proteins are inhibitors of the adjacent protease. Therefore we collectively designated these genes asFLIPPINs (Forsythia Lipoprotein Protease INhibitors). Flippins are small proteins (118-152 residues) whichexhibit no sequence similarity with each other or with any other protein (the only exception is Flippins B1 andB2 which are 82% identical). Therefore we hypothesize that Flippins are outer-membrane anchored proteaseinhibitors with novel structure and function protecting T. forsythia from its own enzymes and thus essential forT. forsythia biological fitness. Furthermore we theorize that they will also inhibit host proteases as well asproteases secreted by other bacteria in the pathogenic subgingival biofilm to protect the native organism.Hence this research proposal will investigate the important and innovative concept that Flippins through theirability to control proteolysis in the biofilm may represent a new and previously unrecognized class of virulencedeterminants or modifiers. Therefore the main objective of this proposal is to characterize functionexpression specificity and role in T. forsythia biology of selected Flippins as outlined in two Specific Aims:(i) characterization of the specificity spectrum and mechanism of protease inhibition by Flippins; and(ii) determination the regulation of selective Flippins expression subcellular localization and their role in T.forsythia biology. The significance and impact of this project is that the functional characterization of Flippinsmay highlight novel regulatory mechanisms to control proteolytic activity and provide new insights on T.forsythia physiology its role in the subgingival biofilm and mechanism of virulence. This knowledge will createnovel perspectives in the treatment of periodontitis.

project_terms:
Address;Bacteria;Biological;Biology;Cells;Chronic;Complex;Data;DegP protease;Development;Drug Targeting;Environment;Enzyme Precursors;Enzymes;Exhibits;Family;Forsythia;Genes;Genetic Transcription;Genomics;Gram-Negative Anaerobic Bacteria;Growth;Homeostasis;Hydrolysis;Immune response;Inflammation;Inflammatory;Kinetics;Knowledge;Light;Lipoproteins;Membrane;Messenger RNA;Metalloproteases;Microbial Biofilms;Natural Immunity;Operon;Oral;Organism;Pathogenicity;Peptide Hydrolases;Peptides;Periodontal Diseases;Periodontitis;Physiology;Porphyromonas gingivalis;Process;Production;Prokaryotic Cells;Protease Inhibitor;Proteins;Proteolysis;Regulation;Research;Research Proposals;Resistance;Role;Serine;Specificity;Structure;Subtilopeptidase A;Surface;Symbiosis;System;Therapeutic Intervention;Tissues;Transcript;Treponema denticola;Virulence;Virulence Factors;antimicrobial;base;biological systems;drug development;fitness;in vivo;inhibitor/antagonist;innovation;insight;member;novel;novel therapeutics;oral bacteria;pathogen;periplasm;repaired;screening;subgingival biofilm;targeted treatment

public_health_relevance:
Tannerella forsythia is a Gram-negative anaerobic bacterium a member of dysbiotic subgingival bacterial floraconsidered the causative agent of a chronic inflammatory disease of the periodontium (chronic periodontitis). Inaddition to proteolytic enzymes known to interfere with the host immune response this bacterium produces sixunique protease inhibitors with the potential to control both bacterial and host proteases. As such theseinhibitors may represent a new and previously unrecognized class of virulence factors that are capable ofmodifying the dysbiotic character of the subgingival bacterial biofilm. In this study our results will cast light onthe structure and function of these unique proteins and may provide targets for therapeutic intervention againstperiodontitis.


application_id: 9355100
project_number: 5R42AG055375-04
project_title: Development of An Integrated High Throughput Imaging and Image Analysis Platform for Muscle
administering_ic: NIA
award_notice_date: 2017-06-14
opportunity_number: PA-14-072
application_type: 5
activity_code: R42
ic: AG
serial_number: 055375
program_official: WILLIAMS, JOHN
project_start_date: 2013-07-15
project_end_date: 2019-05-31
study_section: Special Emphasis Panel[ZRG1-MOSS-Q(14)B]
contact_pi_person_id: 12598388
contact_pi: YANG, LIN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078357046
primary_uei: LA54LAMKQ5A6
duns_number: 078357046
uei: LA54LAMKQ5A6
fips: US
organization_id: 10032028
organization_name: CYTOINFORMATICS, LLC
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403568852
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  There is growing awareness that weakness of muscle is a significant biomedical health issue associated with many different chronic diseases and aging. There are a variety of different diseases that affect muscle including muscular dystrophy fibromyalgia cerebral palsy amyotrophic lateral sclerosis and myasthenia gravis each of which carries its own unique set of symptoms accompanied by a myriad of genetic and molecular abnormalities. There is agreement within the basic research and clinical communities that important morphological characteristics of muscle fibers such as fiber cross sectional area fiber type the number and position of myonuclei cellular infiltration and fibrosis are among many critical factors that determine the health and functionality of the muscle. Until now the imaging equipment available is relatively low throughput and the quantification is still largely based on manual or at best semi-automatic methods that require extensive human intervention. In Phase I CytoInformatics LLC has developed a software called CytoQuant which can accurately perform automatic segmentation and provide accurate boundaries of each muscle fiber for a cropped image patch. The goal of CytoInformatics LLC in Phase II is to 1) deliver the first version of the CytoQuant software to the market 2) develop the second version of CytoQuant by continuously improving its performance especially in handling large scale whole slide images and also 3) develop an integrated multiplexing imaging hardware and analysis software framework as a seamless solution for high throughput automated image analysis of muscle specimens. After careful investigation in Phase I (please refer to the details in business plan) we conclude that this integrated software/hardware platform with cutting-edge technologies in advanced imaging large scale machine learning and big data is commercially attractive to the entire muscle community including research institutes hospitals and pharmaceutical and athletic companies demonstrated by strong enthusiasm among end users and many supporting letters. The specific aims are: 1) Deliver the first version of CytoQuant developed in Phase I to the market continue to develop the second version of CytoQuant which will focus on improving the robustness and speed in handling whole slide images; 2) Develop an integrated platform that provides unified imaging hardware and image analysis software to handle whole slide images labeled with multiple bio-relevant markers. This unified whole-slide based software and hardware solution will deliver an efficient and specialized imaging platform that seamlessly integrates with a high throughput multi-marker and automatic image analysis software specifically designed for muscle.

project_terms:
Affect;Aging;Agreement;Amyotrophic Lateral Sclerosis;Area;Athletic;Awareness;Basic Science;Big Data;Biological Markers;Biology;Businesses;Cellular Infiltration;Cerebral Palsy;Characteristics;Chronic Disease;Clinical;Communities;Computer software;Development;Discipline;Disease;Eosine Yellowish;Equipment;Exhibits;Feedback;Fiber;Fibromyalgia;Fibrosis;Fluorescence;Future;Goals;Health;Hematoxylin;Hospitals;Human;Image;Image Analysis;Imagery;Immunofluorescence Immunologic;Immunohistochemistry;Institutes;Intervention;Intuition;Investigation;Label;Laboratory Research;Learning;Learning Module;Letters;Machine Learning;Manuals;Marketing;Methods;Microscopy;Molecular Abnormality;Morphology;Muscle;Muscle Fibers;Muscle Weakness;Muscle function;Muscular Dystrophies;Myasthenia Gravis;Noise;Performance;Pharmacologic Substance;Phase;Positioning Attribute;Principal Investigator;Qi;Recruitment Activity;Reporting;Research Institute;Research Personnel;Scanning;Signal Transduction;Slide;Software Design;Software Framework;Specimen;Speed;Staining method;Stains;Symptoms;Technology;Tissue Sample;Tissue imaging;Universities;Update;Variant;Yang;adaptive learning;base;bioimaging;commercialization;design;experience;gigabyte;graphical user interface;image processing;image visualization;imaging Segmentation;imaging modality;imaging platform;imaging system;improved;interest;member;muscle form;novel;optical imaging;programs;public health relevance;success;technology development;user-friendly

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  In Phase II CytoInformatics is proposing a unified whole-slide multispectral imaging (MSI) system that seamlessly integrates with a high throughput accurate and automated software to provide fast and efficient multiplexed imaging and quantitative muscle image analysis simultaneously. This will be the first integrated hardware/software solution that is specifically designed for muscle.


