# projects

application_id: 9959981
project_number: 1R56AG064234-01
project_title: Regulation of microglial activation state in neurodegeneration
administering_ic: NIA
award_notice_date: 2019-07-22
opportunity_number: PA-18-484
application_type: 1
activity_code: R56
ic: AG
serial_number: 064234
program_official: OPANASHUK, LISA A
project_start_date: 2019-08-01
project_end_date: 2020-02-29
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 2275110
contact_pi: BIEBERICH, ERHARD
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:
AbstractFunctional genome wide association studies have indicated that dysregulated microglia activationis a major contributing factor for neurodegeneration and cognitive decline in Alzheimer's disease(AD). Thus regulating the microglia activation state could have profound therapeutic potential forAD. However the underlying mechanisms by which microglia transition between different statesduring normal and disease conditions are largely unknown. S1P-signaling has been implicated toplay important roles in AD. Yet the function of S1P in AD is not clear due to conflicting reports.On one hand the level of S1P is reduced in postmortem AD patient brains suggesting aprotective role of S1P. On the other hand there are also reports indicating that S1P might playthe opposite. Although has been tested in A-related AD mouse models and showed promisingresults the role of FTY720 in tau pathology is elusive. Further FTY720 can function as an agonistfor all S1PRs except S1PR2 as a functional antagonist for S1PR1 or as a ceramide mimicdepending on the cellular context and treatment procedure which makes interpretation of S1P'srole challenging. Thus the function of S1P-signaling in AD is more complex than assumed anddemands further investigation Our preliminary studies suggest that Spinster homolog 2 (Spns2)an S1P transporter critically modulates microglial transition from inflammatory to anti-inflammatory states when treated with A peptide. This data is exciting in that it reveals microgliastates could be regulated through Spns2 and/or S1P. Our goal in this application is to define thefunction and underlying mechanism of Spns2 in microglial responses in AD. Our overarchinghypothesis is that Spns2 contributes to AD pathogenesis by promoting microglial pro-inflammatory activation induced by A and tau. By focusing on the S1P transporter Spns2 thisproposal holds a unique premise to reveal novel aspects of S1P-signaling in AD. We will (1) testthat Spns2-mediated S1P transport enhances inflammatory responses in microglia in AD modelsin vitro (2) determine the downstream signaling mediated by Spns2/S1P in inflammatoryresponse in AD models in vitro and (3) test that Spns2KO ameliorates AD-related phenotypes ina murine AD model. By focusing on the S1P transporter Spns2 in microglia biology this proposalholds a unique premise to reveal novel aspects of the function of Spns2 and S1P in AD.

project_terms:
Affect;Agonist;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Anti-inflammatory;Autopsy;Biology;Brain;Ceramides;Clinical;Clinical Data;Complex;Conflict (Psychology);Data;Disease;Drug Kinetics;Extracellular Space;Goals;Homologous Gene;Impaired cognition;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Inorganic Phosphate Transporter;Investigation;Knock-out;Knockout Mice;Lipids;MAPK14 gene;MAPT gene;Measures;Mediating;Microglia;Mus;NF-kappa B;Nerve Degeneration;Neurodegenerative Disorders;Neurofibrillary Tangles;Onset of illness;Pathogenesis;Pathologic;Pathology;Pathway interactions;Patients;Peptides;Phenotype;Play;Procedures;Process;Proteins;Public Health;Regulation;Reporting;Research;Role;Senile Plaques;Signal Pathway;Signal Transduction;Sphingosine-1-Phosphate Receptor;Stimulus;Testing;Therapeutic;Transgenic Organisms;astrogliosis;chemokine;cognitive function;cytokine;extracellular;genome wide association study;improved;in vitro Model;mitogen-activated protein kinase p38;mouse model;neuroinflammation;novel;novel therapeutic intervention;pre-clinical;response;sphingosine 1-phosphate;sphingosine kinase;tau Proteins

public_health_relevance:
The function of S1P-signaling in AD is more complex than assumed and demands furtherinvestigation. Our research will test a novel hypothesis that the S1P transporter Spns2 contributesto AD pathogenesis by promoting microglial pro-inflammatory activation induced by A and tau.By focusing on Spns2 this proposal holds a unique premise to reveal novel aspects of S1P-signaling in AD


application_id: 9959391
project_number: 5R21DC017247-03
project_title: Mechanotransduction-Dependent Remodeling of the Stereocilia Cytoskeleton
administering_ic: NIDCD
award_notice_date: 2020-06-04
opportunity_number: PAR-16-057
application_type: 5
activity_code: R21
ic: DC
serial_number: 017247
program_official: FREEMAN, NANCY
project_start_date: 2018-07-01
project_end_date: 2022-06-30
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 12084410
contact_pi: VELEZ ORTEGA, ALEJANDRA CATALINA
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:
PROJECT SUMMARY/ABSTRACT Mechanosensitivity of the inner ear hair cells depends on actin-filled cellular projections known asstereocilia. We recently found that the stability of the stereocilia cytoskeleton depends on the constantinflux of calcium ions through the mechano-electrical transduction (MET) channels that are located atthe tips of stereocilia (Velez-Ortega et al. eLife 2017). We showed that the blockage of MET channelsor the breakage of the tip links that gate these channels leads to the selective shortening of transducingstereocilia in the bundle (i.e. only the middle and short row stereocilia harbor MET channels). Once theMET blockage is removed or the tip links regenerate the shortened stereocilia regrow. An increase inintracellular calcium buffering also led to the selective remodeling of transducing stereocilia indicatingthat calcium ions are the main component of the MET current regulating the stereocilia morphology.Stereocilia remodeling in response to variations in the resting MET current represents an activity-dependent plasticity of the stereocilia actin cytoskeleton which may initiate profound changes in thehair bundle morphology in various types of hereditary or acquired hearing losses. Therefore this projectbegins the search for the molecular players involved in the MET-dependent remodeling of thestereocilia cytoskeleton. Aim 1 will determine the MET-dependent changes in the actin incorporationinto the stereocilia potential actin treadmill and actin isoform composition. Given that myosin XVdelivers the elongation machinery to the tips of stereocilia Aim 2 will test for the contribution of myosinXV isoforms in the MET-dependent regulation of the stereocilia height. This study is significantbecause it may uncover the molecular mechanisms of the fine adjustments of the staircase architectureof the hair cell bundles. Moreover stereocilia shorteningand perhaps eventual stereociliadisappearancecould occur after noise exposure (when the MET current is reduced due to tip linkbreakage) or in certain cases of congenital deafness (due to impaired MET current). Therefore thisstudy will expand our knowledge of the molecular mechanisms of various types of hearing loss.

project_terms:
Acquired Deafness;Actins;Affect;Antibodies;Architecture;Area;Auditory;Buffers;Calcium;Calcium ion;Cells;Cilia;Cochlea;Cytoskeleton;Exhibits;Growth;Hair;Hair Cells;Hearing;Height;Impairment;Inherited;Knowledge;Label;Labyrinth;Lead;Link;Maintenance;Molecular;Morphology;Motor;Mus;Mutation;Myosin ATPase;Natural regeneration;Noise;Noise-Induced Hearing Loss;Organelles;Plasmids;Protein Isoforms;Proteins;Regulation;Rest;Role;Sensory;Shapes;Testing;Variant;age related;beta Actin;congenital deafness;depolymerization;gamma Actin;hearing impairment;mechanotransduction;new therapeutic target;polymerization;prevent;response;treadmill

public_health_relevance:
PROJECT NARRATIVE Our sense of hearing relies on the survival of a limited number of inner ear sensory cells throughoutour entire lifetime. This project will provide clues about the molecular machinery regulating the stabilityand shape of the inner ear sensory organelles known as stereocilia. The identification of thesemolecular players might uncover novel therapeutic targets to prevent the loss of stereocilia in sometypes of age-related or noise-induced hearing loss.


application_id: 9957995
project_number: 1R21AI151482-01
project_title: Defining the Intracellular Growth Niche of Foodborne Listeria monocytogenes
administering_ic: NIAID
award_notice_date: 2020-02-24
opportunity_number: PA-19-053
application_type: 1
activity_code: R21
ic: AI
serial_number: 151482
program_official: BAQAR, SHAHIDA
project_start_date: 2020-03-01
project_end_date: 2022-02-28
study_section: Special Emphasis Panel[ZRG1 IDM-B (81)]
contact_pi_person_id: 2545336
contact_pi: D'ORAZIO, SARAH E. F.
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:
Ingestion of Listeria monocytogenes (Lm)-contaminated food results in human disease ranging in severityfrom mild self-limiting gastroenteritis to life-threatening septicemia and meningoencephalitis. The specificfactors that influence disease severity are not well understood and our knowledge of the intestinal phase oflisteriosis in particular is severely limited. We recently developed a mouse model of foodborne infection tostudy the interaction of Lm with intestinal innate immune cells. In preliminary studies we found that themajority of Lm in the gut were extracellular. This was an unexpected result because intracellular growthand spread from cell-to-cell without encountering the extracellular milieu are generally regarded as theprimary virulence strategies for these facultative intracellular bacteria. LplA1-deficient Lm that were unableto replicate intracellularly could readily invade the gut mucosa and establish infection in the underlyinglamina propria but did not persist as well as wildtype Lm and by three days post-infection had a severedefect in spreading to the mesenteric lymph nodes (MLN). This suggests that intracellular growth is notrequired for the initial stages of intestinal infection but replication in some as-yet-unidentified cell type in thegut becomes increasingly more important as the infection proceeds. Multicolor flow cytometry candiscriminate eight different subsets of myeloid-derived phagocytes that are unique to the gut. Preliminarydata provided here verified that intestinal tissue contained at least one cell type that could supportintracellular growth of Lm and ruled out Ly6Chi monocytes and all three subsets of conventional dendriticcells as the intracellular niche. The primary goal of this proposal is to identify the cell type(s) in the gut thatsupport intracellular growth of Lm and to define the innate immune response of intestinal cell types that thatinteract primarily with either intracellular or extracellular Lm. We hypothesize that Lm initially interactprimarily with cell types that that they cannot efficiently invade or survive in and that later in the course ofinfection the bacteria shift to a cell type that serves as a protected intracellular growth niche.!In Aim 1 fourcandidate intestinal myeloid cell types will be sort purified infected directly ex vivo and assayed for bothintracellular localization and replication. In Aim 2 flow cytometry will be used to identify Lm-associated cellsin the lamina propria and submucosa of the ileum and colon as well as the MLN that drain each of thesetissues (SI-MLN and LI-MLN) to track the fate of Lm that invade the gut mucosa in mice. In Aim 3 we willdefine the initial response of all eight subsets of intestinal myeloid cells by measuring the production ofcytokines known to be triggered by either host cell surface bound or cytosolic receptors. These exploratorystudies will fill a key knowledge gap in the field by defining the early events that occur in the gut duringfoodborne transmission of Lm. !

project_terms:
Anatomy;Bacteremia;Bacteria;Biological Assay;Blood;Bypass;C57BL/6 Mouse;Cell surface;Cells;Colon;Cytosol;Data;Defect;Dendritic Cells;Dependence;Disease Outbreaks;E-Cadherin;Eating;Elderly;Environment;Epithelial;Epithelium;Event;Exposure to;Feces;Flow Cytometry;Food;Food Contamination;Food Supply;Gastroenteritis;Gastrointestinal tract structure;Gentamicins;Goals;Growth;Gut Mucosa;Hospitalization;Immune;Immune system;Immunoassay;In Vitro;Incidence;Individual;Infection;Ingestion;Innate Immune Response;Interleukin-12;Interleukin-18;Interleukin-6;Intestinal Diseases;Intestines;Intravenous;Invaded;Knowledge;Lamina Propria;Large Intestine;Lead;Life;Ligation;Listeria monocytogenes;Listeriosis;M cell;Measures;Mediating;Meningoencephalitis;Minor;Modeling;Mus;Myelogenous;Myeloid Cells;Neuraxis;Phagocytes;Phase;Population;Process;Production;Resistance;Route;Sepsis;Septicemia;Severities;Severity of illness;Small Intestines;Stains;Submucosa;Surface;Symptoms;Systemic infection;Therapeutic Intervention;Time;Tissues;Virulence;Work;cell type;cytokine;cytosolic receptor;design;draining lymph node;enteric infection;experience;experimental study;extracellular;feeding;foodborne;foodborne infection;foodborne pathogen;human disease;ileum;in vivo;macrophage;mesenteric lymph node;monocyte;mortality;mouse model;neonate;pathogen;prevent;response;transmission process

public_health_relevance:
Human disease caused by eating food that is contaminated with the bacterium Listeria monocytogenesranges in severity from mild gastroenteritis to severe life-threatening infections of the blood and centralnervous system. The goal of this proposal is to understand how this pathogen is able to survive in the gutand avoid being killed by the immune system. A better understanding of this process could lead to newstrategies to prevent systemic infection particularly in susceptible populations such as neonates and theelderly.!


application_id: 9957066
project_number: 5R01CA215095-04
project_title: Roles of RORalpha in breast cancer development and progression
administering_ic: NCI
award_notice_date: 2020-06-22
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 215095
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2017-07-01
project_end_date: 2022-06-30
study_section: Tumor Microenvironment Study Section[TME]
contact_pi_person_id: 10533977
contact_pi: XU, REN
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:
ABSTRACT Tumor has been described as the wounds that do not heal. The two share some common features such asloss of polarized tissue structure and chronic inflammation. We showed that disruption of tissue polarityinduced macrophage infiltration. However little is known of how disruption of epithelial cell polarity at earlystage of breast cancer development induces macrophage infiltration. We have identified the RAR-relatedorphan nuclear receptor  (ROR) as a potent tumor suppressor by analyzing global gene expression profilesin polarized and non-polarized mammary epithelial cells. Our recent findings show that ROR inhibits ROSgeneration and macrophage infiltration in the syngeneic mouse mammary tumor model. These results suggestthat ROR is a potent suppressor of macrophage infiltration in mammary epithelial cells. We found thatknockdown of ROR significantly induced ROS production in mammary epithelial cells. Reactive oxygenspecies (ROS) are the driver of cancer progression and critical regulator of the NF-B pathway. Based onthese novel findings the central hypothesis of our proposal is that downregulation of ROR in non-polarizedbreast cancer cells increased ROS generation in mitochondria thereby inducing NF-B and macrophageinfiltration. We integrate high-throughput metabolic analysis a novel 3D co-culture system and global geneexpression profiling to delineate mechanisms by which ROR inhibits ROS production and macrophageinfiltration. The long-term goal of this proposal is to define the impact of the ROR/ROS axis in mediatingmammary epithelial cell-macrophage crosstalk and in regulating breast cancer progression. We have proposedfollowing specific aims to test the hypothesis: Aim 1. To elucidate the molecular mechanisms by which RORreduces ROS levels and NF-B activity in polarized mammary epithelial cells; Aim 2. To determine howreduced ROR expression in non-polarized breast cancer cells induces macrophage infiltration and M2polarization; Aim 3. Define the impact of ROR in suppressing breast cancer formation and metastasis. Theproposed study is high impact for its inherent scientific importance and its translational potential. This study willelucidate the molecular mechanism by which disruption of tissue polarity induces macrophageinfiltration/differentiation. Determining roles of ROR in reducing ROS generation and inhibiting NF-Bactivation may identify a novel strategy to inhibit breast cancer development and progression.

project_terms:
3-Dimensional;Agonist;Biological Assay;Biology;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Epithelial Cells;Cell Polarity;Cellular Metabolic Process;Chronic;Coculture Techniques;Complex;Development;Down-Regulation;Epithelial Cells;Expression Profiling;Gene Expression;Gene Expression Profiling;Generations;Glutathione Disulfide;Goals;Human;Hydrogen Peroxide;Immunocompetent;Infiltration;Inflammation;Knockout Mice;Knowledge;Lead;Link;Malignant Neoplasms;Mammary gland;Measurement;Mediating;Metabolic;Metformin;Mitochondria;Modeling;Molecular;Mus;NADP;Nature;Neoplasm Metastasis;Nuclear Orphan Receptor;Oxidation-Reduction;Pathway interactions;Positioning Attribute;Production;Reactive Oxygen Species;Research;Role;Scheme;Source;Structure;Superoxides;System;TP53 gene;Testing;Tissue Microarray;Tissues;Tumor Suppressor Proteins;base;breast cancer progression;cancer cell;cancer prevention;cancer therapy;cytokine;druggable target;healing;improved;inhibitor/antagonist;insight;knock-down;loss of function;macrophage;malignant breast neoplasm;metabolomics;monocyte;multidisciplinary;novel;novel strategies;stable isotope;transcriptome;tumor;tumor microenvironment;tumor progression;wound

public_health_relevance:
Characterizing the molecular link between disruption of mammary tissue polarity and macrophage infiltrationand elucidating the mechanism by which ROR repressing ROS generation and NF-B activity will fill criticalgaps in our knowledge about cancer-associated chronic inflammation and breast cancer progression.Determining whether inducing ROR activity represses breast progression and metastasis will help identifypotential druggable targets.


application_id: 9957015
project_number: 5R21AI146016-02
project_title: Role of the Trophic Forms of Pneumocystis in Lung Response to Infection
administering_ic: NIAID
award_notice_date: 2020-05-04
opportunity_number: PA-18-489
application_type: 5
activity_code: R21
ic: AI
serial_number: 146016
program_official: LOVE, DONA
project_start_date: 2019-06-17
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZRG1-AARR-M(03)M]
contact_pi_person_id: 1945284
contact_pi: GARVY, BETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Pneumocystis (PC) pneumonia continues to be a leading cause of opportunistic infections inpatients living with HIV. Though we are thirty years into the HIV epidemic very little is knownabout the lifestyle of the PC organism and how it interacts with the immune system. The field ishampered by the inability to culture the organisms for more than a couple weeks and theproblem of separating the two identifiable life forms the ascus and trophic forms resulting in apaucity of information regarding how these separate life forms interact with the host and theimmune response. Recently -glucan synthesis inhibitors (a class of drugs calledechinocandins) have been used to eliminate the ascus form of the organisms in vivo giving usthe ability to obtain a purified population of trophic forms and to examine trophic forminteractions with host immune cells. Our preliminary data demonstrates that trophic forms of PCinhibit TNF production of alveolar macrophages after stimulation by lipopolysaccharide (LPS) -glucans or lipoteichoic acid (LTA) in vitro. Additionally in vivo we found that trophic formsinhibit TNF production in the lungs of mice challenged with a small dose of LPS. Wehypothesize that the trophic forms of PC act to temper the inflammatory response to -glucansin the ascus forms of PC. The goal of this proposal is to determine the significance andmechanism of the inhibitory activity of trophic forms of PC. We propose two aims to addressour hypothesis. In aim 1 we will determine whether trophic forms of PC alter the balance ofinflammation induced by -glucan in vivo. In aim 2 we will determine whether trophic forms ofPC dampen inflammation induced by innate immune responses and identify pattern recognitionreceptors on macrophages that interact with tropic forms of PC.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Alveolar Macrophages;Asthma;Binding;Bone Marrow;Cell Wall;Cells;Chronic Obstructive Airway Disease;Cyst;Data;Dendritic Cells;Dose;Environment;Epidemic;Epithelial Cells;Equilibrium;Glucans;Goals;HIV;Immune;Immune response;Immune system;In Vitro;Individual;Infection;Infectious Agent;Inflammation;Inflammation Mediators;Inflammatory Response;Innate Immune Response;Knockout Mice;Knowledge;Lead;Learning;Life;Life Style;Lipopolysaccharides;Lung;Mannose;Molecular;Mus;Opportunistic Infections;Organism;Patients;Pattern;Pattern recognition receptor;Phagocytosis;Pharmaceutical Preparations;Pharmacology;Pneumocystis;Pneumocystis carinii;Pneumocystis carinii Pneumonia;Pneumonia;Population;Production;Proteins;Reproduction spores;Role;System;TNF gene;Time;base;beta-Glucans;beta-glucan receptor;co-infection;cytokine;design;experimental study;genetic manipulation;glucan synthase;immunosuppressed;in vivo;in vivo Model;inflammatory milieu;inhibitor/antagonist;insight;lipoteichoic acid;lung injury;macrophage;mannose receptor;mouse dectin-2;mouse model;nano-string;novel;pathogen;pathogenic fungus;prevent;response;tool

public_health_relevance:
Pneumocystis pneumonia is an AIDS-defining illness caused by an opportunistic fungal pathogen that has twoidentifiable life forms trophic forms and asci or cysts. While much is known about the immune response to theasci very little is known about the interactions of trophic forms with innate immune cells. This project isdesigned to understand how the trophic forms of Pneumocystis contribute to host-pathogen interactions in thelungs.


application_id: 9956980
project_number: 5R01AI145335-02
administering_ic: NIAID
award_notice_date: 2020-05-14
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AI
serial_number: 145335
program_official: O'NEIL, MICHAEL T
project_start_date: 2019-06-17
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-U(02)]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY P.
other_pis: PATWARDHAN, ABHIJIT R.
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-06-01
project_title:
Quantitative Approaches for Drug Testing in Chronic Toxoplasmosis: Leveraging New Insights Into Bradyzoite Biology Within Tissue Cysts In Vivo

project_abstract:
Symptomatic toxoplasmosis in the context of immune suppression is typically associated with the reactivation of the chronic form of the infection mediated by bradyzoites that reside within tissue cysts. Despite their central role in the pathogenesis very little is known about the basic biology of bradyzoites. In fact our work (Watts et al. mBio 2015) was the first to definitively demonstrate that bradyzoites within tissue cysts in vivo are dynamic replication competent entities. This view directly challenged the prevailing dogma of bradyzoites and the tissue cysts that house them were metabolically inert. This view has been proffered as the reason for why bradyzoites are resistant to drugs that effectively kill the actively growing tachyzoites. Understanding the underlying basis for the inherent resistance to drug-mediated clearance needs to be addressed on a mechanistic basis which is now possible given our recent identification of quantifiable markers for the physiological status of individual bradyzoites within tissue cysts. This can further be extended to developing a framework for the evaluation of potential new drugs in vivo that rely on quantifiable physiological readouts that will greatly enhance sensitivity by addressing the behavior of populations of bradyzoites within tissue cysts as opposed to the currently used tissue cyst burden. This crude metric limits the sensitivity of efficacy to 2 orders of magnitude as percentage decreases in cyst burden and little else are measured. Our development of BradyCount1.0 an imaging based application to quantify the actual bradyzoite levels within tissue cysts revealed a previously underappreciated level of heterogeneity in bradyzoite numbers relative to tissue cyst size. We exploited what was known about the dynamics of the scaffold protein TgIMC3 and nuclear morphology in the context of replication to capture not only replicating bradyzoites but also information of their relative age. Additional studies revealed that bradyzoite mitochondrial activity and the accumulation amylopectin granules (AG) a measure of stored energy were also heterogeneous. This provides three distinct and likely interrelated physiological metrics that can be assessed at the level of individual bradyzoites within in vivo derived tissue cysts. With this study we aim to develop a new standard to assess the progression of the chronic Toxoplasma infections and to translate this novel approach to assess the effectiveness of existing and future drugs. Toward this end we propose develop BradyCount 2.0 to morphologically quantify nuclear profiles and bradyzoite scaffolds (as a markers of active and past replication) mitochondrial profiles and the distribution of AG as reporters of energy and intermediary metabolism. By recording multiple parameters individually and collectively on bradyzoites within tissue cysts we will establish a framework to define the chronic infection and the impact of drug intervention employing quantifiable physiological metric. These inputs will be used to refine a Markov Chain-based data-driven computational model to understand this enigmatic phase for which effective treatments are lacking. These studies will greatly improve the sensitivity of testing of both existing and future drugs while providing crucial mechanistic insights.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Age;Amylopectin;Architecture;Automobile Driving;Behavior;Biology;Brain;Budgets;Cell Cycle Progression;Cell Nucleus;Chronic;Clinical;Computer Models;Cyst;Cytoplasmic Granules;DNA biosynthesis;Data;Development;Drug Exposure;Drug resistance;Effectiveness;Energy Metabolism;Evaluation;Funding Mechanisms;Future;Glucose;Gold;Grant;Growth;HIV;Heterogeneity;Image;Imaging technology;Immunosuppression;Individual;Infection;Intervention;Knowledge;Life;Life Cycle Stages;Markov Chains;Measures;Mediating;Metabolic;Metabolism;Mitochondria;Modeling;Morphology;Nature;Nuclear;Parasites;Parasitic infection;Pathogenesis;Pattern;Periodicity;Pharmaceutical Preparations;Phase;Physiological;Physiology;Population;Process;Property;Publishing;Pyrimethamine;Reporter;Reporting;Resolution;Role;Scaffolding Protein;Source;Starch;Sulfadiazine;Technology;Testing;Time;Tissues;Toxoplasma;Toxoplasma gondii;Toxoplasmosis;Training;Translating;Work;atovaquone;base;chronic infection;computer framework;drug efficacy;drug testing;effective therapy;efficacy study;imaging approach;improved;in vivo;insight;markov model;mouse model;novel strategies;novel therapeutics;pathogen;scaffold;simulation;targeted treatment

public_health_relevance:
A significant barrier to the identification of potential drug treatments targeted at the Toxoplasma gondii chronic infection is the lack of suitable quantifiable readouts for the effect of drugs on the encysted bradyzoites. In this study we leverage our findings regarding bradyzoite replication and energy metabolism to establish imaging based approaches and develop a computational model framework to assess drug efficacy in the murine model.


application_id: 9956710
project_number: 5T03OH008437-15
project_title: Occupational Safety and Health Program Improvement
administering_ic: NIOSH
award_notice_date: 2020-05-29
opportunity_number: PAR-15-352
application_type: 5
activity_code: T03
ic: OH
serial_number: 008437
program_official: MAPLES, ELIZABETH
project_start_date: 2016-07-01
project_end_date: 2021-06-30
study_section: ZOH1-DYB(03)
contact_pi_person_id: 14313332
contact_pi: WORTHAM, TRACEY
other_pis: Not Applicable
congressional_district: 01
department: OTHER HEALTH PROFESSIONS
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The purpose of this proposal is to strengthen the preparation of our undergraduate andgraduate level students in occupational safety and health. This will be accomplished byproviding learning environments designed to help the students become more effective entry-level and advanced professionals. The primary focus will be:1. Increased involvement of the internship supervisors in visiting intern sites to observe and improve employer-intern-university relationships.2. Development and enhancement of interdisciplinary/multidisciplinary collaborations with programs in the Jesse D. Jones College of Science Engineering and Technology.3. On-going faculty professional development to keep abreast of changes in the occupational safety and health field.4. Development of seminars and Occupational Safety and Health Training Center courses designed to address current occupational safety and health issues.5. Support for undergraduate and graduate students in the form of travel tuition and fees.6. Improvement and upgrade of the laboratory and computer facilities and equipment within the OSH department.The OSH department had 473 students in the program during the fall 2014 semester whichincluded 409 in the undergraduate program and 64 in the graduate program. Additionally thedepartment placed 165 interns during the 2014-2015 academic year.

public_health_relevance:
The Department of Occupational Safety and Health at Murray State University continues tosupply diversified education and training for occupational safety and health professionals tomeet the local regional and national demand. The various curricula programs and trainingwithin the department are designed to meet the professional preparation of students as well asthe manpower continuing education training and advisory needs of the region and state.


application_id: 9956466
project_number: 1R21ES031712-01
project_title: Translational Control in Cr(VI) Carcinogenesis
administering_ic: NIEHS
award_notice_date: 2020-06-16
opportunity_number: PA-19-053
application_type: 1
activity_code: R21
ic: ES
serial_number: 031712
program_official: TYSON, FREDERICK L
project_start_date: 2020-06-16
project_end_date: 2022-05-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 10534129
contact_pi: SHE, QING-BAI
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 SUMMARYCr(VI) is a common and well-recognized environmental carcinogen that causes lung and other cancers in human.Despite considerable research effort to understand the molecular and cellular mechanisms of Cr(VI)carcinogenesis crucial facets of these mechanisms remain largely unknown; identification of the key molecularregulators and processes the mechanisms of action and strategies for prevention are urgently needed.Remarkable progress has been made that highlights the functional importance of mRNA translation and proteinsynthesis in cancer development and progression. However translational control of Cr(VI) carcinogenesis hasnot yet been investigated. We recently demonstrated that chronic low dose Cr(VI) exposure in human lungbronchial epithelial cells can induce cancer stem cell (CSC)-like properties cell transformation and tumorformation through upregulation of histone-lysine methyltransferases including G9a SUV39H1 and EZH2.Notably we found that chronic Cr(VI) exposure can activate mTOR kinase leading to phosphorylation(inactivation) of the translational repressor 4E-BP1 and thereby promote the recruitment of capping mRNAs andribosomal subunits to the eIF4F translation initiation complex (eIF4E+eIF4G+eIF4A) for active translation inpolysomes. Furthermore we found that on chronic Cr(VI) exposure the EZH2 mRNA is actively translated inpolysomes with no changes in its transcriptional level. Importantly targeted inhibition of mTOR kinase can inhibittranslation of EZH2 mRNA in polysomes and result in growth inhibition of Cr(VI)-transformed cells. Based onthese findings the central hypothesis of the proposed study is that the activation of cap-dependent mRNAtranslation machinery by mTOR kinase is required to selectively upregulate key oncoproteins that confer Cr(VI)-induced tumorigenesis. To test this hypothesis two specific aims are proposed. Aim 1 will define the role ofmTOR-activated translation machinery in Cr(VI)-induced tumorigenesis using a combination of molecularcellular biochemical and pharmacologic approaches as well as genetically engineered mouse models withclinical association schemes. Aim 2 will characterize the molecular mechanism of mTOR-activated cap-dependent translation in Cr(VI) carcinogenicity using a polysome profiling approach to systematically identify aset of key mRNAs that are selectively recruited to polysomes and translated in Cr(VI)-transformed humanbronchial epithelial cells followed by characterization of their functional importance in Cr(VI)-inducedtumorigenicity. Our proposed study will investigate the innovative concept that Cr(VI) induces carcinogenesisthrough dysregulation of the mTOR/4E-BP1-mediated translation initiation process. Elucidating this process willprovide novel insights into the biology and clinical relevance of translational regulation in Cr(VI) carcinogenesis.This research will have the added benefit of identifying Cr(VI)-induced translationally-regulated targets forpotential preventive or interventional therapy.

project_terms:
Appalachian Region;Biochemical;Biology;Cancer Etiology;Cessation of life;Chronic;Clinical;Development;Dose;EIF4EBP1 gene;EZH2 gene;Effectiveness;Environment;Environmental Carcinogens;Environmental Pollutants;Epithelial Cells;Eukaryotic Initiation Factor-4F;Exposure to;FRAP1 gene;Fostering;Gene Expression;Genes;Genetic Transcription;Genetic Translation;Genetically Engineered Mouse;Growth;Histone-Lysine N-Methyltransferase;Human;In Vitro;Incidence;Injury;Kentucky;Knockout Mice;Lung;Lung Inflammation;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Messenger RNA;Metals;Molecular;Molecular Analysis;Molecular Target;Mus;Occupational;Oncologist;Oncoproteins;Outcome Study;Particulate;Pathologist;Patients;Pharmacology;Phosphorylation;Phosphotransferases;Polyribosomes;Positioning Attribute;Post-Transcriptional Regulation;Prevention;Prevention strategy;Preventive therapy;Process;Property;Protein Biosynthesis;Proteins;Public Health;Research;Ribosomes;Role;Scheme;Signal Pathway;Signal Transduction;Specimen;Testing;Therapeutic Intervention;Translating;Translation Initiation;Translational Activation;Translational Regulation;Translations;Tumorigenicity;Up-Regulation;Wild Type Mouse;Work;base;bronchial epithelium;cancer stem cell;carcinogenesis;carcinogenicity;cell growth;cell transformation;cell type;chromium hexavalent ion;clinically relevant;experience;genetic approach;improved;inhibitor/antagonist;innovation;insight;mRNA capping;mTOR inhibition;migration;novel;pollutant;polysome profiling;recruit;response;stem-like cell;targeted biomarker;tumor;tumor growth;tumor progression;tumor xenograft;tumorigenesis;uncontrolled cell growth

public_health_relevance:
PROJECT NARRATIVEHexavalent chromium [Cr(VI)] is one of the most common environmental and occupational pollutants andexposure to Cr(VI) is a world-wide public health concern including for the region of Appalachian Kentucky. Thisproposal investigates the dysregulation of the mTOR/4E-BP1-mediated mRNA translation initiation process inCr(VI) carcinogenesis a study that has never before been attempted. This study is expected to identify newmolecular targets and biomarkers for improving prevention and treatment of Cr(VI)-induced cancers.


application_id: 9955747
project_number: 1R01DA049333-01A1
administering_ic: NIDA
award_notice_date: 2020-09-18
opportunity_number: PAR-18-747
application_type: 1
activity_code: R01
ic: DA
serial_number: 049333
suffix: A1
program_official: DUNSTON, SHEBA KING
project_start_date: 2020-09-30
project_end_date: 2025-07-31
study_section: Health Disparities and Equity Promotion Study Section[HDEP]
contact_pi_person_id: 10667839
contact_pi: STEVENS-WATKINS, DANELLE J
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
arra_indicator: N
project_terms:
Address;Adult;African American;Age;Area;Attention;Buprenorphine;Cessation of life;Characteristics;Child Rearing;Communities;Complex;Comprehension;Criminal Justice;Data;Data Sources;Dimensions;Discrimination;Dose;Drug usage;Employment;Epidemic;Ethnic Origin;Evolution;Female;Future;Gender;Generations;Goals;Health Communication;Healthcare Systems;Heroin;Intervention;Interview;Kentucky;Libraries;Link;Longevity;Mediating;Mental Health;Methadone;Methods;Morbidity - disease rate;National Institute of Drug Abuse;Outcome;Overdose;Pain;Participant;Patients;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Policies;Population;Public Health;Race;Reporting;Research;Research Personnel;Research Project Grants;Risk;Sampling;Stress;Structure;Surveys;Techniques;Testing;Treatment outcome;Underrepresented Groups;base;cohort;design;drug testing;evidence base;experience;health care availability;illicit drug use;improved;insight;low socioeconomic status;male;men;misuse of prescription only drugs;mortality risk;older women;opioid epidemic;opioid overdose;opioid use;opioid user;physical conditioning;pill;prescription opioid;prescription opioid misuse;recruit;response;social;synthetic opioid;theories;treatment services;trend;young woman


application_id: 9955034
project_number: 5R01DC007176-16
project_title: Neurotrophin receptor regulation of adult taste bud innervation and function
administering_ic: NIDCD
award_notice_date: 2020-05-29
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DC
serial_number: 007176
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-03-01
project_end_date: 2022-02-28
study_section: Special Emphasis Panel[ZRG1-IFCN-B(03)]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
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:
Project Summary/Abstract: Taste receptor cells detect chemicals in our food and communicate this information to thenerve fibers innervating them. Our goal is to understand the structural and functionalrelationship between taste receptor cells and innervating neurons. Because taste receptor cellsundergo continuous renewal and must constantly attract and connect to nerve fibers even in theadult some mechanism exists to control this process. Since the neurotrophin BDNF controlsinitial innervation of taste buds and is present in adult taste receptor cells it may have this role.BDNF also can function as a neuromodulator regulating function so it is certainly possible thatBDNF can regulate both innervation and/or function of adult taste buds. Here we are testing thehypothesis that BDNF signaling through its receptor TrkB regulates both the structural andfunctional connections between taste receptor cells and ganglion neurons. The proposedstudies combine sparse cell genetic labeling with 3-dimensional analysis of the taste bud andelectrophysiology in mice where TrkB-signaling can be blocked using a combination ofchemical and genetic approaches to: 1) determine the identity and connectivity of BDNFexpressing taste receptor cells 2) determine the role of BDNF-TrkB-signaling in maintaining thisconnectivity and 3) determine if BDNF-TrkB signaling regulates taste function. Together theseexperiments will determine how specific taste receptor cells (BDNF-expressing) becomeinnervated by a subset of taste ganglion neurons (TrkB-expressing) during taste cell renewaland will determine if BDNF-TrkB-signaling is an important gustatory system neuromodulator ofthis pathway.

project_terms:
Adult;Agonist;Basic Science;Brain;Brain-Derived Neurotrophic Factor;Cells;Chemicals;Citric Acid;Clinical;Defect;Development;Disease;Electrophysiology (science);Excision;Eye;Fiber;Food;Ganglia;Genetic;Goals;Health;Ion Channel;Knock-out;Label;Location;Mus;Nerve;Nerve Fibers;Nerve Growth Factor Receptors;Nerve Regeneration;Neuromodulator;Neurons;Neurotransmitter Receptor;Pathway interactions;Pattern;Peripheral;Persons;Process;Quality of life;Receptor Cell;Regulation;Resolution;Role;Sensory;Signal Transduction;Sodium Chloride;Specificity;Stimulus;Structure;Structure of geniculate ganglion;Taste Bud Cell;Taste Buds;Taste Disorders;Taste Perception;Techniques;Testing;Therapeutic;Three-Dimensional Imaging;Three-dimensional analysis;Transgenic Mice;Tyrosine Kinase Inhibitor;base;cell type;chemical genetics;epithelial Na+ channel;experimental study;ganglion cell;genetic approach;imaging approach;nerve supply;neurotrophic factor;receptor;relating to nervous system;response;sensory system;small molecule;taste system

public_health_relevance:
Project NarrativeTaste disorders can have detrimental effects on a person's health and quality of life. Theunderlying mechanisms of these disorders are not understood but could result from disruptionof the connections between taste buds and the neurons carrying taste information to the brain.Here we are looking at the role of neurotrophins in maintaining these connections andevaluating the effects of potentially therapeutic neurotrophin agonists and antagonists on tastefunction with an eye toward basic research applicable to the larger clinical question of nerveregeneration in adulthood.


application_id: 9954175
project_number: 5F31NS105443-03
administering_ic: NINDS
award_notice_date: 2020-07-02
opportunity_number: PA-16-309
application_type: 5
activity_code: F31
ic: NS
serial_number: 105443
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2018-07-01
project_end_date: 2021-02-28
study_section: Special Emphasis Panel[ZRG1-F01A-F(20)L]
contact_pi_person_id: 14385763
contact_pi: KOPPER, TIMOTHY JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
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: 2020-07-01
project_title:
Contributions of Myelin Derived Arachidonic Acid to Macrophage Polarization and Secondary Damage after Spinal Cord Injury

project_abstract:
Project summary/Abstract Spinal cord injury (SCI) produces a chronic inflammatory state primarily mediated by resident microgliaand infiltrating monocytes (here collectively referred to as macrophages). These chronically activated SCImacrophages adopt a pro-inflammatory pathological state that continues to cause additional damage after theinitial injury and inhibits recovery. Myelin debris generated after SCI can directly stimulate macrophages toadopt these maladaptive functions; however the mechanisms by which this stimulation occur are poorlyunderstood. Myelin contains an inflammatory lipid molecule arachidonic acid stored in an inactive form withinmyelin's extensive membranes. After injury macrophages clear and accumulate myelin debris long after injury.Here we propose that the inflammatory environment within the SCI lesion induces the expression of theenzyme cytosolic phospholipase A2 (cPLA2) within macrophages. cPLA2 releases arachidonic acid fromcellular membranes. Free active arachidonic acid invokes direct pro-inflammatory functions or throughsynthesis forms various eicosanoids with pro-inflammatory properties. This is the basis for the centralhypothesis that increased cPLA2 activity in SCI macrophages releases arachidonic acid from myelindebris thereby driving chronic SCI inflammation and tissue damage. . Using in-vitro and in-vivo approaches Aim 1 of this proposal will identify cPLA2 as the regulator ofmyelin-mediated inflammation in macrophages. We will thereby demonstrate the importance of myelin-derivedarachidonic acid in these critical inflammatory responses. Aim 2 will utilize cPLA2-/- bone marrow chimeric miceto interrogate the importance and influence of macrophage cPLA2 in the pathogenesis of SCI. Chronic pro-inflammatory macrophage activation is a key mediator of secondary damage and impaired recovery after SCIyet the mechanisms behind this process are poorly understood. Here I propose a novel mechanism by whichmyelin debris and subsequent processing by macrophage cPLA2 continuously produces free arachidonic acidthereby driving the chronic inflammation observed after SCI.

project_terms:
Address;Adopted;Affect;Anatomy;Animals;Arachidonic Acids;Automobile Driving;Behavioral;Biological Assay;Bone Marrow;Cellular Membrane;Chest;Chimera organism;Chronic;Cytosolic Phospholipase A2;Data;Eicosanoids;Environment;Enzyme-Linked Immunosorbent Assay;Enzymes;Fatty Acids;Genes;Health Care Costs;Immunohistochemistry;Impairment;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Injury;Knock-out;Lesion;Lipids;Macrophage Activation;Mass Fragmentography;Measures;Mediating;Mediator of activation protein;Membrane;Microglia;Molecular;Mus;Myelin;Nerve Degeneration;Paralysed;Pathogenesis;Pathologic;Pathology;Patients;Peripheral;Phagocytes;Phagocytosis;Phenotype;Phospholipase;Phospholipids;Process;Property;Proteins;Publishing;Reactive Oxygen Species;Recovery;Reporting;Role;Spinal Cord Contusions;Spinal cord injury;Stimulus;Tissues;base;cytokine;in vivo;inflammatory milieu;inhibitor/antagonist;injury recovery;macrophage;membrane model;monocyte;novel;repaired

public_health_relevance:
Project NarrativeAfter spinal cord injury (SCI) there is incomplete recovery often resulting in chronic paralysis and expensivehealth care costs for patients. One major contributor to this inability to recover is a chronic inflammatoryresponse that inhibits the normal repair process. While the negative effects of this inflammatory response havebeen well studied the molecular mechanisms that drive this inflammation long after the initial injury remainunclear; to address this this proposal will examine the mechanisms by which the cellular debris generatedafter injury can be continuously broken down into a potent inflammatory stimulus.


application_id: 9952417
project_number: 5R01HL141356-03
project_title: Mitochondrially Targeted Therapies for Sepsis Induced Diaphragm Dysfunction
administering_ic: NHLBI
award_notice_date: 2020-05-29
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 141356
program_official: ZHOU, GUOFEI
project_start_date: 2018-07-01
project_end_date: 2022-05-31
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 1879110
contact_pi: SUPINSKI, GERALD S.
other_pis: CALLAHAN, LEIGH A
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:
Severe ICU acquired diaphragm dysfunction is present in the majority of mechanically ventilated MICUpatients. Importantly recent work indicates that patients with weak diaphragms have a much longerrequirement for mechanical ventilation and a markedly higher mortality. As a result therapies that increasediaphragm function have the potential to improve MICU patient outcomes. These recent studies also suggestthat a major risk factor for ICU acquired diaphragm weakness is infection. Infections elicit a marked increasein diaphragm mitochondrial free radical production and these free radicals contribute to weakness andfatigue. The present proposal therefore will test the hypothesis that pharmacological therapiesdesigned to either inhibit mitochondrial free radical generation or induce mitochondrial repair willprevent and/or reverse sepsis mediated diaphragm dysfunction. This theory will be tested in fourgroups of studies:Aim 1 studies will test the hypothesis that sepsis induced diaphragm dysfunction can be reduced by usingagents which inhibit mitochondrial free radicals. Experiments will utilize the cecal ligation puncture sepsismodel (CLP) and compare diaphragm function in sham operated CLP CLP plus drug and sham plus druggroups. Drugs to be tested include mitoTEMPOL SKQ1 and necrostatin.Aim 2 studies will test the hypothesis that administration of activators of mitochondrial biogenesis canimprove infection induced diaphragm dysfunction. Sepsis will again be produced with CLP and we willexamine the ability of three treatments (i.e. AICAR+PQQ PQQ and AICAR+GW1506) to prevent CLPinduced diaphragm dysfunction.Aim 3 studies will evaluate the mechanisms by which Aim 1 and Aim 2 drugs produce their effects onmuscle cells. These experiments will also test the hypothesis that these agents induce release of myokineswhich have autocrine effects to attenuate cytokine induced muscle cell damage.Aim 4 studies will test the hypothesis that myokine administration can be used as a pharmacologicaltreatment to attenuate sepsis induced diaphragm dysfunction in animals. Myokines to be tested include irisinand other proteins found in Aim 3 studies to block cytokine induced muscle cell damage in vitro.

project_terms:
Animal Model;Animals;Antioxidants;Attenuated;Biogenesis;Cell Size;Clinical;Contractile Proteins;Critical Illness;Development;Electron Transport;Fatigue;Free Radicals;Functional disorder;Generations;In Vitro;Infection;Intensive Care Units;Ligation;Mechanical ventilation;Mechanics;Mediating;Medical;Mitochondria;Modeling;Morbidity - disease rate;Muscle;Muscle Cells;Muscle Mitochondria;Muscle Weakness;Muscle function;Muscular Atrophy;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Peritoneal Sepsis;Peritonitis;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacology;Pharmacotherapy;Process;Production;Proteins;Puncture procedure;Reactive Oxygen Species;Research;Respiratory Diaphragm;Risk Factors;Saline;Sepsis;Skeletal Muscle;Testing;Work;autocrine;base;cecal ligation puncture;cell injury;cytokine;design;experimental study;improved;improved outcome;indexing;inhibitor/antagonist;mortality;muscle strength;neuromuscular function;paracrine;prevent;repaired;response;targeted treatment;theories;therapy design

public_health_relevance:
Diaphragm muscle weakness is a major contributor to morbidity and mortality in critically ill MICU patients butcurrently there is no drug therapy available to treat this problem. The studies in this proposal are designed toidentify treatments to prevent and/or restore muscle function in these patients. We believe this work has thepotential to define new treatments that can have a major impact to improve the clinical outcomes of critically illpatients.


application_id: 9951267
project_number: 1R21AG066865-01
project_title: Pumping iron: Loss of iron homeostasis causes microglia degeneration in AD
administering_ic: NIA
award_notice_date: 2020-04-16
opportunity_number: PA-19-053
application_type: 1
activity_code: R21
ic: AG
serial_number: 066865
program_official: OPANASHUK, LISA A
project_start_date: 2020-05-01
project_end_date: 2023-04-30
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
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:
Evidence from genetic biochemical and neuropathological studies has shown that loss of homeostatic microglia function contributes to Alzheimers disease (AD) pathogenesis. From our work and the work of others dystrophic microglia are now known to be a common feature of AD and other neurodegenerative diseases but little is known about the causes and consequences of dystrophic microglia in AD. Our pilot data from an unbiased proteomic screening of AD brains has identified ferritin light chain (FTL) as a top candidate protein. FTL is used to store excess iron in microglia. Prior studies have shown that dystrophic microglia in the AD brain express high amounts of ferritin. Regulation of iron homeostasis occurs by the influx storage and efflux of iron from cells. Our project is a departure from prior work on microglia in AD as we will define the mechanisms leading to a primary glial pathology  dystrophic microglia. Our hypothesis that dysregulation of iron homeostasis is a driving force in microglial degeneration is novel. By using complementary histological biochemical and flow cytometry methods in human brain tissue we will define this human-specific gliadegeneration. We hypothesize that a dysregulation of iron homeostasis is a driver of dystrophic microglia in neurodegenerative disease. Using biosamples from the University of Kentucky Alzheimers Disease Center biobank of well-characterized tissue encompassing the full spectrum of disease severity we will address the following specific aims:Aim 1: Define iron influx pathway in dystrophic microglia  Aim 2: Define iron storage pathway in dystrophic microglia  Aim 3: Define iron efflux pathway in dystrophic microglia Overall impact: Successful completion of this project will lead to the discovery of a novel target in microglia iron homeostasis to restore the healthy function of microglia and prevent the degeneration of these cells.

project_terms:
Address;Alzheimer disease screening;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease risk;Amyloid beta-Protein;Area;Autopsy;Biochemical;Brain;Cells;Ceruloplasmin;Collaborations;Complex;Data;Development;Ferritin;Flow Cytometry;Genes;Genetic;Goals;Histologic;Homeostasis;Human;Iron;Kentucky;Light;Measures;Mediating;Metals;Methods;Microglia;Molecular;Morphology;Mutation;Myelin;Nerve Degeneration;Neurodegenerative Disorders;Neuroglia;Pathogenesis;Pathology;Pathway interactions;Phenotype;Physiological;Proteins;Proteomics;Pump;Regulation;SLC11A2 gene;Severity of illness;TFRC gene;Therapeutic Intervention;Time;Tissues;Universities;Work;aged;biobank;brain tissue;cell injury;cell type;digital;driving force;experimental study;limbic-predominant age-related TDP-43 encephalopathy;metal transporting protein 1;non-demented;novel;prevent;receptor

public_health_relevance:
Loss of physiological microglia function is now believed to contribute to the development of Alzheimers disease. Dystrophic microglia are now known to be a common feature of AD and thus necessitate mechanistic exploration of this poorly defined glia pathology. Successful completion of this project will lead to the discovery of a novel target in microglia iron homeostasis to restore the healthy function of microglia and prevent the degeneration of these cells.


application_id: 9949700
project_number: 5R01DK074816-11
project_title: RORalpha and Hepatic Zonal Regulation
administering_ic: NIDDK
award_notice_date: 2020-06-03
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 074816
program_official: BURGESS-BEUSSE, BONNIE L
project_start_date: 2007-09-01
project_end_date: 2022-06-30
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 1879406
contact_pi: SPEAR, BRETT
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:
The restricted expression of specific hepatic genes in pericentral or periportal regions ofthe adult liver a phenomenon known as zonal regulation is a fascinating aspect of liverbiology. Elegant studies in the past 10 years have uncovered the role of the b-cateninsignaling pathway in controlling zonal expression. Our recent studied using a novelmouse model system developed by us indicates that the retinoic acid-related orphanreceptor alpha (RORa) also plays a role in controlling zonal gene expression.Furthermore studies in other tissues have shown that RORa contributes to thedifferentiation and proliferation of stem cells but this property has not been evaluated inthe liver. We propose to use genetically modified mice and contemporary high-throughput genomic technologies to explore the role of RORa in the function and stemcell properties of pericentral hepatocytes. Since many hepatotoxins including ethanoland pharmaceuticals such as acetaminophen specifically damage pericentralhepatocytes a better understanding of the mechanisms controlling gene expression inand the self-renewing properties of this subpopulation of hepatocytes will help developstrategies to reduce hepatocyte injury in humans.

project_terms:
Acetaminophen;Adult;Binding;Binding Sites;Biological Models;Biology;Carbon Tetrachloride;Cell Lineage;Cell Separation;Cell Surface Proteins;Central Vein;ChIP-seq;Conflict (Psychology);Data;Enhancers;Ethanol;Exhibits;Flow Cytometry;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genomics;Goals;Grant;Hepatic;Hepatocyte;Human;Individual;Knockout Mice;Link;Liver;Liver Regeneration;Lobule;Methods;Modeling;Mus;Mutate;Mutation;Natural regeneration;Nucleic Acid Regulatory Sequences;Orphan;Partial Hepatectomy;Pattern;Pharmacologic Substance;Play;Property;RORA gene;Regulation;Response Elements;Role;Signal Pathway;Site;Staggerer Mouse;Technology;Testing;Tissues;Transgenes;Transgenic Mice;Transgenic Organisms;Tretinoin;alpha-Fetoproteins;beta catenin;fascinate;hepatocyte injury;hepatotoxin;improved;in vivo;insight;interest;liver function;liver injury;mouse model;novel;promoter;receptor;self-renewal;stem cell division;stem cell proliferation;stem cells;transcription factor;transcriptome sequencing

public_health_relevance:
Many hepatotoxins and pharmaceuticals specifically damage a subset of hepatocytesthat are found in the pericentral region of the adult liver. Studies proposed in the grantwill investigate the role of the transcription factor RORa as well as the factors Rev-erba/b in the function and stem cell properties of these unique pericentral hepatocytes.The long-term goal of these studies is to improve strategies that will reduce liver injury inhumans.


application_id: 9948659
project_number: 5T35EY026509-04
project_title: Summer Vision Sciences Training Program
administering_ic: NEI
award_notice_date: 2020-04-08
opportunity_number: PA-16-151
application_type: 5
activity_code: T35
ic: EY
serial_number: 026509
program_official: CLAYTON, EDWIN C
project_start_date: 2017-07-01
project_end_date: 2022-04-30
study_section: ZEY1-VSN(03)
contact_pi_person_id: 1925445
contact_pi: CERESA, BRIAN P.
other_pis: GUIDO, WILLIAM
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:
Project Summary/Abstract This application is a resubmission for a T35 summer medical student training program invision research with two Specific Aims: 1) To provide hands-on training in basic and clinicalvision research to medical students in a structured mentored environment and 2) To provide aninteractive educational experience that introduces medical students the fundamental skillsnecessary for basic translational and clinical research in vision biology. The co-directors of thisprogram request support for 6 second-year medical students each summer in vision relatedresearch laboratories that focus on topics such as visual circuitry retinal degeneration cornealepithelial homeostasis uveitis and development of the visual system. Trainees will be selectedfrom the first year class at University of Louisville School of Medicine. Students will reviewresearch projects submitted by 19 faculty funded by the NEI or vision related foundations. Thedirectors will make a special effort to recruit students from ethnic minorities and disadvantagedbackgrounds. Students will review the available projects and enter their 1st-3rd choices allowingmatching of trainees with mentors. Final decisions will be made based on interviews betweenmentors and Trainees. During the 10-week summer training students work with mentors ontheir research project in clinical or laboratory settings complete training in the ResponsibleConduct of Research including topics such as fabrication and falsification of data plagiarismmanaging scientific data publication practices and responsible authorship mentorshipstewardship and conflict of interest. Trainees will complete human subject IRB training andanimal care and handling as required by their specific research projects. All Trainees will attenda 2-hour weekly Vision Sciences Research Training Seminar designed to introduceclinical/translational research in Ophthalmology led by mentors in this T35 program. Theseminar series will culminate with each Trainee presenting his/her research project to peers andmentors. Trainees present the results of their research as posters with peers at a School ofMedicine-wide week-long celebration of research that includes nationally recognized physician-scientists as keynote speakers. Trainees will be encouraged to continue research as part of theDistinction in Research track that is an enrichment program focusing on providing meaningfuland productive research experiences throughout second through fourth years of medical schoolwith ongoing presentations by students with mentors and 4+ weeks of research time in thefourth year toward the goal of developing clinician-researchers. Trainees will be tracked toassess the impact of this T35 program on careers as physician-scientists.

project_terms:
Authorship;Basic Science;Biology;Clinical;Clinical Research;Conflict of Interest;Data;Environment;Faculty;Foundations;Funding;Goals;Homeostasis;Hour;Institutional Review Boards;Interview;Laboratories;Laboratory Research;Medical Students;Mentors;Mentorship;Ophthalmology;Physicians;Plagiarism;Publications;Research;Research Personnel;Research Project Grants;Research Training;Retinal Degeneration;Scientist;Series;Structure;Student recruitment;Students;Time;Training;Training Programs;Translational Research;Universities;Uveitis;Vision;Vision research;Visual;Work;animal care;base;career;corneal epithelium;design;ethnic disadvantage;ethnic minority population;experience;human subject;medical schools;peer;peer coaching;posters;programs;responsible research conduct;skills;vision development;vision science

public_health_relevance:
Program Narrative:This new NEI Short-Term Institutional Training Grant application is to request 5 years of support for 6 risingsecond year Medical Student trainees in our Vision Science laboratories for a 10 week research experience.We will focus on recruitment of under-represented trainees into this program to enhance the diversity of ourmedical workforce. The T35 training grant will be used to entice our medical students into our new Distinctionin Research Track a program that encourages students to participate in laboratory research in years 2-4 ofmedical school with an eye toward scholarly activities in academic medicine to continue to build a pipeline oftranslational clinician-researchers in the future.


application_id: 9948028
project_number: 5R01NS095229-05
project_title: CNS Functions of Calpain 5
administering_ic: NINDS
award_notice_date: 2020-06-03
opportunity_number: PAS-15-029
application_type: 5
activity_code: R01
ic: NS
serial_number: 095229
program_official: RIDDLE, ROBERT D
project_start_date: 2016-09-01
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZRG1-MDCN-C(02)S]
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W.
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract:Calpains are Ca2+-activated neutral (non-lysosomal) proteases implicated in neurodegenerationfollowing acute insults such as stroke and traumatic brain injury as well as in neurodegenerativedisorders such as Alzheimers disease. Calpain research in the CNS has focused almost exclusivelyon the classical calpains Calpains 1 and 2. Calpain 5 (CAPN5) which lacks the penta-EF handdomain of classical calpains is the 2nd most highly expressed calpain in the CNS. Calpain 5 hashomology to other calpains in the cysteine protease domain and also has a unique C2 domain at theC-terminus. C2 domains are involved in binding to membranes and lipids. Very little is knownregarding the functions and substrates of Calpain 5. The C. elegans orthologue of Calpain 5 Tra-3regulates transcriptional activity involved in sex determination. Tra-3 is also required forneurodegeneration induced by TDP-43 toxicity and for necrotic death of sensory neurons followingcalcium overload. At the subcellular level CAPN5 is found in nuclear and crude mitochondrialfractions and associated with promeylocytic nuclear bodies. The purpose of this proposal is gaininsight into the CNS functions of Calpain 5. Aim 1 will identify Calpain 5 binding partners andsubstrates using three complimentary techniques: tandem affinity purification; proximity dependentlocalization; and in vitro affinity capture with each technique paired with mass spectrometry forprotein identification. The binding partners and substrates will be evaluated under both basal andelevated intracellular calcium conditions. The role of the C2 domain in Ca2+ binding along withCAPN5 activation and localization will be evaluated in Aim 2. Aim 3 will explore the physiologicalfunctions of CAPN5 utilizing knockout cell lines generated using CRISPR/Cas-9 and conditionalknockout mice. Preliminary data support the feasibility of each Aim. Together these results willprovide essential information for deciphering the CNS function(s) of CAPN5.

project_terms:
Actins;Active Sites;Acute;Acute Promyelocytic Leukemia;Afferent Neurons;Affinity;Affinity Chromatography;Alzheimer's Disease;Basic Science;Binding;Binding Sites;Biotin;Brain;C2 Domain;CRISPR/Cas technology;Caenorhabditis elegans;Calcium;Calpain;Caspase;Cell Line;Cell Nucleus;Cell membrane;Cells;Cessation of life;Characteristics;Chronic;Cleaved cell;Cysteine;Cytokinesis;Data;Dynein ATPase;EF Hand Motifs;EF-Hand Domain;Family;Genes;Genetic;Genetic Transcription;Human;Impairment;In Vitro;Knock-out;Knockout Mice;Lipids;Long-Term Potentiation;Mass Spectrum Analysis;Membrane;Membrane Lipids;Messenger RNA;Methods;Microtubules;Mitochondria;Necrosis;Nerve Degeneration;Neurodegenerative Disorders;Neurosciences;Nomenclature;Nuclear;Pathologic;Pentas;Peptide Hydrolases;Phenotype;Phospholipids;Physiological;Property;Proprotein Convertase 1;Proprotein Convertase 2;Protease Domain;Protein Isoforms;Proteins;Research;Role;Signal Transduction;Site-Directed Mutagenesis;Spinal Cord;Stroke;Structure;Techniques;Toxic effect;Traumatic Brain Injury;Triad Acrylic Resin;alpha Actinin;alpha Tubulin;base;beta Tubulin;conditional knockout;in silico;in vivo;inhibitor/antagonist;insight;interest;knock-down;member;migration;novel;overexpression;protein TDP-43;response;sensor;sex determination

public_health_relevance:
NarrativeCalpains are calcium-activated proteases which selectively cleave substrate proteins and areimplicated in neuronal degeneration associated with stroke traumatic brain injury and Alzheimersdisease. Calpain 5 is expressed in the brain at relatively high levels compared to the previouslystudied calpains 1 and 2 yet little is known regarding calpain 5s physiological and pathological roles.This basic science neuroscience proposal examines the binding partners/substrates of Calpain 5mechanisms of activation and consequences of genetic deletion to decipher its possible function(s)in the brain.


application_id: 9947747
project_number: 5R01DK116591-03
project_title: miRNA Mechanism of Acute Kidney Injury in Aging
administering_ic: NIDDK
award_notice_date: 2021-09-02
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 116591
program_official: MARIC-BILKAN, CHRISTINE
project_start_date: 2018-07-31
project_end_date: 2023-05-31
study_section: Special Emphasis Panel[ZRG1-VH-C(02)]
contact_pi_person_id: 9501257
contact_pi: SEN, UTPAL
other_pis: TYAGI, SURESH C.
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:
Project SummaryIschemia/reperfusion (I/R)-induced acute kidney injury (AKI) remains a major clinical problem in olderpopulation. Although I/R-induced AKI occurs in a variety of clinical situations such as shock renaltransplantation sepsis and renal artery stenosis the mechanism is multifactorial complex and poorlyunderstood. Under normal physiological conditions kidney produces hydrogen sulfide (H2S) with the aid of fourenzymes: cystathionine -synthase (CBS) cystathionine -lyase (CSE) 3-mercaptopyruvate sulfurtransferase(3MST) and cysteine aminotransferase (CAT). In recent years H2S has been shown to regulate severalphysiological functions and its decrease has been implicated in diseases such as hypertension inflammationatherosclerosis and renal disease progression and failure. MicroRNAs (miRNAs) are small non-coding RNAswhich has the ability to inhibit mRNA transcripts by inducing degradation or blocking protein translation. In I/R-induced AKI several miRNAs have been reported to be differentially expressed. Furthermore in I/R-inducedAKI macrophages play a key role in inflammatory and reparative process. While M1 subset macrophage isinvolved in inflammation subset M2 is involved in repair mechanism. Our preliminary results suggested that inI/R-induced AKI in aging miRNA-21 is upregulated and miRNA-194 is down regulated. The injured kidney alsoshowed decreased expression of CBS and 3MST enzymes leading to diminished H2S production. Theincreased ratio of M1/M2 further suggested prolonged inflammatory phase. In addition expression of matrixmetalloproteinase-9 (MMP-9) and their regulatory molecules EMMPRIN and Meprin-A were also upregulatedin AKI. These changes in concert with endothelial to mesenchymal transition (EndoMT) led us to stronglybelieving a detrimental remodeling in I/R-induced old kidney. Interestingly H2S treatment mitigated remodelingand improved renal function in I/R-induced AKI in old mice. We obtained similar results through miR-21inhibitor treatments. Based on these preliminary findings we hypothesize that H2S is a protective agent againstI/R-induced damage in aging kidney. In further substantiating our concept both male and female old vs youngwild type (WT C57BL/6J) mice will be used to compare severity of I/R-induced kidney injury and dysfunctionand beneficial effects of H2S treatment will be assessed. The gained knowledge will not only help to betterunderstand mechanisms of AKI in aging but will also shed lights on future diagnostic and therapeuticstrategies which will be applicable to older patients suffering from AKI.

project_terms:
3-Mercaptopyruvate sulfurtransferase;Acute Renal Failure with Renal Papillary Necrosis;Aging;Angiography;Animals;Anti-Inflammatory Agents;Antioxidants;Atherosclerosis;Barium;Bilateral;Blood flow;Cardiac Surgery procedures;Clinical;Collagen;Complex;Creatinine;Cystathionine;Cystathionine beta-Synthase;Cysteine;Deposition;Diagnostic;Disease;Disease Progression;Down-Regulation;Endothelium;Enzymes;Equilibrium;Extracellular Matrix;Failure;Female;Fibrosis;Flow Cytometry;Fluorescein-5-isothiocyanate;Functional disorder;Future;Gelatin Zymography;Gelatinase B;Generations;Glomerular Filtration Rate;Goals;Health;Histology;Hydrogen Sulfide;Hypertension;Impairment;Infection;Inflammation;Inflammation Mediators;Inflammatory;Injury to Kidney;Ischemia;Kidney;Kidney Diseases;Kidney Transplantation;Knowledge;Lasers;Lead;Lyase;Matrix Metalloproteinases;Measures;Mediating;Meprin;Mesenchymal;Messenger RNA;Metabolic;Methods;MicroRNAs;Mus;Older Population;Organ Transplantation;Outcome;Peritoneal;Phase;Physiological;Plasma;Play;Population;Prevention strategy;Production;Protective Agents;Proteins;Quality of life;Renal Artery Stenosis;Renal Blood Flow;Renal function;Reperfusion Injury;Reperfusion Therapy;Reporting;Reverse Transcriptase Polymerase Chain Reaction;Roentgen Rays;Sepsis;Severities;Shock;Testing;Therapeutic;Transaminases;Transcript;Translations;Transplantation Surgery;Ultrasonography;Untranslated RNA;Up-Regulation;Vascular Diseases;Western Blotting;base;density;design;differential expression;experimental study;improved;inhibitor/antagonist;kidney dysfunction;kidney fibrosis;kidney vascular structure;macrophage;male;older patient;prevent;renal ischemia;repaired;reparative process;treatment strategy

public_health_relevance:
Project NarrativeIschemia-reperfusion (I/R) is the cut off and re-establishment of blood flow and is a commoncause of acute kidney injury (AKI) in a variety of health conditions including shock infectionorgan transplantation and cardiac surgery. Understanding of I/R mechanism is incomplete andtherefore treatment strategies for AKI are insufficient. This proposal is designed to delineate theunderlying mechanism of kidney I/R injury in older population and to effectively counter AKI witha hydrogen sulfide releasing compound GYY4137.


application_id: 9946497
project_number: 1R01NS116058-01
administering_ic: NINDS
award_notice_date: 2020-03-25
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: NS
serial_number: 116058
program_official: CORRIVEAU, RODERICK A
project_start_date: 2020-04-01
project_end_date: 2025-03-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
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
budget_start_date: 2020-04-01
project_terms:
Acids;Adherence;Adhesions;Aging;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimers disease biomarker;Amyloid;Amyloid beta-42;Amyloid beta-Protein;Arteries;Axon;Behavioral;Biopsy;Blood;Blood Vessels;Blood capillaries;Brain;Cardiovascular system;Carrying Capacities;Cerebral small vessel disease;Cerebrospinal Fluid;Cerebrovascular Circulation;Cerebrovascular system;Cerebrum;Clinical;Clinical Data;Data;Dementia;Deposition;Development;Diabetes Mellitus;Disease;Disease Marker;Elderly;Endocrine;Enrollment;Enzymes;Epoxide hydrolase;Erythrocytes;Genetic;Gliosis;Glucose;Hemoglobin;Hormone Antagonists;Hormones;Human;Hypersensitivity skin testing;Hypoxia;Hypoxic-Ischemic Brain Injury;Impaired cognition;Impairment;Individual;Insulin;Isomerism;Laboratories;Lead;Link;Magnetic Resonance Imaging;Measures;Mediating;Mediator of activation protein;Metabolic dysfunction;Microspheres;Modeling;National Institute of Neurological Disorders and Stroke;Neurologic;Neurologic Deficit;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Pancreas;Participant;Pathologic;Pathologic Processes;Pathology;Pathway interactions;Patients;Pharmacology;Phenotype;Prevention;Prevention strategy;Proteins;Rattus;Regulation;Reporting;Research Project Grants;Sampling;Satiation;Senile Plaques;Signal Pathway;Skin;Techniques;Testing;Therapeutic Intervention;Vascular Cognitive Impairment;Vascular Endothelial Cell;axonal degeneration;beta amyloid pathology;brain cell;cerebral capillary;cerebrovascular;cohort;comorbidity;effective therapy;in vivo;inhibitor/antagonist;innovation;ischemic injury;islet amyloid polypeptide;mild cognitive impairment;neuroinflammation;novel therapeutics;tau Proteins;tool;translational study;vascular cognitive impairment and dementia


application_id: 9946396
project_number: 1R01HD101508-01
project_title: Noninvasive Noncontact High-Density Optical Imaging of Neonatal Intraventricular Hemorrhage
administering_ic: NICHD
award_notice_date: 2020-04-09
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: HD
serial_number: 101508
program_official: KING, TRACY
project_start_date: 2020-04-10
project_end_date: 2025-03-31
study_section: Imaging Technology Development Study Section[ITD]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Aftercare;Autopsy;Biological Markers;Birth;Blood;Blood Vessels;Brain;Brain Injuries;Brain imaging;Calibration;Case Study;Cephalic;Cerebral Ventricles;Cerebrospinal Fluid;Cerebrospinal fluid shunts procedure;Cerebrovascular Circulation;Cerebrum;Chronic Phase;Clinical;Clinical assessments;Complication;Coupled;Coupling;Critical Care;Critical Illness;Detection;Development;Devices;Diffuse;Effectiveness of Interventions;Evaluation;Fiber;Functional Imaging;Goals;Guidelines;Head;Histologic;Homeostasis;Human;Hydrocephalus;Image;Imaging Device;Imaging Techniques;Impairment;Inflammation;Injury;Intervention;Intracranial Hypertension;Intracranial Pressure;Ischemic Brain Injury;Laboratories;Lead;Legal patent;Low Birth Weight Infant;Magnetic Resonance Imaging;Measurement;Measures;Medical;Metabolic;Metabolism;Methods;Modeling;Monitor;Multi-modal optical imaging;Mus;Near-Infrared Spectroscopy;Neonatal;Neonatal Brain Injury;Neonatal Intensive Care Units;Neonatology;Neurologic Deficit;Neurological outcome;Neurosciences Research;Observational Study;Optics;Outcome;Outcome Assessment;Outcome Measure;Outcome Study;Oxygen;Oxygen Consumption;Premature Birth;Premature Infant;Property;Rattus;Recovery;Research;Resolution;Safety;Scalp structure;Signal Transduction;Source;Structure;Survival Rate;System;Technology;Testing;Three-Dimensional Imaging;Time;Tissues;Ultrasonography;algorithmic methodologies;brain health;brain tissue;cerebral hemodynamics;cerebrovascular;clinical application;cranium;density;design;detector;functional disability;high risk;human imaging;imager;imaging modality;improved;in vivo;injury recovery;innovation;intraventricular hemorrhage;metabolic rate;multimodality;neonatal brain;neonate;neuroimaging;novel;optical imaging;portability;pre-clinical;premature;preservation;preterm newborn;prevent;standard care;standard of care;tissue injury;tissue phantom;tomography;tool


application_id: 9945938
project_number: 1R01HL152081-01
administering_ic: NHLBI
award_notice_date: 2020-04-17
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: HL
serial_number: 152081
program_official: HASAN, AHMED A K
project_start_date: 2020-07-01
project_end_date: 2024-06-30
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 10451500
contact_pi: VENDITTO, VINCENT JOSEPH
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
budget_start_date: 2020-07-01
project_terms:
Anti-Inflammatory Agents;Antibodies;Antibody Response;Antigen-Antibody Complex;Antiinflammatory Effect;Apolipoprotein A-I;Apolipoproteins A;Arterial Fatty Streak;Atherosclerosis;Autoantibodies;Autoantigens;Autoimmunity;Blood Circulation;Cardiovascular Diseases;Cardiovascular system;Cell model;Cells;Characteristics;Communities;Complex;Cultured Cells;Data;Death Rate;Development;Disease;Disease Outcome;Disease Progression;Epitopes;Evaluation;Event;Exhibits;Fc Receptor;Foundations;Future;Goals;High Density Lipoproteins;Homeostasis;Human;IgG1;IgG4;Immune Complex Diseases;Immune response;Immunization;Immunoglobulin G;Immunologics;Incidence;Inflammation;Inflammatory;Interleukin-10;Interleukin-12;Investigation;Laboratories;Measures;Mediating;Molecular;Multi-Ethnic Study of Atherosclerosis;Multivariate Analysis;Mus;Myocardial Infarction;Obesity;Outcome;Outcomes Research;Participant;Pathogenesis;Patient-Focused Outcomes;Patients;Phenotype;Plant Roots;Plasma;Procedures;Prospective cohort;Proteins;Protocols documentation;Research;Risk;Risk stratification;Role;Sampling;Signal Transduction;Specificity;Stroke;Testing;adjudicate;atherosclerosis risk;base;burden of illness;cardiovascular disorder risk;cardiovascular health;cardiovascular risk factor;clinical risk;cohort;drug development;follow-up;functional outcomes;human subject;immunoregulation;improved;in vitro activity;in vivo;innovation;male;mouse model;new therapeutic target;novel;novel strategies;novel therapeutics;polarized cell;profiles in patients;programs;protocol development;receptor;response;therapeutic development;treatment strategy;western diet


application_id: 9944476
project_number: 5R01DE011111-27
project_title: P. gingivalis interactions with gingival epithelial cells
administering_ic: NIDCR
award_notice_date: 2020-05-27
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: DE
serial_number: 011111
program_official: MCNEALY, TAMARA L
project_start_date: 1995-04-01
project_end_date: 2024-06-30
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: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Apoptosis;Bacteria;Binding;Biological;Cell Proliferation;Cell Survival;Cells;Characteristics;Communities;Community Actions;Complex;Disease;Effector Cell;Epithelial;Epithelial Cells;Epithelium;Exhibits;FOXO1A gene;Fusobacterium nucleatum;Genetic Transcription;Gingiva;Grant;Homeostasis;Human;Immune;Immune response;Individual;Infection;Inflammation;Inflammation Mediators;Inflammatory;Interleukin-1 beta;Interleukin-6;Maintenance;Modeling;Molecular;Mouth Diseases;Mucous Membrane;Oral;Organism;Outcome;Pathologic;Pathway interactions;Periodontitis;Physiological;Porphyromonas gingivalis;Post-Translational Protein Processing;Process;Production;Property;Protein Dephosphorylation;Regulation;Role;Serine;Signal Pathway;Signal Transduction;Site;Specificity;Streptococcus;Streptococcus gordonii;Streptococcus oralis;Surface;Tissues;alveolar bone;beta catenin;bone metabolism;dysbiosis;immunological status;in vivo;microbial;microorganism;microorganism interaction;mouth squamous cell carcinoma;novel;oral bacteria;oral streptococci;periodontopathogen;programs;promoter;recruit;response;therapy design;transcription factor


application_id: 9941742
project_number: 1R01AG066653-01
project_title: Aberrant Glycogen Modulates Cerebral Glucose Metabolism in Aging and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2020-04-09
opportunity_number: PAR-17-031
application_type: 1
activity_code: R01
ic: AG
serial_number: 066653
program_official: BARRETT, PAUL JOHN
project_start_date: 2020-04-15
project_end_date: 2025-03-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 11838914
contact_pi: SUN, RAMON C.
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:
Abstract:The onset of Alzheimer's disease (AD) increases in incidence with age and an increasing aging demographicmeans the number of individuals suffering from AD is expanding rapidly. Changes in cerebral metabolism arehallmarks of aging therefore it is reasonable to hypothesize that age-associated change in metabolism playmajor roles in AD progression. AD brains show clear metabolic impairments and studies suggest that alteredmetabolism drives a cascade of events leading to AD onset. The mechanisms initiating these metabolicimpairments remain a critical knowledge gap in AD research. We recently discovered that aberrant glycogenaggregates (AD-glycogen) are a universal feature of AD in both human and mice. Increases in AD-glycogencorrelated with higher Braak staging and lower glucose levels in patient specimens. AD-glycogen is bothhyper-phosphorylated and hyper-branched making them architecturally distinct from normal glycogen. Wepresent strong evidence showing that AD-glycogen modulate brain metabolism through direct binding andinactivation of the AMP-activated protein kinase (AMPK) a master regulator of central carbon metabolism. Wewill first elucidate the molecular events leading to abnormal AD-glycogen formation in vitro and in vivo (Aim 1)then we will interrogate the impact of AD-glycogen on cerebral metabolism during aging (Aim 2). Finally wewill assess the efficacy of a novel glycogen-clearing enzyme therapy on brain metabolism cognition and ADneuropathology in vivo (Aim 3). The PI has assembled a multi-disciplinary team of investigators withcomplementary skillsets and state-of-art high resolution and Omic-based techniques to discover potentialtherapeutic options and possibly treat the onset of AD.

project_terms:
5'-AMP-activated protein kinase;Ablation;Age;Aging;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease model;Alzheimer's disease patient;Anabolism;Antibodies;Architecture;Astrocytes;Autopsy;Behavior;Binding;Biochemical;Brain;Carbon;Cerebrum;Characteristics;Clinical;Cognition;Cyclic AMP-Dependent Protein Kinases;Data;Demographic Aging;Disease Progression;Enzymes;Event;Glucose;Glycogen;Glycogen Storage Disease;Human;Impairment;In Vitro;Incidence;Individual;Kentucky;Knowledge;Lead;Learning;Mass Spectrum Analysis;Measures;Memory;Metabolic;Metabolic Pathway;Metabolism;Methods;Molecular;Mus;Nerve Degeneration;Neurons;Onset of illness;Pathogenesis;Pathologic;Patients;Play;Polysaccharides;Positioning Attribute;Premature aging syndrome;Process;Protein Kinase;Reporting;Research;Research Personnel;Resolution;Rodent;Role;Sampling;Severities;Specimen;Staging;Structure;Symptoms;System;Tauopathies;Techniques;Testing;Therapeutic;Transgenes;Universities;age related;aging brain;aging population;amyloid pathology;base;brain metabolism;design;enzyme therapy;glucose metabolism;glycogen metabolism;improved;in vitro Model;in vivo;metabolomics;mouse model;multidisciplinary;mutant;neuropathology;novel;novel therapeutics;pre-clinical;stable isotope;therapeutic target

public_health_relevance:
Project NarrativeCerebral glucose hypometabolism is now considered one of the hallmarks of Alzheimers disease (AD) clinicalAD symptoms almost never occur in the absence glucose hypometabolism and the extent of the metabolicchanges measured strongly correlate with the severity of clinical symptoms. The mechanism(s) that driveglucose hypometabolism remain a critical knowledge gap in AD research. This proposal aims to examine age-related changed in cerebral glucose metabolism in both healthy and AD mouse models to 1) improve ourunderstanding in the metabolic aging process and 2) to identify divergent events that result in the onset of ADfrom the aging population.


application_id: 9940338
project_number: 1S10OD026840-01A1
project_title: Bruker timsTOF Mass Spectrometer
administering_ic: OD
award_notice_date: 2020-04-13
opportunity_number: PAR-19-179
application_type: 1
activity_code: S10
ic: OD
serial_number: 026840
suffix: A1
program_official: CHEN, YONG
project_start_date: 2020-04-15
project_end_date: 2021-04-14
study_section: Special Emphasis Panel[ZRG1 BCMB-T (30)]
contact_pi_person_id: 12584275
contact_pi: LORKIEWICZ, PAWEL K
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:
Project Summary/AbstractThe Bioanalytics Core laboratory within the University of Louisville Diabetes and Obesity Center (DOC) as wellas other laboratories on campus operate mass spectrometers dedicated to meeting ever increasing and complexneeds of NIH-funded investigators. The needs of our investigators far exceed current capabilities with majorlimitations comprising a lack of ability for untargeted adductomic and metabolomic screening lipidomics andstable isotope metabolomics. These major applications are central to several NIH-funded Major and Minor Userswith interests in cardiovascular and metabolic disease environmental toxicology exercise science andimmunology. We propose to add a Bruker timsTOF LC-MS system which would significantly enhance ourbreadth of analyte coverage and open the possibility for biomarker discovery and identification of unknownendogenous and exogenous metabolites in biological samples. This will be important to Major Users engagedin biomarker discovery and the identification of conjugates of reactive species. In addition the system wouldexpand our coverage to hundreds of lipids within multiple lipid classes and would empower stable isotopemetabolomic capabilities beyond central carbon metabolism. Features of the Bruker timsTOF LC-MS systemsuch as the high scan speed and ultrahigh resolution in the MS and MS/MS modes and 5 orders of magnitudedynamic range enables coverage of thousands of analytes in complex biological matrices while maintaining highthroughput analyses. The High Resolution Ion Mobility further adds another dimension for separating ionsallowing for separation of isomeric and isobaric species  a feature of special use in adductomics metabolomicsand lipidomics applications. This application describes the utility of the instrument to six Major Users who arefunded by large NIH multicenter grants and R01s and several Minor Users. Proposed work with instrumentincludes detailed training and education in mass spectrometry and method development which will furtheradvance research in the Center and maximize the utility of the instrument. The DOC has the infrastructure tomaintain and support the new equipment backed by the support of the University.

project_terms:
Back;Biological;Carbon;Cardiovascular Diseases;Complex;Diabetes Mellitus;Dimensions;Equipment;Exercise;Funding;Grant;Immunology;Infrastructure;Ions;Laboratories;Lipids;Mass Spectrum Analysis;Metabolic Diseases;Metabolism;Minor;Obesity;Research;Research Personnel;Resolution;Sampling;Scanning;Science;Speed;System;Training and Education;United States National Institutes of Health;Universities;Work;biomarker discovery;biomarker identification;environmental toxicology;high throughput analysis;instrument;interest;ion mobility;mass spectrometer;meetings;metabolomics;method development;screening;stable isotope

public_health_relevance:
NarrativeWe are requesting a state-of-the-art equipment that will help in many aspects of research into cardiovascularand metabolic disease environmental toxicology exercise and immunology. The instrument will allow us tostudy chemicals present in urine plasma and tissues and find those which are markers of exposure toenvironmental toxicants. The instrument will also provide much needed data to help us uncover and understandthe environmental mechanisms of cardiovascular disease and ways to prevent or minimize them.


application_id: 9940276
project_number: 1S10OD028690-01
project_title: Bruker AVANCE NEO 600 MHz High-Performance Digital NMR Spectrometer
administering_ic: OD
award_notice_date: 2020-07-15
opportunity_number: PAR-19-177
application_type: 1
activity_code: S10
ic: OD
serial_number: 028690
program_official: SPECTOR, JEFFREY O
project_start_date: 2020-07-20
project_end_date: 2022-07-19
study_section: Special Emphasis Panel[ZRG1 BCMB-P (30)]
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_abstract:
ABSTRACTThis proposal requests funds for the purchase of a state-of-the-art Bruker AVANCE NEO 600 MHz high-performance digital NMR spectrometer which will be housed in the University of Kentucky (UK) PharmNMRCenter located in the College of Pharmacy. The requested spectrometer offers capabilities that exceed by farthose of the existing NMR instruments currently accessible to the users of this application on campus oranywhere else in the Commonwealth of Kentucky. At UK there is an urgent need for a high-end high-field NMRspectrometer for biomedical researchers to be able to: (i) determine structures of small molecules (e.g. syntheticand natural products) in very low amounts as well as determine real-time kinetics; (ii) perform 19F NMRexperiments; (iii) establish protein-ligand interactions and/or perform fragment-based drug screening; (iv)determine protein-protein interactions; (v) establish protein dynamics and do relaxation-dispersion experiments;(vi) perform protein structure calculations; (vii) study intrinsically disordered proteins; and (viii) run diffusionordered spectroscopy (DOSY) experiments. All these capabilities will allow UK researchers to perform cutting-edge work in areas of interest to UK namely natural product drug discovery and development infectiousdiseases and bacterial resistance cancer as well as substance use and neurological disorders. The requestedinstrument will support a widely diverse array of collaborative translational research at UK and is expected tohave an immediate and dramatic impact on the NMR-dependent research programs of its NIH-fundedresearchers.

project_terms:
Alcohol or Other Drugs use;Area;Communicable Diseases;Diffusion;Disease;Disease Resistance;Drug Screening;Funding;Kentucky;Kinetics;Ligands;Malignant Neoplasms;NMR Spectroscopy;Natural Product Drug;Natural Products;Performance;Pharmacy facility;Protein Dynamics;Proteins;Relaxation;Request for Proposals;Research;Research Personnel;Running;Spectrum Analysis;Structure;Time;Translational Research;United States National Institutes of Health;Universities;Work;bacterial resistance;base;college;digital;drug development;drug discovery;experimental study;instrument;interest;nervous system disorder;programs;protein protein interaction;protein structure;small molecule

public_health_relevance:
PROJECT NARRATIVEThe acquisition of a state-of-the-art Bruker AVANCE NEO 600 MHz high-performance digital NMR spectrometerwill greatly enhance the research of NIH-funded investigators at the University of Kentucky by providing cutting-edge research capabilities currently not easily accessible or affordable on campus or anywhere else within theCommonwealth. This NMR spectrometer will provide a drastic increase in sensitivity and resolution along withthe ability to study biomolecules and conduct experiments on very small (microgram) quantities of small moleculesamples.


application_id: 9939945
project_number: 1R01HL151419-01
project_title: Biophysical Mechanisms of Hyperoxia-Induced Lung Injury
administering_ic: NHLBI
award_notice_date: 2020-04-15
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: HL
serial_number: 151419
program_official: ZHOU, GUOFEI
project_start_date: 2020-04-15
project_end_date: 2024-03-31
study_section: Lung Injury, Repair, and Remodeling Study Section[LIRR]
contact_pi_person_id: 1860187
contact_pi: WATERS, CHRISTOPHER M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Actins;Acute Lung Injury;Adult Respiratory Distress Syndrome;Alveolar;Animal Model;Antioxidants;Apoptosis;Atomic Force Microscopy;Bacterial Pneumonia;Basement membrane;Biological;Biophysical Process;Biophysics;Bone Marrow;Cell Adhesion;Cell Death;Cell membrane;Cells;Cellular Structures;Clinical;Cultured Cells;Disease;Elements;Endothelial Cells;Endothelium;Epithelial;Epithelial Cells;Epithelium;Exposure to;F-Actin;Focal Adhesions;Gelsolin;Guanosine Triphosphate Phosphohydrolases;Human;Hyperoxia;Incidence;Inflammasome;Inflammation;Inflammatory;Influenza;Injury;Intensive Care Units;Investigation;Knock-out;Lead;Light;Lung;MYLK gene;Masks;Measures;Mechanical ventilation;Mechanics;Mediating;Microtubules;Modeling;Modulus;Mus;Myosin ATPase;Myosin Light Chains;Necrosis;Oxygen;Pathway interactions;Patients;Phosphotransferases;Predisposition;Preparation;Process;Proteins;Resistance;Rho-associated kinase;Rupture;Severities;Signal Pathway;Signal Transduction;Slice;Stretching;Structure;Structure of parenchyma of lung;Testing;Therapeutic Intervention;Tidal Volume;Ventilator-induced lung injury;Work;alveolar bone;alveolar epithelium;biophysical properties;cell injury;ezrin;improved;injured;insight;keratinocyte growth factor;lung injury;macrophage;mechanical pressure;mechanical properties;mechanotransduction;moesin;mortality;mouse model;myosin phosphatase;prevent;radixin protein;response;targeted treatment


application_id: 9939803
project_number: 3U01HL133359-03S1
administering_ic: NHLBI
award_notice_date: 2019-09-17
opportunity_number: PA-18-906
application_type: 3
activity_code: U01
ic: HL
serial_number: 133359
suffix: S1
program_official: ADHIKARI, BISHOW B
project_start_date: 2017-08-03
project_end_date: 2022-07-31
study_section: ZEB1(M1)-S
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
arra_indicator: N
project_title:
Diversity Supplement to Multiscale Modeling of Inherited Cardiomyopathies and Therapeutic Interventions

project_abstract:
AbstractFamilial cardiomyopathies cause long-term geometrical and functional changes in the heart. Hypertrophicdisease is typically associated with larger myocytes thicker ventricular walls myocyte disarray and fibrosis. It'snot yet clear how the mutations that impact myosin function scale up to induce these multiscaled effects. Theparent grant proposed to develop growth and remodeling laws that couple tissue-level deformation to long-termchanges in molecular-level structure and function (via alterations in myosin kinetics sarcomere number/sizeand fibrosis). This will allow the model to evolve over time either remodeling in response to deleteriousmutations or reverse remodeling (that is undergoing beneficial changes) as a result of therapeutic interventions.One of the key phenotypes listed above which is not explored in depth in the parent grant is the developmentof myocyte disarray in the ventricular wall. This disorganization of myofibers can lead to detrimental changesin the deformation patterns in the heart which will ultimately degrade global pump function. It has been shownin patients with hypertrophic cardiomyopathy (HCM) that regional myofiber disarray is linked to ventricularhypokinesis. Despite this clinical relevance few studies have tried to address the growth and remodeling lawsthat are needed to characterize myofiber reorientation in the presence of HCM.The research planned in this supplement seeks to overcome these limitations and develop a new growth andremodeling law that will relate changes in myocardial microstructure (via myofiber disarray) and ventricular strainpatterns. This new law will enhance the ongoing work in the parent grant by coupling changes in ventricular wallvolume (parent grant) to deformation driven changes in myofiber orientation (supplement). Together this law willmore accurately capture the structural alterations caused by HCM. To achieve this the following aims areproposed for the supplement period:Aim 1: Quantify myofiber disarray with diffusion tensor (DT) MRI at the same time points as the strain patternscollected with DENSE MRI. It should be noted that the DENSE MRI data is being collected as part of the parentgrant. The DT MRI data will be collected at multiple time points to capture the evolution of myofiber disarray.Aim 2: Implement a new growth and remodeling law into the finite element framework to account for myofiberdisarry. The finite element code is organized in a modular way which will allow for seamless integration of thenew growth and remodeling law with what is being implemented for the parent grant.

project_terms:
Address;Affect;American;Cardiomyopathies;Code;Computational algorithm;Coupling;Data;Development;Diffusion;Disease;Elements;Evolution;Fibrosis;Growth;Heart;Heart Abnormalities;Hypertrophic Cardiomyopathy;Hypertrophy;Inherited;Kinetics;Knowledge;Laws;Lead;Link;Magnetic Resonance Imaging;Modeling;Molecular;Muscle Cells;Mutation;Myocardial;Myosin ATPase;Patients;Pattern;Phenotype;Pump;Research;Sarcomeres;Structure;Testing;Therapeutic Intervention;Thick;Time;Tissues;Validation;Ventricular;Work;clinically relevant;experimental study;inherited cardiomyopathy;insight;multi-scale modeling;new growth;parent grant;response;scale up

public_health_relevance:
NarrativeFamilial cardiomyopathies are the most frequently inherited heart defect and affect about 700000 Americans.Currently there are few studies that focus on the microstructural changes in myofiber organization which areinduced by this disease. In order to provide deeper insights into the adverse remodeling caused byhypertrophy this supplemental project will quantify myofiber disarray using diffusion tensor magneticresonance imaging and develop computational growth models to predict how ventricular structure and functionchange over time.


application_id: 9939589
project_number: 5R01EB026893-04
project_title: Controllable In Vivo Genome Editing for Immune-Checkpoint Blockade in Solid Tumors
administering_ic: NIBIB
award_notice_date: 2021-07-23
opportunity_number: PAR-16-044
application_type: 5
activity_code: R01
ic: EB
serial_number: 026893
program_official: CHEN, JERMONT
project_start_date: 2018-08-21
project_end_date: 2023-05-31
study_section: Special Emphasis Panel[ZRG1-SBIB-Q(58)R]
contact_pi_person_id: 14341515
contact_pi: TONG, SHENG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
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:
Project SummaryThe blockade of immune-checkpoint pathways has emerged as a promising therapeutic strategy for a varietyof cancers. However the diverse tumor responses to immunotherapy seen in preclinical and clinical studiesprompt the development of combination immunotherapies that can be tailored to the complex immune milieuof individual patients. On the other hand the severe adverse effects associated with the combination therapieswith multiple antagonist antibodies address the necessity for alternative safe and effective therapeuticapproaches. In light of this we aim to develop a hybrid nanoparticle-viral vector system for CRISPR/Cas9-based in vivo therapeutic genome editing which will be used for multiplexed disruption of immune suppressivepathways in the tumor microenvironment. CRISPR/Cas9 systems are very efficient in generating DNA double-strand breaks thus disrupting genes through the non-homologous end-joining (NHEJ) pathway. Howeverinducing uncontrolled CRISPR/Cas9 activities in vivo may lead to systemic genotoxicity. We will develop anovel in vivo gene delivery system that integrates a baculoviral vector (BV) with magnetic nanoparticles(MNPs). Our studies have shown that by taking advantage of the interplay between the MNP-mediated BVmargination and endocytosis and the innate immunity against insect viruses this delivery system can providespatial and temporal control of CRISPR/Cas9 activity. We will use the MNP-BV system to deliver optimizedCRISPR/Cas9 for gene disruption of immune suppressive signals PD-L1 and TGF- in the tumor tissue. Wewill evaluate CRISPR/Cas9 induced anti-tumor immune responses using two well-established mouse modelsan immunogenic model (MC38) where monotherapy with PD-1 blockade is sufficient and non-immunogenicmodels pancreatic ductal adenocarcinoma (PDAC) which portrays most non-immunogenic human solidtumors that require combination strategies. In aim 1 studies we will design and optimize CRISPR/Cas9gRNAs for targeting PD-L1 and TGF- package Cas9 and gRNAs into a BV vector and construct the MNP-BV system. In aim 2 studies we will evaluate MNP-BV-induced multiplexed gene disruption in cell cultureand determine the on-target and off-target indel rates. In aim 3 studies we will test the controlled in vivodelivery of CRISPR/Cas9 determine the immunological and therapeutic effects of local gene disruption vs.systemic blockade with antagonist antibody in mouse tumor models. The success of the proposed studies willprovide a multiplexed intratumoral immunoengineering platform and pave the way for the clinical translationof a highly efficient in vivo genome editing strategy for personalized cancer immunotherapy.

project_terms:
Address;Advanced Malignant Neoplasm;Adverse effects;Agonist;Allografting;Antibodies;Antigen-Antibody Complex;Antitumor Response;Biodistribution;CRISPR/Cas technology;Cancer Patient;Cell Culture Techniques;Clinical;Clinical Research;Clustered Regularly Interspaced Short Palindromic Repeats;Colon Adenocarcinoma;Combination immunotherapy;Combined Modality Therapy;Complex;Coupled;DNA Double Strand Break;DNA Sequence;Data;Development;Disease remission;Drug Kinetics;Endocytosis;Engineering;Gene Deletion;Genes;Genetic;Genome;Guide RNA;Human;Hybrids;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunity;Immunologics;Immunooncology;Immunotherapeutic agent;Immunotherapy;In Vitro;Individual;Insect Viruses;Lead;Light;MC38;Magnetic nanoparticles;Magnetism;Malignant Neoplasms;Mediating;Modeling;Modification;Mus;Natural Immunity;Nonhomologous DNA End Joining;Normal tissue morphology;OX40;Organ;PD-1 blockade;PD-L1 blockade;Pancreatic Ductal Adenocarcinoma;Pathologic Processes;Pathway interactions;Phenotype;Proteins;Signal Transduction;Solid Neoplasm;Specificity;System;Testing;Therapeutic;Therapeutic Effect;Tissues;Treatment Efficacy;Tumor Immunity;Tumor Tissue;Viral;Viral Vector;anti-cancer;anti-tumor immune response;base;cancer heterogeneity;cancer immunotherapy;cancer type;clinical application;clinical translation;design;engineered nucleases;gene delivery system;genome editing;genotoxicity;human disease;image guided;immune checkpoint;immune checkpoint blockade;immunoengineering;immunogenic;in vivo;individual patient;insertion/deletion mutation;iron oxide nanoparticle;magnetic field;mouse model;multiplexed imaging;novel;nuclease;pancreatic ductal adenocarcinoma model;patient subsets;personalized strategies;preclinical study;programmed cell death ligand 1;response;success;therapeutic genome editing;therapeutically effective;transduction efficiency;tumor;tumor microenvironment;vector;vector-induced;viral nanoparticle

public_health_relevance:
Project NarrativeThe blockade of immune checkpoints hold great promise for the treatment of advanced cancer. Here we proposeto develop a hybrid nanoparticle-viral vector system for controlled delivery of engineered nuclease CRISPR/cas9which induces multiplexed gene deletions in the immune checkpoint pathways in the tumor tissue. The successof this project will provide a highly integrated efficient and versatile immunotherapy in which the genetic targetscan be readily designed and implemented according to the immunological profile of individual cancer patients.


application_id: 9939501
project_number: 5R34DA045856-03
project_title: Re-entry XR-NTX for rural opioid dependent women
administering_ic: NIDA
award_notice_date: 2020-06-04
opportunity_number: PA-15-250
application_type: 5
activity_code: R34
ic: DA
serial_number: 045856
program_official: MULFORD, CARRIE FRIED
project_start_date: 2018-09-15
project_end_date: 2022-06-30
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 14909213
contact_pi: STATON, MICHELE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
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:
ABSTRACTThe overall aim of this R34 proposal is to examine the feasibility acceptability and short-term outcomesassociated with an innovative service delivery model to increase adherence to extended-release naltrexone (XR-NTX) during the transition from jail to the community for rural women with opioid use disorder (OUD). Thesignificance of this study is grounded in the public health crisis associated with the opioid epidemic in ruralAppalachia the increased vulnerability of rural women with OUD and the dearth of available and accessibleevidence-based treatment in the region. This R34 has potential to make a significant contribution to the OUDtreatment field by advancing knowledge on innovative service delivery models to increase access to evidence-based treatment to reduce high-risk opioid use and related health disparities among hard-to-reach high-riskunderserved populations. The study will be accomplished through two specific aims: (1) Adapt XR-NTX servicesfor use in community supervision (P&P) offices to increase adherence during re-entry from jail for rural womenwith OUD. (2) Examine feasibility acceptability and short-term outcomes of XR-NTX adherence and relapse toopioid use through a small pilot trial with 60 rural women with OUD. The pilot trial will include OUD screeningmedical evaluation XR-NTX initiation prior to jail release and random assignment to one of two community re-entry treatment models to receive on-going XR-NTX injections in the community after release in either: (1) Alocal rural P&P office (n=30) or (2) Services as Usual (n=30 referral to a community clinic). If this studyestablishes feasibility of this innovative community-based treatment model for XR-NTX in a rural underservedarea findings will be used to develop an R01 application to test the approach in a larger RCT during communityre-entry from jail among high-risk rural women with OUD in Appalachia. The long-term goal of this research is toincrease access to evidence-based treatment for OUD among high-risk underserved populations.

project_terms:
Adherence;Alcohol or Other Drugs use;American College of Obstetricians and Gynecologists;Appalachian Region;Area;Attitude;Cessation of life;Client;Clinical;Communities;Consent;Country;Coupling;Criminal Justice;Dependence;Dose;Drug user;Economics;Education;Evaluation;Evidence based treatment;Goals;HIV Infections;Health Service Area;Hepatitis C;Hepatitis C virus;Impairment;Imprisonment;Injections;Jail;Kentucky;Knowledge;Life;Link;Location;Medical;Modeling;Morbidity - disease rate;Naltrexone;Needle Sharing;Opiate Addiction;Opioid;Outcome;Participant;Pharmaceutical Preparations;Poverty;Prevalence;Prisons;Procedures;Protocols documentation;Provider;Public Health;Quality of life;Randomized;Randomized Clinical Trials;Recording of previous events;Relapse;Research;Rural;Rural Appalachia;Rural Community;Savings;Service delivery model;Services;Severities;Standardization;Supervision;System;Testing;Time;Transportation;Underserved Population;Vulnerable Populations;Woman;community based treatment;community clinic;community reentry;disability;disease transmission;evidence base;follow-up;health care availability;health disparity;high risk;high risk behavior;innovation;meetings;men;opioid epidemic;opioid injection;opioid use;opioid use disorder;parole;pilot trial;prescription opioid;primary outcome;probation;procedure safety;recruit;rural area;rural setting;rural underserved;screening;service delivery;sex;standard care

public_health_relevance:
PROJECT NARRATIVE The overall aim of this R34 proposal is to examine the feasibility acceptability and short-term outcomesassociated with an innovative service delivery model to increase adherence to extended-release naltrexone (XR-NTX) during the transition from jail to the community for rural women with opioid use disorder (OUD). Thesignificance of this study is grounded in the public health crisis associated with the opioid epidemic in ruralAppalachia the increased vulnerability of rural women with OUD and the dearth of available and accessibleevidence-based treatment in the region. This study has potential to make a significant contribution to the OUDtreatment field by advancing knowledge on innovative service delivery models to increase access to evidence-based treatment to reduce the prevalence of opioid use disorders and related health disparities among hard-to-reach high-risk underserved populations.


application_id: 9939476
project_number: 5R01CA196835-06
project_title: Treatment of Castration-resistant Prostate Cancer (CRPC)
administering_ic: NCI
award_notice_date: 2020-06-09
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 196835
program_official: FORRY, SUZANNE L
project_start_date: 2019-01-15
project_end_date: 2021-06-30
study_section: Special Emphasis Panel[ZRG1-BMCT-C(01)S]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
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)  Androgen ablation (castration) is one major approach to treat prostate cancer (PCa) as androgen receptor (AR) signaling is essential for PCa development and growth. Enough evidence supports the notion that AR signaling continues to be active in castration-resistant prostate cancer (CRPC). Consequently abiraterone and enzalutamide two androgen signaling inhibitors (ASI) are becoming the major drugs to treat CRPC post- docetaxel. Unfortunately ASI can only improve the overall patient survival for 2-5 months. Therefore it is urgent to identify new targets and develop novel approaches to treat ASI-resistant CRPC. Accumulating data suggests that the -catenin pathway is a good target for CRPC because the -catenin pathway was identified as one of the top signaling pathways with significant genomic alterations in CRPC and activation of the - catenin pathway contributes to elevation of AR signaling. However how the -catenin pathway can be targeted in CRPC is still elusive. The long-term goals of this study are to identify novel and druggable signaling pathways that offer more effective treatment options for patients with ASI-resistant CRPC. The objective is to define the role of polo-like kinase 1 (Plk1) in regulating the -catenin pathway thus AR signaling and to exploit this unique pathway as a novel therapeutic target for CRPC patients. Axin2 a key regulator of the -catenin pathway was identified as a novel Plk1 substrate. The central hypothesis is that a combination of inhibition of Plk1 with BI2536 and the -catenin pathway with IWR1 is a new approach to treat ASI-resistant CRPC. This hypothesis will be tested by pursuing three Specific Aims - (1) to determine whether a combination of inhibition of Plk1 and -catenin pathway is a novel approach to treat ASI-resistant CRPC using patient- derived xenografts; (2) to test whether inhibition of Plk1 activates the -catenin pathway in genetically engineered mice; and (3) to dissect how Plk1 phosphorylation of Axin2 regulates the -catenin pathway and AR signaling. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing genetic strategies with PCa mouse models culture systems and PCa xenograft methodologies. The rationale for the research is that it will be the first to probe the importance of Plk1 to the -catenin and AR signaling and to examine whether a combination of inhibition of Plk1 and the -catenin pathway is a novel approach to treat ASI-resistant CRPC. This contribution is significant because it will () define the molecular mechanism by which Plk1 regulates the -catenin and AR signaling; and (ii) validate Plk1 as a critical therapeutic target to enhance the efficacy of inhibitors that targt the -catenin pathway. The research is innovative as it approaches the disease from a novel Plk1 signaling pathway challenging the traditional view that Plk1 functions solely to regulate mitotic events. These studies are poised to provide a new paradigm for improved patient therapies by identifying the key regulator of the -catenin and AR signaling that is critical for generating and maintaining the CRPC phenotype.

project_terms:
Ablation;Affect;Androgen Receptor;Androgens;Biochemical;Cancer Patient;Castration;Cell Death;Cell Death Inhibition;Cells;Clinical Research;DNA Sequence Alteration;Data;Development;Disease;Event;Fostering;Genetically Engineered Mouse;Goals;Growth;Growth and Development function;Health;Human;Investigation;Knock-out;Lead;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Methodology;Mission;Mitotic;Modeling;Molecular;Nuclear;Outcome;PLK1 gene;PTEN gene;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phenotype;Phosphorylation;Prevention;Prognostic Marker;Prostate;Public Health;Receptor Signaling;Research;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;System;Testing;Therapeutic;Work;Xenograft Model;Xenograft procedure;abiraterone;beta catenin;castration resistant prostate cancer;design;diagnostic biomarker;docetaxel;effective therapy;genetic approach;improved;in vivo;inhibitor/antagonist;innovation;knock-down;mouse model;new therapeutic target;next generation sequencing;novel;novel strategies;prostate cancer cell;prostate cancer progression;public health relevance;success;therapeutic target;transgenic adenocarcinoma of mouse prostate;tumor growth;tumor xenograft

public_health_relevance:
PUBLIC HEALTH RELEVANCE  The proposed research is relevant to public health because it focuses on discovery of novel signaling pathways that drive castration-resistant prostate cancer. These studies will establish new avenues of investigation to develop improved therapeutics to treat this deadly disease and to greatly improve patient outcome. Thus the proposed research is relevant to NCI's mission of fostering creative discoveries and innovative research strategies for protecting and improving health and reducing the burdens associated with cancer.


application_id: 9939366
project_number: 5R01AG019223-14
project_title: Ceramide and acute phase proteins elevation during aging
administering_ic: NIA
award_notice_date: 2020-05-29
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 019223
program_official: PEREZ MONTES, VIVIANA
project_start_date: 2002-08-01
project_end_date: 2023-05-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 6730250
contact_pi: NIKOLOVA-KARAKASHIAN, MARIANA 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_terms:
Acute-Phase Proteins;Affinity;Aging;Agonist;Alzheimer's Disease;Animals;Asses;Cause of Death;Cell Aging;Cell physiology;Cells;Ceramides;ChIP-seq;Chronic;Clinical;Complex;Diet;Disease;Dose;Drug Prescriptions;Elderly;Enzymes;FOXO1A gene;Fatty Liver;Funding;Gene Delivery;Gene Expression Regulation;Genes;Genetic;Glucocorticoid Receptor;Glucocorticoids;Gluconeogenesis;Goals;Grant;Health;Hepatic;Hepatocyte;Histologic;Homeostasis;Hypersensitivity;IGFBP1 gene;IRAK1 gene;In Vitro;Incidence;Infection;Inflammation;Inflammation Mediators;Inflammatory;Insulin Signaling Pathway;Interleukin-1 beta;Lead;Link;Liver;MAPK8 gene;Medical;Messenger RNA;Metabolic syndrome;Minor;Morbidity - disease rate;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Organ;Organism;Oxidation-Reduction;Pain;Pathway interactions;Pattern;Pharmacology;Phosphorylation;Play;Population;Process;Progress Reports;Protein Phosphatase 2A Regulatory Subunit PR53;Public Health;Rattus;Receptor Signaling;Regulation;Research;Role;Series;Signal Transduction;Sphingomyelinase;Stress;Testing;Transcriptional Regulation;Trauma;Ubiquitination;Work;adenoviral-mediated;aged;experimental study;genome-wide;genome-wide analysis;in vivo;in vivo evaluation;insulin sensitivity;lipid biosynthesis;mouse model;non-alcoholic fatty liver disease;novel;novel strategies;response;senescence;side effect;stressor;transcription factor;transcriptome sequencing


application_id: 9939355
project_number: 5R00AA023560-05
project_title: Analysis of an ethanol-sensitive pathway regulating anterior craniofacial development
administering_ic: NIAAA
award_notice_date: 2020-05-19
opportunity_number: PA-14-042
application_type: 5
activity_code: R00
ic: AA
serial_number: 023560
program_official: DUNTY, JR, WILLIAM
project_start_date: 2018-06-01
project_end_date: 2022-05-31
study_section: NSS
contact_pi_person_id: 10890031
contact_pi: LOVELY, CHARLES BENJAMIN
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Fetal Alcohol Spectrum Disorders (FASD) describes a wide array of ethanol-induced developmental defects including craniofacial dysmorphology such as lower jaw hypoplasia and cleft palate. It affects approximately 1 in 100 children born in the United States each year. Although fetal exposure to alcohol causes FASD virtually nothing of the genetics behind these ethanol-induced craniofacial defects is understood. The majority of the craniofacial skeleton is generated by cranial neural crest cells in part through complex interactions with epithelial tissues. These interactions are orchestrated by among others the Bone Morphogenetic Protein (Bmp) signaling pathway. My preliminary data demonstrates that Bmp signaling specific to the endoderm is required for lower jaw morphogenesis while Bmp signaling regulates palate morphogenesis in part through the transcription factor gata3. These results suggest a model where Bmp signaling regulates anterior craniofacial morphogenesis via multiple signaling pathways. Growing evidence supports that genetic predisposition plays a role in these ethanol-induced defects yet little is understood about these gene-ethanol interactions. The Eberhart lab has helped pioneer genetic screens to identify these ethanol-sensitive genetic loci. From these screens I have compiled a set of mutants with ethanol induced defects suggesting that ethanol interacts with a genetic hierarchy regulating anterior craniofacial development. First through a screen of available zebrafish mutants I found that several members of the Bmp signaling pathway exhibit ethanol-induced defects to the embryonic lower jaw and palate. Second in a forward genetic screen I recovered ethanol-sensitive mutants that phenocopy specific aspects of the Bmp phenotype. These findings support the hypothesis that Bmp signaling regulates a novel ethanol-sensitive pathway regulating morphogenesis of the anterior craniofacial skeleton. In Specific Aim 1 I will 1) determine how ethanol disrupts a Bmp mediated endoderm-oral ectoderm- neural crest pathway using 4D confocal analyses and 2) elucidate the target of ethanol action the Bmp pathway. In Specific Aim 2 I will 1) clone and characterize the ethanol sensitivity of au15 au24 and au25 2) analyze neural crest cell behaviors in ethanol-treated au15 mutants and 3) characterize the mechanism of ethanol action in au15 mutant embryos. In Specific Aim 3 I will a) clone and characterize au26 b) visualize palate morphogenesis in ethanol-treated Bmp mutants and au26 embryos and c) characterize the epistatic relationship between Bmp-pathway members au26 and gata3. Overall the work outlined in this proposal will provide insight into ethanol-sensitive pathways regulating anterior craniofacial development and the gene- ethanol interactions that underlie these pathways. Because of the conservation of gene function between zebrafish and humans this work will directly translate to studies of candidate genes in human populations and allow for better diagnosis and treatment of FASD.

project_terms:
Affect;Anterior;Bone Morphogenetic Proteins;Candidate Disease Gene;Cephalic;Child;Cleft Palate;Complex;Craniofacial Abnormalities;Data;Defect;Development;Diagnosis;Disease;Dysmorphology;Embryo;Endoderm;Epithelial;Epithelium;Ethanol;Etiology;Event;Exhibits;Fetal Alcohol Spectrum Disorder;GATA3 gene;Genes;Genetic;Genetic Epistasis;Genetic Predisposition to Disease;Genetic Screening;Human;Jaw;Maps;Mediating;Modeling;Morphogenesis;Neural Crest;Neural Crest Cell;Palate;Pathway interactions;Patients;Pattern;Phenocopy;Phenotype;Play;Population;Role;Signal Pathway;Signal Transduction;Signaling Protein;Skeleton;Testing;Tissues;Translating;United States;Ursidae Family;Vertebrates;Work;Zebrafish;alcohol exposure;alcohol sensitivity;cell behavior;craniofacial;craniofacial development;gene conservation;gene function;genomic locus;insight;member;mutant;novel;oral ectoderm;prenatal exposure;public health relevance;transcription factor;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The purpose of this proposal is to elucidate the genetics and mechanisms underlying the variability of defects found in patients with Fetal Alcohol Spectrum Disorders (FASD). Results obtained from this proposal will greatly increase our understanding of gene-ethanol interactions and the etiology of FASD.


application_id: 9937756
project_number: 5R01GM129532-03
project_title: Visceral fat gamma delta T cells in sepsis pathogenesis
administering_ic: NIGMS
award_notice_date: 2020-05-29
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: GM
serial_number: 129532
program_official: ZHAO, XIAOLI
project_start_date: 2018-09-01
project_end_date: 2023-05-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 10399494
contact_pi: STARR, MARLENE ELENA
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTSepsis pathophysiology involves activation of both pro- and anti-inflammatory responses along with alterationsin thrombotic and metabolic pathways. We previously revealed that genes for several inflammatory andthrombotic mediators are highly expressed in visceral adipose tissues during sepsis; however what causes thefat tissue to be so reactive and whether adipose-derived factors are mediators of sepsis is currently not known.Our preliminary data using both a preclinical mouse model of sepsis as well as patient-derived samplessuggest that visceral fat is the major source of plasminogen activator inhibitor type 1 (PAI-1) a pro-thromboticfactor which is implicated in the pathogenesis of sepsis and multi-organ failure. In addition we recently foundthat gamma delta ()-T cells a subset of innate-like T cells are surprisingly abundant in visceral fat tissue.These findings have led to our hypothesis that these cells are responsible for PAI-1 overproduction by adiposetissues during sepsis and contribute to the development of organ injury. The major goals of this project are (1)to demonstrate that -T cells are key regulators of PAI-1 production in visceral fat tissue and (2) to establishthat visceral fat-derived PAI-1 promotes organ injury during sepsis. To achieve these goals a series of ex vivoadipose explant culture experiments utilizing tissues from several transgenic mouse strains will be performedand visceral fat tissues will be surgically removed or transplanted from wild-type to PAI-1 knockout mice.Completion of this project will establish the concept that overproduction of PAI-1 from visceral fat contributes tothe pathophysiology of sepsis-associated organ injury and reveal key mechanisms for PAI-1 overproduction.This information will aid in the development of future therapeutic strategies to reduce sepsis severity.

project_terms:
Acute;Adipose tissue;Affect;Anti-Inflammatory Agents;Bioinformatics;Cells;Cellular biology;Clinical;Collaborations;Complex;Creatinine;Critical Care;Critical Illness;Data;Development;Endocrine Glands;Evaluation;Excision;Failure;Fatty acid glycerol esters;Flow Cytometry;Functional disorder;Future;Genes;Goals;Immune;In Vitro;Incidence;Infection;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury to Kidney;Interleukin-17;Knock-out;Knockout Mice;Link;Mediating;Mediator of activation protein;Metabolic Pathway;Molecular Biology;Mouse Strains;Mus;Operative Surgical Procedures;Pathogenesis;Pathologic;Patients;Physiology;Plasma;Plasminogen Activator Inhibitor 1;Play;Procedures;Production;Renal function;Role;Sampling;Sepsis;Series;Serum;Severities;Signal Transduction;Source;Specimen;T-Lymphocyte;Testing;Therapeutic;Thrombosis;Tissues;Transgenic Mice;Transplantation;Visceral;Visceral fat;Wild Type Mouse;aged;clinically relevant;cytokine;design;experimental study;innovation;liver injury;lung injury;mortality;mouse model;multidisciplinary;multiorgan injury;novel;organ growth;organ injury;patient population;pre-clinical;public health relevance;second transplant;statistics;success;therapeutic target; T cells

public_health_relevance:
PUBLIC HEALTH RELEVANCESepsis is a serious clinical condition with a high mortality rate. This project will link inflammatory responses inadipose tissue with the development of organ injury in sepsis by studying gamma-delta T-cell signaling andPAI-1 secretion from adipose tissues. The obtained information will be useful in designing therapeutic targetsfor severe sepsis.


application_id: 9937665
project_number: 5R01AR073906-03
project_title: Epigenetic control of muscle stem cell function by PASK-Wdr5 signaling
administering_ic: NIAMS
award_notice_date: 2020-12-03
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AR
serial_number: 073906
program_official: BOYCE, AMANDA T
project_start_date: 2020-02-25
project_end_date: 2024-11-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 10909082
contact_pi: KIKANI, CHINTAN K
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acetylation;Acute;Adult;Affect;Aging;Binding;Cell Count;Cell physiology;Cells;Collaborations;Complex;Cues;Data;Disease;Epigenetic Process;Equilibrium;FRAP1 gene;Functional disorder;Genetic Transcription;Goals;Histone H3;Histones;Homeostasis;Human;Injury;Insulin;Legal patent;Lysine;Maintenance;Messenger RNA;Metabolism;Modeling;Modification;Molecular;Mus;Muscle;Muscle Cells;Muscle function;Muscle satellite cell;Muscular Atrophy;Muscular Dystrophies;Myoblasts;Myogenin;Myopathy;Natural regeneration;Nutrient;Pathway interactions;Phosphorylation;Phosphotransferases;Physiological;Play;Population;Process;Proliferating;Property;Protein Kinase;Proteins;Publishing;Reagent;Research;Research Proposals;Role;Signal Pathway;Signal Transduction;Structure;Testing;Therapeutic;Transcription Process;Transferase;Trauma;WD Repeat;Wasting Syndrome;age-related muscle loss;base;cell injury;functional loss;hormonal signals;human disease;in vivo;inhibitor/antagonist;interest;member;mouse model;muscle aging;myogenesis;normal aging;novel;novel therapeutics;overexpression;programs;promoter;recruit;regeneration function;regeneration potential;regenerative;response;sarcopenia;self-renewal;stem cell differentiation;stem cell fate specification;stem cell function;stem cells;transcription factor


application_id: 9937631
project_number: 5R01AG055359-04
project_title: Mechanisms mediating severity of acute pancreatitis in the aged
administering_ic: NIA
award_notice_date: 2020-05-21
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 055359
program_official: WILLIAMS, JOHN
project_start_date: 2017-09-01
project_end_date: 2022-05-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8163817
contact_pi: SAITO, HIROSHI
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe objective of this project is to understand the mechanisms leading to the development of severe acutepancreatitis (sAP) a life-threatening illness with high mortality characterized by necrotizing pancreas severesystemic inflammation coagulation multiple organ dysfunction syndrome (MODS). AP is a particularly seriousdisease among the elderly as both incidence and the likelihood for progression to sAP increases dramaticallywith advancing age. Despite recognition of this clinical problem little is known regarding the underlyingbiological mechanisms of this disease or why progression to sAP is more common among elderly patients. Werecently developed an aged mouse model of AP in which only aged mice exhibit sAP that parallels clinicalobservations including prolonged systemic inflammation coagulation MODS and fatality. Our observationswith this mouse model include a dramatic age-dependent increase in tissue damage and cytokine geneexpression within visceral adipose tissue and elevated levels of free fatty acids in the ascitic fluid. Collectivelythese findings suggest that visceral adipose tissues are key mediators promoting the progression of AP to sAPin the aged. The central hypothesis of this project is that aged animals are more prone to develop sAP due topronounced visceral adipose tissue inflammation caused by leakage of pancreas-derived digestive enzymesinto the peritoneum from the damaged pancreas. AP-induced adipose tissue inflammation results in release offree fatty acids inflammatory cytokines and pro-thrombotic factors all promoting MODS. Our hypothesis willbe tested in the following three specific aims: To determine features of visceral adipose tissue inflammation inaged animals with sAP (Aim 1); To demonstrate that increased visceral adipose tissue inflammation promotesthe progression of AP to sAP in the aged (Aim 2); and To develop strategies to prevent the progression of APto sAP in aged animals by suppressing adipose tissue inflammation (Aim 3).

project_terms:
Adipocytes;Adipose tissue;Affect;Age;Agonist;Animal Model;Animals;Antibodies;Area;Biological;Blood Circulation;Cells;Cessation of life;Characteristics;Clinical;Coagulation Process;Creatinine;Cytokine Gene;Development;Diagnostic;Disease;Elderly;Enzymes;Excision;Exhibits;Extravasation;Foundations;Gene Expression;Immune;Incidence;Infiltration;Inflammation;Inflammatory;Interleukin-6;Intraperitoneal Injections;Kidney;Life;Link;Lipase;Lipolysis;Lung;Mediating;Mediator of activation protein;Modeling;Multiple Organ Failure;Mus;Mutant Strains Mice;Necrosis;Nonesterified Fatty Acids;Organ;PPAR alpha;Pancreas;Pathologic;Peritoneal;Peritoneal Fluid;Peritoneum;Phase;Plasminogen Activator Inhibitor 1;Prevention strategy;Production;Public Health;Research;Risk;Severities;Source;Testing;Therapeutic;Thrombosis;Tissues;Visceral;Visceral fat;acute pancreatitis;age related;aged;cytokine;effective therapy;experimental study;inhibitor/antagonist;mortality;mouse model;older patient;organ injury;prevent;release factor;therapeutic development;tissue injury;treatment strategy

public_health_relevance:
PROJECT NARRATIVEThis project is relevant to public health because it will enhance our understanding of how visceral adiposetissue inflammation contributes to increased severity of acute pancreatitis in the elderly. This project will alsoprovide information for the development of diagnostic and treatment strategies to decrease incidence rates anddeaths related to severe acute pancreatitis in the aged. The development of effective therapies for preventingprogression to severe acute pancreatitis of which there are currently none available will be beneficial toelderly patients who suffer from acute pancreatitis.


application_id: 9936388
project_number: 5R01DA043938-04
project_title: Cardiovascular Immune and Psychosocial Benefits of Reduced Cocaine Use
administering_ic: NIDA
award_notice_date: 2020-05-15
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DA
serial_number: 043938
program_official: MANDLER, RAUL N
project_start_date: 2017-09-01
project_end_date: 2023-05-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTPromoting reductions in problem behaviors is common in medical practice wherein at-risk individuals arecounseled to make moderate sustainable changes in lifestyle. Reducing the percentage of heavy drinkingdays in individuals with alcohol use disorder is an accepted intervention target in alcohol addiction treatmentyet for other drug use disorders complete abstinence remains the standard for demonstrating treatmentefficacy. Interventions that promote reductions in drug use should improve biopsychosocial outcomes. Littleresearch has been conducted to demonstrate benefits of reduced drug use however. Demonstrating thebenefits of reduced cocaine (COC) use would significantly advance treatment development by challengingexpectations for outcomes from possible interventions. COC use produces a number of biopsychosocialdetriments (e.g. cardiovascular toxicity disrupted immune function increased psychiatric comorbidities) thatcould be ameliorated by COC use reduction. No studies have prospectively or comprehensively evaluated thispossibility to date although preliminary data support this hypothesis. To fill this critical knowledge gap wepropose a randomized controlled 12-week trial in which financial incentives will be used to reduce COC use.Subjects will be randomly assigned to one of three groups (n=66 completers/ group): 1) high value financialincentives for COC abstinence in which frequency of COC use is expected to be substantially reduced orcompletely eliminated 2) low value financial incentives for COC abstinence in which frequency of COC use isexpected to be reduced or 3) a non-contingent control group in which frequency of COC use is expected toremain stable. This study aims to demonstrate that reduced COC use improves physiological and biochemicalindicators of cardiovascular and immune fitness as well as psychosocial function. The overarching hypothesisis that individuals assigned to the active treatment conditions will display improvements in biopsychosocialdomains compared to individuals assigned to the non-contingent control group. A dose-response is alsoexpected whereby individuals assigned to the high value condition will display greater reductions in COC useand consequently greater improvements relative to the low value condition. This research will advance thefield by: 1) using multifaceted health outcomes to provide prospective evidence supporting reduced drug useas a viable endpoint for COC treatment development 2) identifying biochemical indicators of healthimprovements associated with reduced COC use and 3) laying the foundation for a paradigm-shifting definitionof COC treatment success thereby challenging expectations for outcomes in behavioral and pharmacologicalintervention development. These innovations will accelerate identification of promising treatments for cocaineuse disorder resulting in a sustained and powerful impact on scientific and clinical practice.

project_terms:
Abnormal Cell;Abstinence;Adopted;Adoption;Aftercare;Alcohol dependence;Atherosclerosis;Behavioral;Biochemical;Biological Markers;Blood Platelets;Blood Pressure;Cardiovascular Physiology;Cardiovascular system;Cellular Immunity;Chronic;Clinical;Clinical Trials;Cocaine;Cognitive;Contracts;Control Groups;Counseling;Data;Delayed Hypersensitivity;Diagnosis;Disease;Dose;Drug Use Disorder;Drug usage;Eating;Endothelin-1;Endothelium;Fatty acid glycerol esters;Foundations;Frequencies;Health;Heart Rate;Heavy Drinking;Hypertension;Immune;Immunologic Markers;Incentives;Individual;Infection;Inflammatory;Intervention;Knowledge;Life Style;Measures;Mediating;Medical;Mental Health;Myocardial Infarction;Outcome;Patient Self-Report;Physiological;Problem behavior;Randomized;Research;Risk;Risk Behaviors;Standardization;Stress Tests;Stroke;TNF gene;TNFSF5 gene;Toxic effect;Treatment Efficacy;Unemployment;Vasospasm;active method;alcohol use disorder;behavioral pharmacology;biopsychosocial;cardiovascular fitness;clinical practice;cocaine use;comorbidity;drug use behavior;expectation;experience;financial incentive;fitness;follow-up;immune function;improved;innovation;prevent;prospective;psychosocial;response;success;therapy development;treadmill;vasoconstriction;week trial

public_health_relevance:
PROJECT NARRATIVEReduced drug use is a clinically meaningful target for treatment development but few studies have evaluatedthe positive impacts produced by this behavioral change preventing adoption of this endpoint in clinical trials.The proposed research will fill that critical knowledge gap by demonstrating the biopsychosocial benefits ofreduced cocaine use. These data will be used to change current accepted cocaine treatment endpoints andaccelerate identification of therapies for cocaine use disorder.


application_id: 9934110
project_number: 5R01AI140758-03
project_title: Mechanisms of actin cytoskeleton modulation by Pneumoviruses
administering_ic: NIAID
award_notice_date: 2020-05-07
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AI
serial_number: 140758
program_official: KIM, SONNIE
project_start_date: 2018-06-11
project_end_date: 2023-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-W(02)M]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
other_pis: LEUNG, DAISY W
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_terms:
Actins;Address;Affect;Affinity Chromatography;Bacteria;Binding;Biochemical;Biochemistry;Biological;Biological Assay;Biological Models;Biophysics;Bronchiolitis;Calorimetry;Cell physiology;Cells;Cellular Morphology;Cellular biology;Childhood;Co-Immunoprecipitations;Complex;Coupled;Cytoskeletal Proteins;Cytoskeleton;Data;Deuterium;Disease;Dyes;Elderly;Elements;Family;Fluorescent in Situ Hybridization;Human;Human Metapneumovirus;Hybrids;Hydrogen;Immunocompromised Host;In Vitro;Individual;Infection;Life Cycle Stages;Ligation;Lower Respiratory Tract Infection;Mass Spectrum Analysis;Mediating;Microscopy;Modification;Molecular;Molecular Sieve Chromatography;Mutation Analysis;NMR Spectroscopy;Nature;Nucleocapsid;Pathogenesis;Phosphoproteins;Physiological;Play;Pneumovirus;Pneumovirus Infections;Population;Process;Proteins;RNA;RNA Viruses;Respiratory Syncytial Virus Infections;Respiratory Tract Infections;Respiratory syncytial virus;Role;Structure;System;Testing;Time;Titrations;Viral;Viral Proteins;Virus;Virus Diseases;Virus Replication;X-Ray Crystallography;airway epithelium;cell motility;cellular targeting;effective therapy;human pathogen;insight;intercellular communication;light scattering;member;mutant;new therapeutic target;novel;pathogen;pathogenic virus;polymerization;respiratory;structural biology;therapeutic development;therapeutic target;viral RNA;virology


application_id: 9932457
project_number: 5R01GM127495-03
project_title: Exercise-enhanced resolution of inflammation
administering_ic: NIGMS
award_notice_date: 2020-05-27
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: GM
serial_number: 127495
program_official: ZHAO, XIAOLI
project_start_date: 2018-09-01
project_end_date: 2023-05-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 11169883
contact_pi: HELLMANN, JASON L
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract:Frequent physical activity improves cardiovascular health and prolongs life span whereas physical inactivity isassociated with premature mortality and global burden of chronic disease. The salutary effects of exercise have beenextensively documented in the literature. Exercise promotes skeletal muscle growth cardiac hypertrophy and tissueangiogenesis and it improves cardiovascular disease (CVD) risk factor profile. Nevertheless the beneficial effects ofexercise extend beyond reduction in CVD risk factors (blood pressure lipids) involving mechanisms and processes thatremain largely unknown. This lack of mechanistic understanding underlying the salubrious effects of exercise limits itsoptimization in healthy individuals and hinders extension of its benefits to obese and diabetic individuals who thoughare most likely to gain from exercise cannot exercise or remain impervious to its benefits. Some investigators havesuggested that CVD risk factor-independent effects of exercise may relate to a decrease in inflammation. Inflammationis a carefully orchestrated systemic response targeted to degrade offending components clear tissue debris promotehealing and restore homeostasis. While escalation of inflammation leading to inflammatory cell invasion and cytokineproduction has been extensively studied less is known about how inflammation is resolved. Recent work has shownthat resolution of inflammation is mediated by specialized pro-resolving lipid mediators (SPMs) that limit neutrophilextravasation quell inflammatory signaling and promote macrophage phagocytosis. SPMs are necessary and sufficientto resolve inflammation by binding to cognate G-protein coupled receptors (GPCRs). We propose that the beneficialeffects of exercise relate to its ability to promote resolution of inflammation by stimulating the synthesis of pro-resolvingSPMs. Our preliminary data show that exercise-adapted mice display enhanced SPM synthesis accelerated neutrophilclearance and increased macrophage phagocytosis suggesting that exercise exerts beneficial effects on resolution ofinflammation. We also find that catecholamines which are transiently elevated by exercise activate SPM biosynthesisin macrophages and increase 5-lipoxygenase (5-LO) and 12/15-lipoxygenase (15-LO) enzymes that synthesize SPMs.These observations link processes activated by exercise to key components of inflammation-resolution and have led usto formulate the hypothesis that exercise-mediated production of catecholamines increases pro-resolving lipid mediatorsynthesis and enhances resolution of inflammation. The specific aims are: (1) Determine the effect of exercise onresolution; (2) Delineate the contribution of catecholamines in mediating the effect of exercise on resolution ofinflammation; (3) Elucidate the role of SPMs in exercise-enhanced resolution. Results of this project will generate newinsights into how exercise regulates inflammation; which processes mediate the beneficial effects of exercise; and howexercise affects the resolution of acute and chronic inflammation. Collectively these results would generate new knowledgeabout the processes by which exercise improves cardiometabolic health and inflammation-resolution. This knowledge couldlead to the development of new therapeutic interventions to enhance the benefits of exercise or simulate its salutary effectsin individuals resistant or recalcitrant to its beneficial effects or those unable to exercise.

project_terms:
Acute;Adrenergic Receptor;Affect;Anabolism;Animals;Arachidonate 15-Lipoxygenase;Arachidonate 5-Lipoxygenase;Binding;Blood Pressure;Bone Marrow;Catecholamines;Cell physiology;Cells;Chronic;Chronic Disease;Complex;Data;Development;Diabetes Mellitus;Diabetic mouse;Disease;Docosahexaenoic Acids;Eicosanoids;Eicosapentaenoic Acid;Enzymes;Exercise;Extravasation;FPR2 gene;Female;G-Protein-Coupled Receptors;Health;Heart Hypertrophy;Homeostasis;Human;Immune;Individual;Infection;Inflammation;Inflammatory;Knowledge;Lead;Link;Lipids;Lipoxins;Literature;Longevity;Measures;Mediating;Mus;Obesity;Omega-3 Fatty Acids;Pathway interactions;Peritonitis;Phagocytosis;Physical activity;Premature Mortality;Process;Production;Quality of life;RNA Interference;Research Personnel;Resistance;Resolution;Risk Factors;Role;Running;Signal Transduction;Techniques;Testing;Tissues;Work;adrenergic block;angiogenesis;cardiometabolism;cardiovascular disorder risk;cardiovascular health;cohort;cytokine;diabetic;exercise regimen;exercise training;feeding;gain of function;healing;improved;in vivo;insight;lipid mediator;macrophage;male;microbial;neutrophil;non-diabetic;novel;novel therapeutic intervention;physical inactivity;receptor;response;skeletal muscle growth;tissue injury;trafficking;treadmill

public_health_relevance:
Project NarrativeExercise promotes quality of life and ameliorates inflammatory diseases by largely unknown mechanisms. Inthis project we will examine mechanisms by which exercise antagonizes acute inflammation and assess howchanges in pro-resolving pathways contribute to the benefits afforded by exercise training. These studies willreveal new fundamental mechanisms of resolution inflammation and provide novel insights into theunderstanding of how routine exercise alleviates inflammation.


application_id: 9932258
project_number: 5R01AG061065-03
project_title: Role of Gut Microbial Dysbiosis and Aging on HIV-associated neurocognitive and brain dysfunction
administering_ic: NIA
award_notice_date: 2020-08-20
opportunity_number: RFA-AG-18-023
application_type: 5
activity_code: R01
ic: AG
serial_number: 061065
program_official: MACKIEWICZ, MIROSLAW
project_start_date: 2018-09-30
project_end_date: 2023-05-31
study_section: ZAG1-ZIJ-U(A1)
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: COHEN, RONALD A;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_abstract:
Although AIDS-defining illnesses have decreased the prevalence of HIV-associated non-AIDS conditions suchas HIV-Associated Neurocognitive Disorders (HAND) remains high and is estimated to be over 50%particularly in aging individuals with long-standing HIV infection. However the pathophysiology of HAND inaging HIV+ adults remains unresolved. Current evidence and our preliminary data suggest that interactionsof altered gut microbiome (dysbiosis) gut-derived microbial translocation and systemic inflammationcontribute to neurodegenerative processes. It is becoming increasingly evident that in both HIV-1 infection andaging alterations in gut microbiome (dysbiosis) and ensuing increase in intestinal permeability and microbialtranslocation (MT) are major pathogenic drivers of local and systemic inflammation. Importantly aging-associated microbiota changes are shown to be connected to immunosenescence and inflammaging.Preclinical/clinical studies using bacterial 16S ribosomal RNA (rRNA) gene sequencing indicate that microbialdysbiosis associated with HIV-1 infection or aging has several common pathogenic features. However thesestudies were largely hypothesis-generating with limited sample sizes and were not adequately powered toaddress microbiome endpoints after correction for multiple testing and did not reveal the functional potential ofthe microbiota (pathogenic or beneficial) or yield bacterial resolution to species or strain level. The currentproposal will address these limitations by using an adequately powered longitudinal study and will conduct 16SrRNA gene and Whole Genome Shotgun (WGS) metagenomic sequencing that will determine bacterialcomposition and diversity provide identification at the species and strain level and enable the functionalcharacterization of the bacterial genes. Our overarching hypothesis is that the interactive effects of agingand HIV-1 infection at the level of gut dysbiosis and permeability and ensuing local and systemicinflammation play a major pathogenic role in driving HIV infection and aging-associatedneuroinflammation and cognitive dysfunction. To test these hypotheses we will leverage and utilize HIV+and healthy aging populations from ongoing NIH-sponsored longitudinal studies at the Universities of Louisville(UofL) and Florida (UF) with the following specific aims: Aim 1: To assess longitudinal qualitative andquantitative changes in the gut microbiome (dysbiosis) in older persons living with HIV-1 infection.Aim 2: To determine the impact of HIV-1 infection and age associated gut dysbiosis on (A) intestinalpermeability and microbial translocation (MT) and resultant peripheral endotoxemia andinflammation; and (B) multimodal MRI/MRS measures of neuroinflammation and cerebral metabolicdisturbance. Aim 3: To investigate the impact of gut dysbiosis and peripheral and neuroinflammationand cerebral metabolic disturbance on cognitive dysfunction and functional brain abnormalities (FMRI)relative to age and HIV status.

project_terms:
16S ribosomal RNA sequencing;Acquired Immunodeficiency Syndrome;Address;Adult;Age;Aging;Automobile Driving;Bacterial Genes;Brain;Cerebrum;Clinical Research;Cognitive aging;Data;Diffusion Magnetic Resonance Imaging;Elderly;Endotoxemia;Florida;Functional disorder;Goals;HIV;HIV Infections;HIV-1;HIV-associated neurocognitive disorder;Impaired cognition;Individual;Infection;Inflammaging;Inflammation;Intestinal permeability;Longitudinal Studies;Magnetic Resonance;Magnetic Resonance Imaging;Measures;Metabolic;Nerve Degeneration;Neurocognitive;Neuropathogenesis;Pathogenicity;Peripheral;Permeability;Phylogeny;Play;Population;Prevalence;Process;Resolution;Rest;Role;Sample Size;Serum;Severities;Shotguns;Structure;Taxonomy;Testing;United States National Institutes of Health;Universities;White Matter Hyperintensity;age effect;alcohol research;base;brain abnormalities;brain dysfunction;cognitive function;cooking;cytokine;dysbiosis;gut microbiome;gut-brain axis;healthy aging;immune activation;immunosenescence;metagenomic sequencing;microbial;microbial community;microbiome;microbiome alteration;microbiota;multimodality;neuroinflammation;pre-clinical;rRNA Genes;white matter;whole genome

public_health_relevance:
The goal of this proposal is to conduct collaborative studies to understand the gut-brain relationship in olderpersons living with HIV-1 infection. The study will examine the role of gut-driven mechanisms on HIV-associated Neurocognitive Disorders (HAND) in the aging HIV+ population.


application_id: 9930889
project_number: 1R35GM136295-01
project_title: Mechanisms and functions of Shoc2-transduced cellular signals
administering_ic: NIGMS
award_notice_date: 2020-04-09
opportunity_number: PAR-17-094
application_type: 1
activity_code: R35
ic: GM
serial_number: 136295
program_official: KODURI, SAILAJA
project_start_date: 2020-05-01
project_end_date: 2025-04-30
study_section: Special Emphasis Panel[ZRG1 CB-J (55)]
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_terms:
Address;Biological Markers;Cell Adhesion;Cell physiology;Cells;Clinical;Complex;Congenital Abnormality;Development;Disease;Enzymes;Funding;Future;Genes;Genetic;Intervention;Lead;MAPK3 gene;Malignant Neoplasms;Mediating;Microscopy;Modeling;Molecular;Mutation;National Institute of General Medical Sciences;Outcome;Pathway interactions;Patients;Proteins;Research;Scaffolding Protein;Signal Pathway;Signal Transduction;Sorting - Cell Movement;Spatial Distribution;Specificity;Syndrome;Ubiquitin;Vision;Work;Zebrafish;base;biophysical techniques;cell motility;developmental disease;in vivo;innovation;new therapeutic target;novel diagnostics;novel therapeutics;programs;public health relevance;scaffold;targeted treatment;therapeutic development;transmission process;tumor;virtual


application_id: 9930709
project_number: 1U18FD006760-01
administering_ic: FDA
award_notice_date: 2019-07-23
opportunity_number: RFA-FD-19-018
application_type: 1
activity_code: U18
ic: FD
serial_number: 006760
program_official: WOODOM-COLEMAN, ERIN
project_start_date: 2019-07-25
project_end_date: 2020-06-30
study_section: ZFD1-SRC(99)
contact_pi_person_id: 16381471
contact_pi: JOHNSON, BETH D
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-25
project_title:
Maintenance and Enhancement of ISO/IEC 17025 Accreditation and Whole Genome Sequencing for State Food Testing Laboratories.

project_abstract:
Project Summary:ISO/IEC 17025 accreditation is one of the most important standards for testing laboratories andattests to the competency and technical capability of a laboratory to perform specific tasks. Theresults generated are defensible to a recognized standard. During large-scale events affecting foodsor food products States and Federal authorities can use laboratory test results from accreditedlaboratories to respond rapidly with streamlined analytical review and enforce regulatory complianceto protect the safety of the nation's food supply. The main objective of the Division of LaboratoryServices (DLS) at the Kentucky Department for Public Health is to maintain ISO/IEC 17025accreditation (initial achievement in September 2016 for food chemistry and microbiology testing andreaccreditation in November 2018 to the new ISO/IEC 17025:2017 standards) and enhance testingcapabilities by expanding the scope of current accreditation for additional testing to include foodmicrobiology whole genome sequencing analyses. DLS is the primary servicing laboratory forconducting microbiological and chemical food analyses on behalf of the KY State manufactured foodregulatory program (MFRPS) in the Department for Public Health / Food Safety Branch which has acurrent food safety inspection contract with FDA and is enrolled in the MFRPS. DLS has a qualitymanagement system that is in compliance with the managerial and technical requirements of theISO/IEC 17025:2017 standard. DLS is a Food Emergency Response Network (FERN) Laboratoryand participates in Food proficiency testing and submits laboratory results through electroniclaboratory exchange network (eLEXNET) as requested. The Division of Laboratory Servicess goal isto enhance laboratory activities by bringing in new testing capabilities. DLS has implemented wholegenome sequencing for environmental micro food samples to complement progressive testingperformed on clinical samples in outbreak situations. This will result in faster identification of thefood/pathogens implicated in the outbreak and match clinical and environmental samples. Funding ofthis proposal will assist the KY State MFRPS in achieving conformance with Standard 10 LaboratorySupport and will assist DLS with the continuance of data submission to the FDA via Genome Trakrwith the use of the latest bioinformatics capabilities with BioNumerics software. This allows DLS toprovide reliable data to the FDA much faster which leads to the acceptance of analytical results byFDA and other regulatory agencies for use in enforcement actions surveillance and response tofoodborne outbreaks. In addition DLS can provide insight into the origin of the contaminated food bythe genomic information provided to the GenomeTrakr network which will lead to the development ofa stronger international rapid surveillance system for pathogen trace back.

public_health_relevance:
Project Narrative:By funding this proposal DLS will assist in achieving conformance with standard 10 LaboratorySupport of the Food Safety Branch/KY State MFRPS.This proposal will increase the analyticalcapacity for FDA through the Kentucky Division of Laboratory Services (DLS) and enhance efforts toprotect the nations food supply. In addition DLS will implement whole genome sequencing analysisfor environmental micro food samples to complement progressive testing performed on clinicalsamples in outbreak situations. This would result in faster identification of the food/pathogensimplicated in the outbreak and matching clinical to environmental samples. DLS is accredited toISO/IEC 17025:2017 standards therefore states and federal authorities can use DLS test results forrapid response and surveillance; and these response efforts will enable enforcement of regulatorycompliance to protect the safety of the nations food supply.


application_id: 9930664
project_number: 5R01NS100093-05
project_title: Nrf2-Antioxidant Response Element Neuroprotection in TBI
administering_ic: NINDS
award_notice_date: 2020-05-22
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 100093
program_official: AWWAD, HIBAH OMAR
project_start_date: 2016-08-15
project_end_date: 2021-05-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Oxygen radical-induced lipid peroxidation and protein oxidative damage constitutes one of our mostvalidated secondary injury mechanisms and thus remains a highly rational neuroprotective target thatcontinues to inspire a search for improved free radical scavengers and lipid peroxidation inhibiting drugs.In addition to chemically scavenging free radicals there is increasing interest in the possibility ofpharmacologically inducing endogenous enzymatic antioxidant defense mechanisms as aneuroprotective approach. Attention has recently been focused on the transcription factor Nrf2 (Nuclearfactor E2-related factor) which interacts with the antioxidant response element (ARE) of variouscytoprotective and free radical detoxifying genes as a potential therapeutic target for acute neurologicalinjury. The proposed studies will examine in mouse models of focal controlled cortical impact and diffuseweight drop-induced traumatic brain injury (TBI) the time course of the endogenous induction of specificelements of the Nrf2-ARE pathway compared to the time course of brain oxidative damage in male andfemale mice. This will be followed by a systematic dose-response evaluation of the comparative potencyand efficacy of the prototypical Nrf2-ARE inducing compound carnosic acid in both genders in regards toits ability to speed up and increase the magnitude of post-TBI Nrf2-ARE activation. The most effectivedose of carnosic acid will then be examined for its ability to prevent lipid and protein oxidative damagepreserve mitochondrial respiratory and calcium (Ca++) buffering functions and attenuate Ca++-inducedcalpain-mediated neuronal cytoskeletal damage all surrogate markers of secondary brain injury. Aftercompletion of those experiments the ability of repeated administration of the best dose of carnosic acidwill be tested for actual neuroprotective effects in terms of short term (7 day) post-traumatic motor andcognitive recovery and brain tissue sparing including the therapeutic efficacy window. These studies willtest the hypothesis that pharmacological Nrf2-ARE pathway activation in both focal and diffuse TBImodels can be acutely neuroprotective and form the basis for the discovery of more effective and fast-acting Nrf2 inducing compounds for acute and chronic neurodegeneration.

project_terms:
3-nitrotyrosine;4 hydroxynonenal;Acute;Antioxidants;Attention;Attenuated;Brain;Brain Injuries;Broccoli - dietary;Buffers;Calcium;Calpain;Cell Culture Techniques;Chemicals;Chronic;Defense Mechanisms;Diffuse;Dose;Drops;Elements;Evaluation;Experimental Designs;Failure;Female;Free Radical Scavengers;Free Radical Scavenging;Free Radicals;Future;Gender;Gene Expression;Genes;Herb;Hippocampus (Brain);Histologic;Homeostasis;Injury;Lipid Peroxidation;Lipids;Mediating;Membrane Lipids;Messenger RNA;Mitochondria;Modeling;Motor;Mus;Nerve Degeneration;Nervous System Trauma;Neurodegenerative Disorders;Neurologic;Neurons;Nitrates;Nuclear;Oxidoreductase;Pathway interactions;Peroxides;Pharmaceutical Preparations;Pharmacology;Proteins;Quinones;Reactive Oxygen Species;Recovery of Function;Respiratory physiology;Response Elements;Rosemary;Severities;Speed;Sulforaphane;Surrogate Endpoint;Surrogate Markers;Testing;Therapeutic;Time;Tissues;Transcriptional Activation;Traumatic Brain Injury;Treatment Efficacy;Water;Weight;base;body system;brain tissue;cognitive recovery;cohort;comparative;controlled cortical impact;design;drug discovery;expectation;experimental study;glutathione peroxidase;heme oxygenase-1;improved;injured;interest;male;motor recovery;mouse model;neuroprotection;nitration;novel;object recognition;oxidative damage;preservation;prevent;protective effect;prototype;respiratory;response;salvin;therapeutic target;transcription factor;young adult

public_health_relevance:
PROJECT NARRATIVEThis project will test the hypothesis that activation of the transcription factor Nrf2 (Nuclear factor E2-relatedfactor) which interacts with the antioxidant response element (ARE) of various cytoprotective and free radicaldetoxifying genes is a potential pleiotropic therapeutic pathway for acute neurological injury. Using the potentNrf2-ARE activating compound carnosic acid we will use a careful pharmacological experimental design toexamine the efficacy of that compound in mouse models of focal and diffuse traumatic brain injury (TBI).Multiple endpoints will be employed in both male and female mice including inhibition of lipid peroxidativedamage preservation of mitochondrial function and protection of intracellular calcium homeostasis followed byassessments of improvement in motor and cognitive recovery and decreased neurodegeneration.


application_id: 9930607
project_number: 5R01EY027407-04
project_title: Disinhibition and experience-dependent visual plasticity
administering_ic: NEI
award_notice_date: 2020-05-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: EY
serial_number: 027407
program_official: GREENWELL, THOMAS
project_start_date: 2017-06-01
project_end_date: 2023-05-31
study_section: Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section[SPC]
contact_pi_person_id: 10356866
contact_pi: MCGEE, AARON W
other_pis: TRACHTENBERG, JOSHUA ;XU, XIANGMIN
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThe visual system exhibits a heightened sensitivity to the quality visual experience during an interval late indevelopment termed the critical period. Discordant vision during the critical period is the cause of amblyopia aprevalent visual disorder in children. Treatment of amblyopia is most effective in children before the close ofthe critical period. Subsequently the flexibility with brain circuitry diminishes in adulthood and effective therapyis more difficult. In a mouse model of amblyopia disrupting normal vision by closing one eye for only a fewdays (monocular deprivation MD) during the critical period but not thereafter also perturbs the normalbinocularity of neurons in visual cortex and decreases visual acuity. Yet how these adaptive changes orplasticity first emerge within neurons that form the circuits in visual cortex is poorly understood. Likewise howplasticity propagates from the first neurons to adapt to other neurons connected to these neurons by synapsesis unclear. The short duration of the critical period in mice is one factor impeding the study of how the greaterplasticity confined to the critical period contributes to the induction as well as recovery from amblyopia.The nogo-66 receptor gene (ngr1) is required to close the critical period. In ngr1 mutant mice plasticity duringthe critical period is normal but it is retained in adult mice. Importantly ngr1 mutant mice spontaneouslyrecover visual acuity in this model of amblyopia. In the proposed research we take advantage of this extendedcritical period in ngr1 mice to investigate what is unique about plasticity during the critical period that promotesrecovery from amblyopia. We compare how MD alters the function and connectivity of populations of neuronsin visual cortex with a combination of sophisticated repeated in vivo calcium imaging and laser-scanningphotostimulation synaptic mapping. We will begin to unravel how plasticity within visual cortex proceeds duringabnormal vision (MD) as well as how this plasticity is restricted to the critical period with these experiments. Inaddition to improving understanding of how experience-dependent plasticity changes the function of braincircuits these studies may reveal new avenues for developing therapeutic approaches to treat amblyopia andperhaps other neurodevelopmental disorders that result from maladaptive developmental plasticity.

project_terms:
Address;Adolescent;Adult;Amblyopia;Behavioral;Brain;Calcium;Child;Childhood;Childhood Neurological Disorder;Chronic;Development;Disinhibition;Electrophysiology (science);Exhibits;Eye;Genes;Image;In Vitro;Interneurons;Knock-out;Knowledge;Lasers;Lazy Eyes;Life;Maps;Measures;Mediating;Modeling;Modification;Mus;Mutant Strains Mice;Nervous system structure;Neurodevelopmental Disorder;Neurons;Ocular Dominance;Parvalbumins;Pattern;Phenotype;Population;Receptor Gene;Recovery;Research;Resolution;Scanning;Strabismus;Synapses;Testing;Therapeutic;Vision;Vision Disorders;Visual;Visual Acuity;Visual Cortex;Visual system structure;Wild Type Mouse;brain circuitry;cortex mapping;critical period;developmental plasticity;effective therapy;excitatory neuron;experience;experimental study;flexibility;hippocampal pyramidal neuron;improved;in vivo;in vivo calcium imaging;in vivo imaging;monocular deprivation;mouse model;mutant;neural circuit;neuronal patterning;presynaptic;programs;response;restoration;visual plasticity;visual processing;young adult

public_health_relevance:
PROJECT NARRATIVEAbnormal vision only during a `critical period' in childhood induces amblyopia also known as lazy eye. Thisresearch investigates how abnormal vision changes brain circuits during critical periods and how the closure ofcritical periods is controlled. Understanding these mechanisms will reveal differences between the childhoodand adult nervous system that may provide clues how to better treat not only amblyopia but perhaps a broadrange of other childhood neurologic disorders as well.


application_id: 9930591
project_number: 5R01ES028256-03
administering_ic: NIEHS
award_notice_date: 2020-06-15
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 028256
program_official: TYSON, FREDERICK L
project_start_date: 2018-08-15
project_end_date: 2021-02-28
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 14750127
contact_pi: WANG, ZHISHAN
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
budget_start_date: 2020-06-01
project_title:
Epigenetic mechanism of the synergistic tumorigenic effect of arsenic and benzo[a]pyrene co-exposure

project_abstract:
PROJECT SUMMARY/ABSTRACTArsenic and benzo[a]pyrene (BaP) are among the most common environmental pollutants and human exposure toarsenic and BaP mixture is very common. Our knowledge on the effect and mechanism of arsenic and BaP co-exposure is limited. The goal of this study is to determine the mechanism of the effect of arsenic and BaP co-exposure. Epigenetics refers to heritable changes in the pattern of gene expression that are not caused by changesin DNA sequence but are mediated by DNA methylation histone posttranslational modifications and noncodingRNAs. Cancer stem cells (CSCs) are cancer cells possessing characteristics of normal stem cells. CSCs or CSC-like cells are considered as cancer initiating cells. While the mechanism of arsenic toxic effect is not clearly definedit is thought that the toxic effect of BaP mainly depends on its metabolic activation and DNA adduct formation. Thereported effects of arsenic on DNA adduct level are controversial suggesting that other mechanisms may play akey role in the combined effect of arsenic and BaP co-exposure. Our preliminary studies found: (i) Arsenic and BaPco-exposure has a synergistic effect in inducing cell transformation CSC-like property and lung tumors; (ii) Arsenicand BaP co-exposure has no synergistic effect on BPDE-DNA adduct level. In contrast the co-exposure shows asynergistic effect in epigenetic deregulations as evidenced by increasing the levels of histone H3K9methyltransferase SUV39H1 and H3 repressive methylation mark H3K9me2. Moreover the co-exposure alsoshows a synergistic effect in reducing the level of suppressor of cytokine signaling 3 (SOCS3) and increasing Aktand Erk1/2 activation; (iii) ShRNA knockdown SUV39H1 reduces H3K9me2 level increases SOCS3 level reducesAkt and Erk1/2 activation and soft agar colony formation and CSC-like property; (iv) Stably re-expressing SOCS3reduces Akt Erk1/2 activation soft agar colony formation and CSC-like property; (v) Inhibiting Akt and Erk/1/2reduces soft agar colony formation and CSC-like property; and (vi) Arsenic and BaP co-exposure significantlyincreases aryl hydrocarbon receptor (AhR) nuclear localization and siRNA knockdown AhR greatly reduces thelevel of SUV39H1 in arsenic and BaP co-exposure-transformed cells. Based on our preliminary data our centralhypothesis is: (i) Arsenic and BaP co-exposure up-regulates HMTase SUV39H1 via synergistically activating AhR;(ii) Up-regulation of SUV39H1 leads to SOCS3 down-regulation; and (iii) Down-regulation of SOCS3 causes astronger Akt and Erk1/2 activation which enhances cell transformation and CSC-like property thus increasing lungtumorigenesis. Three aims are proposed: Aim 1: Arsenic and BaP co-exposure significantly enhances celltransformation and tumorigenesis by up-regulating HMTase SUV39H1 via synergistically activating AhR. Aim2: SUV39H1 up-regulation by arsenic and BaP co-exposure enhances cell transformation and tumorigenesisby down-regulating SOCS3 leading to stronger activation of Akt and Erk1/2. Aim 3: Simultaneously inactivatingboth Akt and Erk1/2 by a natural compound Withaferin A impairs the synergistic effect of arsenic and BaP co-exposure in inducing cell transformation and lung tumorigenesis in mice.

project_terms:
A/J Mouse;Agar;Arsenic;Aryl Hydrocarbon Receptor;Benzo(a)pyrene;CISH gene;CRISPR/Cas technology;Carcinogens;Cells;Characteristics;DNA;DNA Adduction;DNA Adducts;DNA Methylation;DNA Sequence;Data;Down-Regulation;Environmental Health;Environmental Pollutants;Epigenetic Process;Epithelial Cells;Exposure to;Gene Expression Profile;General Population;Goals;Heritability;Histone H3;Histones;Human;Impairment;Knock-out;Knowledge;Literature;Lung Neoplasms;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Meat;Mediating;Metabolic Activation;Methylation;Methyltransferase;Molecular Target;Mus;Nuclear Receptors;Nucleotide Excision Repair;Oral Administration;Pharmacology;Play;Post-Translational Protein Processing;Prevention strategy;Property;Reporting;Risk;Role;Small Interfering RNA;Source;Suspensions;Toxic effect;Untranslated RNA;Up-Regulation;arsenic carcinogenesis;base;bronchial epithelium;cancer cell;cancer risk;cancer stem cell;carcinogenesis;carcinogenicity;cell transformation;cigarette smoke;contaminated drinking water;cooking;cytotoxic;disorder prevention;exposed human population;inhibitor/antagonist;insight;knock-down;lung tumorigenesis;novel;overexpression;protective effect;small hairpin RNA;stem cells;stem-like cell;tumorigenesis;tumorigenic

public_health_relevance:
PROJECT NARRATIVEArsenic and benzo[a]pyrene (BaP) are among the most common environmental pollutants and human exposureto arsenic and BaP mixture is very common representing a major environmental health concern. The long termgoal of this study is to determine the mechanism of toxic effect of arsenic and BaP co-exposure and identifymolecular targets for better treatment and prevention of diseases resulting from arsenic and BaP co-exposure.


application_id: 9930051
project_number: 5R13CA168316-08
project_title: Advancing Health Communication Research through the KCHC-DCHC Conference Series
administering_ic: NCI
award_notice_date: 2020-03-20
opportunity_number: PA-16-294
application_type: 5
activity_code: R13
ic: CA
serial_number: 168316
program_official: BLAKE, KELLY D
project_start_date: 2012-04-19
project_end_date: 2023-03-31
study_section: ZCA1-PCRB-G(O1)
contact_pi_person_id: 1974135
contact_pi: HARRINGTON, NANCY GRANT
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract This R13 renewal application requests support to continue the highly successful Kentucky Conference onHealth Communication (KCHC)District of Columbia Health Communication (DCHC) scientific conferenceseries. The overall goal of the annual KCHC-DCHC conferences is to promote health communicationresearch and practice to advance our knowledge and understanding of communication and related social-behavioral sciences; such advances will through translational research subsequently enhance theeffectiveness of interventions designed to promote health and prevent illness. The specific aims are toexpand the impact and scholarly excellence of KCHC-DCHC by 1) enhancing dissemination through moreformal conference proceedings and an innovative online networking initiative; 2) increasing participation byearly career scientists graduate students and underrepresented groups through targeted recruitment andreduced registration rates for students; 3) enhancing training by building in structured mentoring sessions withsenior scholars; 4) increasing innovation and opportunities for research translation by scheduling specialsessions to promote academic and clinical research collaborations; 5) increasing international impact throughopportunities for discussion built into conference programming and increased promotion in internationalarenas; and 6) continuing emphasis on scholarly excellence by inviting distinguished speakers and makingscholarly awards. Across all six aims our goal is to positively influence the field of health communication andincrease its impact by promoting the career development of early career scientists encouraginginterdisciplinary research collaborations and enhancing dissemination and implementation of leading research.Our 2.5-day international interdisciplinary conference involves several disciplines representing communicationpublic health and other social behavioral and health sciences. Topics addressed include interventionsdesigned for health risk behavior reduction in areas such as cancer substance abuse and infectious disease;issues related to underserved populations health disparities and health literacy; interventions throughinterpersonal community media and new technology channels; and international health concerns includingpromoting the development of health communication programs in developing nations. Such communication-focused inquiry is now recognized as instrumental in promoting public health. Past conference attendance hasaveraged 250 participants. The audience primarily includes graduate postdoctoral and academic facultyresearchers as well as healthcare practitioners clinical researchers and representatives from non-profitorganizations and government agencies. We emphasize participation by graduate students and early careerscientists. This audience composition allows the conference series to support one of NIH's goals: to developmaintain and renew scientific humanresources that will ensure the Nation's capability to prevent disease.

project_terms:
Address;Area;Award;Behavioral Sciences;China;Clinical;Clinical Research;Clinical Sciences;Collaborations;Communicable Diseases;Communication;Communication Programs;Communication Research;Communities;Country;Decision Making;Developing Countries;Development;Diabetes Mellitus;Discipline;Disease;District of Columbia;Effectiveness of Interventions;Ensure;Event;Faculty;Foundations;Funding;Germany;Goals;Government;Government Agencies;Growth;Health;Health Communication;Health Personnel;Health Promotion;Health Sciences;Healthcare;Human Resources;Interdisciplinary Study;International;Internet;Intervention;Kentucky;Knowledge;Life;Malignant Neoplasms;Mentors;Mission;Netherlands;Nonprofit Organizations;Participant;Patients;Personal Satisfaction;Public Health;Publications;Request for Applications;Research;Research Personnel;Risk;Risk Reduction Behavior;Role;Russia;Schedule;Scientist;Series;Social Sciences;Structure;Students;Substance abuse problem;Switzerland;Training;Translational Research;Underrepresented Groups;Underserved Population;United States National Institutes of Health;Universities;base;behavioral/social science;cancer risk;career;career development;design;disability;disorder prevention;experience;graduate student;health disparity;health goals;health information technology;health knowledge;health literacy;innovation;new technology;prevent;recruit;skills;substance abuse prevention;symposium;therapy design;tool

public_health_relevance:
Project NarrativeThe Kentucky Conference on Health Communication (KCHC)District of Columbia HealthCommunication (DCHC) conference series will advance health communication research andpractice to reduce the burden of pressing public health problems such as cancer diabetessubstance abuse and infectious disease. The conferences will advance health communicationresearch and practice through structured researcher and practitioner networking andcollaboration opportunities. The conferences will promote career development in the social andbehavioral sciences through involvement of early career scientists and graduate studentsincreasing the number of professionals with expertise in health communication.


application_id: 9929595
project_number: 5T35ES014559-15
project_title: Summer Environmental Health Sciences Training Program
administering_ic: NIEHS
award_notice_date: 2020-04-30
opportunity_number: PA-14-016
application_type: 5
activity_code: T35
ic: ES
serial_number: 014559
program_official: SHREFFLER, CAROL A
project_start_date: 2006-04-01
project_end_date: 2021-08-12
study_section: Environmental Health Sciences Review Committee[EHS(TK)]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: CAVE, MATTHEW C;MCCLAIN, CRAIG J.;PROUGH, RUSSELL ALLEN;SRIVASTAVA, SANJAY
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant)      This application is a competing renewal application for a T35 summer medical student training program in environmental health sciences research that has been funded by NIEHS for 10 years. The 2 specific aims are: 1) To provide hands-on training in basic and clinical environmental health-based research to medical students in a structured mentored environment; and 2) To provide an interactive educational experience that introduces medical students the fundamental skills necessary for basic translational and clinical environmental health-based research. A new feature (Distinction in Research Track) proposed will enhance training for the students to function as environmental health sciences specialists in an Academic Health Center setting. The program has supported the training of 6 second year-medical students each summer in environmental health sciences research topics including environmental cardiology environmental metabolic disease and environmental pulmonary disease with a particular focus on diabetes non-alcoholic fatty liver disease obesity and hormonal regulation of metabolism. Trainees can choose from research projects submitted by 23 mentors in the Schools of Medicine Dentistry and Public Health (ranking them 1-5 for interest) and are selected from the top half of the first year medical class at UofL for appointment to the T35 Training grant.  A successful effort has been made to recruit students from ethnic minorities and disadvantaged backgrounds. During the 11-week summer training students work with mentors on their research project in clinical or laboratory settings and complete training in the Responsible Conduct of Research (including topics on fabrication and falsification of data plagiarism managing scientific data publication practices and responsible authorship mentorship stewardship and conflict of interest). Trainees working with human subjects complete human subject and IRB training prior to beginning their research. Likewise trainees who will use vertebrate animals in their research are required to complete a training course for animal research. All trainees will attend a weekly "Environmental Health Sciences Conference" designed to introduce clinical and translational research in environmental health sciences to T35 trainees. The conference culminates with each Trainee presenting his/her research project to peers and mentors. Trainees also present the results of their research as posters with peers at a School of Medicine week-long celebration of research that includes nationally recognized physician scientists as keynote speakers. Training in the NIEHS T35 program will encourage students to participate in the new Distinction in Research (DIR) Track in the Medical School for a continued longitudinal research experience in years 2-4 of medical training which allows them to develop research-oriented skills and to complete a translational research project in the third/fourth years. Publication of peer-reviewed articles as some have achieved will serve as outcomes of DIR training as well as the strength of residency training and first/future permanent positions.

project_terms:
Animal Experimentation;Appointment;Authorship;Cardiology;Clinical;Clinical Research;Conflict of Interest;Data;Dentistry;Diabetes Mellitus;Environment;Environmental Health;Funding;Future;Grant;Health;Institutional Review Boards;Laboratories;Lung diseases;Medical;Medical Students;Mentors;Mentorship;Metabolic Diseases;Metabolism;National Institute of Environmental Health Sciences;Obesity;Outcome;Peer Review;Physicians;Plagiarism;Positioning Attribute;Public Health;Publications;Research;Research Project Grants;Research Training;Residencies;Scientist;Specialist;Structure;Student recruitment;Students;Training;Training Programs;Training Support;Translational Research;Vertebrates;Work;base;design;ethnic disadvantage;ethnic minority population;experience;health science research;hormone regulation;human subject;interest;medical schools;non-alcoholic fatty liver disease;peer;peer coaching;posters;programs;responsible research conduct;skills;student training;symposium

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This NIEHS Short-Term Institutional Training Grant (5T35ES014559) application is to request annual support for 6 medical student trainees for a 10-week training experience for the next 5 years. The overarching scientific theme of research that links the faculty to this T35 Training Grant is the common interest of the faculty in researchtraining of medical students in the investigators' laboratories in elucidating the health outcomes of exposure of normal and obese individuals to various environmental or common chemicals in the environment. In addition the investigators will use the T35 Training Grant to entice our medical students into their new Distinction in Research Track designed to allow students to pursue research interests throughout the 2-4 years of Medical School curriculum with an eye toward building a pipeline of diverse translational clinician-researchers in the future.


application_id: 9928871
project_number: 5R01AG057290-04
project_title: Programming amylin secretion to slow brain aging - an animal model
administering_ic: NIA
award_notice_date: 2020-04-27
opportunity_number: RFA-AG-17-050
application_type: 5
activity_code: R01
ic: AG
serial_number: 057290
program_official: PEREZ MONTES, VIVIANA
project_start_date: 2017-09-15
project_end_date: 2022-04-30
study_section: 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_abstract:
PROJECT SUMMARYProteostasis dysfunction of pancreatic -cells results in accumulation of oligomerized amylin within pancreaticislets which is a hallmark of type-2 diabetes. We recently showed that oligomerized amylin also incorporatesinto the brain blood vessel walls forms neuritic deposits and co-localizes with Alzheimer's disease (AD) -amyloid peptides (A) as mixed A-amylin plaques in brains of individuals with late-onset AD as well as familialearly-onset AD. It is unknown whether cerebral amylin deposits are a consequence of AD or type-2 diabetesor a hidden trigger of AD. Moreover we found that overexpressing human amylin within pancreatic islets inrats induces systemic amylin dyshomeostasis brain amylin accumulation microglia activation and behaviorchanges. Furthermore elevated human amylin in the periphery greatly accelerates behavior changes in a ratmodel of AD pathogenesis. These findings suggest the hypothesis that amylin dyshomeostasis in pancreaticislets and subsequent secretion of oligomerized amylin in the blood can affect the progression of AD bycompromising the ability of microglia to efficiently clear A and by inducing mixed A-amylin pathology. Thusameliorating amylin dyshomeostasis in the periphery can limit the progression of AD. The overarching goal ofthis proposal is to test our hypothesis and investigate molecular mechanisms underlying the interaction ofamylin with A pathology. We will accomplish this goal by characterizing novel transgenic mice with inducibleand reversible expression of human amylin in the pancreas (HuAmy line). We will carefully dissect proteostasisdysfunction of pancreatic -cells in the periphery and the consequent liability it imposes on the central nervoussystem. We will also cross HuAmy line and 85Dbo line to generate APP/PS1 transgenic mice with regulatedexpression of human amylin in the periphery. We predict that turning off the human amylin transgeneexpression at early time points during aging mitigates the disease progression in HuAmy:APP/PS1 mice bylimiting the blood-brain barrier injury and rescuing the ability of microglia to clear A. This investigation usingnovel regulated amylin expression represents the most direct in vivo approach to rigorously test theinvolvement of peripheral amylin in the biological pathways of AD pathogenesis. The completion of these aimswill elucidate the interplay of amylin dyshomeostasis with the progression of A pathology and whetherameliorating amylin dyshomeostasis in the periphery can reduce or reverse AD in a preclinical model. Webelieve that the proposed investigation fills significant gaps in our understanding of the molecular link betweentype-2 diabetes and AD.

project_terms:
APP-PS1;Affect;Age;Aging;Alzheimer's Disease;Alzheimer's Disease Pathway;Alzheimer's disease brain;Alzheimer's disease model;Amyloid;Amyloid beta-Protein;Amyloidosis;Animal Model;Behavior;Biological;Blood;Blood - brain barrier anatomy;Blood Vessels;Brain;Cerebrum;Data;Deposition;Development;Diabetes Mellitus;Disease Progression;Early Onset Familial Alzheimer's Disease;Feasibility Studies;Functional disorder;Genes;Goals;Heart;Heart failure;Hormones;Human;Impaired cognition;Individual;Injury;Insulin;Intravenous;Intravenous infusion procedures;Investigation;Islets of Langerhans;Kidney;Late Onset Alzheimer Disease;Link;Longevity;Mediating;Microglia;Molecular;Mus;Neuraxis;Neuronal Dysfunction;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Pancreas;Pathogenesis;Pathology;Pericytes;Peripheral;Pre-Clinical Model;Protein Isoforms;Rattus;Structure of beta Cell of islet;Synapses;Testing;Time;Transgenes;Transgenic Mice;aging brain;amyloid formation;apolipoprotein E-4;behavior change;beta amyloid pathology;cognitive performance;design;diabetic patient;early onset;in vivo;islet amyloid polypeptide;mouse model;neural network;non-diabetic;novel;overexpression;proteostasis;transgene expression;transgenic model of alzheimer disease;uptake

public_health_relevance:
NarrativeRecent studies suggest that proteostasis dysfunction of pancreatic -cells is linked with Alzheimer's disease bythe brain accumulation of oligomerized amylin. Our proposed studies will elucidate the interplay of amylindyshomeostasis in the periphery with the progression of  amyloid pathology and whether ameliorating amylindyshomeostasis in the periphery can reduce or reverse Alzheimer's disease in a preclinical model.


application_id: 9928038
project_number: 5R34DA046005-03
administering_ic: NIDA
award_notice_date: 2020-05-28
opportunity_number: PA-15-250
application_type: 5
activity_code: R34
ic: DA
serial_number: 046005
program_official: HIGHSMITH, KEISHER S
project_start_date: 2018-07-01
project_end_date: 2021-07-31
study_section: Special Emphasis Panel[ZRG1-NRCS-V(08)]
contact_pi_person_id: 9641889
contact_pi: ASHFORD, KRISTIN H.
other_pis: FALLIN-BENNETT, AMANDA
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 NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-06-01
project_title:
Behavioral and Enhanced Perinatal Intervention for Cessation (B-EPIC): Reducing Tobacco use among Opioid Addicted Women

project_abstract:
ABSTRACT:Each year 225000 infants in the United States are exposed prenatally to illicit drugs. Women with substance usedisorders particularly those with opioid dependence are highly vulnerable to cigarette smoking during the perinatalperiod. Pregnant opioid dependent patients seeking medication-assisted treatment (MAT) have high rates of smokingranging from 88% to 95%. Smoking during pregnancy is an independent risk factor (outside of illicit drug use) for severaladverse outcomes including ectopic pregnancy premature birth orofacial clefts and sudden infant death syndrome. Illicitopioid use magnifies these risks; among women who use opioids during pregnancy there is a 6-fold greater risk forintrauterine growth restriction third trimester vaginal bleeding preterm delivery and a majority also will experienceneonatal abstinence syndrome (NAS). Prenatal tobacco use significantly increases the severity and duration of NAS yet isnot commonly treated among opioid dependent pregnant women receiving MAT. On average the healthcare cost perdischarged infant with NAS ranges from $39400 to $53400; and 77.6% is paid for by Medicaid. MAT has been shown todecrease the severity of NAS compared to no treatment; yet most opioid dependent women in MAT still continue tosmoke cigarettes throughout pregnancy clearly suggesting that there is a significant need for a comprehensive evidence-based tobacco treatment intervention. To date there is no specific pharmacologic or non-pharmacologic tobacco-treatment standard for opioid dependent pregnant women in MAT. More research is needed to develop and test tailoredtobacco treatment interventions for pregnant opioid dependent women. The purpose of this trial is to test a novelintervention for tobacco cessation Behavioral and Enhanced Perinatal Intervention for Cessation (B-EPIC) in anestablished community MAT clinic. B-EPIC is designed to reduce tobacco-associated morbidity (e.g. preterm birthNAS) and healthcare expenditures in pregnant women who are tobacco users receiving buprenorphine for opioiddependence. This two-group randomized and controlled clinical trial (n =100) will provide critical preliminary data to testlarger-scale trials. As nearly all B-EPIC services are billable services via public and private insurers; there is highlikelihood for sustainability.

project_terms:
Accident and Emergency department;Address;Adoption;Behavior;Behavioral;Birth;Buprenorphine;Child;Childhood;Cigarette;Clinic;Communities;Control Groups;Cotinine;Counseling;DSM-IV;Data;Diagnosis;Ectopic Pregnancy;Emergency department visit;Epidemic;Expenditure;Feedback;Fetal Growth Retardation;Frequencies;Gestational Age;Goals;Health;Health Care Costs;Health Expenditures;Hemorrhage;Hospitalization;Illicit Drugs;Infant;Insurance Carriers;Intervention;Length;Length of Stay;Medicaid;Medical;Medical Records;Morbidity - disease rate;Morphine;Neonatal Abstinence Syndrome;Neonatal Intensive Care Units;Opiate Addiction;Opioid;Outcome;Outpatients;Participant;Patients;Pharmacology;Pharmacotherapy;Postpartum Women;Pregnancy;Pregnant Women;Premature Birth;Privatization;Randomized Controlled Clinical Trials;Readiness;Research;Respiratory Tract Infections;Risk;Risk Factors;Services;Severities;Smoke;Smoking;Substance Use Disorder;Sudden infant death syndrome;Surveys;Testing;Third Pregnancy Trimester;Time;Tobacco;Tobacco Dependence;Tobacco use;United States;Urine;Vagina;Visit;Woman;adverse outcome;biomarker validation;cigarette smoke;cigarette smoking;cost;cost-effectiveness ratio;design;ear infection;effectiveness research;evidence base;experience;health care service utilization;hospital readmission;illicit drug use;illicit opioid;incremental cost-effectiveness;infant outcome;maternal tobacco use;medication-assisted treatment;novel;opioid use;opioid use in pregnancy;orofacial cleft;perinatal intervention;perinatal period;perinatal women;pregnant;prenatal;prenatal exposure;reduce tobacco use;smoking cessation;smoking during pregnancy;standard care;tobacco cessation intervention;tobacco user;treatment as usual

public_health_relevance:
PROJECT NARRATIVEEach year 225000 infants in the United States are exposed prenatally to illicit drugs. The proposed study uses abehavioral and enhanced perinatal intervention for cessation (B-EPIC) to address this epidemic and will provide thenecessary data to develop and prepare larger scale trials with the ultimate goal of reducing tobacco-associated morbidityand health care expenditures in pregnant and postpartum women with substance use disorders.


application_id: 9927019
project_number: 7R01ES026446-04
project_title: Developmental Effects of Manganese Exposure in Rural Adolescents: The CARES Cohort Comes of Age
administering_ic: NIEHS
award_notice_date: 2019-08-03
opportunity_number: PA-18-590
application_type: 7
activity_code: R01
ic: ES
serial_number: 026446
program_official: MARTIN, LINDSEY ANN
project_start_date: 2016-09-30
project_end_date: 2021-08-31
study_section: Neurological, Aging and Musculoskeletal Epidemiology Study Section[NAME]
contact_pi_person_id: 7102409
contact_pi: HAYNES, ERIN N
other_pis: CECIL, KIM M
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Manganese (Mn) plays an essential role in normal growth and development; howeveroverexposure to Mn can result in neurotoxicity. This dual role of Mn as essential mineral andneurotoxicant appears as a biphasic dose-response curve for neurodevelopmental healthoutcomes in children. Children may be particularly susceptible to the neurotoxic effects ofambient Mn exposure as their brains are undergoing a dynamic process of growthdifferentiation pathway direction and apoptosis all of which can be influenced byenvironmental factors. Recent developments in magnetic resonance imaging (MRI) andspectroscopy (MRS) can provide novel quantitative information about the effects of Mn on brainanatomy and physiology; yet these imaging methods have never been applied to an adolescentpopulation exposed to chronic ambient Mn. Given the role of Mn as both nutrient andneurotoxicant we anticipate that biomarkers of Mn exposure will exhibit a biphasic dose-response association with adolescent neurobehavior neuromotor function brainanatomy and physiology and hypothesize that both low (1st quartile) and high (4thquartile) levels of exposure will be significantly associated with deficits in thesedomains. This overarching hypothesis will be addressed through two specific aims.Specific Aim 1: Evaluate neurodevelopment with historic and current biomarkers of Mn in acohort of rural adolescents in order to evaluate the impact of Mn from essential to excess onexecutive function attention and reaction time cognition achievement behavior andneuromotor status. Specific Aim 2: Conduct a sub-study of adolescents based on previouslydetermined Mn biomarkers using quantitative MRI/S in order to evaluate the effects of Mnexposure from essential to excess on neuroanatomy metabolism organization function andconnectivity. Neuroimaging outcomes (volume metabolite concentrations metrics for diffusiontensor functional activation and network connectivity) will be compared with historic andcurrent biomarkers of Mn. This well-characterized longitudinal cohort study of adolescents willadvance our understanding of the impact of Mn on neurodevelopment and brain anatomy andphysiology using innovative MRI methodologies. These patterns may be useful in defining thelines of essential benefit and neurotoxicological harm from Mn. The findings from this study willhave regional national and global implications for advancement of neuroscience and will beused to inform policy related to Mn in gasoline and ambient air standards. This proposalleverages the only cohort available in the United States that can directly address these aims.

project_terms:
Achievement;Address;Adolescence;Adolescent;Air;Anatomy;Apoptosis;Attention;Axonal Transport;Basal Ganglia;Behavior;Biliary;Biological Markers;Blood;Brain;Bypass;Cerebellum;Child;Chronic;Cognition;Cohort Studies;Communities;Deposition;Development;Diagnosis;Diffusion;Dose;Elements;Emotional;Environmental Risk Factor;Environmental Tobacco Smoke;Event;Excretory function;Exhibits;Exposure to;Follow-Up Studies;Gait;Gasoline;Globus Pallidus;Growth;Growth and Development function;Health;Infant;Ingestion;Inhalation;Lead;Longitudinal cohort study;Magnetic Resonance Imaging;Manganese;Measures;Metabolism;Methodology;Methods;Minerals;Motor;Multimodal Imaging;Musculoskeletal Equilibrium;Neuraxis;Neuroanatomy;Neuropsychology;Neurosciences;Neurotoxins;Nose;Nutrient;Ohio;Outcome;Parkinson Disease;Pathway interactions;Pattern;Pediatric cohort;Physicians;Physiology;Play;Policies;Population;Prefrontal Cortex;Process;Protocols documentation;Psyche structure;Reaction Time;Research;Risk;Risk-Taking;Role;Rural;Rural Appalachia;Source;Structure;Structure of subthalamic nucleus;Substantia nigra structure;United States;Work;adverse outcome;base;cognitive function;cohort;executive function;frontal lobe;high risk;imaging modality;innovation;myelination;nervous system development;neurobehavior;neurodevelopment;neuroimaging;neurotoxic;neurotoxicity;novel;olfactory bulb;putamen;relating to nervous system;response;spectroscopic imaging;synaptogenesis;white matter

public_health_relevance:
Narrative: This study will innovatively examine the impact of manganese exposure along withother known neurotoxicants including lead and environmental tobacco smoke in a follow-upstudy of a rural Appalachian cohort. We will examine the impact of these exposures onneurobehavior postural balance and gait brain anatomy and physiology.


application_id: 9926428
project_number: 3P42ES007380-21S4
project_title: Chloro-Organic Degradation by Polymer Membrane Immobilized Iron-Based Particle Sy
administering_ic: NIEHS
award_notice_date: 2019-05-17
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S4
program_official: HENRY, HEATHER F
study_section: ZES1-LKB-K
subproject_number: 7485
contact_pi_person_id: 8534525
contact_pi: BHATTACHARYYA, DIBAKAR
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
project_abstract:
PROJECT SUMMARY (Project 5 - Bhattacharyya Ormsbee) Due to their relative chemical stability and ubiquitous nature chlorinated organic compounds such as polychlorinated biphenyls (PCBs) and trichloroethylene (TCE) continue to pose both remediation challenges and human health risks. At many Superfund sites past remediation efforts using traditional treatment strategies (e.g. reactive barriers six phase heating etc.) have proven to be highly costly and largely ineffective. Alternative strategies include both reductive and oxidative pathways for chloro-organic degradation to non-toxic compounds. The development of nanosized iron-based materials has brought important and promising techniques into the field of environmental remediation. In recent years zero-valent nanoscale metal (especially iron) particles have attracted growing attention in groundwater remediation of chlorinated solvents. For more rapid and complete reductive dechlorination a second metal is often added resulting in bimetallic nanoparticles. In the past utilization of such approaches at actual Superfund sites has been limited due to concerns about particle agglomeration or release into the environment. Project 5 will address the need for targeted remediation strategies by developing integrated cost-effective technologies which incorporate both reductive and oxidative strategies in order to allow the complete remediation of chlorinated organic compounds without the production of toxic byproducts Three specific aims are to: 1) create a porous common polymer membrane immobilized platform for synthesis of reactive and stable iron-based nanoparticles using environmentally safe approaches to prevent aggregation and loss of particles; 2) embed immobilized nanoparticles in responsive membrane domain to allow highly effective PCB and TCE dechlorination by both reductive and oxidative approaches; 3) determine whether PCB demineralization with reduction by bimetallic (iron and palladium) nanoparticles as a first step followed by oxidation with iron oxide nanoparticles immobilized in polymer membrane domain will eliminate the formation of toxic chlorine-substituted intermediates as verified by toxicity tests. To accomplish the aims a polymer/ membrane platform will be developed in both lab scale and full-scale for environmentally benign nanostructured iron synthesis and individual and combined technology strategies will be established to reduce the toxicity of chloro-organics (selected PCBs and chloroethylenes). The proposed approach should address the agglomeration and toxicity concerns associated with the use of bimetallic nanoparticles and allow for the complete breakdown of chlorinated organic compounds to nontoxic and biodegradable intermediates. The project will include collaborations with the U.S. Environmental Protection Agency's (EPA's) National Risk Management Research Laboratory focused on nanoparticle synthesis and characterization using EPA facilities. As in the past the project will work with diverse primary stakeholders at state and federal levels to implement the developed technologies at the Paducah Gaseous Diffusion Plant Kentucky largest Superfund site.

project_terms:
Address;Adsorption;Aftercare;Attention;Benign;Biological Sciences;Carbon;Chemicals;Chemistry;Chlorine;Collaborations;Development;Diffusion;Drug Metabolic Detoxication;Engineering;Environment;Environmental Health;Free Radicals;Funding;Generations;Health;Heating;High temperature of physical object;Human;Hydrogen Peroxide;Hydroxyl Radical;Immobilization;Individual;Inflammatory;Iron;Kentucky;Knowledge;Laboratories;Laboratory Research;Lead;Literature;Manufacturer Name;Medical;Membrane;Metals;Methods;Modeling;Nanostructures;Nature;Outcome Study;Palladium;Pathway interactions;Phase;Plants;Poison;Polychlorinated Biphenyls;Polymers;Production;Public Health;Reaction;Research;Risk;Risk Management;Science;Scientist;Site;Soil;Solvents;Source;Structure;Superfund;System;Techniques;Technology;Temperature;Testing;Toxic effect;Toxicity Tests;Translational Research;Trichloroethylene;United States Environmental Protection Agency;Vinyl Chloride;Water;Work;aryl hydrocarbon receptor ligand;base;chemical stability;contaminated water;cost;cost effective;dechlorination;demineralization;design;drinking water;global environment;ground water;hazard;hydrodynamic flow;innovation;iron oxide;iron oxide nanoparticle;metal oxide;microbial;nanoparticle;nanoscale;nanosized;novel;nutrition;oxidation;particle;pollutant;prevent;remediation;scaffold;sensor;superfund chemical;superfund site;technology validation;treatment strategy

public_health_relevance:
PROJECT NARRATIVE The persistence of toxic pollutants at Superfund sites poses a major environmental public health problem and a serious need for environmental solutions to reduce risk. Our research is expected to lead to cost-effective technologies for remediation of chemicals known as PCBs and TCE that allow for their complete breakdown to nontoxic and biodegradable intermediates while eliminating the two primary concerns associated with the use of nanoparticle systems: their tendency to adhere to each other and their toxicity. Our approaches to develop new membrane-based materials to degrade toxic chemicals may lead to an advanced technology solution in the field of remediation science and engineering.


application_id: 9926427
project_number: 3P42ES007380-21S4
project_title: Biomimetic Magnetic Nanocomposites as a Platform Technology for the Capture and S
administering_ic: NIEHS
award_notice_date: 2019-05-17
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S4
program_official: HENRY, HEATHER F
study_section: ZES1-LKB-K
subproject_number: 7484
contact_pi_person_id: 8239234
contact_pi: HILT, JAMES ZACH
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
project_abstract:
PROJECT SUMMARY (Project 4 - Hilt Dziubla) Due to their relative chemical stability and pervasive contamination of the environment chlorinated organics such as polychlorinated biphenyls (PCBs) pose serious risks to human health. Given the lack of highly reliable rapid screening tools a convincing evidence base supports study of biological binding domains as a viable strategy for advances in PCB detection. Specifically novel nanomaterials will be developed and will result in a platform technology that allows for the inclusion of biomimetic domains into a variety of system designs facilitating the rapid detection of PCB congeners in the ppm levels needed for useful screening. Furthermore the biomimetic polymer coatings on the magnetic nanoparticles will allow for capture analysis remediation and release on demand. Despite a production ban in 1979 and decades of remediation efforts PCBs remain a persistent environmental contaminant. Gas chromatography mass spectrometry (GC-MS) remains the current standard for sensitivity and specificity in detecting PCBs in the environment. However GC-MS requires intricate time-consuming extraction and sample purification techniques. It has been reported that the binding domains of PCB-specific antibodies (e.g. S2B1) form sterically constrained highly aromatic (e.g. tryptophan tyrosine) pockets allowing for pi-pi bond stacking interactions. These same environments can also be seen in tests of PCB soil distribution (e.g. humin containing matter) and biodistribution (e.g. lipid rafts PCB-binding proteins). We hypothesize that synthetic biomimetic PCB-binding domains can be synthesized by incorporating phenolic and related moieties into polymeric coatings. In preliminary studies we showed that PCB binding was increased through the incorporation of phenolic moieties in our polymeric coatings. The overall goal of this project is to develop a magnetic nanocomposite platform that allows for the selective capture of PCB congeners with a range of affinities and selectivities. The specific aims follow: (1) synthesize and characterize physicochemical properties of magnetic nanocomposites (i.e. biomimetic polymeric networks coated on the surface of magnetic nanoparticles) with the ability to capture/release or capture/sense PCB congeners with tunable affinity and selectivity; (2) characterize the functionality of synthesized nanomaterials including binding capture/release and fluorescence sensing analysis; and (3) apply these novel nanomaterials for the selective capture and sensing of PCBs and mixtures including coplanar non-coplanar and mixed congener PCBs and mixtures (e.g. PCBs 126 153 118). The coatings will be engineered to have precise nanoscale thickness tunable affinity/selectivity and reversible binding using surface initiated polymerizations incorporating phenolic moieties and applying molecular imprinting approaches. These nanomaterials will have broader impact through their potential application in remediation and biomedical applications.

project_terms:
Address;Affinity;Antibodies;Binding;Binding Proteins;Biodistribution;Biological;Biomimetics;Characteristics;Chemistry;Consumption;Coupled;Detection;Dioxins;Engineering;Environment;Environmental Health;Environmental Pollution;Excision;Flavonoids;Fluorescence;Goals;Health;Human;Kentucky;Light;Magnetic nanoparticles;Magnetism;Mass Fragmentography;Membrane Microdomains;Methods;Milk;Molecular;Phenols;Plants;Poison;Polychlorinated Biphenyls;Polymers;Process;Production;Property;Proteins;Reporting;Research;Resources;Risk;Sampling;Screening procedure;Sensitivity and Specificity;Soil;Solubility;Specificity;Superfund;Surface;System;Techniques;Technology;Testing;Thick;Time;Toxic effect;Tryptophan;Tyrosine;Universities;Work;aqueous;base;bisphenol A;chemical stability;design;disorder prevention;evidence base;exposed human population;exposure route;fundamental research;global environment;ground water;imprint;nanocomposite;nanomaterials;nanoscale;novel;novel strategies;nutrition;pi bond;pollutant;polyphenol;rapid detection;remediation;screening;superfund chemical;superfund site

public_health_relevance:
PROJECT NARRATIVE The selective capture and sensing of PCBs is critical for understanding environmental contamination by this class of toxic compounds and its impact on human health. The novel nanomaterials developed in this work will provide a solution to the problem widespread contamination at Superfund sites which poses serious global environmental health challenges. Addressing this fundamental research problem will directly impact disease prevention efforts.


application_id: 9926426
project_number: 3P42ES007380-21S4
project_title: Polychlorinated Biphenyls Nutrition and Diabetes - Project 3
administering_ic: NIEHS
award_notice_date: 2019-05-17
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S4
program_official: HENRY, HEATHER F
study_section: ZES1-LKB-K
subproject_number: 7483
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
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
project_abstract:
PROJECT SUMMARY (Project 3 - Cassis) Recent studies demonstrate a strong association between serum levels of polychlorinated biphenyls (PCBs) and an increased odds ratio for type 2 diabetes (T2D). This proposal tests the hypothesis that coplanar PCBs act at adipocyte aryl hydrocarbon receptors (AhR) to increase expression of proinflammatory cytokines resulting in reductions in glucose uptake and the development of insulin resistance. Further we hypothesize that the polyphenol resveratrol can be used to prevent and/or treat PCB-induced elevations in adipocyte proinflammatory cytokine expression and impaired glucose homeostasis during weight loss. We demonstrated that administration of coplanar PCBs to low fat fed male and female mice induces glucose and insulin intolerance associated with adipose-specific elevations in tumor necrosis factor- (TNF-). Remarkably when mice were made obese from consumption of a high fat (HF) diet effects of PCB to impair glucose homeostasis were lost when lipophilic PCBs were sequestered at higher levels within adipose tissue lipids. However upon weight loss PCBs impaired glucose and insulin tolerance limiting beneficial effects of weight loss to improve glucose homeostasis. These results suggest that obesity increases body burden of PCBs and that release of PCBs during weight loss from adipose lipids may be harmful in the context of T2D. The anti-oxidant polyphenol and putative AhR antagonist resveratrol abolished acute effects of PCBs to impair glucose tolerance in mice and protected against PCB-induced reductions in insulin signaling and glucose uptake in adipocytes. Aim 1 will define the role of adipocyte AhR in PCB-induced impairment of glucose and insulin tolerance in lean male and female mice and in obese mice experiencing weight loss. Results from these studies will define whether the enhanced accumulation of lipophilic PCBs to adipose tissue results in adipocyte-specific impairment of glucose uptake. Aim 2 will define the adipocyte-specific effects of resveratrol on PCB-induced impairment of glucose homeostasis in obese male and female mice exhibiting weight loss. Results from this aim will determine if resveratrol acts to protect against PCB-induced impairment of glucose uptake and insulin resistance through an adipocyte-specific mechanism and whether this therapeutic strategy have utility in the setting of weight loss. The impact of this research is identification of mechanisms linking PCB exposures to T2D and development of a therapeutic strategy resveratrol to protect against harmful effects of PCBs on glucose homeostasis in lean subjects as well as obese subjects experiencing weight loss.

project_terms:
Acute;Adipocytes;Adipose tissue;Affect;Antioxidants;Aryl Hydrocarbon Receptor;Body Burden;Body Weight decreased;Community Health;Consumption;Data;Development;Diabetes Mellitus;Dioxins;Environmental Exposure;Exhibits;Exposure to;Fatty acid glycerol esters;Female;Glucose;Health Surveys;High Fat Diet;Impairment;Insulin;Insulin Resistance;Intervention;Laboratories;Link;Lipids;Mediating;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Obesity;Odds Ratio;Overweight;Oxidative Stress;Plasma;Polychlorinated Biphenyls;Population;Research;Resveratrol;Risk;Role;Serum;TNF gene;Testing;Therapeutic;Thinness;Toxic Environmental Substances;Toxic effect;Treatment Efficacy;Weight;World Health Organization;aryl hydrocarbon receptor ligand;blood glucose regulation;clinically significant;cytokine;experience;glucose tolerance;glucose uptake;impaired glucose tolerance;improved;insulin signaling;insulin tolerance;lipophilicity;male;nutrition;persistent organic pollutants;polyphenol;prevent;superfund chemical

public_health_relevance:
PROJECT NARRATIVE (Project 3 - Cassis) The overall impact of this research is to identify mechanisms whereby polychlorinated biphenyls (PCBs) lipophilic environmental toxins promote the development of insulin resistance and type 2 diabetes. Moreover our approach will identify whether the natural polyphenol resveratrol can be used as an interventional strategy to protect against harmful effects of PCBs on glucose homeostasis in lean subjects and in obese subjects experiencing weight loss.


application_id: 9926425
project_number: 3P42ES007380-21S4
project_title: Postnatal Complications of Perinatal Polychlorinated Biphenyl Exposure - Project
administering_ic: NIEHS
award_notice_date: 2019-05-17
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S4
program_official: HENRY, HEATHER F
study_section: ZES1-LKB-K
subproject_number: 7482
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
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
project_abstract:
PROJECT SUMMARY (Project 2 - Pearson Swanson) Polychlorinated biphenyls (PCBs) one of a number of chlorinated organic pollutants are highly lipid-soluble toxins that are characterized by relative chemical stability and prevalence in the environment. These traits are responsible for their widely recognized role as a source of serious environmental public health risks. PCBs have been shown to cross the placenta and enter breast milk and a recent paper suggests that prenatal organochlorine levels contribute to gender-specific obesity development in children. In a mouse model additional observations revealed that offspring exposed perinatally to PCB 126 a coplanar PCB that acts through the aryl hydrocarbon receptor had significantly worse fat and lean mass profiles compared to offspring born to vehicle-treated dams. Further mature offspring born to PCB-exposed dams had impaired glucose tolerance compared to offspring from vehicle-treated dams. The principal investigator's group has shown that short-term maternal voluntary exercise prior to and during healthy pregnancy and nursing can enhance long- term glucose homeostasis in offspring. The goal of the proposed research is to elucidate the potential long- term health complications and mechanisms of PCB toxicity during the critical periods of in utero and early postnatal life and to explore maternal exercise as a transgenerational intervention. Specific Aim 1 will establish the importance of the timing of perinatal PCB exposure (unexposed/in utero exposure/postnatal exposure/in utero + postnatal exposure) that precipitates impaired glucose tolerance in offspring. A subset of offspring will be fed a high fat diet to determine whether a 'second hit' will exacerbate the PCB-induced detriments. Specific Aim 2 will elucidate the mechanism of impaired glucose tolerance in offspring born to PCB-exposed dams. Specific Aim 3 will test if voluntary maternal exercise can be used as an intervention to protect adult offspring from the long-term effects of perinatal PCB exposure. The proposed studies will provide new etiological evidence supporting current observations that perinatal exposures to environmental PCBs are important contributors to the epidemic of diabetes in the United States. This work will also contribute innovative new insights to understanding the role of exercise in mitigating the environmental health impacts of PCB exposure by highlighting pregnancy as a sensitive period when environmental pollutants could have significant and long- lasting effects on offspring metabolism and when interventions could prove effective in ameliorating the detrimental health outcomes. Anticipated results are particularly significant in that they highlight early developmental stages i.e. fetal and neonatal as potential periods of particular vulnerability to lasting effects of toxic environmental insult from PCB contamination.

project_terms:
Adipose tissue;Adult;Adult Children;Agonist;Aryl Hydrocarbon Receptor;Attenuated;Beta Cell;Biochemical;Body Composition;Child;Chlorinated Hydrocarbons;Data;Development;Diabetes Mellitus;Discipline of Nursing;Dose;Environment;Environmental Health;Environmental Impact;Environmental Pollutants;Environmental Pollution;Epidemic;Erythroid;Etiology;Exercise;Exposure to;Fatty acid glycerol esters;Female;Fetal Liver;Fostering;Functional disorder;Funding;Gender;Glucose Clamp;Glucose Intolerance;Goals;Gold;Health;High Fat Diet;Human Milk;Impairment;Inflammation;Inflammatory;Insulin;Insulin Resistance;Intervention;Laboratories;Life;Life Cycle Stages;Lipids;Long-Term Effects;Measures;Messenger RNA;Metabolism;Methods;Molecular;Mus;Neonatal;Nuclear;Obesity;Outcome;Oxidative Stress;Paper;Partner in relationship;Perinatal;Perinatal Exposure;Phenotype;Placenta;Play;Polychlorinated Biphenyls;Predisposition;Pregnancy;Prevalence;Principal Investigator;Public Health;Research;Risk;Role;Running;Serum;Source;Techniques;Testing;Thinness;Tissues;Toxic effect;Toxin;United States;Weaning;Work;blood glucose regulation;chemical stability;cost effective;critical period;cytokine;exposed human population;fasting glucose;fetal;glucose tolerance;healthy pregnancy;impaired glucose tolerance;improved;in utero;in vivo Model;innovation;insight;insulin sensitivity;insulin signaling;lifestyle intervention;mouse model;novel;nutrition;obesity development;offspring;perinatal complications;perinatal development;pollutant;postnatal;pregnant;prenatal;prenatal exposure;sedentary;superfund chemical;trait;trend

public_health_relevance:
PROJECT NARRATIVE Obesity and diabetes are at epidemic levels and the toxicity of environmental contaminants during perinatal development could be a significant contributor to these trends. The proposed studies will provide novel information on the detrimental impact that pollutants can have on maternal and offspring health and will test whether the lifestyle intervention maternal exercise can attenuate these effects.


application_id: 9926424
project_number: 3P42ES007380-21S4
project_title: Superfund Chemicals Nutrition and Endothelial Cell Dysfunction - Project 1
administering_ic: NIEHS
award_notice_date: 2019-05-17
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S4
program_official: HENRY, HEATHER F
study_section: ZES1-LKB-K
subproject_number: 7481
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
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
project_abstract:
PROJECT SUMMARY (Project 1 - Hennig Morris) Due to their relative chemical stability and ubiquity in the environment chlorinated organic contaminants such as polychlorinated biphenyls (PCBs) continue to pose significant environmental public health risks. The toxic insult from these highly lipid-soluble toxic compounds is known to correlate with a range of post-exposure human health impacts including endocrine disruption and vascular inflammation. In particular coplanar PCBs which act as an agonist of the aryl hydrocarbon receptor have been shown to exert particularly toxic effects on the endothelium and associated vasculature. Atherosclerosis a chronic inflammatory disease initiated by vascular endothelial cell dysfunction remains the leading cause of death in the United States. Exposure to Superfund chemicals such as persistent chlorinated organic pollutants (e.g. PCBs) has been implicated as a risk factor for the development of atherosclerosis. Furthermore PCB-induced toxicity has been linked to increased expression of caveolin-1 the major structural protein in caveolae membrane domains. Caveolae are particularly abundant in endothelial cells where they are believed to play a major role in the regulation of endothelial vesicular trafficking and cell signal transduction. PCBs are also known to affect the cellular redox status which may initiate antioxidant responses through nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling. Increasing evidence suggests that diets high in plant-derived bioactive food components (e.g. polyphenols) and omega-3 lipids are associated with a reduced risk of chronic inflammatory diseases such as atherosclerosis. Current data suggest that endothelial cell dysfunction and inflammatory events induced by exposure to coplanar PCBs can be markedly downregulated by polyphenols such as flavonoids as well as by omega-3 polyunsaturated fatty acids. Preliminary data suggest that caveolae and cytosolic Nrf2 signaling are sensitized by dietary omega-3 lipids and polyphenols. We propose three specific aims to test the hypotheses that: 1) PCB-induced endothelial toxicity and associated inflammatory events are regulated through the crosstalk between caveolae and Nrf2 related proteins such as Keap1; 2) dietary protective components including polyphenols and omega-3 lipids sensitize Nrf2 and caveolae signaling pathways leading to a more effective anti-inflammatory cellular response against PCB insults; 3) dietary intervention in vivo can modify PCB-mediated initiation of inflammation and atherosclerosis through caveolae and/or Nrf2 signaling. Novel experimental methodologies including gene control constructs and bioanalytical technologies will be utilized to understand the interplay between Nrf2 and caveolae signaling. Results from our mechanistic studies will support the paradigm that healthful nutrition interventions may offer a powerful strategy to reduce disease risks associated with environmental toxic insults and to prevent inflammatory diseases such as atherosclerosis that have been linked to exposure to persistent chlorinated organic pollutants.

project_terms:
Address;Affect;Agonist;Anti-inflammatory;Antioxidants;Arterial Fatty Streak;Aryl Hydrocarbon Receptor;Atherosclerosis;Biological Assay;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Catechin;Cause of Death;Caveolae;Caveolins;Cells;Chemicals;Chronic;Complement;Consumption;Data;Development;Diabetes Mellitus;Diet;Dietary Fats;Dietary Intervention;Dietary Polyphenol;Disease;Ecology;Endocrine disruption;Endothelial Cells;Endothelium;Environment;Environmental Health;Environmental Pollutants;Epigallocatechin Gallate;Erythroid;Event;Exposure to;Flavonoids;Foundations;Functional disorder;Genes;Green tea;Hazardous Waste Sites;Health;Health Food;Human;Hypertriglyceridemia;In Vitro;Inflammation;Inflammatory;Investigation;Kentucky;Knockout Mice;Link;Lipids;Mediating;Membrane;Methodology;Modeling;Nuclear;Nutritional;Nutritional status;Omega-3 Fatty Acids;Omega-6 Fatty Acids;Oxidation-Reduction;Plants;Play;Poison;Polychlorinated Biphenyls;Preventive measure;Process;Proteins;Public Health;Regulation;Research;Risk;Risk Assessment;Risk Factors;Role;Severities;Signal Pathway;Signal Transduction;Small Interfering RNA;Structural Protein;Superfund;Technology;Testing;Time;Toxic effect;United States;Universities;Vascular Diseases;Vascular Endothelial Cell;Work;bioactive food component;caveolin 1;chemical stability;cost;design;disorder risk;exposed human population;genetic manipulation;global environment;heme oxygenase-1;in vivo;lipophilicity;mouse model;novel;nutrition;organic contaminant;pollutant;polyphenol;prevent;programs;protective effect;protein structure;remediation;response;stressor;superfund chemical;superfund site;toxicant;trafficking;vascular inflammation

public_health_relevance:
PROJECT NARRATIVE (Project 1 - Hennig Morris) This project explores connections between two major public health concerns: widespread contamination of the environment by a class of toxic chemical contaminants known as PCBs and vulnerability to one of the nation's leading health challenges vascular disease. The project also tests dietary interventions that may disrupt the disease processes initiated by exposure to PCBs and reduce the risk to people who reside near Superfund or other hazardous waste sites where PCBs are prevalent.


application_id: 9926423
project_number: 3P42ES007380-21S4
project_title: Training Core - Core E
administering_ic: NIEHS
award_notice_date: 2019-05-17
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S4
program_official: HENRY, HEATHER F
study_section: ZES1-LKB-K
subproject_number: 7480
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
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
project_abstract:
PROJECT SUMMARY (Training Core - Hennig Hilt) The University of Kentucky Superfund Research Center (UK-SRC) provides an integrated transdisciplinary research and training environment focused on a central research problem: the enduring presence of persistent chlorinated organics both at Superfund sites and elsewhere. These pollutants pose serious environmental health challenges and mandate the pursuit of protective measures for both reducing exposures and mitigating exposure-related health impacts. The Training Core aims to prepare future environmental leaders equipped to tackle such 21st century challenges by combining interdisciplinary research strategies real-world skills training active participation in research translation and community engagement and strong public health education. This training paradigm will prepare our scholars with the tools necessary not only to better understand pressing environmental problems but also to employ solution-oriented science to improve the health of our Superfund communities and beyond. Environmental problems affect all aspects of human life and therefore they cannot be effectively addressed from the perspective of individual disciplines. The study of environmental problems requires integration of knowledge and scientific methods from both biomedical and environmental science- based disciplines while also considering the social cultural and ethical dimensions. A training program has been established in a way that not only promotes strong disciplinary training but also encourages trainees to become interdisciplinary thinkers to develop scientific problem-solving skills to acquire knowledge of socio- economic aspects related to environmental issues and to be effective communicators. The Specific Aims are to: 1) build on past success to further develop an interdisciplinary training program that prepares a new generation of investigators with a solid scientific education as well as real-world knowledge needed to solve environmental problems 2) enhance career development by expanding trainee interactions with our College of Public Health and the Center for Clinical and Translational Science as well as with the Administrative Research Translation and Community Engagement Cores and 3) identify and recruit highly motivated graduate students and postdoctoral scholars foster interdisciplinary collaborations between biomedical and environmental science projects and provide skills training (e.g. grantsmanship responsible conduct of research) for success in academic research. Motivated individuals and students especially those from underrepresented groups will be recruited through various means including our web page and presentations at relevant institutions. The Training Core will be evaluated on a regular basis to assess its progress in meeting the goals of the program.

project_terms:
Address;Affect;Clinical Sciences;Communication;Communities;Complex;Detection;Dimensions;Discipline;Ecology;Education;Educational workshop;Environment;Environmental Health;Ethics;Fostering;Foundations;Future;Generations;Goals;Grant;Health;Human;Individual;Institution;Interdisciplinary Study;Internships;Intervention;Kentucky;Knowledge;Leadership;Life;Link;Measures;Medical Ethics;Mentors;Methods;Mission;Policies;Problem Solving;Public Health;Public Health Education;Research;Research Personnel;Research Training;Science;Scientific Advances and Accomplishments;Series;Signal Recognition Particle;Solid;Students;Superfund;Targeted Research;Toxic effect;Toxicology;Training;Training Activity;Training Programs;Translational Research;Underrepresented Groups;Universities;Writing;base;biomedical scientist;career;career development;college;graduate student;health knowledge;improved;interdisciplinary collaboration;knowledge integration;meetings;nutrition;outreach;pollutant;programs;recruit;remediation;responsible research conduct;skill acquisition;skills;skills training;social;socioeconomics;success;superfund chemical;superfund site;symposium;tool;web page

public_health_relevance:
PROJECT NARRATIVE (Training Core - Hennig Hilt) The UK-SRC focuses on better understanding the health effects of chlorinated organic pollutants and the pursuit of protective measures for both reducing exposures and mitigating exposure-related health impacts. The Training Core will be the focal point for coordinating the interdisciplinary training activities of the UK-SRC. This core program aims to prepare qualified individuals for careers that will have a significant impact on the environmental health agenda of our nation.


application_id: 9926422
project_number: 3P42ES007380-21S4
project_title: Community Engagement Core - Core D
administering_ic: NIEHS
award_notice_date: 2019-05-17
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S4
program_official: HENRY, HEATHER F
study_section: ZES1-LKB-K
subproject_number: 7479
contact_pi_person_id: 8535399
contact_pi: GAETKE, LISA 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
project_abstract:
PROJECT SUMMARY (Community Engagement Core - Gaetke Ormsbee) Responding to community needs UK-SRC's Community Engagement Core (CEC) has provided support and guidance through critical information on nutrition and environmental issues to meet the needs of individuals and communities affected by environmental pollutants. This purpose is underscored through the title of its activities Superfund Community Action through Nutrition (SCAN). During previous funding the CEC established a close collaboration with community groups in eastern and western Kentucky and SCAN activities endorsed by these two communities provided a new service resource for nutrition and scientific information. The aim of SCAN is to empower affected individuals and communities to take proactive steps toward their own health by drawing on the strength of the nutrition-related research from the UK-SRC. The specific aims of the CEC include: 1) establish trust with and assess the needs of affected individuals and communities with consideration of sensitive issues at the previously established site in Appalachia and a newly established third site in central Kentucky; 2) engage individuals communties health professionals trusted community leaders Kentucky Cooperative Extension agents Environmental Protection Agency and Agency for Toxic Substances and Disease Registry personnel and other partners to work together through bidirectional exchanges to guarantee effective communication and to build capacity in the affected communities to foster community participatory processes; 3) inform and translate the research information from UK-SRC researchers through community-requested activities developed by Registered Dietitians (RDs) and to evaluate outcome measures that demonstrate community sustainability and improved knowledge attitudes and health behaviors of the nutrition and environmental health focus; and 4) provide related community feedback outcomes and evaluations to UK-SRC's nutrition and environmental researchers in order to refine and develop safe evidenced-based nutrition and environmental health strategies that reduce the toxicity of PCB's and related compounds and improve public health. Exposure to Superfund chemicals has been shown to affect public health by contributing to an increased risk for chronic diseases especially in combination with poor diet. Through collaboration with the community and community partners the CEC's SCAN activities will empower affected individuals to make more informed decisions about their diet and health and will improve nutrition and environmental health knowledge and behaviors to serve all interested individuals families and communities and thereby enhance public health.

project_terms:
Affect;Appalachian Region;Area;Attitude;Chronic Disease;Collaborations;Communication;Communities;Community Actions;Community Services;County;Diet;Dietitian;Environmental Health;Environmental Pollutants;Evaluation;Exposure to;Family;Feedback;Food;Fostering;Funding;Hazardous Waste Sites;Health;Health Professional;Health Status;Health behavior;Human Resources;Individual;Kentucky;Knowledge;Life Style;Location;Methods;Nurses;Nutritional;Outcome;Outcome Measure;Outcomes Research;Physicians;Poison;Polychlorinated Biphenyls;Population;Prevalence;Process;Public Health;Recommendation;Research;Research Personnel;Resources;Risk;Services;Site;Superfund;Toxic effect;Translating;Trust;United States Environmental Protection Agency;Work;base;design;disease registry;evidence base;health knowledge;improved;interest;nutrition;programs;response;superfund chemical

public_health_relevance:
PROJECT NARRATIVE (Community Engagement Core - Gaetke Ormsbee) Exposure to Superfund chemicals contributes to an increased risk for chronic diseases especially in combination with poor diet. Kentucky has an increased prevalence of hazardous waste sites chronic diseases and poor lifestyle choices. In response to exposed Kentucky community requests nutrition may be one method to improve health status and behavior and advance public health.


application_id: 9926421
project_number: 3P42ES007380-21S4
project_title: Research Translation Core - Core C
administering_ic: NIEHS
award_notice_date: 2019-05-17
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S4
program_official: HENRY, HEATHER F
study_section: ZES1-LKB-K
subproject_number: 7478
contact_pi_person_id: 8535916
contact_pi: ORMSBEE, LINDELL E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY (Research Translation Core - Ormsbee Gaetke Hoover) To ensure optimal and effective translation of research outputs generated by the University of Kentucky Superfund Research Center (UK-SRC) the Research Translation Core (RTC) functions as the lead UK-SRC component responsible for external linkages and active communication with diverse relevant stakeholders. The UK-SRC addresses environmental health impacts of chlorinated organics focusing on polychlorinated biphenyls (PCBs) and trichloroethylene (TCE). The Center's five research projects are integrated around the study of specific PCBs and positive lifestyle modifications (e.g. nutrition) to tackle the four national Superfund Research Program (SRP) mandates. Specific aims explicitly address SRP program priorities. Thus the RTC will 1) work with UK-SRC projects and cores to develop an integrated program that translates program- and project-specific outcomes to appropriate stakeholders including NIEHS SRP staff and RTCs at other SRP centers nationally; translation mechanisms include electronic communication and participation in such SRP- wide activities as workshops seminars webinars and the annual meeting; 2) build on past successes to strengthen multidirectional agency partnerships including the U.S. Environmental Protection Agency's Region 4 and National Risk Management Research Laboratory Agency for Toxic Substances and Disease Registry U.S. Department of Energy via the Paducah Gaseous Diffusion Plant (PGDP) National Priorities List site the Kentucky Cabinet for Energy and the Environment and the Kentucky Cabinet for Health and Family Services; 3) develop targeted research translation projects that leverage existing university resources including the Center for Clinical and Translational Science the Cooperative Extension Service the Kentucky Water Resources Research Institute (an EPA-designated Center for Excellence for Watershed Management) the Kentucky Research Consortium for Energy and the Environment the Public Health Practice-Based Research Network Program and the Dissemination and Implementation Sciences Consortium. The RTC will also continue supporting UK-SRC project technology implementation at the PGDP; and 4) implement multidirectional strategies and best communication practices to disseminate program- and project-specific information to other end users. Communication channels include an interactive website a risk management workshop an expanded monthly seminar series and targeted print and online materials related to specific research projects and emerging findings. The RTC will partner with UK resources and with other SRP RTCs to ensure broad-based information dissemination to relevant stakeholders. With the UK-SRC Community Engagement Core the RTC will establish multidirectional relationships with two Superfund-impacted communities: 1) Dayhoit Kentucky in Appalachia home to a Kentucky NPL site and 2) Floyds Fork Watershed Community a six-county area in central Kentucky home to two NPL sites and near several others.

project_terms:
Address;Advisory Committees;Appalachian Region;Area;Cardiovascular system;Chemicals;Clinical Sciences;Collaborations;Communication;Communities;County;Decision Making;Department of Energy;Diffusion;Documentation;Educational workshop;Electronic Mail;Engineering;Ensure;Environment;Environment and Public Health;Environmental Health;Event;Exercise;Exposure to;Family;Fostering;Future;Goals;Health;Home environment;Housing;Human Resources;Information Dissemination;Infrastructure;Interdisciplinary Study;Kentucky;Laboratory Research;Lead;Leadership;Life Style Modification;Maintenance;Medicine;Mentors;Mentorship;National Institute of Environmental Health Sciences;Outcome;Outcomes Research;Output;Pharmacology;Physiological;Plants;Poison;Polychlorinated Biphenyls;Positioning Attribute;Process;Productivity;Program Development;Public Health;Public Health Practice;Public Policy;Reporting;Research;Research Activity;Research Infrastructure;Research Institute;Research Project Grants;Research Support;Resources;Risk;Risk Management;Role;Scientist;Series;Services;Site;Superfund;Targeted Research;Toxic effect;Toxicology;Training;Translating;Translational Research;Translations;Trichloroethylene;United States Environmental Protection Agency;Universities;University resources;Water;Work;base;community center;disease registry;experience;health science research;implementation science;innovation;meetings;nano;new technology;nutrition;pollutant;practice-based research network;program dissemination;programs;success;superfund chemical;technology validation;web site;webinar

public_health_relevance:
PROJECT NARRATIVE (Research Translation Core - Ormsbee Gaetke Hoover) The Research Translation Core (RTC) uses multidirectional strategies and best communication practices to translate University of Kentucky Superfund Research Center research outcomes into decision-making public policy new technologies practice innovations and ultimately improvements in public health.


application_id: 9926420
project_number: 3P42ES007380-21S4
project_title: Research Support Core - Core B
administering_ic: NIEHS
award_notice_date: 2019-05-17
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S4
program_official: HENRY, HEATHER F
study_section: ZES1-LKB-K
subproject_number: 7477
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
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
project_abstract:
PROJECT SUMMARY (Research Support Core - Morris Stromberg) The Research Support Core (RSC) of the University of Kentucky Superfund Research Center (UK-SRC) provides vital access to expertise research resources and state-of-the-art instrumentation to researchers engaged in all aspects of the component biomedical and environmental science research projects. The RSC enhances the productivity quality and consistency of these projects by providing a formalized mechanism for access to expert investigators and professional staff and by enabling efficient use of expensive and sophisticated instrumentation that would otherwise be beyond the capabilities of individual laboratories to acquire and support. To reflect the evolving needs of the participating investigators the RSC has been reorganized to combine activities in systems biology and bioinformatics/ biostatistics into a single "Quantitative Biology" component that provides biostatistics support for experimental design and computational infrastructure for data management analysis and sharing. Our analytical capabilities have been greatly expanded and now constitute a "Bioanalytical" component that provides technologies for quantitation and structural analysis of toxins nutritional protectants and markers and mediators of oxidative stress and inflammation. In addition to their importance to the biomedical component projects these analytical capabilities are critical for validation of polychlorinated biphenyl (PCB) sensor/capture technologies monitoring mechanisms of PCB detoxification and remediation and evaluating toxicities associated with these approaches that are being developed by the non-biomedical projects. The RSC offers an additional range of analytical services that are of specific value to the biomedical projects is engaged in UK-SRC driven discovery research to identify biomarkers of PCB exposure and nutritional and lifestyle-based interventions that protect from these toxins and participates the full repertoire of UK-SRC translational and training/educational functions.

project_terms:
Address;Advanced Development;Animal Model;Animals;Area;Basic Science;Bioinformatics;Biological Markers;Biology;Biometry;Calibration;Cardiovascular Diseases;Cell model;Cells;Center for Translational Science Activities;Clinical;Clinical Research;Cultured Cells;Data;Data Analyses;Data Base Management;Data Set;Detection;Development;Dose;Drug Metabolic Detoxication;Ecology;Ensure;Experimental Designs;Funding;Gene Expression Profiling;Generations;Health Hazards;Health Services Research;High Pressure Liquid Chromatography;Individual;Inflammation;Informatics;Infrastructure;Intervention;Investments;Kentucky;Laboratories;Life Style;Mass Fragmentography;Mass Spectrum Analysis;Mediator of activation protein;Metabolic;Metabolic Diseases;Methods;Monitor;Nutritional;Nutritional Study;Outcome;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Polychlorinated Biphenyls;Productivity;Proteomics;Public Health;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Services;Structure;Superfund;Suspensions;Systems Biology;Technology;Toxic effect;Toxin;Training;Universities;Validation;base;biomarker discovery;biomarker identification;computer infrastructure;data acquisition;data management;data sharing;design;diphenyl;experimental study;exposed human population;instrumentation;metabolomics;nutrition;programs;remediation;sensor;sensor technology;small molecule;superfund chemical;translational scientist

public_health_relevance:
PROJECT NARRATIVE Polychorinated biphenyls pose a significant public health hazard. Researchers studying the effects of these toxins on cells and animals and devising methods and strategies for nutritional protection from these toxic effects or to sense and degrade these toxins require access to state of the art instrumentation and expertise for experiment design data acquisition storage and analysis. The Research Support Core addresses this critical need of our Superfund Basic Research Program investigators.


application_id: 9926199
project_number: 5R56AG057191-02
project_title: Genomic Architecture of a Key Alzheimer's Disease Mimic: CARTS
administering_ic: NIA
award_notice_date: 2020-03-17
opportunity_number: PAR-15-356
application_type: 5
activity_code: R56
ic: AG
serial_number: 057191
program_official: PETANCESKA, SUZANA
project_start_date: 2019-05-15
project_end_date: 2022-08-31
study_section: Special Emphasis Panel[ZRG1-PSE-P(55)]
contact_pi_person_id: 9594976
contact_pi: FARDO, DAVID WILLIAM
other_pis: Not Applicable
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Brain diseases other than Alzheimers disease (AD) are common but understudied causes of dementia. Aparticularly prevalent subtype of non-Alzheimers dementia is termed hippocampal sclerosis dementia orcerebral age-related TDP-43 with sclerosis (CARTS). This neuropathology (NP) defined disease which is oftenmisdiagnosed clinically as AD affects ~20% of the elderly with substantial impact on cognition. The long-termgoal is to resolve the genomic factors that modulate CARTS severity and heterogeneity. To accomplish this wewill establish test and apply a robust pipeline to elucidate the mechanisms influenced by genetic risk factors forCARTS factoring in other non-AD brain pathologies. This requires a seasoned multidisciplinary team withexpertise in NP molecular biology neuroimaging large data analyses and in particular statistical genomics.The central hypothesis based on considerable preliminary data is that alleles modifying CARTS risk that werediscovered via candidate gene and genome-wide association studies (GWAS) are proxies for phenomena moredirectly involved in disease pathogenesis. To test this hypothesis the team will execute the following SpecificAims: 1. Develop and validate a classification framework to analyze the genetic drivers of CARTS. Theproposed effort to optimize classification of CARTS for genotyping will test and validate a revised set ofpathology-based criteria to differentiate CARTS AD-related TDP-43 pathology and brain arteriolosclerosis (B-ASC) to refine understanding of disease-defining border zones. Disease severity will be operationalized for useas a quantitative trait and rubrics for disease subtypes will be developed for correlation with genomic studies.2. Construct a robust and harmonized omics database and localize genetic regions influencing CARTS.Genetics data augmented with rich NP endophenotypes will enable discovery and refinement of novel insightsregarding the mechanisms driving CARTS dementia. Large-scale datasets (NACC ADGC ADNI ADSP AMP-AD) will be aggregated and harmonized to test the genetic drivers of clinical and NP-based CARTSendophenotypes prioritizing subtype-specific candidate genetic regions.3. Develop a systems biology analytic pipeline that extends beyond DNA variation to establish and testcandidate functional molecular outcomes of specific gene variants/regions that are associated withCARTS pathology. Most GWAS findings are not causal but rather proxies for true underlying genetic influencesof disease manifested through mechanisms that include (a) expression quantitative trait loci (eQTL) (b)differential isoform splicing QTL (sQTL) (c) brain imaging QTL (iQTL) and (d) protein QTL (pQTL). These willbe detected with recently developed statistical methodologies. Successful completion of the aims will producemechanistic insights into CARTS potentially leading to new therapeutics. The proposed studies are distinct fromprior efforts exploiting next-generation sequencing focusing on a common yet recently characterized braindisease (CARTS). We will deposit results online via NIAGADS for use by the research community.

project_terms:
Affect;Aging;Alleles;Alzheimer's Disease;American;Architecture;Automobile Driving;Autopsy;Biological;Brain Diseases;Brain Pathology;Brain imaging;Brain region;Candidate Disease Gene;Cerebrum;Classification;Clinical;Cognition;Communities;Complex;DNA;Data;Data Analyses;Data Storage and Retrieval;Databases;Dementia;Deposition;Diagnosis;Diagnostic;Disease;Disease Progression;Elderly;Future;Genetic;Genetic Risk;Genetic Variation;Genetic study;Genomics;Genotype;Goals;Impaired cognition;Individual;Knowledge;Life;Measures;Methodology;Molecular;Molecular Biology;Molecular Genetics;National Institute on Aging;Nature;Neurocognitive;Outcome;Pathogenesis;Pathologic;Pathology;Phenotype;Play;Process;Protein Isoforms;Proxy;Public Health;Quantitative Trait Loci;RNA Splicing;Research;Research Personnel;Research Project Grants;Risk Factors;Role;Sclerosis;Seasons;Severity of illness;Site;Systems Biology;Terminology;Testing;Time;Variant;age related;aging brain;analysis pipeline;base;brain arteriolosclerosis;clinically relevant;cognitive testing;comorbidity;delta protein;disease diagnosis;disease heterogeneity;disease phenotype;disorder risk;disorder subtype;endophenotype;evidence base;experimental study;genetic risk factor;genetic variant;genome wide association study;genome-wide analysis;hippocampal sclerosis;insight;large scale data;member;multidisciplinary;neuroimaging;neuropathology;next generation sequencing;nonalzheimer dementia;novel;novel therapeutics;precision medicine;prevent;protective allele;protective factors;protein TDP-43;risk variant;targeted treatment;trait;transcriptomics;web site

public_health_relevance:
PROJECT NARRATIVEUnderstanding better the biological mechanisms that underlie complex diseases of brain aging can aid in theability to diagnose disease early track disease progression and identify drug targets for treatment. Thegenetic knowledge to be garnered from this proposal is critical to discover and refine risk factors and theassociated biological mechanisms of diseases of brain aging.


application_id: 9925835
project_number: 5R01AI127970-04
project_title: Mechanisms of successful vaccine adjuvants
administering_ic: NIAID
award_notice_date: 2020-06-01
opportunity_number: PAS-15-055
application_type: 5
activity_code: R01
ic: AI
serial_number: 127970
program_official: JOFFE, AARON MICHAEL
project_start_date: 2017-06-26
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZRG1-IMM-U(90)S]
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
arra_indicator: N
project_abstract:
Project SummaryAdjuvant options for subunit vaccine design are extremely limited. Apart from alum just two adjuvants areapproved for use in the US: squalene and the combination adjuvant system AS04 which combinestraditional alum with a partial agonist of TLR4 monophosphoryl lipid A (MPL). MPL adjuvant is notablebecause it is the first and only purified TLR agonist in a licensed vaccine in the US was tested extensivelyfor safety and efficacy in large clinical trials and shows promise as an adjuvant in ambitious vaccineprojects such as the RTSS/AS01 vaccine to prevent malaria. Alum+MPLA is currently the best example wehave of a clinically successful adjuvant but the factors that make it successful are poorly understood.Moreover MPL is a heterogeneous mixture of lipid A structures in which a hexa-acylated structure isthought to be the active component but the functions of other components have never been tested inhuman immune cells. Preliminary studies support the hypothesis that MPL adjuvant contains animmunomodulatory inhibitor of human TLR4 that constrains endotoxic responses with less impact onadaptive priming. This project will identify the inhibitor determine if and how it has differential effects onMyD88- vs TRIF-signaling and evaluate synthetic analogues of MPL with amplified properties as adjuvants.

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;T cell response;TLR4 gene;Testing;Therapeutic;Tissues;Tonsil;Toxic effect;Transgenic Organisms;Vaccinated;Vaccine Adjuvant;Vaccine Design;Vaccines;Work;aluminum sulfate;analog;clinical development;cytokine;human pathogen;immunoregulation;improved;inhibitor/antagonist;mimetics;neutrophil;next generation;novel;novel vaccines;peripheral blood;preclinical study;predictive modeling;prevent;prophylactic;research study;response;success;vaccine safety

public_health_relevance:
Project NarrativeProphylactic immunization has been exceptionally successful at improving public health. However thereare still no vaccines available for many infectious diseases and it is thought that more powerful ways tostimulate the immune system will be needed in order for them to be successful. Adjuvants are additives forvaccines designed to stimulate the immune response better than before without causing harm to thepersons being vaccinated; the goal of this project is to build on the success of an existing combinationadjuvant by learning how it works and applying those lessons for development of new vaccine adjuvants.


application_id: 9925649
project_number: 5R25ES027684-04
project_title: Summer Research in Environmental Health Sciences
administering_ic: NIEHS
award_notice_date: 2020-06-01
opportunity_number: PAR-15-184
application_type: 5
activity_code: R25
ic: ES
serial_number: 027684
program_official: HUMBLE, MICHAEL C
project_start_date: 2017-05-01
project_end_date: 2023-04-30
study_section: ZES1-LKB-J(R)1
contact_pi_person_id: 1883439
contact_pi: SWANSON, HOLLIE ISABEL
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:
AbstractThe overall goal of this proposal is to develop and implement a 10-week summer program(Summer Undergraduate Research in Environmental Health Sciences (SURES) that willimmerse upper-level undergraduates in environmental health science research. The program isdesigned to introduce students to the highly interdisciplinary and collaborative nature ofenvironmental health science research that is focused on solving key global health problems.An additional focus is preparing underprivileged and under-represented students for successfulcareers in relevant fields. The SURES program will leverage the substantial and ongoingefforts at the University of Kentucky driven to enhance the undergraduate experience with therobust environmental health science research programs of involved faculty mentors. Studentswill be recruited from the Commonwealth of Kentucky with an emphasis on those from theAppalachian region. The SURES program will commence with a week-long session thatintroduces students to research laboratory safety and scientific ethics. The students will thenexperience hands-on research by performing experiments in the laboratories of their chosenmentors. Professional development and a sense of belonging to the environmental healthsciences community will be built via student participation in weekly breakfasts lunches net-working opportunities tours of research facilities and social activities including movie nightswhere films depicting environmental issues will be viewed and discussed. The SURES programwill culminate in a poster session attended by the faculty staff and students of the participatingdepartments. Dissemination of the approaches used in this program and their outcomes willbuild upon the expansion of the traditional environmental health sciences research training fromthe graduate and post-doctoral level to the undergraduates at a national level.

project_terms:
Address;Affect;Appalachian Region;Area;Communities;Critical Thinking;Development;Ecology;Economics;Educational workshop;Elevator;Engineering;Environment;Environmental Health;Ethics;Evaluation;Faculty;Film;Future;Goals;Individual;Interview;Kentucky;Laboratories;Life;Measures;Mentors;Mission;National Institute of Environmental Health Sciences;Nature;Oral;Outcome;Play;Population Heterogeneity;Postdoctoral Fellow;Professional Competence;Reporting;Research;Research Project Grants;Research Training;Role;Safety;Science;Scientist;Speech;Students;Surveys;Technology;Training;Training Programs;Underrepresented Students;United States;Universities;Work;career;college;design;experience;experimental study;faculty mentor;global health;hands on research;health science research;improved;interest;member;movie;multidisciplinary;outreach;peer;posters;programs;recruit;research facility;retention rate;skills;social;stem;student mentoring;student participation;success;summer program;summer research;supportive environment;undergraduate education;undergraduate research;undergraduate student

public_health_relevance:
NarrativeThe overall objective of the Summer Undergraduate Research Experience in EnvironmentalHealth Sciences (SURES) program is to develop a research-intensive program that willintroduce students from the impoverished region of Appalachia to the multidisciplinary nature ofenvironmental sciences and opportunities for pursuing relevant careers. The program willprovide exceptional training in a wide variety of research areas working with interdisciplinarycollaborative research groups who are housed in multiple departments and colleges. Inaddition students will be engaged in seminars outreach opportunities and workshops toprepare them for successful environmental health related careers.


application_id: 9925199
project_number: 5R01AG054459-04
project_title: Multi-Modal MRI to Assess Alzheimer's Disease Prevention in an APOE4 Mouse Model
administering_ic: NIA
award_notice_date: 2020-06-03
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 054459
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
arra_indicator: N
project_abstract:
Project SummaryApolipoprotein 4 (APOE4) allele is the strongest genetic risk factor for Alzheimers disease (AD).Neuroimaging studies in humans have shown that cognitively normal APOE4 carriers develop vascularmetabolic and structural deficits decades before the aggregation of beta-amyloid (A) and neurofibrillary tautangles. Interventions that can restore these deficits to normal would be critical to potentially prevent thedevelopment of AD related neuropathology and cognitive impairment. The rationale of the study is to use thestate-of-the-art in vivo MRI methods to identify a potential intervention Rapamcyin for AD prevention in amouse model that overexpresses human A via 5 familial-AD mutations and expresses human APOE4(E4FAD). The central hypothesis is that multi-modal MRI can be used as surrogate markers to assess efficacyof Rapamycin for restoring brain vascular metabolic and structural functions in mice that carry APOE4 genes.We will also validate our MRI results by comparison with biochemical assays and finally compare withbehavioral outcomes. The hypothesis will be tested by pursuing three specific aims: 1) Test the hypothesis thatRapamycin restores neurovascular functions; 2) Test the hypothesis that Rapamycin protects neurometabolicfunctions; and 3) Test the hypothesis that Rapamycin preserves structural and cognitive functions. The projectis innovative because it employs cutting-edge multi-disciplinary novel technology to focus on earlyinterventions that may become an effective way to prevent AD-induced dementia for APOE4 carriers. Theproject is significant because with validation these multimodal MRI methods will dramatically enhance futureresearch for identifying potential therapeutics using animal models in the fields related to AD and other age-related neurodegenerative disorders. We can also translate our approach to future human studies because allthe MRI methods used in the proposal are readily able to be used in humans. Because Rapamycin is FDA-approved the findings from the study will also provide valuable information and may pave a way for futureRapamycin clinical trials to prevent dementia for pre-symptomatic APOE4 carriers.!

project_terms:
Aftercare;Alleles;Alzheimer disease prevention;Alzheimer like pathology;Alzheimer's Disease;Alzheimer's disease risk;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;Molecular;Mus;Mutation;Myelin;Neurons;Oligodendroglia;Pharmacology;Public Health;Radial;Reporting;Research;Sirolimus;Structure;Surrogate Markers;Synapses;Technology;Testing;Therapeutic Uses;Transgenic Mice;Translating;Treatment Efficacy;Validation;abeta accumulation;age related neurodegeneration;arm;base;behavior test;behavioral outcome;brain tissue;cerebrovascular;cognitive function;cohort;density;familial Alzheimer disease;flexibility;genetic risk factor;glucose metabolism;gray matter;human model;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;preservation;prevent;tau aggregation;time use;tool;water maze;white matter

public_health_relevance:
NarrativeThe proposed research is relevant to public health because we will use multi-modal MRI as surrogate markersto assess efficacy of Rapamycin for restoring brain vascular metabolic and structural functions in mice thatcarry APOE4 genes the strongest genetic risk factor for Alzheimer's disease (AD). Because MRI methods arereadily able to be used in humans and Rapamycin is FDA-approved the findings from the study will providevaluable information and may pave a way for future Rapamycin clinical trials to prevent AD for pre-symptomatic APOE4 carriers.


application_id: 9924640
project_number: 5R01HL130174-05
project_title: Metabolic optimization of cell therapy
administering_ic: NHLBI
award_notice_date: 2020-05-21
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 130174
program_official: SCHWARTZ, LISA
project_start_date: 2016-06-01
project_end_date: 2022-05-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTType 2 diabetes is an independent risk factor for the development of heart failure. It contributes to adversecardiac remodeling and it increases heart failure mortality. While cell therapy offers promise for treating heartfailure in nondiabetic patients the efficacy of cell therapy in diabetic hearts remains uncertain. Our preliminarystudies show that diabetes impairs cardiac progenitor cell (CPC) growth survival and differentiation and thatCPCs isolated from diabetic hearts fail to promote myocardial recovery after myocardial infarction (MI). We findthat CPCs express Glut1 and that their rate of glucose utilization increases in the presence of high extracellularglucose independently of insulin. Moreover CPCs isolated from diabetic mice exhibit a marked and sustainedincrease in aerobic glycolysis accompanied by an elevated level of 6-phophofructo-2-kinase/fructose-26-bisphosphatase 3a phosphofructokinase 2 isoform known to sustain high rates of glycolysis. Our studiesalso show that increased glycolytic activity in diabetic CPCs is associated with lower glucose-derived carbonflux through the pentose phosphate and hexosamine biosynthetic pathways but higher flux through theglycerolipid biosynthetic pathway. These results indicate that high rates of glycolysis in CPCs alter the activityof ancillary pathways of glucose metabolism which are important for biosynthetic reactions maintaining redoxbalance and for resistance to stress. That such changes in glucose metabolism affect CPC function isindicated by our observation that increasing glycolysis at the PFK step is sufficient to decrease CPCproliferation in vitro. Informed by these observations we suspect that diabetic dysfunction in CPCs is at leastin part caused by a dysregulation of glucose metabolism and that correcting this metabolic defect will be aviable approach to optimize cell therapy for the diabetic heart. We propose to test the hypothesis that diabetesleads to an increase in the glycolytic activity in CPCs which diminishes flux through key ancillary pathways ofglucose metabolism. This metabolic dysregulation decreases CPC proliferation survival and secretory activityand impairs the capacity of CPCs to promote myocardial repair. To test this hypothesis we will: (1) examinehow diabetes affects CPC competence and therapy; (2) elucidate the role of glucose metabolism in mediatingCPC dysfunction in diabetes; and (3) determine whether rescuing defects in glucose metabolism improves celltherapy in the diabetic heart. Successful completion of the project will provide new understanding of themetabolic pathways that regulate stem/progenitor cell function and how they affect the outcomes of celltherapy for heart failure. These findings would facilitate the optimization of cell therapy protocols and informongoing and future cell therapy trials for the treatment of heart failure in both nondiabetic and diabetic patients.

project_terms:
6-Phosphofructo-2-kinase;Affect;Attenuated;Biochemical;Carbon;Cardiac;Cause of Death;Cell Survival;Cell Therapy;Cell Transplantation;Cell physiology;Cells;Cicatrix;Clinical Treatment;Competence;Defect;Development;Diabetes Mellitus;Diabetic mouse;Enzymes;Equilibrium;Exhibits;Fatty acid glycerol esters;Fibrosis;Fructose-26-bisphosphatase;Functional disorder;Future;Glucose;Glycolysis;Heart;Heart failure;Hexosamines;Impairment;In Vitro;Inflammation;Insulin;Intervention;Measurement;Mediating;Metabolic;Metabolic Pathway;Modeling;Mus;Myocardial;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Oxidation-Reduction;Pathway interactions;Patients;Pentosephosphate Pathway;Pentosephosphates;Pharmacology;Phosphoric Monoester Hydrolases;Phosphotransferases;Property;Protein Isoforms;Protocols documentation;Radiolabeled;Reaction;Recovery;Resistance;Risk Factors;Role;Stem cell transplant;Stress;Testing;Tissues;Tracer;Transplantation;aerobic glycolysis;cardiogenesis;cell growth;cellular transduction;db/db mouse;diabetic;diabetic patient;extracellular;glucose metabolism;heart function;impaired capacity;improved;inhibitor/antagonist;metabolomics;mortality;non-diabetic;novel therapeutic intervention;repaired;stable isotope;stem;stem cell proliferation;stem cells;tissue injury

public_health_relevance:
PROJECT NARRATIVEHeart failure is a leading cause of death and is prominent in patients with diabetes. In this project we willexamine the mechanisms by which diabetes impairs cell therapy and how cell therapy can be improved toameliorate heart failure. These studies could lay the groundwork for the development of novel therapeuticinterventions to improve cardiac function in both nondiabetic and diabetic patients with heart failure.


application_id: 9924439
project_number: 5R01AI129959-04
project_title: Enhanced diagnostic assessment in lupus using differential scanning calorimetry
administering_ic: NIAID
award_notice_date: 2020-03-30
opportunity_number: PAR-16-242
application_type: 5
activity_code: R01
ic: AI
serial_number: 129959
program_official: RICE, JEFFREY S
project_start_date: 2017-05-05
project_end_date: 2022-04-30
study_section: Bioengineering, Technology and Surgical Sciences Study Section[BTSS]
contact_pi_person_id: 11129807
contact_pi: GARBETT, NICHOLA C.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYSystemic lupus erythematosus (SLE) is a prototypic autoimmune disease which is particularly difficult todiagnose because of highly diverse clinical manifestations. Current diagnosis is based on clinical historyphysical exam and laboratory studies including serological markers. Despite much effort the development ofimproved diagnostic approaches is still in its infancy and has yet to have a clinical impact. Therefore there is asubstantial unmet clinical need for an investment in improving the diagnostic arsenal particularly approachesthat would lead to enhanced diagnostic accuracy of SLE differentiation of SLE from other autoimmune classesand would provide information concerning disease activity and pathobiology for development of targeted andpersonalized therapies. We have recently demonstrated the use of differential scanning calorimetry (DSC) as anew diagnostic approach for the analysis of blood plasma samples for the characterization of human diseases.Our data has shown that changes in thermodynamic properties of the high abundance plasma proteomedetected by DSC correlate with disease status and therapeutic response in a number of disease settingsincluding cervical cancer lung cancer melanoma amyotrophic lateral sclerosis type 1 diabetes Lyme diseaseand SLE. We have collected preliminary data on SLE patient samples that have revealed significantdifferences in thermograms between SLE patients and controls. Comparison of results using DSC profiles (orthermograms) to standard clinical antibody tests revealed significant improvements in sensitivity and overallaccuracy with the inclusion of thermogram data. The long term goal of this proposal is to address a criticalbarrier to early diagnosis thus facilitating effective treatment of SLE patients by developing thermograms as adiagnostic technology. To this end we will determine the sensitivity of thermograms to multiple SLE clinicaland serological factors disease severity and activity as well as determine the ability of thermograms todistinguish SLE from other autoimmune and related comorbidities. In addition we will determine thecorrelation of thermograms to changes in disease activity organ involvement and therapeutic interventionduring the longitudinal assessment of SLE patients. Finally we will apply mass spectrometry approaches tointerrogate the proteome of SLE patient plasma samples to dissect the biochemical mechanisms by whichthermogram modulation occurs in SLE to reveal new biologic information for diagnostic application in SLE.The data gained from this proposal will determine the utility of thermograms for enhanced diagnosticassessment and monitoring of SLE patients and additionally could identify new biomarkers associated withSLE pathobiology which could improve our understanding of the disease process and lead to the developmentof more specific diagnostic tests.

project_terms:
Address;Affect;Albumins;Amyotrophic Lateral Sclerosis;Antibodies;Attention;Autoantibodies;Autoimmune Diseases;Autoimmune Process;Biochemical;Biological;Biological Markers;Characteristics;Classification;Clinical;Clinical Trials;Cross-Sectional Studies;Data;Degenerative polyarthritis;Development;Diagnosis;Diagnostic;Diagnostic Procedure;Diagnostic tests;Differential Scanning Calorimetry;Disease;Disease remission;Early Diagnosis;Emerging Technologies;Goals;Immunologics;Insulin-Dependent Diabetes Mellitus;Investments;Laboratories;Laboratory Study;Lead;Liquid substance;Lupus;Lyme Disease;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Mass Spectrum Analysis;Medical Technology;Molecular;Monitor;Organ;Pathology;Patient Monitoring;Patients;Performance;Plasma;Post-Translational Protein Processing;Process;Property;Protein Denaturation;Proteome;Recording of previous events;Rheumatoid Arthritis;Sampling;Sensitivity and Specificity;Serologic tests;Serological;Severity of illness;Source;Structure;Systemic Lupus Erythematosus;Technology;Testing;Therapeutic Intervention;Thermodynamics;Urine;base;comorbidity;diagnostic accuracy;diagnostic assay;diagnostic biomarker;effective therapy;human disease;improved;infancy;melanoma;novel diagnostics;novel marker;outcome forecast;personalized medicine;serological marker;targeted treatment;therapy development;tool;treatment response

public_health_relevance:
NARRATIVEThere is a critical need for improved diagnostic approaches to enhance diagnosis and management of SLE.Differential scanning calorimetry (DSC) is an emerging technology for medical diagnostics utilizing differencesin the thermodynamic properties of high abundance disease proteomes for the characterization of clinicalstatus. This proposal determines the utility of DSC profiles for diagnostic assessment and longitudinalmonitoring of SLE and characterizes the biochemical basis associated with DSC differences in SLE whichcould lead to the identification of new biomarkers in the SLE disease proteome.


application_id: 9924408
project_number: 5U01DP006199-05
project_title: Kentucky Pregnancy Risk Assessment Monitoring System (PRAMS) program
administering_ic: NCCDPHP
award_notice_date: 2020-03-21
opportunity_number: RFA-DP-16-001
application_type: 5
activity_code: U01
ic: DP
serial_number: 006199
project_start_date: 2016-05-01
project_end_date: 2021-04-30
study_section: ZDP1-KVA(A1)
contact_pi_person_id: 10799084
contact_pi: JEWELL, TRACEY DANIELLE
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-05-01
project_abstract:
PRAMS Project SummaryThe Kentucky Department for Public Health is seeking CDC grant funding to developimplement and maintain the Pregnancy Risk Assessment Monitoring System (PRAMS)program. The establishment of this surveillance system will provide Kentucky access to highquality data of selected maternal attitudes behaviors and experiences prior to during andshortly after pregnancy. The data collected will fill gaps in existing maternal and child healthdata and will be used for the purposes of planning enhancing and evaluating maternal andchild health programs. Data from PRAMS will also assist in monitoring Kentucky's progress inreaching national and state performance measures for Title V and progress towards programgoals for maternal and infant health as well as Healthy People 2020.The Healthy People 2020 goals and objectives encompass a variety of health outcomesbehaviors and health systems indicators that impact the health and well-being of women infantsand children. PRAMS data may be utilized in Kentucky to monitor progress towards meetingthese national goals. In particular PRAMS provides data on social determinants of maternalhealth such as pre-pregnancy health behaviors and health status which may be influenced byfactors such as access to services and stress. Social determinants of infant health includingracial disparities income levels education and health insurance coverage are also included inthe PRAMS survey. These data are critical to implement a life course perspective focused onimproving maternal and infant health outcomes. In addition data from PRAMS will provide therequired information to monitor progress towards national and state performance measures forthe Title V block grant.PRAMS data will also enhance the ability of Kentucky to evaluate existing MCH programs anddevelop new strategies. PRAMS data may be helpful in determining whether programs areadequately reaching the targeted population. For example the PRAMS survey providesinformation on the number of women who need resources regarding smoking cessation servicesand the number of women who actually received those services. Additionally PRAMS mayprovide information on changes in the health outcome of interest for a specificprogram/intervention.

public_health_relevance:
PRAMS Project NarrativeThe purpose and main objectives of this grant is to allow Kentucky to develop implement andmaintain the PRAMS surveillance system which will allow the Cabinet access to high qualitymaternal and infant data through the implementation of a state-specific population-based surveyon selected maternal attitudes behaviors and experiences that occur prior to during and shortlyafter pregnancy. Data from PRAMS will be analyzed based on a written analysis plan designedto inform programmatic activities and public health practice that can guide programdevelopment and evaluation in collaboration with a state-level steering committee and will alsobe utilized for monitoring progress toward state-specific priority needs and outcomes.


application_id: 9923667
project_number: 5P30ES026529-04
project_title: Community Outreach and Engagement Core
administering_ic: NIEHS
award_notice_date: 2020-03-30
opportunity_number: RFA-ES-16-001
application_type: 5
activity_code: P30
ic: ES
serial_number: 026529
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 7094
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN J
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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
PROJECT SUMMARY  Community Outreach and Engagement CoreThe aims of the UK Center for Appalachian Research in Environmental Sciences (UK-CARES) CommunityOutreach and Engagement Core (COEC) are to: 1) Increase awareness and knowledge among communitypartners about the environmental health research being conducted at the Center across the entire spectrumfrom basic science to community and population health research; 2) Increase community and stakeholderparticipation in community-engaged research to identify and communicate environmental concerns to UK-CARES investigators; and 3) Increase enrollment in citizen and academic training in science communication toleverage community-academic environmental health science partnerships. In Aim 1 we use multi-modaloutreach strategies (e.g. community events media advocacy social media written materials/website) thatengage community partners in developing dissemination plans and culturally appropriate outreach andmessaging approaches. Aim 2 uses multi-directional channels through which researchers can listen to theneeds and concerns of local residents and community stakeholder organizations. Strategies includeconducting focus groups with community health coalitions environmental activists work groups ad hoccommunity groups and healthcare entities. In Aim 3 we adapt evaluate and integrate sciencecommunication workshops into our career development activities and ensure effective science communicationwith community stakeholders and recognize excellence in community engagement. UK-CARES COEC isuniquely positioned to lead this effort due to our longstanding community-engaged research partnerships withcitizens and community stakeholder organizations in three contiguous Area Development Districts located insoutheastern Kentucky: Big Sandy Kentucky River and Cumberland Valley. Community members identify airand water quality impacts due to mining and fracking as critical concerns. We partner with five majorcommunity stakeholder organizations (Appalachian Citizens Law Center Appalachian Voices Area HealthEducation Centers Center for Rural Strategies and Headwaters Inc.) and five community residents to advisethe COEC. The COEC values the complex heterogeneous nature of the communities of AppalachianKentucky and their rich heritage self-reliance and pride of place. The COEC is tightly integrated into theorganizational structure of UK-CARES with direct impact on community-informed Center decision making. Thelong-term goal is to create a strong sustained community-academic partnership to support meaningfulcommunity engagement and environmental health literacy leveraging these community perspectives tofacilitate new understandings of environmental factors in disease initiation progression outcomes andcommunity impacts.

project_terms:
Academic Training;Acute;Address;Advocacy;Air;Appalachian Region;Area;Area Health Education Centers;Awareness;Basic Science;Cardiovascular Diseases;Chemicals;Child Health;Chronic Obstructive Airway Disease;Colorectal Cancer;Communication;Communities;Community Health;Community Outreach;Complex;Decision Making;Development;Diabetes Mellitus;Disease;Ecology;Educational Background;Educational workshop;Employment;Enrollment;Ensure;Environmental Exposure;Environmental Health;Environmental Risk Factor;Event;Exposure to;Focus Groups;Goals;Healthcare;Heavy Metals;Interest Group;Kentucky;Knowledge;Laws;Lead;Link;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic Diseases;Mining;Mission;Modeling;Nature;Obesity;Outcome;Particulate;Plague;Positioning Attribute;Poverty;Pulmonary Heart Disease;Radon;Recording of previous events;Research;Research Personnel;Resources;Rivers;Rural;Science;Trust;Voice;Work;career development;community involvement;dissemination research;early life exposure;health literacy;malignant breast neoplasm;member;multimodality;operation;organizational structure;outreach;population health;programs;self reliance;social media;success;water quality;web site;working group


application_id: 9923663
project_number: 5P30ES026529-04
project_title: Analytical Services Core
administering_ic: NIEHS
award_notice_date: 2020-03-30
opportunity_number: RFA-ES-16-001
application_type: 5
activity_code: P30
ic: ES
serial_number: 026529
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 7093
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
PROJECT SUMMARY- ANALYTICAL COREThe overarching goal of the Analytical Core is to improve the capacity quality efficiency and cost-effectiveness of environmental disease research at the University of Kentucky (UK). This will be achieved byproviding UK-Center for Appalachian Research in Environmental Science (UK-CARES) researchers withpremium access to expert advice consultation and technical support to develop and validate analyticalmethods using state-of-the-art technologies for studies spanning the range of environmental disease researchareas represented in the center. These services are needed to detect and measure environmental pollutantsand biomarkers of environmental exposures which requires sophisticated instrumentation and technicalexpertise that is unavailable to individual investigators. Our partner facility cores the Small Molecule MassSpectrometry Core laboratory (SMMSC) and Resource Center for Stable Isotope Resolved Metabolomics (RC-SIRM) can provide the entire range of analytical capabilities required for state-of-the-art environmentaldisease research. However effective use of these facilities by environmental disease researchers oftenrequires new method development validation and pilot studies to establish analyte levels and technicalreproducibility. The properties of the target analytes and the need to measure them at low levels inenvironmental and biological samples frequently present unique challenges for sample preparation. Withvalidated analytical methods in hand data analysis can be challenging particularly since biological and healthoutcomes are dictated by exposures to multiple agents often requiring precise accurate and simultaneousmeasurements of multiple analytes or biomarkers of environmental exposures and informatics approaches toenable integrated analysis of large data sets. The Analytical Core addresses these limitations by providingconsultation in the design execution and interpretation of studies that require use of advanced analyticalinstrumentation for environmental disease research. The core staff will then develop and validate samplepreparation and analytical methods for detection and quantitation of environmental pollutants and biomarkersin complex samples and provide consultation and assistance with statistical methods for the analysis ofdatasets generated using these analytical methods. Finally the Analytical Core will provide education andtraining in analytical and data analysis methods for environmental disease research through personal outreachcourses and workshops enabling integration of analytical and metabolomics technologies into the research ofUK-CARES members. Overall the Analytical Core will add considerable value to environmental diseaseresearch at UK by leveraging existing institutional and NIH investments in research infrastructure to achievethe goals of our UK-CARES research team.

project_terms:
Address;Analytical Chemistry;Appalachian Region;Area;Award;Big Data;Biological;Biological Assay;Biological Markers;Biometry;Complex;Consultations;Core Facility;Coupled;Data;Data Analyses;Data Analytics;Data Set;Detection;Diet;Disease;Ecology;Educational workshop;Ensure;Environmental Exposure;Environmental Pollutants;Evaluation;Exposure to;Feasibility Studies;Flame Retardants;Funding;Goals;Grant;Hand;Health;Individual;Informatics;Investments;Ions;Kentucky;Laboratories;Life Style;Mass Spectrum Analysis;Measurement;Measures;Metal exposure;Methods;Monitor;Outcome;Pesticides;Pharmacologic Substance;Pilot Projects;Plastics;Polychlorinated Biphenyls;Polymers;Preparation;Property;Quality Control;Reproducibility;Research;Research Design;Research Infrastructure;Research Personnel;Resources;Sampling;Schedule;Services;Smoking;Statistical Data Interpretation;Statistical Methods;Technical Expertise;Technology;Training;Training and Education;United States National Institutes of Health;Universities;Use Effectiveness;advanced analytics;analytical method;cost effectiveness;data archive;design;disorder risk;experience;improved;in vitro Model;instrument;instrumentation;large datasets;member;metabolomics;method development;outreach;pollutant;programs;quality assurance;small molecule;stable isotope;statistics;validation studies


application_id: 9923662
project_number: 5P30ES026529-04
project_title: Integrative Health Sciences Facility Core
administering_ic: NIEHS
award_notice_date: 2020-03-30
opportunity_number: RFA-ES-16-001
application_type: 5
activity_code: P30
ic: ES
serial_number: 026529
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 7092
contact_pi_person_id: 6457660
contact_pi: BAUER, JOHN ANTHONY
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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
PROJECT SUMMARY  Integrative Health Sciences Facility CoreThe University of Kentucky Center for Appalachian Research in Environmental Sciences (UK-CARES) isdesigned to facilitate discovery and new understandings of environmental factors in disease initiationprogression and outcomes as well as their community impacts and to advance the careers of scientists whoare interested in tackling challenging environmental health questions. A critical element to this endeavor isdevelopment of a well-equipped Integrative Health Sciences Facility Core (IHSFC) to facilitate and enable thedevelopment and conduct of translational studies based on the current environmental health research baseand on emerging new scientific directions as well. The Center draws its theme in part from the challengesendemic to the disadvantaged rural population in southeastern Kentucky and the documented healthdisparities in this area of Appalachian Kentucky that have been linked to environmental factors. The proposedIHSFC serves as the primary institutional access point to specifically facilitate environmentally relatedtranslational and clinical studies providing the critical central infrastructure to enable transformation andexpansion of a portfolio of projects focused on environmental health. The IHSFC offers investigators guidanceassistance and operational support for multi-directional translational and clinical research development. Todeliver this support effectively the Core will also function as a model for integration of other UK-CARES coreresources and of cooperating UK campus centers to meet the needs of Center investigators. Further theIHSFC will leverage resources relevant to our target communities. Thus this core provides critical linkages toother UK-CARES cores and has collaborative connections to relevant cooperating UK centers and theirfacilities: UKs Center for Clinical and Translational Science NCI-designated Markey Cancer Center KentuckyChildrens Hospital and the UK Center of Excellence in Rural Health which is located in the Kentucky RiverDistrict to best serve the needs of the focus communities. Participation by these four entities will facilitatepriority access by UK-CARES members to such services as study design regulatory support datamanagement and clinical informatics subject recruitment and retention specimen management and cell andanimal systems support. The central goal of the IHSFC is to enable progressive translational clinical andpopulation-based research projects that address environmental health concerns in our region. We will achievethis goal via these specific aims: 1) provide support for collaborative and team-driven efforts among basicscientists clinical researchers community engagement experts and public health researchers; 2) provide andmanage resources to facilitate the progression of environmental health sciences from basic mechanistic andtoxicological research to translational programs that improve public health and clinical practice in our affectedcommunities; 3) facilitate reverse-translational research activities by addressing community concerns orcommunity-level study findings and developing programs to stimulate preclinical research activities.

project_terms:
Address;Affect;Air;Analytical Chemistry;Animal Model;Animals;Appalachian Region;Area;Basic Science;Biological;Biological Models;Biometry;Cancer Center;Cell Culture Techniques;Cells;Clinical;Clinical Informatics;Clinical Research;Clinical Sciences;Coal;Communication;Communities;Complex;Core Facility;Development;Disadvantaged;Disease;Ecology;Elements;Environmental Health;Environmental Risk Factor;Evaluation;Exposure to;Fostering;Funding;Gases;Geology;Goals;Health;Health Sciences;Heavy Metals;High Prevalence;Infrastructure;Institution;Integrative Medicine;Interest Group;Intervention Studies;Kentucky;Life;Link;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic Diseases;Mining;Modeling;Outcome;Particulate;Pediatric Hospitals;Pilot Projects;Poison;Population;Population Research;Population Sciences;Population Study;Public Health;Public Health Practice;Pulmonary Heart Disease;Radon;Research;Research Activity;Research Design;Research Personnel;Research Project Grants;Research Proposals;Resources;Rivers;Rural Health;Rural Population;Sampling;Scientist;Services;Specimen;Structure;Support System;Time;Tobacco smoke;Tobacco use;Toxicology;Translational Research;United States;Universities;Work;base;career;clinical center;clinical practice;data management;design;early life exposure;epidemiology study;flexibility;hazard;health disparity;improved;instrumentation;interest;laboratory equipment;lung injury;member;patient oriented;pre-clinical research;programs;recruit;research and development;success;tobacco exposure;translational study


application_id: 9923661
project_number: 5P30ES026529-04
project_title: Administrative Core
administering_ic: NIEHS
award_notice_date: 2020-03-30
opportunity_number: RFA-ES-16-001
application_type: 5
activity_code: P30
ic: ES
serial_number: 026529
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 7091
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
PROJECT SUMMARY  Administrative CoreThe University of Kentucky Center for Appalachian Research in Environmental Sciences (UK-CARES) will beestablished as a transdisciplinary Environmental Health Sciences Core Center (EHS CC) designed to developand operationalize strategic infrastructure assets relevant to cutting-edge environmental health research andprovide leadership for scientific and programmatic activities supporting ongoing new and evolving studies inthis area. The Administrative Core is an essential component of this EHS CC providing communicationcoordination and oversight to ensure overall operations and scientific integration of all UK-CAREScomponents. In addition the Administrative Core facilitates integration of goals with community needs andconcerns through dynamic community outreach and engagement activities to enable effective translation offindings to and from the affected communities. The Administrative Core staff will closely monitor theeffectiveness of UK-CARES programs and initiatives to ensure that the Center resources enhance memberresearch productivity. Specific aims are to 1) provide scientific and programmatic leadership and coordinateand integrate the Centers components and activities as well as to facilitate communications and interactionsacross all Center components and with affected communities and community stakeholders; 2) organize andfacilitate program activities internal and external communications and research discussions among Centermembers community members and internal and external advisory board members including retreatsconsultant interactions seminars Research Interest Group meetings and media and newsletters; integratecommunity outreach and engagement activities to ensure that multi-directional translation and communicationremain at the forefront of UK-CARES efforts; 3) provide financial oversight facilitate resource support andensure regulatory compliance related to the Centers research and community activities and maintain Centerrecords and measures of success including use of UK-CARES facilities and publications pilot project awardsand new grant applications resulting from preliminary data enabled by UK-CARES; 4) coordinate the CareerDevelopment Program to promote collaboration among basic clinical and population scientists with a broadrange of skills within a rich environment for early stage investigators to develop diverse professional skills andto attract mid-level investigators and scientists in other fields through opportunities to focus on environmentallyinduced disease; and 5) evaluate the productivity effectiveness and appropriateness of UK-CARES activitiesdetermine the Center membership assess scientific opportunities and areas for collaboration among membersand citizen scientists and coordinate UK-CARES infrastructure assessments as intellectual needs change toaccommodate new opportunities for collaboration. The expected outcome is a set of seamless interactionsthroughout UK-CARES.

project_terms:
Affect;Appalachian Region;Applications Grants;Area;Award;Clinical;Collaborations;Communication;Communication Research;Communities;Community Outreach;Core Facility;Data;Decision Making;Development;Disadvantaged;Disease;Ecology;Effectiveness;Employment;Ensure;Environment;Environmental Health;Environmental Impact;Environmental Risk Factor;Event;Goals;Group Meetings;Health;Health education;Individual;Infrastructure;Interest Group;Journals;Kentucky;Leadership;Life;Malignant Neoplasms;Measures;Medicine;Metabolic Diseases;Mission;Monitor;Newsletter;Outcome;Pilot Projects;Play;Population;Process;Productivity;Program Development;Publications;Pulmonary Heart Disease;Records;Research;Research Personnel;Resource Sharing;Resources;Role;Rural Population;Science;Scientist;Series;Socioeconomic Status;Strategic Planning;Time;Training;Translations;Universities;career;career development;citizen science;college;design;innovation;interest;meetings;member;operation;programs;skills;success


application_id: 9922897
project_number: 5R01DA045023-03
project_title: A translational determination of the mechanisms of maladaptive choice in cocaine use disorder
administering_ic: NIDA
award_notice_date: 2020-04-17
opportunity_number: PA-17-111
application_type: 5
activity_code: R01
ic: DA
serial_number: 045023
program_official: GRANT, STEVEN J
project_start_date: 2018-07-01
project_end_date: 2023-04-30
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: BECKMANN, JOSHUA ;WESLEY, MICHAEL J
congressional_district: 06
department: PSYCHIATRY
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:
ABSTRACT Cocaine use disorder (CUD) is characterized by the decision to use cocaine at the expense of other activities.Lab-based efforts to address this problem have therefore included cocaine choice self-administration proceduresthat incorporate a non-drug alternative to model this defining feature. Studies using these procedures havetypically scheduled competing reinforcers so that the probabilities are certain. However such deterministicoutcomes are not representative of real-world scenarios in which the consequences from drug-related decisionsare often unpredictable. Importantly decision-making in a dynamic uncertain context significantly alters thevalue of choice options and requires continuous updating of option values which engages learning processesand related corticostriatal networks that might be functioning abnormally in CUD. Decision-making in dynamicenvironments has been successfully modeled using probabilistic reinforcement-learning choice (PRLC) tasks.The integration of these tasks with reinforcement-learning (RL) modeling has been used to capture moment-to-moment changes in the mechanisms of dynamic choice and the application of neuroscience techniques hasbegun to identify the underlying neurobiology. This approach has uncovered biologically-based decision-makingabnormalities in multiple brain disorders but has yet to be systematically applied to the experimental study ofCUD The translation of combined RL and neuroscience approaches to CUD is logical considering themaladaptive choice behavior that typifies the disorder the varying reinforcement probabilities in cocaine usersnatural environments and the learning impairments and neuroadaptations that have been documented inindividuals with CUD. Thus there are critical gaps in our understanding of the mechanisms underlying dynamiccocaine use decisions and a strong scientific premise for applying an RL framework to fill these gaps. Thisproject proposes rigorous PRLC tasks RL modeling neuromodulation/fMRI neuroimaging techniques andcomplementary translational study designs in rats and humans to study dynamic choice in CUD. The first set ofcross-species experiments will demonstrate the impact of problematic cocaine use on dynamic decision-makingand reveal the neurobehavioral and neurobiological processes underlying this abnormal task performance. Thesecond set of experiments will use a PRLC task in which intravenous cocaine is available as an alternative tothe non-drug reinforcer to determine the behavioral and neural profile associated with the decision to usecocaine and reduced cocaine choice during treatment. Amphetamine maintenance and non-drug alternativereinforcer treatments reduce cocaine choice which will be leveraged here to uncover behavioral and neuralmechanisms that can be targeted for future treatment development. This project will have a significant impacton the field by establishing the experimental application of reinforcement-learning theory to the study ofmaladaptive dynamic decision-making in CUD.

project_terms:
Address;Amphetamines;Animals;Back;Behavioral;Behavioral Mechanisms;Biological;Brain Diseases;Brain region;Choice Behavior;Clinical;Clinical Trials;Cocaine;Cocaine Users;Complement;Cues;Data;Decision Making;Disease;Environment;Food;Functional Magnetic Resonance Imaging;Future;Human;Impairment;Individual;Intake;Intervention;Intravenous;Knowledge;Learning;MRI Scans;Maintenance;Methods;Modeling;Nature;Neurobiology;Neurosciences;Outcome;Pharmaceutical Preparations;Postdoctoral Fellow;Probability;Procedures;Process;Psychological reinforcement;Rattus;Recording of previous events;Research;Research Design;Safety;Schedule;Self Administration;Signal Transduction;System;Task Performances;Techniques;Therapeutic Effect;Time;Translating;Translations;Update;base;cocaine use;contingency management;drug of abuse;experimental study;human subject;innovation;nervous system disorder;neuroadaptation;neurobehavioral;neuroimaging;neuromechanism;neuroregulation;non-drug;novel;reinforcer;relating to nervous system;theories;therapy development;translational study

public_health_relevance:
PROJECT NARRATIVE Cocaine use disorder (CUD) is characterized by the decision to use cocaine at the expense of other activitiesbut lab-based studies have not modeled naturalistic dynamic decision-making. This translational rat and humanproject will use an innovative reinforcement-learning approach and neuroscience methods to uncover themechanisms of maladaptive dynamic choice in CUD and the effects of established interventions in order toreveal novel treatment targets.


application_id: 9921477
project_number: 5K99HL145117-02
project_title: Macrophage Pyroptosis in Abdominal Aortic Aneurysm
public_health_relevance: Project Narrative
administering_ic: NHLBI
award_notice_date: 2020-04-16
opportunity_number: PA-18-398
application_type: 5
activity_code: K99
ic: HL
serial_number: 145117
program_official: CHARETTE, MARC F
project_start_date: 2019-05-01
project_end_date: 2021-11-30
study_section: NHLBI Mentored Transition to Independence Study Section[MTI(JA)]
contact_pi_person_id: 14992976
contact_pi: WU, CONGQING
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:
Project SummaryThe purpose of this K99/R00 application is to (1) provide me with necessary training in research andcareer development for my transition to a successful independent researcher; (2) study the role ofpyroptosis a novel form of programmed cell death in the rupture of Abdominal Aortic Aneurysm (AAA).AAA is a progressive pathological dilation and weakening of the aorta. AAA is associated with extremerates of death (up to 80%) in the event of aortic rupture. There has no medical therapy to prevent or treataortic rupture which is largely attributed to that mechanisms underlying AAA rupture have not beendefined. AAA is characterized by inflammation and frequent presence of thrombus. Inflammatory lesionsoften contain dead cells. Until recently programmed cell death was thought to occur only in one formcalled apoptosis. In 2015 and 2016 four Nature publications from three groups revealed gasdermin D(GSDMD)-dependent mechanisms of pyroptosis. GSDMD forms pores on cell surface and ruptures cellmembrane. In ruptured cell membrane phosphatidylserine which is exclusively located in the innermonolayer in living cells freely flip into outer monolayer and forms a procoagulant surface for tissuefactor by facilitating the assembly of proteins of clotting cascade. We recently discovered thatmacrophage pyroptosis caused septic death through tissue factor release which triggered disseminatedintravascular coagulation in mice. My preliminary data show that genetic deficiency of GSDMD protectsagainst AAA rupture in angiotensin II-infused mice. In this proposal I will test the hypothesis thatmacrophage pyroptosis promotes AAA rupture through tissue factor-dependent thrombus propagation.Two aims will be addressed to test this hypothesis. In Aim 1 I will profile macrophage pyroptosis inangiotensin II-induced AAA rupture using caspase-1 and Caspase-11 deficient mice (K99 PHASE). InAim 2 I will determine how macrophage pyroptosis through tissue factor-mediated mechanismscontributes to AAA rupture (R00 PHASE). Together I will examine the causal relationship betweenthrombus and AAA rupture and test the concept of a feedforward loop between macrophage pyroptosisand tissue factor/thrombus until AAA rupture. This project is important because GSDMD and pyroptosismay represent a therapeutic target. This project is innovative because it defines a novel procoagulantmechanism in AAA. I will also examine macrophage biology and pyroptosis in human aortic aneurysmtissues available in Dr. LeMaires Aortic Disease Biobank at Baylor College of Medicine to enhance thetranslational aspects of my proposed research.

project_terms:
Abdominal Aortic Aneurysm;Address;Angiotensin II;Animal Model;Antibodies;Aorta;Aortic Aneurysm;Aortic Diseases;Aortic Rupture;Apoptosis;Biology;CASP1 gene;Caliber;Caspase;Cause of Death;Cell membrane;Cell surface;Cells;Cessation of life;Clinical Trials;Coagulation Process;Complement;Conflict (Psychology);Data;Death Rate;Disseminated Intravascular Coagulation;Elderly man;Event;Future;Genetic;Growth;Human;Inflammasome;Inflammation;Inflammatory;Infusion procedures;Interleukin-1 beta;Interleukin-18;Knowledge;Lesion;Ligands;Location;Lytic;Mediating;Medical;Medicine;Modeling;Molecular;Molecular Probes;Movement;Mus;Myeloid Cells;Nature;Necrosis;Outcome;Pathogenicity;Pathologic;Pathway interactions;Phosphatidylserines;Production;Proteins;Publications;Publishing;Reporting;Research;Research Personnel;Role;Rupture;Ruptured Abdominal Aortic Aneurysm;Severities;Signal Transduction;Stimulus;Surface;Testing;Thromboplastin;Thrombosis;Thrombus;Time;Tissues;Training;Western Blotting;Wild Type Mouse;biobank;career development;college;innovation;insight;macrophage;microvesicles;monolayer;mortality;mouse model;novel;prevent;release factor;research and development;response;septic;therapeutic target


application_id: 9919535
project_number: 5R01DA048617-02
project_title: Influence of Orexin Antagonism on Motivation for Cocaine
administering_ic: NIDA
award_notice_date: 2020-04-13
opportunity_number: PA-18-345
application_type: 5
activity_code: R01
ic: DA
serial_number: 048617
program_official: GRANT, STEVEN J
project_start_date: 2019-05-01
project_end_date: 2023-04-30
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
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:
ABSTRACTCocaine use disorder continues to be a significant public health concern. Despite great strides in ourunderstanding of the neurobiological underpinnings of cocaine addiction in preclinical models a limited amountof research has translated those findings into clinical populations. Such translation is crucial to identifyneurobiological circuits that contribute to the problems posed by cocaine use disorder and guide treatmentbased on those clinical neuroscience findings. One area of intense interest in preclinical research is the role ofthe orexin (also known as hypocretin) system in addiction. Through extrahypothalamic transmission the orexinsystem plays a key part in motivation for maladaptive rewards like drugs of abuse. Antagonism of the orexinsystem attenuates motivation for cocaine escalation of cocaine intake and reinstatement of cocaine seekingbehavior. The first and only clinically available orexin antagonist suvorexant (Belsomra) attenuatesmotivation for cocaine and cocaine conditioned place preference as well as cocaine-associated impulsiveresponding in non-human animals. Orexin antagonism generally does not alter adaptive behaviors like food orwater intake nor does it change cocaine-induced locomotion. Taken together these preclinical findingssuggest that orexin system antagonism selectively reduces motivation for cocaine as well as othermaladaptive cocaine-associated behaviors. Although a robust preclinical literature supports the premise thatorexin antagonism attenuates motivation for cocaine along with cocaines other abuse-related effects thisarea remains unstudied in humans. The overarching goal of this project is to translate promising preclinicalfindings into clinical populations thereby demonstrating that the orexin system plays a key role in motivationfor cocaine in humans. To this end non-treatment seeking human subjects meeting diagnostic criteria forcocaine use disorder will sample doses of intravenous cocaine in experimental sessions following maintenanceon a range of oral suvorexant doses. A placebo-controlled double-blind within-subjects design will be usedsuch that all subjects experience all dose conditions in random order. After sampling a cocaine dose subjectswill make choices between that dose and an alternative reinforcer on a concurrent progressive-ratio choicetask that was developed and validated in our laboratory. The use of concurrent progressive-ratio schedules ofdrug and non-drug reinforcer availability will allow inferences to be made about the relative influence of orexinantagonism on motivation to obtain these two types of reinforcers. A battery of subjective drug-effect measuresand cognitive tasks will also be completed to evaluate how orexin antagonism influences other cocaine-associated outcomes in humans. This research will translate findings from preclinical research and provide theinitial evidence that orexin antagonism reduces motivation for cocaine as well as other cocaine-associatedmaladaptive behaviors in active cocaine users. The proposed work seeks to expand the scope of currentclinical neuroscience research on cocaine addiction by focusing on orexin.

project_terms:
Adaptive Behaviors;American;Animals;Area;Attenuated;Basic Science;Behavior;Clinical;Cocaine;Cocaine Dependence;Cocaine Users;Cues;Diagnostic;Disease;Dopamine;Dose;Double-Blind Method;Eating;Genetic;Goals;Human;Hypothalamic structure;Impulsivity;Intake;Intravenous;Knock-out;Laboratories;Lateral;Literature;Locomotion;Maintenance;Measures;Motivation;Neurobiology;Neuropeptides;Neurosciences;Neurosciences Research;Oral;Outcome;Peptides;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Placebos;Play;Population;Pre-Clinical Model;Public Health;Reporting;Research;Rewards;Role;Sampling;Schedule;Self Administration;Short-Term Memory;Signal Transduction;System;Time;Translating;Translations;Visual;Water consumption;Work;addiction;analog;attentional bias;base;cocaine overdose;cocaine use;cognitive task;conditioned place preference;design;drug of abuse;experience;genetic manipulation;human subject;hypocretin;interest;knock-down;meetings;men;non-drug;opioid overdose;pre-clinical;pre-clinical research;preclinical study;receptor;reinforcer;response;sleep regulation;transmission process

public_health_relevance:
PROJECT NARRATIVEThe orexin system is increasingly being recognized for its key role in motivation to engage in maladaptivebehaviors including cocaine taking in preclinical models. No clinical neuroscience research has advancedthese preclinical findings limiting our ability to determine whether the orexin system also contributes to cocaineuse in humans. The proposed research will fill that gap by determining how administration of an orexinantagonist suvorexant impacts motivation for cocaine and other abuse-related effects of cocaine.


application_id: 9919474
project_number: 5R01AG053999-05
project_title: Role of Systemic Amylin Dyshomeostasis in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2020-05-28
opportunity_number: PAR-15-358
application_type: 5
activity_code: R01
ic: AG
serial_number: 053999
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2016-09-15
project_end_date: 2022-11-30
study_section: Special Emphasis Panel[ZRG1-MDCN-C(56)R]
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
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:
AbstractWe propose that an early and possibly treatable contributor to the multifactorial etiology of Alzheimer's disease(AD) involves dyshomeostasis of amylin a pancreatic hormone that crosses the blood brain barrier and hasamyloidogenic properties similar to those of the -amyloid (A) peptide. This hypothesis is supported byrecent work from our lab and others showing large amylin deposits in brains of AD patients. Moreover wefound >4-fold higher brain amylin level in ApoE4 carriers particularly in patients with type-2 diabetessuggesting a link of the accumulation of amylin in the brain with ApoE and metabolic risk factors. Using ratsexpressing human amylin in the pancreas and amylin knockout we found that the brain amylin accumulation islikely promoted by elevated blood levels of oligomerized amylin via the interaction with plasma low densitylipoproteins and causes neuroinflammation and neurologic deficits. Here we propose to test these ideas.Planned studies will determine physiological and functional changes in the brain using a rat modelexpressing human amylin in the pancreas and appropriate controls (Aim 1). We will specificallyidentify therapeutic targets to reduce amylin-induced cytotoxicity in the brain. Pharmaceuticalinterventions will reinforce mechanistic insights while also informing on mechanisms that underlie thebrain amylin accumulation and potential functional effects in humans. Human studies will elucidateamylin-APOE and amylin-A interactions contributing to AD pathology (Aim 2). Here we collaboratewith the University of Kentucky AD Center which has a large repository of brain plasma andcerebrospinal fluid specimens from clinically well-characterized subjects. We also collaborate with theQueen Square Brain Bank for Neurological Disorders of the University College of London andMedical Research Council of King's College London which provided for this project brain specimensfrom early onset familial AD patients (PSEN1 and APP mutation carriers). These brain specimens willbe used to elucidate a potential relationship between the brain amylin accumulation and AD-type ofplaque i.e. early onset familial AD (associated with increased A oligomerization) vs. late onset AD(attributed to the impaired A clearance). To further elucidate the pathobiology of amylin-Ainteraction we crossed the human amylin expressing rat with the TgF344-19 rat model of AD. Thesuccessful completion of this project offers the potential to refining diagnosis and tailoring specifictherapies to modify/ delay/ prevent brain injury and cognitive decline in aging and metabolic disorders.

project_terms:
4 hydroxynonenal;Abeta clearance;Aging;Alleles;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease patient;Alzheimers disease biomarker;Amyloid;Amyloid beta-Protein;Animal Model;Apolipoprotein E;Blood;Blood - brain barrier anatomy;Blood Vessels;Brain;Brain Diseases;Brain Injuries;CREB1 gene;Carnosine;Cell Culture Techniques;Cell model;Cerebrospinal Fluid;Cerebrovascular Circulation;Clinical;Clinical Data;Cognitive;Data;Dementia;Deposition;Diagnosis;Disease Progression;Early Onset Familial Alzheimer's Disease;Eicosanoids;Etiology;Genotype;Goals;Hormones;Human;Hypertrophy;Impaired cognition;Impairment;Injections;Injury;Interleukin-1 beta;Intervention;Kentucky;Knock-out;Knowledge;Late Onset Alzheimer Disease;Lead;Link;Lipid Peroxidation;London;Low-Density Lipoproteins;Malondialdehyde;Measures;Mediating;Medical Research;Membrane;Metabolic;Metabolic Diseases;Modeling;Neurologic Deficit;Non-Insulin-Dependent Diabetes Mellitus;Pancreas;Pancreatic Hormones;Pathologic;Pathology;Pathway interactions;Patients;Peptides;Peroxides;Pharmacologic Substance;Physiological;Plasma;Prevention strategy;Property;Protein Isoforms;Rattus;Research Project Grants;Rest;Risk Factors;Role;Signal Transduction;Smooth Muscle Myocytes;Specimen;Testing;Toxic effect;Transgenic Animals;Universities;Vascular Diseases;Work;apolipoprotein E-4;brain tissue;cerebrovascular;clinically relevant;college;cytotoxicity;data modeling;diabetic;diabetic rat;experimental study;human data;human disease;human tissue;inflammatory milieu;inhibitor/antagonist;insight;islet amyloid polypeptide;lipid peroxidation inhibitor;mutation carrier;nervous system disorder;neuroinflammation;neurotoxicity;neurovascular unit;novel;presenilin-1;prevent;repository;therapeutic evaluation;therapeutic target

public_health_relevance:
NarrativeWe have recently discovered that in addition to plaques laden with -amyloid brains of Alzheimer's diseasepatients contain large deposits of amylin an amyloidogenic hormone secreted from the pancreas. In thisresearch project we propose to use human tissue clinical data transgenic animals and cell models to 1)decipher mechanisms of brain amylin pathology in humans 2) determine the impact of amylin deposition onthe neurovascular unit and 3) test clinically relevant therapies to modify/ reduce/ prevent amylin-mediateddeleterious effects in the brain. The successful completion of this project offers the potential to refiningdiagnosis and tailoring specific therapies to modify/ delay/ prevent cerebrovascular injury and cognitive declinein aging and metabolic disorders.


application_id: 9919097
project_number: 7R01DA044311-03
project_title: Dynamic Signaling of NRG3-ErbB4 in the Hippocampus Mediates Nicotine Withdrawal Phenotypes
administering_ic: NIDA
award_notice_date: 2019-07-19
opportunity_number: PA-16-160
application_type: 7
activity_code: R01
ic: DA
serial_number: 044311
program_official: LOSSIE, AMY C
project_start_date: 2018-04-01
project_end_date: 2023-01-31
study_section: Molecular Neuropharmacology and Signaling Study Section[MNPS]
contact_pi_person_id: 10484112
contact_pi: TURNER, JILL R.
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:
Accounting;Affective;Animals;Anxiety;Awareness;Behavior;Behavioral Model;Calcium;Cells;Cholecystokinin;Chronic;Complex;Data;Development;Drosophila acetylcholine receptor alpha-subunit;Electrophysiology (science);ErbB4 gene;Fluorescent in Situ Hybridization;Genes;Genetic;Glutamates;Goals;Hippocampus (Brain);Human;Image;Interneurons;Interruption;Knock-in Mouse;Knowledge;Ligands;Location;Mediating;Modeling;Molecular;Mus;NRG3 gene;Nicotine;Nicotine Dependence;Nicotine Withdrawal;Nicotinic Receptors;Outcome;Phenotype;Property;Publishing;Pyramidal Cells;Reporting;Risk;Role;Signal Pathway;Signal Transduction;Signaling Molecule;Single Nucleotide Polymorphism;Smoker;Smoking;Surgeon;Testing;Therapeutic;Time;Tissues;Tobacco smoking behavior;United States;Western Blotting;Withdrawal;Withdrawal Symptom;anxiety-like behavior;base;behavior test;cell type;cohort;confocal imaging;density;genetic information;mRNA Expression;novel;preventable death;protein expression;receptor;receptor coupling;smoking cessation;tool;voltage sensitive dye;withdrawal-induced anxiety


application_id: 9918887
project_number: 5R01GM077422-11
project_title: Targeting Nucleic Acids with an Integrated Virtual and Actual Screen
administering_ic: NIGMS
award_notice_date: 2020-04-07
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: GM
serial_number: 077422
program_official: SAKALIAN, MICHAEL
project_start_date: 2007-02-01
project_end_date: 2022-04-30
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
arra_indicator: N
project_abstract:
We seek a second renewal for our program to refine and apply an integrated virtual and actual screeningplatform for the discovery of new lead compounds to inhibit telomerase. Progress during the current fundingperiod was outstanding and we have achieved most of the specific aims proposed. During the next fundingperiod we will focus on the discovery of lead compounds that bind selectively to biologically important higher-order telomeric DNA quadruplexes and targeting the single strand telomere:POT1 interface. Telomerase hasbeen identified as a target for over 20 years but there are no approved drugs that inhibit its activity so newapproaches are required. We will inhibit POT1 (Protection of Telomere 1) a protein essential for telomeraseactivity by targeting the telomeric DNA substrate and by directly targeting the POT1 telomeric DNA bindingfunction. We now propose fundamental studies that will continue to develop and refine our integratedscreening platform. Nucleic acids remain underrepresented targets for small molecule therapeutic agents. There is mountingevidence to indicate that non-B DNA structures play prominent roles in gene expression and especially in thefunction of telomeres. Targeting these structural elements is an attractive and innovative strategy for thedevelopment of new therapeutic agents. The higher-order DNA quadruplex structures formed by the singlestrand of the human telomere remain a very poorly and improperly investigated target as traditional structuralbiology approaches have been unsuccessful. We have used a combination of computational modeling andexperimental biophysics to derive consistent structural models for telomeric DNA sequences of up to 192bases or eight quadruplex repeats in the current grant period. The higher-order quadruplex stackinginterfaces thus represent a new target for small molecule stabilization of telomeric DNA. This stabilizationshould inhibit telomerase by locking the substrate DNA in an unusable form. An even more under representedtarget than non-B DNA is the nucleic acid-protein interaction particularly single stranded DNA:proteincomplexes as exist with POT1. We will target both the DNA substrate and the DNA-binding function of POT1which could lead to synergistic inhibition of telomerase. This is a natural progression from our current fundingperiod where we targeted biologically relevant quadruplex structures to telomere-like higher-order quadruplexnucleic acid structures and the telomere ssDNA binding protein POT1 which is essential for telomeric DNAreplication. The Specific Aims are: 1) Targeting higher-order telomeric quadruplex structures using integratedvirtual and actual screens; 2) Characterizing the specific interactions of POT1 with higher-order quadruplexes;3) Targeting POT1 using integrated virtual and actual screens; 4) Characterizing the biological properties ofhigher-order G-quadruplexes and POT1 binding agents.!

project_terms:
Binding;Binding Proteins;Biological;Biological Assay;Biophysics;Characteristics;Computer Models;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 lead compound;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;virtual screening

public_health_relevance:
This project will refine and apply an integrated computational and experimental screening platform for thediscovery of new drugs that target specific structures of functional importance within the genome. The currentfunding period for this project was successful and productive and we will continue our efforts. Several noveltelomeric functionally important quadruplex structures were characterized. We will characterize the interactionsof these with their protein partner and use this information to target both.


application_id: 9917946
project_number: 1P30ES030283-01A1
project_title: PILOT PROJECT
administering_ic: NIEHS
award_notice_date: 2020-07-15
opportunity_number: RFA-ES-18-003
application_type: 1
activity_code: P30
ic: ES
serial_number: 030283
suffix: A1
study_section: Environmental Health Sciences Review Committee[EHS (P)]
subproject_number: 6994
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY W.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-06-01
project_terms:
Accountability;Applications Grants;Area;Award;Benchmarking;Categories;Collaborations;Communities;Data Collection;Disease;Environmental Exposure;Environmental Health;Event;Experimental Designs;Exposure to;Extramural Activities;Feedback;Fostering;Funding;General Population;Goals;Grant;Grant Review;Health;Human;Individual;Life Cycle Stages;Malignant Neoplasms;Mentors;Monitor;National Institute of Environmental Health Sciences;Pilot Projects;Publications;Recommendation;Reporting;Research;Research Peer Review;Research Personnel;Research Project Grants;Research Support;Technology;Toxic Environmental Substances;Toxicology;Translational Research;Universities;Ursidae Family;Work;base;career;career development;citizen science;design;improved;lifestyle factors;meetings;member;novel;programs;stem;success;symposium


application_id: 9917945
project_number: 1P30ES030283-01A1
project_title: Integrated Toxicomics & Environmental Measurement Facility Core
administering_ic: NIEHS
award_notice_date: 2020-07-15
opportunity_number: RFA-ES-18-003
application_type: 1
activity_code: P30
ic: ES
serial_number: 030283
suffix: A1
study_section: Environmental Health Sciences Review Committee[EHS (P)]
subproject_number: 6993
contact_pi_person_id: 8638276
contact_pi: MERCHANT, MICHAEL L
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
budget_start_date: 2020-06-01
project_abstract:
The Center for Integrated Environmental Health Sciences (CIEHS) goals are to understand how lifestyle factors interact with exposure to environmental toxicants in human health and disease and toenhance the capacity for environmental health research at the University of Louisville (UofL). UofLshared resource facility cores offer cutting edge scientific services enabling access to high-endequipment advanced techniques and specialized expertise that would typically be inaccessible for aninvestigator. It is essential for the modern environmental health scientist to understand the numerousavailable shared resource facility cores; in terms of accessibility effective experimental design data-acquisition and -analyses. The Integrated Toxicomics and Environmental Measurement Facility Core(ITEMFC) will create a central resource for CIEHS members allowing them to understand access andeffectively use environmental omics resources. The ITEMFC will coordinate activities between CIEHSmembers and the existing UofL shared resource facility cores. The ITEMFC will be comprised of sixdiscrete technology-centric components: genomics/ transcriptomics proteomics metabolomicsmetallomics metagenomics and controlled inhalation exposure studies. The ITEMFC will focus itsefforts on advising investigators on study design facilitating shared resource facility cores use andeducating Center members and trainees on these technologies. Additionally the ITEMFC will facilitatethe transfer of omics data to the Biostatistics and Informatics Facility Core (BIFC). It will accomplishthese goals through the following specific aims: Aim 1. Increase access and facilitate use of UofLshared resource facility cores. ITEMFC will serve our members by (a) explaining the various cores andhow they operate (b) establishing direct interactions with the right shared resource director to selectthe appropriate technology. We will aid in experimental design and closely collaborate with all FacilityCores to streamline sample handling and data analysis. The ITEMFC will also supplement the cost ofmember studies. Aim 2. Cultivate awareness interest and understanding of the ITEMFC sharedresource facility cores. The ITEMFC will support CIEHS members by (a) drawing attention to theshared resource facility cores (b) suggesting how the ITEMFC may enhance their approach inanswering their research questions and (c) support educating the next generation of environmentalscientists in the various technologies. Aim 3. Facilitate submission of CIEHS members grantapplications proposing to use ITEMFC Resources. The ITEMFC will support CIEHS members in theirgrant applications that include omics-based aims. The integrated services and expertise of the ITEMFCare essential to achieve CIEHS goals and to make progress with regard to understanding the diversepathological consequences of exposure to environmental toxicants together with lifestyle factors.

project_terms:
Applications Grants;Attention;Award;Awareness;Biometry;Budgets;Cells;Chronic Disease;Communities;Core Facility;DNA;Data;Data Analyses;Disease;Environmental Health;Equipment;Event;Experimental Designs;Exposure to;Funding;Genomics;Goals;Grant;Health;Health Sciences;Human;Informatics;Inhalation;Inhalation Exposure;Institution;Interest Group;Investments;Laboratories;Malignant Neoplasms;Measurement;Measures;Metabolic;Metagenomics;Metals;Modernization;National Institute of Environmental Health Sciences;Pathologic;Pilot Projects;Pollution;Proteins;Proteomics;RNA;Research;Research Design;Research Personnel;Resource Sharing;Resources;Running;Sampling;Scientist;Services;Suggestion;Techniques;Technology;Tissues;Toxic Environmental Substances;Toxicogenetics;Toxicology;Universities;Work;base;citizen science;cost;data acquisition;environmental toxicology;faculty community;health science research;interest;lifestyle factors;medical schools;member;metabolomics;neurodevelopment;next generation;programs;shared attention;toxicant interaction;transcriptomics


application_id: 9917944
project_number: 1P30ES030283-01A1
project_title: Biostatistics and Informatics Facility Core
administering_ic: NIEHS
award_notice_date: 2020-07-15
opportunity_number: RFA-ES-18-003
application_type: 1
activity_code: P30
ic: ES
serial_number: 030283
suffix: A1
study_section: Environmental Health Sciences Review Committee[EHS (P)]
subproject_number: 6992
contact_pi_person_id: 9753394
contact_pi: RAI, SHESH N.
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
budget_start_date: 2020-06-01
project_terms:
Address;Animals;Area;Basic Science;Bayesian Method;Big Data;Bioinformatics;Biomedical Research;Biometry;Cancer Center;Centers of Research Excellence;Chronic Disease;Clinical;Clinical Data;Clinical Informatics;Clinical Research;Communities;Computational Biology;Consultations;Core Facility;Data;Data Analyses;Deposition;Diagnosis;Disease;Environmental Epidemiology;Environmental Exposure;Environmental Health;Exposure to;Funding;Gender;Genetic;Goals;Grant;Health;Human;Human Resources;Informatics;Infrastructure;Kentucky;Life;Life Style;Measurement;Measures;Mediator of activation protein;Methods;Milieu Therapy;Modeling;Multiomic Data;National Institute of Environmental Health Sciences;Network Infrastructure;Phase;Play;Pollution;Population Research;Population Study;Prevention therapy;Public Health;Research;Research Activity;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Role;Science;Services;Strategic Planning;Superfund;Techniques;Toxic Environmental Substances;Training;Universities;alcohol research;bioinformatics tool;cofactor;cost efficient;data infrastructure;design;disorder risk;epidemiology study;health science research;interest;lifestyle factors;member;patient oriented;pollutant;population health;pre-clinical;spatiotemporal;statistics;tool


application_id: 9917943
project_number: 1P30ES030283-01A1
project_title: Integrated Health Science Facility Core
administering_ic: NIEHS
award_notice_date: 2020-07-15
opportunity_number: RFA-ES-18-003
application_type: 1
activity_code: P30
ic: ES
serial_number: 030283
suffix: A1
study_section: Environmental Health Sciences Review Committee[EHS (P)]
subproject_number: 6991
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
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
budget_start_date: 2020-06-01
project_terms:
Adult;Affect;Basic Science;Biological;Biological Markers;Biometry;Charge;Charities;Childhood;Chronic Disease;Clinical;Clinical Research;Clinical Trials;Clinical Trials Unit;Communities;Consent;Consultations;Core Facility;Data;Data Analyses;Development;Disease;Doctor of Medicine;Early Diagnosis;Ensure;Environmental Health;Evaluation;Fee-for-Service Plans;Goals;Health;Health Sciences;Health Services Accessibility;Human;Human Resources;Human Subject Research;Informatics;Infrastructure;Institutes;Interdisciplinary Study;Interest Group;Intervention;Knowledge;Life;Measurement;Measures;Metagenomics;Metals;Milieu Therapy;National Institute of Environmental Health Sciences;Nature;Performance;Pharmaceutical Preparations;Physicians;Pilot Projects;Pollution;Population Research;Prevention therapy;Program Evaluation;Proteomics;Public Health Practice;Randomized;Reporting;Research;Research Design;Research Personnel;Research Support;Retrieval;Sampling;Scientist;Services;Technology;Therapeutic Intervention;Time;Training and Education;Translating;Translational Research;Universities;base;biobank;clinical practice;cohort;community involvement;community organizations;cost effective;design;experience;follow-up;human data;human subject;implementation research;improved;innovation;instrument;instrumentation;interest;lifestyle factors;member;metabolomics;multidisciplinary;patient oriented;programs;recruit;response;sample collection;sex;transcriptomics;volatile organic compound


application_id: 9917942
project_number: 1P30ES030283-01A1
project_title: COMMUNITY ENGAGEMENT
administering_ic: NIEHS
award_notice_date: 2020-07-15
opportunity_number: RFA-ES-18-003
application_type: 1
activity_code: P30
ic: ES
serial_number: 030283
suffix: A1
study_section: Environmental Health Sciences Review Committee[EHS (P)]
subproject_number: 6990
contact_pi_person_id: 12053538
contact_pi: HUNTINGTON-MOSKOS, LUZ G
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
budget_start_date: 2020-06-01
project_terms:
Address;Agriculture;Area Health Education Centers;Awareness;Chronic Disease;Communication;Communities;Core Facility;Decision Making;Diabetes Mellitus;Disease;Ensure;Environmental Exposure;Environmental Hazards;Environmental Health;Exposure to;Family;Gender;Goals;Health;Health Personnel;Health Resources;Health Sciences;Healthcare Systems;Housing;Human;Huntington Disease;Hypertension;Industry;Kentucky;Knowledge;Leadership;Life;Malignant Neoplasms;National Institute of Environmental Health Sciences;Newspapers;Obesity;Pilot Projects;Pollution;Public Health;Research;Research Personnel;Resources;Role;Rural;Structure;Toxic Environmental Substances;Translating;Translational Research;Translations;Universities;Vision;Work;Youth;base;burden of illness;catalyst;community involvement;community organizations;experience;faculty research;health knowledge;health literacy;health science research;healthcare community;household environmental exposure;lifestyle factors;literacy;member;outreach;programs;rural area;social media;superfund site;urban area


application_id: 9917941
project_number: 1P30ES030283-01A1
project_title: ADMINISTRATIVE CORE
administering_ic: NIEHS
award_notice_date: 2020-07-15
opportunity_number: RFA-ES-18-003
application_type: 1
activity_code: P30
ic: ES
serial_number: 030283
suffix: A1
study_section: Environmental Health Sciences Review Committee[EHS (P)]
subproject_number: 6989
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
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
budget_start_date: 2020-06-01
project_terms:
Advisory Committees;Applications Grants;Area;Award;Biometry;Collaborations;Communication;Communities;Core Facility;Data;Disease;Effectiveness;Electronic Mail;Ensure;Environmental Health;Evaluation;Exposure to;Faculty;Focus Groups;Fostering;Gender;Genetic;Goals;Grant;Health;Health Personnel;Health Sciences;Human;Individual;Informatics;Institutes;Interdisciplinary Study;Interest Group;Lead;Leadership;Life;Life Style;Measurement;Measures;Mediating;Mentors;Mentorship;Methods;Monitor;National Institute of Environmental Health Sciences;Outcome;Output;Pilot Projects;Pollution;Prevention;Process;Productivity;Program Development;Publications;Recruitment Activity;Reporting;Research;Research Personnel;Resources;Schedule;Scientist;Societies;Telephone;Toxic Environmental Substances;Toxicology;Translational Research;Translations;Universities;Vision;Youth;career;career development;cofactor;design;disorder risk;health science research;improved;interest;lifestyle factors;meetings;member;patient population;pollutant interaction;programs;recruit;repository;success;symposium


application_id: 9917940
project_number: 1P30ES030283-01A1
project_title: University of Louisville Center for Integrative Environmental Health Sciences
administering_ic: NIEHS
award_notice_date: 2020-07-15
opportunity_number: RFA-ES-18-003
application_type: 1
activity_code: P30
ic: ES
serial_number: 030283
suffix: A1
program_official: THOMPSON, CLAUDIA L
project_start_date: 2020-07-15
project_end_date: 2025-03-31
study_section: Environmental Health Sciences Review Committee[EHS (P)]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
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
project_terms:
Adult;Agriculture;Alcohol consumption;Alcohols;Area;Basic Science;Biological Models;Biometry;Cardiovascular system;Chemicals;Childhood;Chronic;Chronic Disease;Clinical;Clinical Trials;Clinical Trials Unit;Collaborations;Communication;Communities;Complex;Core Facility;County;Development;Diabetes Mellitus;Diet;Disease;Disease Outcome;Ecosystem;Environment;Environmental Health;Environmental Risk Factor;Etiology;Exposure to;Funding;Gender;Genetic;Genetic Predisposition to Disease;Genotype;Geographic Locations;Goals;Grant;Health;Health Personnel;Health Sciences;Human;Individual;Industrialization;Informatics;Interdisciplinary Study;Interest Group;Investigation;Kentucky;Knowledge;Laboratories;Leadership;Life;Malignant Neoplasms;Measurement;Mental disorders;Mentors;Mentorship;Metals;Modification;Obesity;Pathogenesis;Pilot Projects;Play;Pollution;Polychlorinated Biphenyls;Positioning Attribute;Predisposition;Preventive Intervention;Program Development;Research;Research Personnel;Research Training;Resources;Role;Rural;Toxic Environmental Substances;Toxicant exposure;Toxicology;Translating;Translations;United States;Universities;Vinyl Chloride;Vision;Youth;addiction;built environment;career development;citizen science;community based participatory research;design;health science research;improved;lifestyle factors;man;member;metropolitan;multidisciplinary;next generation;pollutant;programs;recruit;response;rural environment;rural healthcare;skills;socioeconomics;stressor;tobacco exposure;tobacco products


application_id: 9917801
project_number: 5P20GM103436-20
project_title: Developmental Research Project Program
administering_ic: NIGMS
award_notice_date: 2020-04-30
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-RCB-9
subproject_number: 7347
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-05-01
budget_end_date: 2021-04-30
project_terms:
Address;Applications Grants;Award;Biomedical Research;Career Mobility;Core Facility;Data;Development;Discipline;Educational workshop;Faculty;Faculty Recruitment;Funding;Goals;Grant;Howard Temin Award;Infrastructure;Institution;Kentucky;Mentors;Pilot Projects;Process;Productivity;Program Research Project Grants;Research;Research Personnel;Research Support;Research Training;Services;Training;United States National Institutes of Health;Universities;Work;Writing;base;career;career development;college;experience;faculty research;postdoctoral investigator;programs;recruit;research and development;success;undergraduate student


application_id: 9917799
project_number: 5P20GM103436-20
project_title: Statistics Core
administering_ic: NIGMS
award_notice_date: 2020-04-30
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-RCB-9
subproject_number: 7345
contact_pi_person_id: 8252047
contact_pi: STROMBERG, ARNOLD JAMES
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
budget_start_date: 2020-05-01
budget_end_date: 2021-04-30
project_terms:
Applications Grants;Appointment;Area;Biological;Biomedical Research;Centers of Research Excellence;Consultations;Data Analyses;Data Security;Department chair;Development;Doctor of Philosophy;Educational workshop;Ensure;Experimental Designs;Faculty;Goals;Grant;Infrastructure;Institution;Kentucky;Laboratories;Lead;Manuscripts;Mentors;Mentorship;Methodology;Methods;Persons;Preparation;Reporting;Research;Research Assistant;Research Personnel;Resources;Site Visit;Statistical Data Interpretation;Students;Training;United States National Institutes of Health;Universities;Visit;Work;college;data management;experience;experimental study;graduate student;improved;member;professor;statistical service;statistics;symposium


application_id: 9917796
project_number: 5P20GM103436-20
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2020-04-30
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-RCB-9
subproject_number: 7342
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-05-01
budget_end_date: 2021-04-30
project_terms:
Advisory Committees;Applications Grants;Award;Bioinformatics;Biomedical Research;Budgets;Businesses;Educational workshop;Equilibrium;Evaluation;Goals;Institution;Kentucky;Leadership;Logistics;Mentors;Output;Process;Research;Research Personnel;Services;Site Visit;Structure;Students;Training;Travel;Work;investigator training;meetings;programs;sound;symposium;undergraduate research;undergraduate student


application_id: 9917748
project_number: 5UM1DA049406-02
project_title: Kentucky CAN HEAL (Communities and Networks Helping End Addiction Long-term)
administering_ic: NIDA
award_notice_date: 2020-04-09
opportunity_number: RFA-DA-19-016
application_type: 5
activity_code: UM1
ic: DA
serial_number: 049406
program_official: HIGHSMITH, KEISHER S
project_start_date: 2019-04-17
project_end_date: 2023-03-31
study_section: ZDA1-TXW-S(16)R
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
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:
ABSTRACTThe Kentucky CAN (Communities and Networks) HEAL (Helping End Addiction Long-term) [KCH] study is alarge-scale community intervention project submitted in response to the HEALing Communities request forproposals to test the immediate impact of implementing an integrated set of evidence-based interventionswith the aim of reducing opioid overdose deaths by 40% in three years. KCH represents a partnership betweenthe University of Kentucky Kentucky State government officials and numerous community organizations. Thisproject will employ an incomplete stepped-wedge cluster randomized design to deploy an integrated set ofevidence-based practices in 17 highly affected counties in Kentucky in two waves of assignment. Highlyaffected counties were identified through an empirical algorithm that incorporated the requisite epidemiologicalcriteria for opioid overdose and structural systems in place to support the deployment of evidence-basedinterventions (EBIs). Prior to randomization a systematic implementation science-based approach will be usedto assess barriers attitudes and assets and to enhance implementation of EBIs. Primary intervention aims areto improve and expand treatment with medications for opioid use disorder (MOUD) by increasing capacityentry and retention expand overdose prevention approaches in the community and reduce opioid supply bydecreasing high risk prescribing and increasing safe drug disposal. Community partners include thoserepresenting behavioral health healthcare public health criminal justice and community coalitions.Interventions will include those focused on 1) development of a Care Navigation network in MOUD treatmentprograms (FQHCs OTPs and OBOT providers) syringe service programs jails and parole and probationoffices to increase the number of individuals screened referred to initiating evidence-based care retained intreatment and receiving ancillary recovery support services; 2) enhancing and expanding the treatmentworkforce through increased DATA 2000 waiver trainings and weekly support through expert telehealthguidance using the ECHO model; 3) increasing overdose education and naloxone distribution in treatmentsettings syringe services programs jails parole and probation; and the community; 4) increasing access tosyringe services programs; 5) reducing risky opioid prescribing and dispensing; and 6) enhancing drugdisposal. By targeting individuals who are at highest risk (e.g. out of treatment reentering the community) anddeploying a community-wide health communication strategy to increase awareness and demand for EBIs wehypothesize that KCH will reduce overdose deaths by 40% in three years. KCH will leverage existing fundingand resources to enhance its effectiveness and the health economics of these interventions will be evaluatedin order to have meaningful and translatable impact on public policy.

project_terms:
Address;Affect;Age;Algorithms;Attitude;Awareness;Benzodiazepines;Buprenorphine;Caring;Cessation of life;Communities;Community Networks;County;Criminal Justice;Data;Death Rate;Development;Diagnosis;Education;Effectiveness;Emergency Situation;Ensure;Epidemiology;Evidence based intervention;Evidence based practice;Fentanyl;Funding;Government Agencies;Government Officials;Guidelines;Health Communication;Health Professional;Health Services Accessibility;Healthcare;Heroin;Individual;Intervention;Jail;Kentucky;Life Expectancy;Methadone;Modeling;Naloxone;Needle-Exchange Programs;Opioid;Opioid Antagonist;Outcome;Overdose;Pharmaceutical Preparations;Pharmacists;Phase;Policies;Prevention;Prevention approach;Professional Education;Provider;Public Health;Public Policy;Randomized;Recovery;Request for Proposals;Research;Resources;Rural;Services;Site;State Government;Structure;System;Testing;Training;Training Support;United States;Universities;Work;addiction;barrier to care;base;behavioral health;community center;community intervention;community organizations;cost;design;evidence base;experience;healing;health economics;high risk;illicit drug use;implementation science;implementation strategy;improved;metropolitan;mortality;opioid epidemic;opioid misuse;opioid mortality;opioid overdose;opioid use disorder;overdose death;overdose prevention;parole;prescription monitoring program;prescription opioid;probation;programs;response;screening;social stigma;stem;synthetic opioid;telehealth;theories;treatment program;waiver

public_health_relevance:
PROJECT NARRATIVEThe Kentucky CAN HEAL (Communities and Networks Helping End Addiction Long-Term) project aims toreduce opioid overdose deaths by 40% within three years. This initiative is a partnership between theUniversity of Kentucky and the Commonwealth of Kentucky along with numerous other academic andcommunity partners. This large-scale community-based project will leverage many evidence-basedinterventions to reduce overdose including expanding access to treatment overdose prevention trainingnaloxone distribution improving opioid prescribing practices and safe disposal of opioids.


application_id: 9917672
project_number: 5P50AA024337-05
project_title: Mechanisms of Alcohol-Induced Lung and Liver Injury
administering_ic: NIAAA
award_notice_date: 2020-05-29
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8305
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
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
budget_start_date: 2020-05-01
budget_end_date: 2021-04-30
project_abstract:
Chronic ethanol abuse leads to increased susceptibility to acute lung injury (ALI) and mortality in the setting of sepsis. We believe that this is due in part to alterations in the expression of tissue remodeling genes that prime the lung to disrepair after injury. This is supported by our own findings showing that lungs harvested from rodents treated with ethanol show increased expression of fibronectin matrix metalloproteinases and transforming growth factor ; we also demonstrated activation of matrix remodeling in alcoholics. Together with changes in oxidative stress and epithelial cell dysfunction these alterations represent key features of what has been termed the alcoholic lung phenotype. Despite the above advances we still do not understand the mechanisms that lead to these changes nor the role of matrix remodeling in the alcoholic lung. Importantly the mechanisms by which these changes render the lung susceptible to disrepair after injury remain unclear. We hypothesize that chronic ethanol promotes redox stress that triggers extracellular matrix (ECM) remodeling resulting in the `re-pavement' of the lung with a `pro-inflammatory' ECM characterized by increased expression of fibronectin EDA and collagen V two molecules implicated in tissue disrepair. Upon injury of the alcoholic lung epithelial cells trying to populate denuded areas become exposed to this aberrant ECM resulting in increased permeability while incoming immune cells exposed to this ECM experience exaggerated activation. Together these processes enhance inflammation and epithelial cell dysfunction leading to disrepair and ultimately ALI. We have observed similar derangements in the aging lung and speculate that ethanol-induced redox stress promotes accelerated aging of the lung through epigenetic modifications that drive ECM remodeling. Our hypothesis is supported by several in vivo studies demonstrating a role for the ECM in the lung's response to injury. Second we showed that primary lung cells harvested from ethanol-treated animals deposit a pro-inflammatory matrix. Third we found that alveolar epithelial cells cultured on different matrices show alterations in their expression of claudins resulting in barrier dysfunction. Fourth like ethanol we found that aging also promotes ECM remodeling and this defect is associated with epigenetic histone modifications that drive fibronectin gene expression; we speculate that similar mechanisms are taking place here. Finally recent studies in our laboratory suggest that the above effects might be dependent on ethanol-induced redox stress and could potentially be ameliorated by dietary interventions targeting redox stress. We aim to test the hypothesis in specific aims designed to: 1) Examine the effects of ethanol-induced ECM remodeling on immune cells and epithelial cells in vitro and explore its role in susceptibility to ALI in vivo; 2) Examine ethanol- dependent gene-specific promoter-associated epigenetic modifications regulating ECM gene expression in lung fibroblasts; and 3) Investigate how ethanol-induced redox stress promotes ECM remodeling and determine the effect of anti-oxidant dietary interventions on ethanol-induced ECM remodeling and susceptibility to ALI.

project_terms:
Acute Lung Injury;Aging;Alcohol abuse;Alcohols;Animals;Antioxidants;Area;Cell surface;Cells;Chronic;Collagen;Complement Factor B;Cultured Cells;Defect;Deposition;Development;Dietary Intervention;Epigenetic Process;Epithelial Cells;Ethanol;Ethanol dependence;Exposure to;Extracellular Matrix;Fibroblasts;Fibronectins;Fibrosis;Functional disorder;Gene Expression;Genes;Glycoproteins;Growth Factor;Harvest;Immune;In Vitro;Inflammation;Inflammatory;Injury;Interleukin-1 beta;Laboratories;Lead;Lung;Matrix Metalloproteinases;Modeling;Modification;Mus;Nicotinic Receptors;Organ Transplantation;Oxidation-Reduction;Oxidative Stress;Permeability;Phenotype;Play;Predisposition;Process;Production;Rodent;Role;Sepsis;Stress;Testing;Tissues;Transforming Growth Factors;Work;alcohol effect;alveolar epithelium;cytokine;design;experience;histone modification;in vivo;indium-bleomycin;injury and repair;liver injury;lung injury;monocyte;monolayer;mortality;nutrition;organ injury;problem drinker;programs;promoter;response to injury;sensor


application_id: 9917671
project_number: 5P50AA024337-05
project_title: Sulforaphane-mediated epigenetic modulation of ethanol-induced apoptosis and teratogenesis
administering_ic: NIAAA
award_notice_date: 2020-05-29
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8304
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
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
budget_start_date: 2020-05-01
budget_end_date: 2021-04-30
project_abstract:
Prenatal ethanol exposure is the leading known cause of mental retardation. Growing evidence suggests that excessive cell death is a major component of the pathogenesis of ethanol-induced birth defects. However there is a fundamental gap in understanding how ethanol leads to apoptotic cell death in embryos. Sulforaphane (SFN) is a chemical that is abundant in broccoli sprouts. Compelling evidence indicates that SFN or SFN-rich broccoli sprouts trigger the induction of antioxidant enzymes through activation of Nrf2 signaling and prevent cancer and other diseases. It was recently discovered that SFN can regulate gene expression through epigenetic mechanisms. We have recently demonstrated that SFN can significantly diminish ethanol- induced apoptosis in neural crest cells (NCCs). Our long-term goal is directed toward the development of effective strategies against ethanol's teratogenesis; strategies based on prevention of ethanol-induced apoptosis through targeting specific pathways involved in apoptosis. The overall objective of this particular proposal is to elucidate the epigenetic mechanisms by which SFN epigenetically regulates the anti-apoptotic gene expression and prevent ethanol-induced apoptosis and to develop a safe and effective regimen to diminish the incidence and severity of FASD using SFN a safe nutraceutical. The central hypothesis of this project is that ethanol-induced epigenetic alterations lead to aberrant expression of the anti-apoptotic genes resulting in excessive apoptosis and malformations in embryos which can be prevented by epigenetic modulation elicited by SFN or SFN-rich broccoli sprout extract. Our hypothesis has been formulated on the basis of strong preliminary data produced in our laboratory. To test our hypothesis the following specific aims will be addressed: Aim 1: To identify the anti-apoptotic genes that are epigenetically silenced by ethanol and derepressed by SNF in ethanol-exposed NCCs and mouse embryos. Aim 2: To elucidate the mechanisms by which SFN epigenetically modulates the expression of the anti-apoptotic genes and apoptosis in ethanol- exposed NCCs and mouse embryos. Aim 3: To test the hypothesis that epigenetic modulation of the anti- apoptotic genes by maternal dietary SFN-rich broccoli sprout extract (BSE) represents a novel therapeutic strategy for preventing ethanol-induced teratogenesis. The proposed work is innovative because it focuses on a novel approach epigenetic modulation of the anti-apoptotic genes to preventing ethanol-induced teratogenesis. The theoretical concept described in the application is also highly innovative because this is the first study attempting to prevent FASD through the use of bioactive compounds derived from a vegetable. The results from this study will be significant because they are expected to illustrate the potential of a practical nutraceutical-based therapeutic strategy for FASD.

project_terms:
Acetylation;Address;Alcohol consumption;Alcohols;Antioxidants;Apoptosis;Apoptotic;Attenuated;Broccoli - dietary;Cell Death;Cells;Chemicals;Congenital Abnormality;Consumption;CpG Islands;DNA Modification Methylases;Data;Development;Diet;Disease;Disease model;Embryo;Epigenetic Process;Ethanol;Fetal Alcohol Exposure;Fetal Alcohol Spectrum Disorder;Gene Expression;Gene Expression Regulation;Gene Silencing;Genes;Goals;Histone Deacetylase;Incidence;Intake;Laboratories;Lead;Malignant Neoplasms;Mediating;Mental Retardation;Methylation;Modification;Mus;Neural Crest Cell;Nutraceutical;Oral;Pathogenesis;Pathway interactions;Population;Prevention;Promoter Regions;Regimen;Role;Severities;Signal Transduction;Sulforaphane;Testing;Therapeutic;Transcriptional Activation;Vegetables;Work;alcohol exposure;antioxidant enzyme;base;effective intervention;epigenetic regulation;histone modification;in vivo;innovation;malformation;non-genetic;novel strategies;novel therapeutics;nutrition;organ injury;prevent;programs;promoter;response;teratogenesis


application_id: 9917670
project_number: 5P50AA024337-05
project_title: HDAC Mediated Epigenetic Mechanisms in Alcohol-Induced Abnormal Gut-Liver Axis
administering_ic: NIAAA
award_notice_date: 2020-05-29
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8303
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-05-01
budget_end_date: 2021-04-30
project_abstract:
There is increasing evidence that demonstrates a critical pathogenic role for the gut-liver axis in the development of alcoholic liver disease (ALD). The major goal of this proposal is to conduct studies that determine the mechanisms underlying chronic alcohol induced pathogenic changes in the gut-liver axis leading to ALD. Chronic alcohol consumption-mediated enteric microbiota (dysbiosis) and impairment of the gut barrier function leads to increased intestinal permeability and exposes the liver to gut-derived microbial products including endotoxin. The consequent hepatic steatosis and inflammation can in turn promote gut dysfunction. Our recent work has begun to identify specific alcohol-induced alterations in enteric microbiome and shows that chronic alcohol consumption leads to a significant expansion of pathogenic gram-negative bacteria that may lead to the development of systemic endotoxemia. Significantly the alcohol-induced intestinal and hepatic pathogenic changes were markedly attenuated by supplementation with the probiotic Lactobacillus rhamnosus Gorbach-Goldin (LGG).  There is gathering evidence and increasing interest regarding the contributory role of epigenetic mechanisms in the development of ALD. In this regard it has been observed that histone associated epigenetic modifications play a significant role in the development of hepatic pathology induced by chronic as well as binge alcohol exposure. Our recent work showed that binge alcohol treatment decreases hepatic class I II and IV HDACs with a sole increase in HDAC3 and a correspondent increase in the global hepatic histone H3 acetylation (H3Ac) status. Subsequently we demonstrated that increased HDAC3 plays a critical role in the binge alcohol-induced suppression of the carnitine palmitoyltransferase 1 (Cpt1a) gene expression and development of hepatic steatosis. Besides altered hepatic HDAC expression our recent preliminary data also show that chronic ethanol feeding leads to a significant increase in the intestinal HDAC1 expression. Accordingly the current proposal examines the unifying hypothesis that chronic alcohol induced alterations in the intestinal as well as hepatic HDACs and histone modifications constitute critical epigenetic mechanisms driving the abnormal gut-liver axis and liver disease. Importantly the proposal also pursues translational studies that examine the efficacy of nutrition based therapeutic interventions targeted at intestinal dysbiosis and HDAC inhibition in mitigating alcohol-induced gut-liver axis changes and liver disease. The specific aims of the proposal are: Aim 1 - Determine the effect of chronic alcohol on intestinal and hepatic HDAC expression and global histone modifications underlying gut-liver axis changes in ALD; Aim 2 - Determine the impact of alcohol-induced HDAC alterations on gene-specific histone modifications and consequent pathogenic expression affecting the gut-liver axis in ALD and; Aim 3 - Evaluate the efficacy of nutrition-based therapeutic interventions in ALD. We expect that the results of our study will provide critical molecular insights and facilitate the development of therapeutic interventions for ALD.

project_terms:
Acetylation;Affect;Alcoholic Liver Diseases;Alcohols;Attenuated;Automobile Driving;Bacteria;Butyrates;Carnitine Palmitoyltransferase I;Chronic;Data;Development;Diet;Endotoxemia;Endotoxins;Epigenetic Process;Ethanol;Fatty Acids;Fatty Liver;Functional disorder;Gene Expression;Genes;Goals;Gram-Negative Bacteria;HDAC1 gene;HDAC3 gene;Hepatic;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone H3;Histones;Impairment;Inflammation;Injury;Intestinal permeability;Intestines;Lactobacillus;Lactobacillus casei rhamnosus;Lead;Liver;Liver diseases;Mass Spectrum Analysis;Mediating;Modification;Molecular;Pathogenesis;Pathogenicity;Pathology;Permeability;Play;Prevention strategy;Probiotics;Prodrugs;Proteomics;Role;Testing;Therapeutic Intervention;Work;alcohol abuse therapy;alcohol effect;alcohol exposure;alcohol response;base;chronic alcohol ingestion;dysbiosis;enteric dysbiosis;epigenetic regulation;feeding;gut microbiome;gut microbiota;gut-liver axis;histone modification;insight;interest;intestinal barrier;lipid metabolism;metabolomics;microbial;nutrition;organ injury;probiotic supplementation;programs;promoter;therapeutic development;translational study;treatment strategy;tributyrin


application_id: 9917669
project_number: 5P50AA024337-05
project_title: Role of Dietary Fat in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2020-05-29
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8302
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-05-01
budget_end_date: 2021-04-30
project_abstract:
Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the US and worldwide. Although substantial progress has been made in ALD pathogenesis the specific mechanism(s) responsible for ALD development and progression remain incompletely understood. Importantly there is no FDA approved therapy for any stage of ALD. Recent studies from our laboratory and others demonstrated that dietary unsaturated fat rich in linoleic acid (LA) increased intestinal permeability to gut-derived endotoxins and exacerbated liver inflammation and injury in an experimental animal model of ALD. In addition our preliminary data show elevated levels of circulating oxidized LA metabolites (OXLAMs) specifically 9- and 13-hydroxy- octadecadienoic acids (9-and 13-HODEs) and concomitant up-regulation of hepatic 12/15 lipoxygenase (12/15-LO) the key enzyme involved in the oxidation of LA. These findings suggest that OXLAMs which act as natural ligands to the transient receptor potential vanilloid 1 (TRPV1 subfamily V member 1) contribute to the pathogenesis of ALD. TRPV1 is a ligand-gated non-selective cation channel with high permeability for Ca2+. A number of recent studies have shown a critical role for intracellular Ca2+ in inflammasome activation. NLRP3 Inflammasome activation with release of interleukin-1 (IL-1) and interleukin-18 (IL-18) is an important pro- inflammatory response in ALD. Many factors are involved in inflammasome priming and activation network including gut-derived endotoxin lipopolysaccharide (LPS). These findings in conjunction with our preliminary data have led us to hypothesize that dietary unsaturated fat (linoleic acid enriched) exacerbates alcohol- mediated liver inflammation and injury via oxidized linoleic acid metabolites that induce gut barrier disruption and hepatic inflammasome activation. To address our hypothesis we propose the following four specific aims: Aim 1. Determine the role of dietary unsaturated fat specifically linoleic acid and its oxidation products in the development and/or progression of ALD. Aim 2. Assess whether hepatic inflammasome activation is mediated by OXLAMs-TRPV1-Ca2+ pathway in an animal model of ALD. Aim 3. Evaluate the molecular mechanism(s) by which dietary saturated fat attenuates and unsaturated fat exacerbates alcohol- mediated gut barrier disruption endotoxemia and liver injury. Aim 4. Explore the role of OXLAMs 12/15-LO and TRPV1 in monocyte inflammasome activation in human alcoholic hepatitis. The proposed studies will lead to a better understanding of the molecular mechanisms contributing to the pathogenesis of alcohol-induced liver inflammation and injury. These studies will also help us to better understand alcohol-diet interactions which may lead to identification of new drug targets and potential dietary interventions for treating ALD as well as help to explain why only some people who drink heavily develop clinically important ALD. This proposal extensively interacts with other projects pilots and cores and it incorporates the ULARC theme of nutrition and alcohol-induced organ injury.

project_terms:
Address;Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Arachidonate 15-Lipoxygenase;Attenuated;Cations;Clinical;Consumption;Data;Development;Diet;Dietary Fats;Dietary Intervention;Down-Regulation;Endotoxemia;Endotoxins;Enzymes;Ethanol;Experimental Animal Model;FDA approved;Genetic;Heavy Drinking;Hepatic;Human;Inflammasome;Inflammation;Inflammatory;Inflammatory Response;Interleukin-1 beta;Interleukin-18;Intestinal permeability;Intestines;Kupffer Cells;Laboratories;Lead;Ligands;Linoleic Acids;Lipopolysaccharides;Mediating;Molecular;Morbidity - disease rate;Oral;Oxides;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Permeability;Pharmacology;Play;Production;Proteins;Role;Severities;Signal Pathway;Supplementation;TRPV1 gene;Testing;Tight Junctions;Translating;Unsaturated Fats;Up-Regulation;Vanilloid;Whole Blood;base;cytokine;fecal metabolome;gut microbiome;human study;inflammatory disease of the intestine;liver inflammation;liver injury;member;monocyte;mortality;new therapeutic target;nutrition;octadecadienoic acid;organ injury;overexpression;oxidation;peripheral blood;prevent;programs;receptor;saturated fat


