# projects

application_id: 9688200
project_number: 5R01DA043938-03
project_title: Cardiovascular Immune and Psychosocial Benefits of Reduced Cocaine Use
administering_ic: NIDA
award_notice_date: 2019-05-28
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: 2022-05-31
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;Comorbidity;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;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: 9688128
project_number: 5R01NS093920-05
project_title: Microglia responses to CNS injury: targeting p38 MAPK signaling
administering_ic: NINDS
award_notice_date: 2019-04-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 093920
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2015-05-01
project_end_date: 2020-04-30
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
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:
DESCRIPTION (provided by applicant): Microglia are the resident tissue myeloid cell in the brain. Acute isolation and molecular profiling of adult microglia have clearly identified a microglia-specific gene expression profile not found in other macrophage populations or other cells in the CNS. As a molecular and functionally unique population of cells microglia exhibit a remarkable ability to survey the brain and rapidly undergo a spectrum of responses to insults or tissue damage. These coordinated responses normally result in protection against injury but can be dysfunctional and exacerbate or even cause neurological disease. An added layer of complexity occurs when monocytes are recruited to the brain following disease or injury. As a functionally distinct population newly recruited monocytes/macrophages make different contributions to disease progression compared to microglia. One of the top canonical pathways in microglia/macrophages is the p38 MAPK pathway a well-established signaling pathway important in stress responses. In the last funding period we documented the importance of the p38alpha isoform in microglia proinflammatory cytokine production and found that suppression of p38alpha can prevent the inflammatory response that causes subsequent neuronal/synaptic damage. In two mouse models of diffuse traumatic brain injury (TBI) we found that deletion of p38alpha in myeloid cells was associated with decreased microglia activation and a rescue of vestibulomotor deficits cognitive impairments and synaptic protein loss. Our data demonstrating the importance of p38alpha in regulating key functions of macrophages/microglia that are altered by a brain injury provides a strong precedent for further mechanistic and translational studies. We have now developed an exceptionally specific small molecule p38alpha inhibitor (termed MW150) that is CNS- penetrant has drug-like properties and no adverse effects at very high doses. MW150 is a novel reagent with high translational relevance for future therapeutic development. As a foundation for future development we now propose to address mechanistically how to target p38alpha to improve outcomes following a TBI. To this end we need to answer: 1) When can p38alpha be targeted; i.e. what is the optimal therapeutic window after TBI? 2) Where and how can p38alpha be targeted; i.e. does p38alpha in other inflammatory cell types besides microglia (infiltrating macrophages astrocytes endothelial cells)contribute to neuroinflammatory responses after TBI? Our studies will provide key mechanistic information about how injury-induced p38alpha-dependent inflammatory responses in multiple cell types synergize and cross-talk to drive neurologic impairments. We will test the hypothesis that suppression of p38alpha signaling in appropriate therapeutic windows and appropriate cell types after CNS injury can lead to selective beneficial outcomes. Our aims are: Aim 1. Establish the post-injury therapeutic window for efficacy of our small molecule p38a inhibitor. Aim 2. Define the contribution of p38a in resident microglia versus infiltrating macrophages to TBI-induced impairments. Aim 3. Determine how p38alpha in other CNS inflammatory cell types (astrocytes and endothelial cells) contributes to injury-induced responses.

project_terms:
AD pathology;Acute;Address;Adult;Adverse effects;Alzheimer's disease model;Astrocytes;Brain;Brain Injuries;Cells;Central Nervous System Diseases;Chronic;Clinical;Cognitive deficits;Craniocerebral Trauma;Data;Development;Diffuse;Disease;Disease Progression;Dose;Drug Kinetics;Endothelial Cells;Exhibits;Foundations;Functional disorder;Funding;Future;Gene Expression Profile;Immune response;Impaired cognition;Impairment;Inflammatory;Inflammatory Response;Injury;Intervention;Knockout Mice;Lead;MAPK14 gene;Medical;Microglia;Mitogen-Activated Protein Kinases;Modeling;Molecular;Molecular Profiling;Morbidity - disease rate;Mus;Myeloid Cells;Nervous System Physiology;Nervous System Trauma;Neuroglia;Neurologic;Neurons;Outcome;Paracrine Communication;Pathway interactions;Pharmaceutical Preparations;Phenotype;Phosphotransferases;Population;Production;Property;Protein Isoforms;Proteins;Reagent;Reporting;Research;Role;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Site;Surveys;Synapses;Testing;Therapeutic;Therapeutic Intervention;Tissues;Traumatic Brain Injury;analog;biological adaptation to stress;cell type;central nervous system injury;clinical development;cytokine;defined contribution;dementia risk;effective therapy;improved outcome;inhibitor/antagonist;macrophage;mitogen-activated protein kinase p38;monocyte;mouse model;nervous system disorder;neuroinflammation;novel;prevent;public health relevance;recruit;response;small molecule;small molecule inhibitor;stressor;targeted treatment;therapeutic development;therapeutic target;translational study

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Traumatic brain injury represents a major unmet medical need for which there is no effective therapy to improve outcome and prevent the cognitive impairment long-term neurologic morbidity or increased risk of dementia and other medically intractable complications. Successful completion of these studies will define when where and how the important inflammatory kinase p38alpha can be targeted for beneficial outcomes. Our results will provide a foundation for the future clinical development of p38alpha inhibitors for head injury.


application_id: 9687647
project_number: 5R01AG026307-13
project_title: Self-Regulation and Brain and Cognitive Health in Older Adults
administering_ic: NIA
award_notice_date: 2019-04-01
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 026307
program_official: NIELSEN, LISBETH
project_start_date: 2006-07-15
project_end_date: 2022-03-31
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Summary The typical older adult experiences declines in brain structure and cognitive function but these mean declines occur in the context of what can be very different individual trajectories. The purpose of this project is to measure individual differences and changes in self-regulation (control of thoughts emotions behaviors and impulses) over time in older adults and to link self-regulation to physical activity inflammation and trajectories of neurocognitive health relevant to development of Alzheimers disease. This is a competing renewal of this longitudinal study which began in 2001 and received R01 funding in 2006 submitted by a research team with expertise in aging self-regulation exercise science neuropsychology neuroimaging Alzheimers disease and longitudinal design and analysis. The previous renewal period focused on relationships among facets of self-regulation and their relationship to immunological and cardiovascular health. The renewal continues assessment of these measures to provide continuity in this longitudinal dataset and adds innovation in the inclusion of repeated neuroimaging and assessment of infectious disease burden. Specifically the aims of the study are: (1) to test the effects of facets of self-regulation (conscientiousness self-regulation executive cognitive function and heart rate variability) on measures of neurocognitive health associated with aging and risk for Alzheimers disease; (2) to test the degree to which the relationship between self-regulation and neurocognitive health is mediated by physical activity and inflammation; (3) to test whether neurocognitive health associated with executive cognitive functions (e.g. dorsolateral frontal lobe volume) contributes to better self-regulation higher physical activity and lower inflammation; and (4) to test effects of infectious disease burden (latent viruses Toxoplasma gondii) on self-regulation inflammation and neurocognitive health and risk for Alzheimers disease. At 6-month intervals older adults (N = 175) will complete measures of self-reported self-regulation; executive cognitive functions including inhibition shifting and working memory; and resting HRV. Physical activity BMI and waist circumference will be measured at each visit. Blood draws will be synchronized with these visits and assays performed on these samples will capture serum proinflammatory cytokines and antibodies against latent infections. The sample has follow-back data on many of these measures from 1-15 years and an eligible subset (N = 90) will already have baseline neuroimaging. Neuroimaging will be repeated twice at 2-year intervals. This renewal will be innovative in its longitudinal assessment of a dynamic system that includes brain behavior and immunity; integration of neuroimaging measures with other domains of healthy and unhealthy aging; and multimodal assessment of neurocognitive health including measures associated with risk for Alzheimers disease and other dementias: subjective cognitive health cognitive function volumetric imaging measures connectivity fractional anisotropy and resting cerebral blood flow.

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

public_health_relevance:
NarrativeWith age come changes in the brain that can increase the risk of cognitive decline and neurological disease.However not all older adults experience these changes to the same degree. This project will continue to tracka cohort of older adults examining psychological and immunological factors that may be protective for brainand cognitive health and vice versa.


application_id: 9686503
project_number: 5R01AG054130-04
administering_ic: NIA
award_notice_date: 2019-03-11
opportunity_number: PAR-16-365
application_type: 5
activity_code: R01
ic: AG
serial_number: 054130
program_official: MCLINDEN, KRISTINA
project_start_date: 2016-07-15
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZRG1-BBBP-V(55)R]
contact_pi_person_id: 10700978
contact_pi: MOGA, DANIELA CLAUDIA
other_pis: JICHA, GREGORY A
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-04-01
project_title:
INtervention for Cognitive Reserve Enhancement in delaying the onset of Alzheimers Symptomatic Expression: The INCREASE study

project_abstract:
Alzheimer's disease (AD) represents one of the most important public health issues our society is facing today.An estimated 5 million people age 65 and older in the United States (US) are currently living with AD and thisnumber may nearly triple by 2050. To address this impeding population burden the National Alzheimer's ProjectAct (NAPA) 2015 report emphasized the need for identifying preventive strategies that can delay symptomaticdisease onset. While much emphasis has been placed on developing and testing effective disease-modifyingstrategies targeting this asymptomatic preclinical phase of AD (pAD) little emphasis has been placed oncurrently available strategies that target cognitive reserve resulting in (1) delaying symptom onset (2) shorteningthe overall course of symptomatic disease and (3) substantially reducing the financial and societal impact of AD.We hypothesize that targeted reductions in inappropriate medication use (Beers Criteria 2015) will bolstercognitive reserve in subjects at risk for AD delaying the onset of clinical symptoms and reducing the prevalenceand duration of symptomatic disease. The impact of this strategy if successful includes a dramatic reduction inoverall health care expenditures for the millions affected by AD by delaying the symptomatic phase of diseasein accord with NAPA aims. Our specific aims are:Specific Aim 1. Conduct a 12-month randomized placebo-controlled trial to evaluate the impact of our patient-centered pharmacist-physician team MTM intervention in reducing unnecessary and inappropriate medicationuse in community-dwelling elderly non-demented subjects. Primary outcome measures will include pre- to post-intervention measures of: (1) use of inappropriate medications as measured by the Medication AppropriatenessIndex (MAI); 2) Cognitive Reserve Change Score (CRCS) defined as the difference in the scopolamine-challenged vs unchallenged measures on the neurocognitive score.Specific Aim 2 Evaluate the impact of preclinical amyloid burden on cognitive reserve deficits and decline(measured as CRCS) to evaluate efficacy of delaying symptomatic disease progression in pAD.While not eliminating AD or shortening duration of biological disease the delay in symptom onset andprogression to functional decline resulting from reduction in inappropriate medication use could lessen ADprevalence and significantly reduce healthcare expenditures related to not only AD but potentially all forms ofdementia involving a prodromal asymptomatic period. Study results would enable the larger implementation ofsimilar medication management strategies in clinical practice to address the need for multifaceted preventivestrategies to maintain cognitive health in the aging population.

project_terms:
AD pathology;Address;Adverse drug effect;Aerobic Exercise;Affect;Alzheimer's Disease;Alzheimer's disease risk;American;Amyloid;Amyloid beta-Protein;Anti-Cholinergics;Beer;Biological;Brain;Clinical;Cognitive;Communities;Comorbidity;Complex;Data;Dementia;Diet;Disease;Disease Progression;Drug usage;Elderly;Enrollment;Health;Health Care Costs;Health Expenditures;Impaired cognition;Intervention;Intervention Trial;Measures;Medical;Medication Management;Neurocognitive;Neurofibrillary Tangles;Onset of illness;Outcome Measure;Pathologic;Pathology;Patients;Pharmaceutical Preparations;Pharmacists;Pharmacology;Pharmacy facility;Phase;Physicians;Population;Positron-Emission Tomography;Prevalence;Prevention strategy;Public Health;Reporting;Research;Scopolamine;Senile Plaques;Societies;Standardization;Symptoms;Testing;Time;United States;aging population;base;clinical practice;cognitive reserve;disability;exhaust;functional decline;human old age (65+);indexing;insight;non-demented;older patient;patient oriented;placebo group;post intervention;pre-clinical;preservation;primary outcome;psychosocial;public health relevance;randomized placebo controlled trial;randomized trial;stressor;therapy design;uptake

public_health_relevance:
Public Health Relevance StatementThe study will examine the impact on cognitive reserve of a pharmacist-physician patient-centered medicationtherapy management intervention to address inappropriate medication use as identified by the Beers 2015 list.By bolstering cognitive reserve our project will directly address the National Alzheimer's Project Act 2015priorities serving to delay onset of symptoms in preclinical dementia. The results of this study will providevaluable insights on how to expand this intervention to reduce the prevalence and associated healthcare costsof symptomatic Alzheimer's disease.


application_id: 9685940
project_number: 5R01HL139748-02
project_title: Atherosclerosis Mechanisms: Angiotensin II production and action
administering_ic: NHLBI
award_notice_date: 2019-03-29
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 139748
program_official: HASAN, AHMED A K
project_start_date: 2018-05-01
project_end_date: 2022-03-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 9382938
contact_pi: LU, HONG SHEN
other_pis: DAUGHERTY, ALAN
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:
Abstract The renin angiotensin system (RAS) plays a critical role in the development ofatherosclerosis. Mechanisms by which the RAS contributes to atherosclerosis have beenfocusing on effects of angiotensin II (AngII) production and its action through AT1a receptorswithin atherosclerotic lesions. On the basis of our preliminary data we challenge this conceptand propose a new hypothesis: Renal AngII production through a megalin-mediatedpathway in proximal convoluted tubules (PCTs) promotes atherosclerosis via its localstimulation of AT1a receptors. Angiotensinogen (AGT) the substrate of the RAS derivedfrom hepatocytes is filtered through glomeruli and retained by megalin a member of LDLreceptor superfamily in PCTs. Our protein sequence and structure analyses identified twoconserved sequences that may associate with its binding to megalin. Aim 1 will define howhepatocyte-derived AGT regulates renal AngII production and contributes to atherosclerosis.We will use site-mutagenesis surface plasmon resonance and cell culture system to determinehow AGT and megalin interact in vitro. Subsequently we will use an adeno-associated viral(AAV) system to manipulate conserved sequences of AGT in hepatocyte-specific AGT deficientmice to determine whether conserved sequences of AGT influence renal AngII production andatherosclerosis. Effects of megalin on renal AngII production and atherosclerosis will bedetermined using PCT-specific megalin deficient mice. Since AGT is cleaved by two criticalenzymes renin and angiotensin-converting enzyme (ACE) to produce AngII Aim 2 will firstdetermine whether renin or ACE derived from PCTs contributes to renal AngII production andatherosclerosis using PCT-specific renin and ACE deficient mice respectively. Studiesproposed in Aim 1 for AGT and megalin interaction and Aim 2 for the two enzymes (renin andACE) do not provide direct evidence whether AngII produced in PCTs contributes toatherosclerosis. To answer this question we will use a transgenic mouse model that hasrestricted production of AngII in PCTs. AngII promotes atherosclerosis through AT1a receptor-mediated mechanism. Therefore subsequent experiments will determine whether PCTs are thelocation for AT1a receptors to promote atherosclerosis. Completion of proposed studies willprovide evidence whether renal PCTs are the major source for each classic RAS component topromote atherosclerosis. Demonstration of this new concept may change our understanding ofthe AngII/AT1a receptor-mediated mechanisms of atherosclerosis which may also provideinsights into developing new therapeutic strategies.

project_terms:
Address;Amino Acid Sequence;Androgens;Angiotensin II;Angiotensin Type 1a Receptor;Angiotensinogen;Arterial Fatty Streak;Atherosclerosis;Binding;Breeding;Cell Culture System;Cleaved cell;Color;Conserved Sequence;Data;Development;Elements;Endocrine system;Endothelial Cells;Enzymes;Fibroblasts;Genes;Hepatocyte;Human;In Vitro;Infusion procedures;Kidney;LDL-Receptor Related Protein 2;Lesion;Leukocytes;Literature;Location;Low Density Lipoprotein Receptor;LoxP-flanked allele;Mediating;Methods;Mus;Mutagenesis;Nephrons;Pathway interactions;Peptidyl-Dipeptidase A;Pharmacology;Play;Production;Proteins;Renin;Renin-Angiotensin System;Reproducibility;Role;Site;Smooth Muscle Myocytes;Source;Structural Protein;Surface Plasmon Resonance;System;Techniques;Testing;Therapeutic;Transgenes;Transgenic Mice;Viral;base;cell type;enzyme deficiency;experimental study;hypercholesterolemia;insight;member;mouse model;mutant;novel therapeutic intervention;prevent;promoter;protein structure;receptor;urinary

public_health_relevance:
Project NarrativeThe renin angiotensin system plays a critical role in the development of atherosclerosis. Thisproposal aims to understand the mechanisms and source of this hormonal system onatherosclerosis thereby providing new insights into developing potential therapeutic strategies.


application_id: 9685847
project_number: 5R01AI120244-05
project_title: Molecular and Cellular Pathogenesis of Legionella
administering_ic: NIAID
award_notice_date: 2019-04-15
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 120244
program_official: ERNST, NANCY L
project_start_date: 2015-05-01
project_end_date: 2021-04-30
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In the aquatic environment Legionella pneumophila (Lp) proliferates within amoeba but upon transmission to humans it causes pneumonia with high morbidity and mortality. Within amoeba and human macrophages Lp proliferates within the Legionella-containing vacuole (LCV) which evades lysosomal fusion and is remodeled by the endoplasmic reticulum (ER). Biogenesis of the LCV is controlled by the Dot/Icm type IV secretion system which injects into the host cell ~300 protein effectors that modulate a myriad of cellular processes to enable intracellular proliferation of Lp. Very few of this large battery o Lp effectors such as AnkB and AnkH are required for the intracellular infection. To attain biological function in the host cell many injected bacterial effectors require post- translationalmodification by various host machineries. Post-translational modification of eukaryotic proteins by Asparagine (Asn) hydroxylation impacts their protein-protein interaction and has been widely studied during hypoxic conditions in inflammatory foci. It is not known whether any injected bacterial effector is post-translationally modified by the host asparagine hydroxylase FIH. The Asn hydroxylation motif has been identified within many human Ankyrin repeats-containing proteins (Ank) that have been shown to be modified by FIH. Our bioinformatics preliminary data have identified an Asn hydroxylation motif within the ankyrin repeats of the AnkB and AnkH effectors of Lp and we show that both effectors are modified by the host FIH Asparagine hydroxylase. We show that the host FIH is rapidly recruited to the LCV membrane where AnkH and AnkB are exclusively localized. Our in silico genomic analyses have identified the Asn hydroxylation motif in eight other translocated effectors of Lp. Importantly RNAi-mediated knockdown or chemical inhibition of FIH abolishes intracellular proliferation of Lp and promotes fusion of the LCV to the lysosomes. Therefore our hypothesis is: host-mediated Asn hydroxylation of Lp effectors by FIH is required for their functions in biogenesis of the LCV and intracellular proliferation of Lp. To test our hypothesis our specific aims are to characterize th following: I) Asn hydroxylation of AnkH and its role in the intracellular infection; II) Asn hydroxylation of AnkB and its role in the intracellular infection; and III) Asn hydroxylation of oter Lp effectors and its role in biogenesis of the LCV. Upon completion of our proposed studies the biological function and host targets of AnkH will be known and the ubiquitination substrates of AnkB will be identified. The role of host FIH-mediated Asn hydroxylation in the biological function of AnkH and AnkB will be uncovered. This is significant since both effectors are two of very few of the battery of ~300 Lp effectors to be required for intra-vacuolar proliferation. We wil report on our novel discovery of the acquisition of the FIH complex by a pathogen-containing vacuole and its role in modification of several Lp effectors. We will uncover the role of FIH-mediated Asn hydroxylation of several Lp effectors in lysosomal evasion by the LCV. Our proposed studies on Lp-primary hMDMs interaction and specific manipulation of the host post- translational modification by FIH are innovative with broad high impact and significance not only for Lp but for other pathogens. This is evident from our discovery of Asn hydroxylation of the YopM effector of Yersinia and potential Asn hydroxylation of the IpaH4.5 effector of Shigella and the EsxF effector of Mycobacterium.

project_terms:
Alveolar Macrophages;Amoeba genus;Ankyrin Repeat;Asparagine;Bacterial Proteins;Binding;Biogenesis;Bioinformatics;Biological Process;Cell physiology;Cells;Chemicals;Complex;Computer Simulation;Data;Disease;Endoplasmic Reticulum;Environment;Enzymes;Genetic Transcription;Genomics;Genus Mycobacterium;Human;Hydroxylation;Hypoxia;Infection;Inflammatory;Legionella;Legionella pneumophila;Legionnaires' Disease;Lysosomes;MMP14 gene;Mediating;Membrane;Mixed Function Oxygenases;Modification;Molecular;Morbidity - disease rate;Organism;Pathogenesis;Phagocytes;Pneumonia;Post-Translational Protein Processing;Proliferating;Proteins;Proteome;RNA Interference;Reporting;Role;Shigella;System;Testing;Type IV Secretion System Pathway;Ubiquitination;Vacuole;Yersinia;genome-wide;innovation;knock-down;liquid chromatography mass spectrometry;macrophage;microbial;monocyte;mortality;novel;pathogen;protein protein interaction;public health relevance;recruit;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Very little is known about how intracellular pathogens evade killing by phagocytic cells through manipulation of various cellular processes to facilitate intracellular bacterial proliferation and manifestation of disease. Our proposed studies on Legionella pneumophila explores how this pathogen utilize the bacterial proteins such as AnkH and AnkB which the pathogen injects into the host cell to manipulate the host cell to enable microbial proliferation. These injected microbial proteins are modified by the host modification machineries and this modification is required for the functions of the injected bacterial effector. Our proposed studies will identify the host protein substrates that interact with these injected AnkH and AnkB effectors and the role of host-mediated modifications of the effector in intracellular proliferation of L. pneumophila. We have identified eight additional Legionella proteins that are also injected into the host and have the potential to be modified by the host and this will be investigated in our proposed studies.


application_id: 9685835
project_number: 5R01AG057187-03
project_title: Novel pathogenetic mechanism for hippocampal sclerosis a common Alzheimers mimic
administering_ic: NIA
award_notice_date: 2019-04-09
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 057187
program_official: OPANASHUK, LISA A
project_start_date: 2017-07-15
project_end_date: 2022-03-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
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:
Hippocampal sclerosis of aging (HS-Aging) is a major pathologic substrate of dementia but there currently areno validated strategies in the clinical setting to diagnose or treat the disease. HS-Aging affects ~15% ofelderly persons and is associated with substantial cognitive impairment. Our group has studied this areaextensively leading to the following major hypothesis: thyroid hormone (TH) dysregulation contributesto HS-Aging pathogenesis. This novel pathogenetic mechanism may provide the basis to diagnose HS-Aging during life using CSF analyses and to develop a therapeutic strategy. However critical knowledgegaps remain in terms of characterizing the specific association between TH dysfunction and brain pathologyand the potential to target the mechanism for therapeutic purposes. We propose a research program to fillthese knowledge gaps while testing key hypotheses via the following Specific Aims:Hypothesis 1: Clinical TH status is associated with presence and severity of HS-Aging pathology.Specific Aim 1: Test the hypothesis in a convenience sample (n=205 including cognitively intact and diversenon-HS-Aging dementia controls) from the University of Kentucky AD Center biobank. We will apply rigorousquantitative digital pathologic methods to assess TDP-43 pathology AD plaques/tangles and -synucleinopathy for correlation with clinical TH status: self-reported TH disease and TH medications are well-documented. As expected in aged persons more than 25% of the subjects exhibited clinical TH dysfunction.Hypothesis 2: CSF TH levels are associated with HS-Aging pathology and may provide a novel biomarker.Specific Aim 2: Evaluate TH (triiodothyronine or T3) in CSF as a clinical biomarker of HS-Aging. We willassess human CSF TH levels with direct correlation with various subtypes of pathology. We also will test THin clinical CSF from lumbar punctures correlated with established AD-related biomarkers (A and tau) andHS-Aging SNPs with the goal of developing a new method to diagnose HS-Aging in living persons. We haveobtained CSF from autopsied individuals (n=104) and clinical CSF samples (n=195) to accomplish this Aim.Hypothesis 3: Specific HS-Aging risk-associated gene variants induce altered brain TH levels with extensiveimpact on brain gene expression and orally available drugs can alter this pathogenetic mechanism.Specific Aim 3: Define gene expression changes relevant to TH and HS-Aging. We will analyze humangenomics databases to define how gene changes linked to HS-Aging risk contribute to variability in ABCC9and SLCO1C1 (a major brain TH transporter) expression. We will test human cells (cultured human hESCastrocytes and lymphoblastoid cells transformed with DNA from people with known genotypes and pathology)to determine the potential for manipulating the levels of ABCC9 of TH transporter SLCO1C1 and of other TH-regulated genes. Finally in mice we will test how TH-responsive gene expression neuropathology andneurobehavior are affected in vivo by treatment with TH and/or the ABCC9 agonist drug glimepiride.

project_terms:
ABCC9 gene;Affect;Age;Aging;Agonist;Alzheimer's Disease;Alzheimers disease biomarker;American;Area;Astrocytes;Autopsy;Behavior;Biological Markers;Biometry;Blood specimen;Brain;Brain Diseases;Brain Pathology;Cell Culture Techniques;Cells;Clinical;Cognitive;DNA;Data;Databases;Dementia;Development;Diagnosis;Disease;Elderly;Exhibits;Functional disorder;Future;Gene Expression;Genes;Genetic;Genotype;Glimepiride;Goals;Hippocampus (Brain);Hormone Responsive;Human;Impaired cognition;Individual;Infarction;Interdisciplinary Study;Kentucky;Knockout Mice;Knowledge;Life;Link;Metformin;Methods;Modeling;Morbidity - disease rate;Mus;Mutation;Neurofibrillary Tangles;Oral;Pathogenesis;Pathologic;Pathology;Patient Self-Report;Persons;Pharmaceutical Preparations;Pharmacology;Phenotype;Regulator Genes;Research;Research Personnel;Risk;Sampling;Severities;Spinal Puncture;Testing;Therapeutic;Thyroid Gland;Thyroid Hormones;Thyroxine;Transcript;Triiodothyronine;Universities;Widespread Disease;aged;base;biobank;cell transformation;clinical biomarkers;cohort;dementia risk;digital;experimental study;genetic variant;genomic biomarker;hippocampal sclerosis;human embryonic stem cell;human genomics;in vivo;neurobehavior;neuropathology;novel;novel marker;prevent;programs;protein TDP-43;risk variant;synucleinopathy;therapeutic target

public_health_relevance:
PROJECT NARRATIVEWe are performing studies of a brain disease (hippocampal sclerosis of aging) thatmimics Alzheimer's disease in the clinical setting and which affects millions ofAmericans. Our group has studied this disease extensively leading to the followingmajor hypothesis: thyroid hormone dysregulation contributes to hippocampalsclerosis dementia. The experiments described in this proposal are necessary fordeveloping future clinical strategies aimed at detecting and ultimately preventing thisunderappreciated prevalent and high-morbidity brain disease.


application_id: 9683079
project_number: 1F31DC017660-01
project_title: Connectivity of periperal taste neurons
administering_ic: NIDCD
award_notice_date: 2018-08-20
opportunity_number: PA-18-671
application_type: 1
activity_code: F31
ic: DC
serial_number: 017660
program_official: RIVERA-RENTAS, ALBERTO L
project_start_date: 2018-09-01
project_end_date: 2021-08-31
study_section: Special Emphasis Panel[ZDC1 SRB-R (36)]
contact_pi_person_id: 15039557
contact_pi: OHMAN, LISA C
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/AbstractWhile the function of taste neurons (that connect taste receptor cells to the brain) has been well-studiedalmost nothing is known about individual taste neuron morphology or peripheral connectivity. Specifically it isunclear how many taste receptor cells provide input to a single neuron or even if those receptor cells are all thesame type. This lack of knowledge contributes to our relatively poor understanding of peripheral taste codingmechanisms. This project will use a combination of sparse cell genetic labeling and serial blockface scanningelectron microscopy (SBF-SEM) to 1) examine the number of taste receptor cells likely contacted by chordatympani neurons of differing complexity 2) determine if individual neurons contact receptor cells of the sametype or more than one type. I will accomplish these goals via three specific Aims. In Aim 1 I will determine ifthere are any structural motifs present at synapses or non-synaptic structural connections using SBF-SEMwhich can also be identified in 3-D confocal images of sparsely labeled nerve fibers and taste receptor cells.The goal is to permit better interpretation of the anatomical relationships between receptor cells and nervefibers at the light level. In Aim 2 I will reconstruct separate fibers entering the taste bud using SBF-SEM whichwill determine the rules of connectivity of simply vs. sparsely branched fibers within the fungiform taste bud.These data will be compared with the contacts identified using image analysis software at the light levelbetween individual fibers entering the taste bud. In Aim 3 I will analyze the morphology of whole chordatympani nerve fibers innervating anywhere from 1 to 7 taste buds and relate their branching complexity to thenumber and types of peripheral contacts made with taste receptor cells. Together these experiments will testthe hypothesis that heavily branched neurons contact many more taste receptor cells of multiple typescompared to simply branched neurons which will contact only a few receptor cells of a single type. This projectwill be the first to examine the peripheral connectivity of individual chorda tympani neurons and may reveal ananatomical substrate for the physiological finding that some neurons are narrowly tuned (respond to one tastestimulus) whereas others are broadly tuned (respond to multiple taste stimuli). Determining the peripheralconnectivity of individual neurons will likely inform future experiments designed to look at taste coding. Thesebaseline data for the normal connectivity of the peripheral taste system can be used to compare the potentialdisruption of connectivity that may result from disease states or manipulations of molecular factors regulatingthe formation of these connections.

project_terms:
3-Dimensional;Anatomy;Axon;Brain;Cell Count;Cells;Characteristics;Code;Complex;Computer software;Data;Defect;Disease;Electron Microscopy;Face;Fiber;Future;Ganglia;Genetic;Goals;Image;Image Analysis;Immunohistochemistry;Individual;Knowledge;Label;Laboratories;Length;Light;Location;Maps;Mentors;Methodology;Molecular;Morphology;Mus;Nerve Fibers;Neurons;Peripheral;Peripheral Nerves;Pharmaceutical Preparations;Physiological;Quality of life;Receptor Cell;Role;Scanning Electron Microscopy;Signal Transduction;Structure of geniculate ganglion;Synapses;Taste Buds;Taste Disorders;Taste Perception;Testing;Variant;Work;base;cell type;chemotherapy;chorda tympani;design;experimental study;fiber cell;light microscopy;novel;taste stimuli;taste system

public_health_relevance:
Project NarrativeTaste disorders impact quality of life yet little is known about the underlying defects and mechanisms thatresult in these perceptual deficits. Diseases and drugs (i.e. chemotherapies) that disrupt taste function couldhave their effects by disturbing taste receptor cell neuron peripheral connectivity. This project will develop abaseline connectivity map of peripheral nerve fibers with taste receptor cells; both the map and novelmethodological approach can be used to dissect the role of connectivity in taste disorders.


application_id: 9682743
project_number: 1F30DE028166-01A1
project_title: Regulation of ZEB1 by Porphyromonas gingivalis in gingival epithelial cells
administering_ic: NIDCR
award_notice_date: 2018-08-30
opportunity_number: PA-18-673
application_type: 1
activity_code: F30
ic: DE
serial_number: 028166
suffix: A1
program_official: FRIEDEN, LESLIE A
project_start_date: 2018-09-01
project_end_date: 2022-08-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 14903180
contact_pi: FITZSIMONDS, ZACKARY R
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Amanitins;Anaerobic Bacteria;Apical;Apoptosis;Binding;Biopsy;Blood Circulation;Cancer Patient;Cell Cycle;Cell Cycle Progression;Cell Nucleus;Cells;Co-Immunoprecipitations;Complex;Data;Development;Diagnosis;E-Cadherin;E1A-associated p300 protein;Embryonic Development;Environment;Epidemiology;Epithelial;Epithelial Cells;Epithelium;Esophageal Squamous Cell Carcinoma;Family;Foundations;Future;Gene Expression;Genes;Genetic Transcription;Germ Cells;Gingiva;Homeobox;Human;Immunofluorescence Immunologic;Immunohistochemistry;Immunoprecipitation;Intercept;Invaded;Knowledge;Laboratories;Lead;Literature;Luciferases;MADH2 gene;MADH3 gene;MADH4 gene;MADH6 gene;MADH7 gene;MMP9 gene;Malignant Neoplasms;Measures;Mediating;Mesenchymal;MicroRNAs;Microbe;Migration Assay;Molecular;N-Cadherin;Neoplasm Metastasis;Nuclear;Oncogenic;Oral;Oral cavity;Pathway interactions;Patients;Periodontal Diseases;Periodontitis;Phenotype;Phosphorylation;Plasmids;Play;Porifera;Porphyromonas gingivalis;Primary carcinoma of the liver cells;Process;Property;Quantitative Reverse Transcriptase PCR;RNA;RNA Synthesis Inhibitors;Ramp;Regulation;Role;Sampling;Signal Pathway;Signal Transduction;Speed;Survival Rate;TGF Beta Signaling Pathway;Testing;Tight Junctions;Time;Tongue Neoplasms;Transcription Coactivator;Transcription Repressor/Corepressor;Transforming Growth Factor beta Receptors;Translating;Untranslated RNA;Up-Regulation;Western Blotting;Zinc Fingers;arm;cancer cell;cancer diagnosis;differential expression;dysbiosis;epithelial to mesenchymal transition;expression vector;human tissue;knock-down;mRNA Expression;mRNA Stability;malignant mouth neoplasm;mouth squamous cell carcinoma;new therapeutic target;novel;novel diagnostics;novel therapeutics;outcome forecast;overexpression;prevent;promoter;recruit;response;scaffold;synergism;transcription factor;tumor


application_id: 9681423
project_number: 5R37CA227656-02
project_title: The phosphatase PRL3 as a MYC target and pro-survival oncogene in Acute Lymphoblastic Leukemia
administering_ic: NCI
award_notice_date: 2019-03-29
opportunity_number: PA-16-160
application_type: 5
activity_code: R37
ic: CA
serial_number: 227656
program_official: JHAPPAN, CHAMELLI
project_start_date: 2018-04-06
project_end_date: 2023-03-31
study_section: Cancer Molecular Pathobiology Study Section[CAMP]
contact_pi_person_id: 10310607
contact_pi: BLACKBURN, JESSICA S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute Lymphocytic Leukemia;Adult;Adverse effects;Apoptosis;Binding Sites;Biochemical;Biotin;Cancer Patient;Cells;Cessation of life;Child;Clinic;Clinical Trials;Cytotoxic Chemotherapy;DNA-Binding Proteins;Data;Defect;Development;Developmental Delay Disorders;Diagnosis;Disease;Disease Progression;Drug Targeting;Enhancers;FDA approved;Family;Gene Chips;General Population;Genes;Genetic Transcription;Growth;Human;Human Cell Line;In Vitro;Kinetics;Knowledge;Leukemic Cell;Life;Ligase;Link;MYC gene;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;Methods;Mission;Modeling;Molecular Target;Normal Cell;Nucleic Acid Regulatory Sequences;Oncogenes;Oncogenic;Organ;Outcomes Research;Pathway interactions;Patients;Phenotype;Phosphoric Monoester Hydrolases;Play;Preclinical Testing;Protein Array;Protein Tyrosine Phosphatase;Public Health;Regimen;Relapse;Research;Role;Sampling;Second Primary Cancers;Signal Pathway;Single Nucleotide Polymorphism;TP53 gene;Testing;Therapeutic;Transcriptional Regulation;Transplantation;Tumor Suppressor Proteins;Xenograft procedure;Zebrafish;acute lymphoblastic leukemia cell;base;cancer type;chemotherapy;in vivo;inhibitor/antagonist;innovation;knock-down;leukemia;member;molecular targeted therapies;novel;outcome forecast;pediatric patients;phosphatase inhibitor;preclinical trial;side effect;small molecule;targeted cancer therapy;targeted treatment;therapeutic target;transcription factor;translational impact;tumor progression


application_id: 9678368
project_number: 5R01HL138179-03
project_title: Platelet Endocytosis in Innate Immunity
administering_ic: NHLBI
award_notice_date: 2019-03-26
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 138179
program_official: YANG, YU-CHUNG
project_start_date: 2017-07-01
project_end_date: 2020-03-31
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Surprisingly platelets are capable of many cellular processes (i.e. RNA splicing translationglycosylation endocytosis); however their effects on platelet function are often unclear. Ascirculating sentries platelets sample the vasculature via endocytosis. Some of theendocytosed cargo (i.e. fibrinogen) traffics to granules; however other material initiatesplatelet responses. In this proposal we show that pathogen endocytosis induces immuno-activation of platelets. This likely contributes to the increased cardiovascular risks associatedwith persistent infections (as seen in HIV-1/AIDS patients). In this application we build onour novel findings hypothesizing that platelet endocytosis is critical for innate immuneresponse to viral infections. To test this hypothesis we focus on how platelet endocytosisfacilitates Toll-like Receptor (TLR)-based signaling in an animal model that mimics chronicHIV-1/AIDS. Using novel genetically-altered mice (Arf6-/- VAMP-3-/- and Syntaxin-2/4-/-)which are defective at different endocytic steps we will address the roles routes andmechanisms of platelet endocytosis with specific focus on how platelets interact with HIV-1virus. We propose two specific aims: Aim 1. Determine the effects of defective plateletendocytosis on innate immune responses in a model of viremia. Aim 2. Determine themechanisms and routes of the platelet endocytosis system. Our proposal advances plateletsas active monitors of the vasculature continuously interacting with and interpreting theirenvironment while circulating. In this scenario platelets use endocytosis to continuouslysample their microenvironment and through endocytic trafficking process and evaluate cuesthat initiate responses to what the platelets have endocytosed. Our work will yield insights intoplatelet function during systemic infections thus reshaping the uses of anti-thrombotictherapies. Finally understanding platelet endocytosis will uncover novel strategies to increasethe efficiency of loading platelets with therapeutics that can be used to treat CVD.

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

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


application_id: 9678326
project_number: 5R01AI129959-03
project_title: Enhanced diagnostic assessment in lupus using differential scanning calorimetry
administering_ic: NIAID
award_notice_date: 2019-05-01
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;Comorbidity;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;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: 9677125
project_number: 5R21CA219252-02
project_title: HNRNPA2B1 as a reader of RNA methylation in breast cancer
administering_ic: NCI
award_notice_date: 2019-04-01
opportunity_number: PA-16-177
application_type: 5
activity_code: R21
ic: CA
serial_number: 219252
program_official: HILDESHEIM, JEFFREY
project_start_date: 2018-04-02
project_end_date: 2021-03-31
study_section: Cancer Molecular Pathobiology Study Section[CAMP]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: SCHANER-TOOLEY, CHRISTINE E
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:
Project Summary AbstractA major limitation of endocrine therapies targeting estrogen receptor  (ER) is thedevelopment of acquired resistance to therapies such as tamoxifen in initially responsivepatients. Altered microRNA expression plays a role in endocrine resistance; however little isknown about what regulates microRNA in breast cancer. This exploratory study addresses PA-16-177 Role of RNA modifications in cancer biology (R21) Question 1: What are the cancer-associated alterations in readers writers and erasers of reversible RNA modifications? Herewe will address the role of the RNA methylation reader Heterogeneous NuclearRibonucleoprotein A2/B1 (HNRNPA2B1) in tamoxifen-resistant breast cancer. The rationale forour proposed experiments is that increased N(6)-methyladenosine (m6A) in primary-microRNAs(pri-miRNAs) was associated with increased levels of the corresponding mature miRNA in atriple negative breast cancer cell line. HNRNPA2B1 is a reader of the m6A mark in pri-miRNAsand interacts directly with DGCR8 (a component of the DROSHA complex in the nucleus) topromote processing of pri-miRNAs to precursor-miRNAs (pre-miRNAs). We present preliminarydata showing that HNRNPA2B1 is increased in tamoxifen-resistant ER+ LCC9 cells derivedfrom tamoxifen-sensitive ER+ MCF-7 breast cancer cells. Using online data we found thathigh HNRNPA2B1 transcript levels in primary breast tumors are associated with reduced overallsurvival. A new report showed increased HNRNPA2B1 in breast tumor specimens and celllines. The proposed experimental plan addresses the hypothesis that HNRNPA2B1overexpression stabilizes pri-miRNAs that promote endocrine resistance.

project_terms:
Address;Adjuvant;American Cancer Society;Androgens;Aromatase Inhibitors;Biological;Breast Cancer Cell;Breast Cancer cell line;Cancer Biology;Cell Line;Cell Nucleus;Cells;Complex;Data;Development;Diagnosis;Disease;Disease-Free Survival;Endocrine;Enzymes;Epigenetic Process;Estrogen Receptor alpha;Estrogens;Fulvestrant;Goals;Heterogeneous-Nuclear Ribonucleoproteins;Human;Immunoprecipitation;Letrozole;MCF7 cell;MDA MB 231;Malignant Neoplasms;Mammary Neoplasms;Methylation;Methyltransferase;MicroRNAs;Modification;Neoplasm Metastasis;Patients;Play;Postmenopause;RNA;RNA methylation;RNASE3L gene;Reader;Recurrence;Reporting;Research Personnel;Resistance;Role;Sampling;Specimen;Stains;Tamoxifen;Testing;Time;Tissue Microarray;Transcript;Woman;biobank;crosslink;experimental study;hormone therapy;mRNA Expression;malignant breast neoplasm;men;overexpression;patient response;pre-miRNA;pri-miRNA;targeted treatment;therapy resistant;triple-negative invasive breast carcinoma

public_health_relevance:
Project NarrativeFor 2017 the American Cancer Society estimates that 252710 US women and 2470 men will be diagnosedwith invasive breast cancer and 41070 women will die from disease metastases. The major goals of thisexploratory project are to determine if HNRNPA2B1 a reader of N(6)methyladenosine in miRNA 1) drivestamoxifen/endocrine resistance and 2) is a possible marker for resistance in primary breast tumors.


application_id: 9676986
project_number: 5R24OD021479-04
project_title: Developing Regeneration Resources for a Model Amphibian
administering_ic: OD
award_notice_date: 2019-04-04
opportunity_number: PAR-13-252
application_type: 5
activity_code: R24
ic: OD
serial_number: 021479
program_official: MIROCHNITCHENKO, OLEG
project_start_date: 2016-06-01
project_end_date: 2022-03-31
study_section: Special Emphasis Panel[ZRG1-CB-J(55)R]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: THORSON, JON SCOTT
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_abstract:
DESCRIPTION (provided by applicant): This Multi-PD/PI application seeks to develop resources that will better enable studies of a highly regenerative amphibian the Mexican axolotl (Ambystoma mexicanum). There is need to probe axolotl regeneration more deeply with the same powerful approaches that have proven so effective in genetic model organisms. Specific Aim 1 will accomplish the first chemical genetic screen of axolotl regeneration using an embryo tail regeneration assay. Using pre-feeding axolotl embryos that are efficiently reared in micro-titer plates up to 10000 soluble chemicals from commercial clinical-stage and novel natural products libraries will be tested for impact on tail regeneration. Preliminary data show that the chemical screen and tail regeneration assay are likely to identify new molecules that impact regeneration. Positive hits from this screen including previously identified inhibitors of Wnt Tgf and Fgf signaling will be reported to the community and investigated further under Specific Aim 2 using cellular and transcriptional approaches. In particular assays will be developed to assess chemical effects on formation of the wound epidermis which acts as an early signaling center in the recruitment of progenitor/stem cells. Also assays will be developed to assess cellular proliferation and de- differentiation two processes that are associated with endogenous regeneration. Genes found to be expressed differently between control and chemically treated embryos will be prioritized for knock out using the CRISPR/Cas9 method. For each gene target two gRNA pairs will be designed and injected into single cell axolotl embryos. Embryos will be reared to assess viability and then administered tail amputations to confirm CRISPR gene editing and test for regeneration competence. Embryos associated with CRISPRs that block or cause abnormal regeneration will be prioritized for founding stable lines. Specific Aim 3 will generate fluorescent reporter lines to assay signaling activity through major pathways known to function in regeneration and will also compare efficacies of two methods for developing gene-specific reporter lines using as tester loci genes already known to mark cell populations critical for regenerative responses (neural stem cells glia muscle satellite cells). The chemical and genetic hits and biological information arising from this model will be shared through a community website (Sal-Site). The proposed transgenics will be distributed by the Ambystoma Genetic Stock Center. Overall this project integrates expertise across chemical screening pharmacology histology transcription transgenesis and vertebrate biology to discover reagents and develop tools that are needed to enhance the axolotl for stem cell and regenerative biology.

project_terms:
Amaze;Ambystoma;Ambystoma mexicanum;Amphibia;Amputation;Animal Model;Bacterial Artificial Chromosomes;Biological;Biological Assay;Biological Process;Biology;CRISPR/Cas technology;Candidate Disease Gene;Cell Lineage;Cell Proliferation;Cells;Chemical Models;Chemicals;Chimeric Proteins;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Competence;Couples;Data;Development;Embryo;Event;Expression Profiling;FDA approved;Future;Gene Expression;Gene Targeting;Gene Transfer Techniques;Genes;Genetic;Genetic Models;Genetic Screening;Genetic Transcription;Guide RNA;Histology;Hormone use;Infrastructure;Insertional Mutagenesis;Investigation;Knock-out;Libraries;Mediating;Methods;Modeling;Molecular;Monitor;Mosaicism;Muscle satellite cell;Mutagenesis;Mutation;Natural Products;Natural regeneration;Neuroglia;Organism;Pathway interactions;Pharmacology;Phenotype;Population;Process;Production;Reagent;Regenerative Medicine;Regenerative response;Reporter;Reporting;Research;Resources;Salamander;Signal Pathway;Signal Transduction;Site;Somatic Cell;Stem Cell Research;Stem cells;Tail;Testing;Thyroid Hormones;Time;Tissues;Transforming Growth Factor beta;Transgenic Organisms;Tretinoin;Vertebrate Biology;blastema;chemical genetics;comparative efficacy;design;dosage;feeding;in vivo monitoring;inhibitor/antagonist;mutant;nerve stem cell;network models;notch protein;novel;progenitor;promoter;public health relevance;recruit;regenerative;screening;stem cell biology;tool;web site;wound;wound epidermis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This application seeks to develop resources that will better enable the fundamental study and application of a highly regenerative amphibian the Mexican axolotl (Ambystoma mexicanum). Specifically this project integrates unique infrastructure and expertise to discover reagents and develop tools that are needed to enhance the axolotl for stem cell biology and regeneration.


application_id: 9676231
project_number: 5R01AT009268-03
project_title: Mechanisms underlying anabolic effects of cyclic compressive loading in muscle
administering_ic: NCCIH
award_notice_date: 2019-03-26
opportunity_number: PA-14-168
application_type: 5
activity_code: R01
ic: AT
serial_number: 009268
program_official: MUDD, LANAY MARIE
project_start_date: 2017-04-01
project_end_date: 2022-03-31
study_section: Special Emphasis Panel[ZRG1-MOSS-R(02)M]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
other_pis: BUTTERFIELD, TIMOTHY ALAN
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acquired Immunodeficiency Syndrome;Acute;Address;Adult;Aging;Animals;Atrophic;Attention;Attenuated;Biochemical Pathway;Biology;Clinical;Complementary Health;Complementary therapies;Complex;Congestive Heart Failure;Contralateral;Data;Development;Devices;Disease;Disuse Atrophy;Elderly;Endocrine;Exercise;Extracellular Matrix;Focal Adhesion Kinase 1;Focal Adhesions;Growth;Immune response;Integrative Medicine;Intervention;Investigation;Knowledge;Lead;Limb structure;Maintenance;Malignant Neoplasms;Manipulative Therapies;Massage;Mechanical Stimulation;Mechanics;Mediating;MicroRNAs;Modality;Morbidity - disease rate;Muscle;Muscle Weakness;Muscular Atrophy;NIH Program Announcements;Neurons;Pathway interactions;Patients;Periodicity;Play;Protein Biosynthesis;Proteins;Quality of life;Rattus;Recovery;Reproducibility;Research;Rodent;Role;Skeletal Muscle;Standardization;Symptoms;Testing;Therapeutic Intervention;aged;clinical pain;cytokine;direct application;disability;exosome;functional decline;innovation;integrin-linked kinase;mechanotransduction;mortality;muscle form;novel;pain relief;patient population;prevent;relating to nervous system;response;restoration;satellite cell;sensory feedback;skeletal muscle wasting


application_id: 9674393
project_number: 5R01CA188118-05
project_title: Determine the Functional Role Dub3 in Breast Cancer Progression and Metastasis
administering_ic: NCI
award_notice_date: 2019-03-18
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 188118
program_official: AULT, GRACE S
project_start_date: 2015-04-01
project_end_date: 2021-03-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Basal-like breast cancer (BLBC) presents with an aggressive clinical history development of recurrence distant metastasis shorter survival and usually occurs in young women. BLBC has an activated epithelial-mesenchymal transition (EMT) program which provides cells with the increased phenotypic and cellular plasticity required during embryonic development tissue remodeling wound healing and metastasis. Our long-term goal is to discover the molecular circuitry that governs the functional plasticity of BLBC cells in metastasis and to identify molecules that may serve as druggable targets for treating this deadly disease. In the last nine years we have systematically studied the function of Snail and the molecular mechanism by which Snail represses E-cadherin expression in BLBC. Our studies clearly indicate that Snail levels are regulated predominantly through protein ubiquitination. High levels of Snail due to protein stabilization contribute significantly to theincreased invasion therapeutic resistance CSC-like properties and tumor recurrence. However the mechanism by which Snail escapes ubiquitination and degradation remains unknown; uncovering this mechanism is crucially important for the development of novel approaches to treat BLBC. Recently we discovered that Dub3 is a bona fide deubiquitinase of Snail and contributes to Snail stabilization in breast cancer. Dub3 is evolutionarily conserved from Drosophila to humans. Dub3-knockout downregulated Snail and disrupted gastrulation (an event that requires EMT) in Drosophila. Elevated expression of Dub3 correlates unequivocally with Snail expression in BLBC samples and cell lines. Overexpression of Dub3 in luminal breast tumor MCF7 and T47D cell lines which contain no detectable endogenous Dub3 and Snail induces transformation to a basal-like phenotype; whereas Dub3-knockdown downregulates Snail and suppresses cell migration. Intriguingly Dub3 was an early response gene that appeared after exposure to inflammatory cytokines. We hypothesize that Dub3 is the long-sought "missing molecule" that regulates cellular plasticity by controlling the level of Snail during EMT and metastasis. The objective of this proposal is to characterize the function and regulation of the Dub3-Snail axis and explore the clinical value of Dub3 as a prognostic biomarker and a druggable target for treating metastatic breast cancer. Guided by strong preliminary data we will test this hypothesis by pursuing three specific aims: (1) to delineate the molecular mechanism by which Dub3 controls EMT; (2) to determine the function and regulation of Dub3 in breast cancer; and (3) to define the function and therapeutic efficacy of Dub3 in vivo. Our proposal is innovative and significant because it will not only uncover a new paradigm that significantly increases our understanding of the regulation of cellular plasticity during tumor progression and metastasis but also leads to the development of specific Dub3 inhibitors for treating metastatic breast cancer.

project_terms:
Address;Brain;Breast;Breast Cancer Cell;Breast cancer metastasis;Cell Line;Cells;Chromatin;Clinical;Coupled;Crystallization;Data;Deubiquitination;Development;Diagnosis;Disease;Distant Metastasis;Drosophila genus;E-Cadherin;ERG gene;Embryonic Development;Environment;Enzymes;Epithelial;Event;Exposure to;Genes;Goals;Growth;Human;Inflammatory;Intrinsic factor;Investigation;KDM1A gene;Knock-out;Knowledge;Libraries;Location;Lung;MCF7 cell;Malignant Neoplasms;Mammary Neoplasms;Mass Spectrum Analysis;Mesenchymal;Metabolic;Metastatic breast cancer;Modeling;Molecular;Mus;Neoplasm Metastasis;Oncologist;Pathologist;Pharmaceutical Preparations;Phase;Phenotype;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Prognostic Marker;Property;Proteins;Public Health;Reagent;Recording of previous events;Recurrence;Regulation;Research;Role;Sampling;Signal Transduction;Site;Small Interfering RNA;Snails;Specimen;Stromal Neoplasm;Structural Biologist;Structure;T47D;Talents;Testing;Therapeutic;Tissues;Treatment Efficacy;Tumor Cell Invasion;Tumor-associated macrophages;Ubiquitination;Validation;Wound Healing;Xenograft procedure;aerobic glycolysis;base;beta-Transducin Repeat-Containing Proteins;breast cancer progression;cancer stem cell;cancer therapy;cell growth regulation;cell motility;cytokine;diagnostic biomarker;druggable target;experimental study;functional plasticity;gastrulation;glycogen synthase kinase 3 beta;in vivo;inhibitor/antagonist;innovation;knock-down;loss of function;malignant breast neoplasm;multidisciplinary;neoplastic cell;new therapeutic target;novel strategies;outcome forecast;overexpression;prevent;prognostic;programs;promoter;public health relevance;recruit;screening;stem-like cell;success;targeted biomarker;targeted treatment;therapy resistant;tumor;tumor microenvironment;tumor progression;ubiquitin-protein ligase;virtual;young woman

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Our proposal is innovative since we will have a significant impact to public health through its potential to influence cancer treatment. The knowledge gained will expand our understanding of the molecular mechanism in controlling early-phase of tumor cell invasion dissemination and metastasis. When successfully completed these studies will offer new therapeutic target and diagnostic biomarker to prevent and treat metastatic basal- like breast cancer.


application_id: 9674332
project_number: 5R01AI118814-05
project_title: Lead Optimization of ML336 a Potent VEEV Inhibitor
administering_ic: NIAID
award_notice_date: 2019-04-18
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 118814
program_official: DAVIS, MINDY I
project_start_date: 2015-05-01
project_end_date: 2021-04-30
study_section: Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section[DDR]
contact_pi_person_id: 9658299
contact_pi: CHUNG, DONGHOON
other_pis: GOLDEN, JENNIFER E.;JONSSON, COLLEEN B
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The New World alphaviruses Venezuelan (VEEV) Eastern and Western Equine Encephalitis viruses are emerging pathogens that are endemic throughout the Americas. They cause encephalitis in humans and equines thus presenting serious health and economic problems. Despite the urgent need neither approved drugs nor vaccines are available for treatment of these diseases in humans. Broad long-term objectives: The research objectives stated herein and in future studies that build upon these findings will deliver analogs of ML336 a promising lead compound as small molecule therapeutic candidates for future clinical evaluation targeting diseases caused by VEEV and other alphaviruses. Specific aims/hypothesis: The specific aims address two hypotheses. In aims 1 and 2 we hypothesize that medicinal chemical optimization of ML336 can afford a safe and specific therapeutic preclinical candidate to treat New World alphaviral diseases. In aim 3 we test the hypothesis that ML336 blocks VEEV RNA synthesis through disruption of interactions required for replicase assembly and/or directly inhibits an enzymatic activity required for viral RNA synthesis. Research design and methods: Aim 1 will derive a robust pharmacological profile suitable for in vivo efficacy through structure-activity and structure-property relationshi (SAR-SPR) studies. Specifically Dr. Golden will lead efforts to generate analogs of ML336 with an improved pharmacological profile that includes increased solubility and BBB permeability and reduced metabolic liability to improve exposure and clearance parameters. In Aim 2 Dr. Guo will assess the biodistribution and pharmacokinetics/dynamics of ML336 and 2-3 lead compounds each year showing suitable and robust pharmacological and antiviral (in vitro and in vivo) profiles. Dr. Jonsson will lead in vivo efficacy testing studies of two of the most promisinglead candidates to define the optimal dosing regimen using the VEEV Trinidad Donkey strain. Finally Dr. Chung will dissect the mechanism of action of ML336 using in vitro assays focused on replication (Aim 3) in consultation with Dr. Sawicki.

project_terms:
Address;Alphavirus;Americas;Amidines;Antiviral Agents;Asses;Biodistribution;Biotechnology;Chemicals;Chemistry;Consultations;Disease;Dose;Drug Kinetics;Encephalitis;Equus caballus;Future;Human;In Vitro;Knowledge;Lead;Metabolic;Molecular Bank;Mus;Nonstructural Protein;Outcome;Permeability;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Preclinical Drug Development;Property;RNA Viruses;RNA chemical synthesis;Regimen;Replication-Associated Process;Research;Research Design;Research Methodology;Resistance;Series;Solubility;Structure;Structure-Activity Relationship;Testing;Therapeutic;Toxic effect;Trinidad;United States National Institutes of Health;Vaccines;Venezuelan;Venezuelan Equine Encephalitis Virus;Virus Inhibitors;Western Equine Encephalitis Virus;analog;cytotoxicity;efficacy study;efficacy testing;health economics;high throughput screening;improved;in vitro Assay;in vitro activity;in vivo;insight;interest;lead candidate;lead optimization;mouse model;novel;pathogen;pre-clinical;preclinical study;public health relevance;replicase;research clinical testing;small molecule;small molecule therapeutics;therapeutic candidate;viral RNA;viral resistance

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The New World alphaviruses Venezuelan Eastern and Western Equine Encephalitis viruses are emerging pathogens that are endemic throughout the Americas. They cause encephalitis in humans and equines thus presenting serious health and economic threats. Despite the urgent need neither approved drugs nor vaccines are available for treatment of these diseases in humans. We propose to address this gap by advancing analogs of ML336 a promising small molecule as preclinical therapeutic candidates.


application_id: 9673307
project_number: 2P20GM103436-19
project_title: Alteration and Renovation
administering_ic: NIGMS
award_notice_date: 2019-04-17
opportunity_number: PAR-18-262
application_type: 2
activity_code: P20
ic: GM
serial_number: 103436
study_section: Special Emphasis Panel[ZGM1 RCB-9 (IN)]
subproject_number: 7348
contact_pi_person_id: 9257147
contact_pi: HARE, JANELLE M
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: 2019-05-01
budget_end_date: 2020-04-30
project_abstract:
Alteration & Renovation (MoSU) - Project SummaryMorehead State University (MoSU) has been a regional comprehensive partner institution of theKentucky INBRE organization (KBRIN) since 2002. MoSUs collaboration with KBRIN has beenextremely productive in both enhancing faculty productivity in grant funding from the NIH and insupporting student biomedical research experiences. The goal of the Alteration and Renovationproject proposed by MoSU is to increase its capacity to conduct up-to-date molecular cellulardevelopmental and neurobiology research with students. This will be accomplished by therenovation and alteration of one large 1700 ft2 50 year-old teaching laboratory into tworesearch-capable spaces. Faculty benefitting from this alteration will primarily include onecurrently NIH AREA R15-funded MoSU professor as well as a newly assistant professor to benamed (hiring currently underway in March 2018). Specifically this project will focus onrenovating and altering an existing chemistry lab located in Lappin Hall a life science building atMoSU. Currently this rectangular room is configured for a teaching laboratory with 3 longbenches each containing a central water trough and deteriorating cabinetry. First these itemswill be removed and a wall installed across the middle of the rectangular room to form twolaboratories. Then replacement shelving cabinetry flooring and sinks containing eyewashesand hand-held showers will be installed. As no deionized water is available in this room formolecular biological work the project will install a deionized water line to this laboratory and atied-in benchtop ultrapure water purification system. Numerous upgrades to the infrastructurewill include additional connections to the MoSU Ethernet to coordinate modern instrumentationfor data acquisition and analysis and backup electrical connections for uninterrupted power tofreezers. Two freezers and a refrigerator will add to the functionality of the newly formed LappinHall 424 from the existing 423 room. Two small dedicated use anterooms will be outfitted withstorage shelving and a dishwasher for (i) general chemical storage and lab clean-up and (ii)delicate task wet-lab work including the vertebrate surgical procedures and embryo injectionsused by current MoSU faculty member. As the only other dedicated biomedical research spacein Lappin Hall is a 2300 ft2 interdisciplinary molecular biology that is currently shared by fiveother faculty and their students MoSU needs this proposed renovation to continue to grow itsbiomedical research capacity. Through this project MoSU will significantly enhance the facilitiesin which biologists will be able to conduct modern relevant research offer biomedical researchopportunities to students and contribute to the future funding success of MoSU investigators.

project_terms:
Area;Award;Biological;Biological Sciences;Biology;Biomedical Research;Chemicals;Chemistry;Collaborations;Data Analyses;Direct Costs;Educational process of instructing;Embryo;Equipment;Expenditure;Faculty;Floor;Freezing;Funding;Future;Goals;Grant;Growth;Hand;Infrastructure;Injections;Institution;Kentucky;Laboratories;Laboratory Research;Modernization;Molecular;Molecular Biology;Names;Operative Surgical Procedures;Productivity;Research;Research Activity;Research Personnel;Science;Students;System;Time;United States National Institutes of Health;Universities;Update;Water;Water Purification;Work;cost;data acquisition;developmental neurobiology;experience;instrumentation;member;professor;programs;repaired;success;teaching laboratory;tenure track


application_id: 9673306
project_number: 2P20GM103436-19
project_title: Developmental Research Project Program
administering_ic: NIGMS
award_notice_date: 2019-04-17
opportunity_number: PAR-18-262
application_type: 2
activity_code: P20
ic: GM
serial_number: 103436
study_section: Special Emphasis Panel[ZGM1 RCB-9 (IN)]
subproject_number: 7347
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
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: 2019-05-01
budget_end_date: 2020-04-30
project_abstract:
Developmental Research Program (DRPP) - Project SummaryThe Development Research Project Program provides an array of support programs to developcompetitive biomedical research faculty in Kentuckys colleges and universities. The primaryassumption underlying this program is that each Kentucky institution needs a critical mass ofindependent biomedical research faculty in order to provide the highest quality biomedicalresearch training to undergraduate students. Furthermore Kentucky research faculty must beprovided with the infrastructure to succeed in their research careers in order to provide first-rateresearch experiences to undergraduate students which will inspire them to join the biomedicalworkforce. With the overarching goal of increasing biomedical research capacity in Kentucky theDevelopmental Research Project Program aims to address the existing low numbers ofindependent research faculty and existing deficits in infrastructure by enhancing facultyrecruitment promoting the research and career development of junior faculty and building asustainable research network. Based upon our past successes we will focus our efforts oninstitutions eligible for NIH R15 funding. These institutions are primarily undergraduate institutions(PUIs) so this concentration provides the greatest benefit to undergraduate students. At theseinstitutions we focus our efforts on developing faculty to increase success rates in obtaining R15funding. In this way we have been successful in increasing the numbers of independent researchfaculty and building a sustainable research network.

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: 9673303
project_number: 2P20GM103436-19
project_title: Genomics Core
administering_ic: NIGMS
award_notice_date: 2019-04-17
opportunity_number: PAR-18-262
application_type: 2
activity_code: P20
ic: GM
serial_number: 103436
study_section: Special Emphasis Panel[ZGM1 RCB-9 (IN)]
subproject_number: 7344
contact_pi_person_id: 1969307
contact_pi: ZACHARIAS, WOLFGANG
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: 2019-05-01
budget_end_date: 2020-04-30
project_terms:
Applications Grants;Award;Bioinformatics;Biomedical Research;Centers of Research Excellence;Clinical;Collaborations;Communities;Core Facility;DNA;Data Analyses;Development;Disease;Environment;Equipment;Etiology;Experimental Designs;Floor;Future;Gene Expression Profiling;Genes;Genetic;Genetic Medicine;Genomics;Genotype;Grant;Health Sciences;Health behavior;Healthcare;Human;Human Resources;Imagery;Individual;Infrastructure;Institution;Kentucky;Laboratory Research;Life;Logistics;Manuscripts;Methods;MicroRNAs;Molecular;Molecular Medicine;Molecular Target;Nucleic Acids;Patients;Pilot Projects;Population;Preparation;RNA;Research;Research Infrastructure;Research Personnel;Sampling;Services;Technology;Training;Translational Research;Universities;base;cancer research center director;combat;cost;data acquisition;equipment acquisition;field study;functional genomics;gene product;genetic makeup;genomic data;human disease;innovative technologies;programs;student training;therapy development;transcriptome;transcriptome sequencing;whole genome


application_id: 9673302
project_number: 2P20GM103436-19
project_title: Bioinformatics Core
administering_ic: NIGMS
award_notice_date: 2019-04-17
opportunity_number: PAR-18-262
application_type: 2
activity_code: P20
ic: GM
serial_number: 103436
study_section: Special Emphasis Panel[ZGM1 RCB-9 (IN)]
subproject_number: 7343
contact_pi_person_id: 7948398
contact_pi: ROUCHKA, ERIC 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: 2019-05-01
budget_end_date: 2020-04-30
project_terms:
Algorithms;Area;Bioinformatics;Biomedical Research;Collaborations;Computational Biology;Computers;DNA Sequence;Data;Engineering;Faculty;Funding;Genetic Transcription;Genomics;Health Sciences;High-Throughput Nucleotide Sequencing;Institution;Kentucky;Lead;Modeling;Network Infrastructure;Postdoctoral Fellow;RNA Sequence Analysis;Reporting;Research;Research Personnel;Resources;Scientist;Sequence Analysis;Services;Students;Technology;Time;Training;Training Activity;Training and Education;Universities;base;circular RNA;cloud based;computer science;design;experience;member;metagenomic sequencing;novel;recruit;ribosome profiling;student training;transcriptome sequencing;transcriptomics


application_id: 9673301
project_number: 2P20GM103436-19
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2019-04-17
opportunity_number: PAR-18-262
application_type: 2
activity_code: P20
ic: GM
serial_number: 103436
study_section: Special Emphasis Panel[ZGM1 RCB-9 (IN)]
subproject_number: 7342
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
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: 2019-05-01
budget_end_date: 2020-04-30
project_abstract:
Administrative Core SummaryThe primary purpose of the administrative core is to provide sound management of theINBRE-award on behalf of the network. In addition this core will provide leadership anddirection to enable the network to grow in a purposeful and managed way. Theadministrative core will provide leadership and oversight of the bioinformatics andresearch cores as well as all other activities adjusting and balancing the commitmentsand needs of each such that the overall network is productive and impactful. The corewill be responsible for tracking and evaluation of all network activities including mentoringand training.

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: 9673257
project_number: 1R01AG061898-01
administering_ic: NIA
award_notice_date: 2019-01-23
opportunity_number: PAR-18-175
application_type: 1
activity_code: R01
ic: AG
serial_number: 061898
program_official: RYAN, LAURIE M
project_start_date: 2019-02-01
project_end_date: 2021-11-30
study_section: Special Emphasis Panel[ZRG1 BBBP-Z (55)]
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: WATTERSON, DANIEL MARTIN
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: 2019-02-01
project_abstract:
ABSTRACTThere are no approved disease-modifying drugs to prevent delay or slow disease progression of Alzheimer'sdisease (AD) and related dementias. The overwhelming majority of AD clinical trials targeted the beta-amyloidpathway with disappointingly ineffective outcomes in >99% of the studies. Therefore there is an urgent need todiversify the portfolio of disease modifying approaches that are distinct from prior art. Our unbiased discoverystrategy for the campaign described here focused on targeting a particular form of dysregulated inflammationinjurious proinflammatory cytokine overproduction in the brain that is a key contributor to synaptic dysfunctionneurodegeneration and cognitive decline in diverse neurodegenerative diseases. We seek funding for therequired phase 1 clinical safety studies of MW01-2-151SRM (=MW151). MW151 is a novel CNS-penetrantorally bioavailable small molecule candidate that selectively suppresses stressor-induced proinflammatorycytokine overproduction. MW151 ameliorates synaptic damage and cognitive impairment at low doses indiverse animal models where proinflammatory cytokine dysregulation is established as a contributor to diseaseprogression. MW151 has no liabilities in investigational new drug (IND)-enabling safety pharmacology andtoxicology tests such as respiratory and cardiovascular safety pharmacology rat and dog 28-day repeatadministration toxicology and genotoxicity. The low risk aspect of MW151 safety is reinforced by an analogdeveloped for the demanding intravenous route of administration and its progression through phase 1a andpromising status in phase 1b. We hypothesize that MW151 will be a successful oral candidate for futuretreatment of individuals with MCI/AD. This application seeks to progress through the required first-in-human(FIH) safety clinical trials. Our specific aims are:Aim 1: Conduct a first-in-human (FIH) phase 1a single ascending dose (SAD) study. This study will determinesafety and tolerability maximum tolerated dose and pharmacokinetics (PK) of MW151 in healthy adultvolunteers. Plasma cytokine levels will be measured to provide baseline data for a future exploratorypharmacodynamic (PD) endpoint in phase 2a clinical trials.Aim 2: Conduct a phase 1b multiple ascending dose (MAD) study of MW151. This study will determine safetyand tolerability maximum tolerated dose and PK of MW151 in healthy adult volunteers. In addition a cohort ofelderly healthy subjects and exploratory PD inflammatory cytokine endpoints in CSF will be included.Aim 3: Prepare clinical protocol and investigators brochure for a future phase 2a clinical trial of MW151 in earlyAD. Based on the outcomes of the proposed phase 1 studies we will design a phase 2a trial and prepare thedocuments required. This will allow immediate progress to future FIP studies for AD.Overall MW151 represents a unique opportunity for development as a first-in-class disease-modifyingtherapeutic.

project_terms:
Address;Adult;Age;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease related dementia;Amyloid beta-Protein;Animal Model;Animals;Anti-inflammatory;Arts;Attenuated;Award;Bioavailable;Brain;Canis familiaris;Cardiovascular system;Central Nervous System Diseases;Characteristics;Chemicals;Clinical;Clinical Investigator;Clinical Protocols;Clinical Trials;Coenzyme A;Data;Development;Disease;Disease Progression;Dose;Drug Kinetics;Elderly;Exhibits;Formulation;Functional disorder;Funding;Future;Homeostasis;Human;Immunosuppression;Impaired cognition;Individual;Inflammation;Inflammatory;Injury;Intravenous;Investigational Drugs;Maximum Tolerated Dose;Measures;Metabolic;Modeling;Nerve Degeneration;Neurodegenerative Disorders;Neuroglia;Oral;Outcome;Pamphlets;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Pharmacology and Toxicology;Phase;Phase I Clinical Trials;Plasma;Population;Predisposition;Public Health;Rattus;Risk;Route;Safety;Synapses;Testing;Therapeutic;Toxicology;analog;base;clinical development;cohort;cytokine;design;dose information;drug candidate;effective therapy;first-in-human;genotoxicity;healthy volunteer;neuroinflammation;novel;novel therapeutic intervention;phase 1 study;physical property;pre-clinical;preclinical development;prevent;respiratory;restoration;safety study;small molecule;stressor;success;volunteer

public_health_relevance:
NARRATIVESuccess in the proposed first-in-human phase 1 clinical trial in healthy adult volunteers will provide safety anddosing information required to progress to the next stage of development for MW151 a promising brain-penetrant small molecule drug candidate that targets dysregulated inflammation in the brain. MW151 has thepotential to be a first-in-class disease modifying therapy for MCI/Alzheimers disease.


application_id: 9673160
project_number: 5P20GM113226-04
project_title: Effects of Dietary Fat on the Hepatotoxicity of Environmental Arsenic
administering_ic: NIGMS
award_notice_date: 2019-04-01
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6176
contact_pi_person_id: 1902836
contact_pi: WATSON, WALTER H
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-04-01
budget_end_date: 2020-03-31
project_abstract:
One of every three American adults is obese and is afflicted with some form of non-alcoholic fatty liver disease(NAFLD). The majority of obese individuals will have steatosis (fatty liver) but only about 20% will have themore serious condition of steatohepatitis (fatty liver with inflammation and liver injury). There is still no FDA-approved therapy for any stage of NAFLD. Therefore it is critical that we understand the multiple factors thatpromote progression from steatosis to steatohepatitis in NAFLD. Our previous studies have shown thatconsumption of arsenic-contaminated drinking water is an important risk factor for progression of NAFLD.Preliminary proteomic analysis demonstrated that the abundance of a number of proteins that are controlled atthe transcriptional level by HNF-4a was decreased in the livers of mice with arsenic-enhanced NAFLD.Mechanistic studies showed that the expression of this zinc finger transcription factor was not altered but thatits DNA binding activity was inhibited at the post-translational level. HNF-4a is known to be regulated by post-translational modifications (PTMs) and arsenic has the potential to affect zinc binding cysteine oxidationarginine methylation and lysine acetylation. Very little is known about how PTMs of HNF-4a are regulated orhow disruption of these regulatory processes contributes to liver disease. To follow up on these importantfindings the objective of the current proposal is to delineate the mechanisms by which environmental arsenicexposure promotes the progression from steatosis to steatohepatitis in mice fed a Western-style diet that ishigh in saturated fat. The central hypothesis to be tested is that alterations in HNF-4a-mediated geneexpression induced by arsenic play a critical role in the progression of NAFLD from steatosis to steatohepatitisin this model. This hypothesis will be tested in three Specific Aims. First we will define the specific molecularinteractions of arsenic with the zinc finger domain of HNF-4a. Second we will analyze the mechanisms bywhich arsenic affects PTMs of HNF-4a and how these changes translate into altered DNA binding activity andtransactivation potential. Third we will define the post-translational modifications of hepatic HNF-4a in mice feda high fat diet and exposed to arsenic-contaminated drinking water and relate these changes to the occupancyof HNF-4a-response elements in genes involved in lipid metabolism and inflammation. This model ofinflammatory liver injury is relevant to the United States population where high fat diets are common andarsenic exposure levels are typically below the threshold for overt hepatotoxicity. The new information obtainedfrom these studies will delineate pathways that are altered by arsenic and that are important in the etiology ofNAFLD.

project_terms:
Acetylation;Adult;Affect;American;Animal Model;Arginine;Arsenic;Arsenites;Benign;Binding;Cells;Centers of Research Excellence;ChIP-seq;Chemicals;Cirrhosis;Clinical;Consumption;Cysteine;DNA;DNA Binding;DNA Binding Domain;Diet;Dietary Fats;Disease;Disease Progression;Disease model;Environment;Etiology;Exposure to;FDA approved;Fatty Liver;Fatty acid glycerol esters;Fibrosis;Gene Expression;Genes;Genetic;Genetic Transcription;Hepatic;Hepatotoxicity;High Fat Diet;In Vitro;Incubated;Individual;Inflammation;Inflammatory;Injury;Knowledge;Liver;Liver diseases;Lysine;Mediating;Methylation;Modeling;Modification;Mus;Obesity;Pathway interactions;Pharmacology;Play;Population;Post-Translational Protein Processing;Process;Proteins;Proteomics;Response Elements;Risk Factors;Role;Signal Pathway;Steatohepatitis;Techniques;Testing;Tissues;Toxic effect;Toxicology;Transactivation;Translating;United States;Zinc;Zinc Fingers;cell injury;contaminated drinking water;drinking water;experimental study;follow-up;genetic regulatory protein;innovation;lipid metabolism;liver injury;non-alcoholic fatty liver disease;novel;oxidation;promoter;response;saturated fat;transcription factor;transcriptome sequencing


application_id: 9673158
project_number: 5P20GM113226-04
project_title: Mechanisms of Probiotics in Alcoholic Liver Disease
administering_ic: NIGMS
award_notice_date: 2019-04-01
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6175
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-04-01
budget_end_date: 2020-03-31
project_abstract:
Severe alcoholic liver disease (ALD) has a high morbidity and mortality. Recent studies demonstrated thatprobiotics reversed alcohol-induced hepatic steatosis and inflammation and improved liver enzymes in animalmodels and in patients. Our laboratory showed that administration of a probiotic strain Lactobacillus rhamnosusGorbach-Goldin (LGG) significantly improved liver enzymes and histology in alcohol treated mice. These micealso had reduced intestinal permeability and plasma endotoxin levels. Gut-derived endotoxins normallypenetrate the gut epithelium only in trace amounts due to tightly regulated intestinal barrier function. Howeverendotoxin leakiness is increased under pathological conditions including alcohol abuse. We recently reportedthat chronic alcohol intake in mice caused a marked reduction in the intestinal expression of the mastertranscription factor hypoxia inducible factor (HIF) and two HIF related proteins cathelin-related antimicrobialpeptide (CRAMP) and intestinal trefoil factor (ITF) in the intestine. ITF plays a critical role in the formation andstabilization of the intestinal mucus barrier enhancement of rapid intestinal repair (restitution) and modulationof mucosal differentiation processes and immune responses while CRAMP is important in blocking intestinalbacterial overgrowth/dysbiosis. In addition our preliminary data demonstrate a significant decrease of shortchain fatty acids (SCFAs) in particular butyric acid in the intestinal lumen following alcohol exposure inrodents. Our hypothesis is that alcohol consumption causes decreased intestinal CRAMP and ITF expressionand intestinal lumen butyric acid concentration resulting in bacterial overgrowth/dysbiosis and disruptedgut-barrier function; LGG supplementation attenuates these deleterious effects and protects the liver fromalcohol-induced injury. To test this hypothesis we will have 3 specific aims. Specific aim 1 will determine therole of CRAMP and the beneficial effects of LGG on CRAMP in alcohol-mediated changes in gut microbiotahomeostasis. The experiments will be performed using a metagenomic approach in CRAMP knockout mice.Specific aim 2 will determine the role of LGG in promoting ITF expression and will evaluate whether ITFpositively modulates intestinal tight junctions as a mechanism for improved intestinal barrier integrity. We willuse goblet and intestinal epithelial cell culture and recombinant ITF to delineate the effect of ITF. Specific aim 3will determine the role and mechanisms of butyric acid in the beneficial effects of LGG on intestinal tightjunctions using a butyric transporter knockout mouse model. This study will have a major impact on thedevelopment of probiotic-based new therapeutic strategy for the prevention and treatment of ALD.

project_terms:
Acute;Alcohol abuse;Alcohol consumption;Alcohol-Induced Disorders;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Attenuated;Bacteria;Bacterial Translocation;Biological Assay;Butyrates;Butyric Acids;Carbohydrates;Cell Culture Techniques;Cell Line;Centers of Research Excellence;Chronic;Cirrhosis;Data;Development;Disease Progression;Endotoxins;Enzymes;Epithelial;Epithelial Cells;Etiology;Experimental Models;Fatty Liver;Functional disorder;Future;Goals;Goblet Cells;Health;Histology;Histone Deacetylase;Homeostasis;Human;Hypoxia Inducible Factor;Immune response;Impairment;Inflammation;Injury;Intervention;Intestinal Diseases;Intestinal permeability;Intestines;Knockout Mice;Laboratories;Lactobacillus casei rhamnosus;Leaky Gut;Link;Liver;Liver diseases;Mediating;Metagenomics;Morbidity - disease rate;Mucous Membrane;Mucous body substance;Mus;Oral Administration;Pathologic;Patients;Pilot Projects;Plasma;Play;Prevention strategy;Probiotics;Process;Production;Proteins;Proteomics;Recombinants;Regulation;Reporting;Rodent;Role;Sampling;Supplementation;Testing;Therapeutic;Tight Junctions;Toxicology;Volatile Fatty Acids;alcohol exposure;bacterial metabolism;base;cathelicidin antimicrobial peptide;comparative efficacy;dysbiosis;experimental study;gastrointestinal epithelium;gut microbiota;improved;in vivo;lipid metabolism;liver inflammation;liver injury;metabolomics;mortality;mouse model;novel therapeutic intervention;occludin;prevent;protective effect;repaired;transcription factor;trefoil factor


application_id: 9673157
project_number: 5P20GM113226-04
project_title: High fat diet induced hepatocyte exosomes-promoted hepatic inflammation and tumorigenesis
administering_ic: NIGMS
award_notice_date: 2019-04-01
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6174
contact_pi_person_id: 11629370
contact_pi: DENG, ZHONG-BIN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-04-01
budget_end_date: 2020-03-31
project_abstract:
ABSTRACTThe overall goal of this proposal is to study the role of hepatocyte exosomes in high fat diet mediatedpromotion of liver cancer development. Further we will determine whether using novel edible fruit exosomesas a delivery vehicle for targetable delivery of an anti-inflammatory agent to tumor cells for treatment of livercancer. Our preliminary data has indicated that hepatocyte exosomes are present in the peripheral blood ofobese mice and obese individuals and the hepatocyte exosomes from mice fed a high-fat diet (HFD-exosomes) promote inflammatory responses and the growth of liver cancer in mouse model. These dataimplicate the production of hepatocyte exosomes in the inflammatory responses associated with liver cancer.Our preliminary data indicate that the HFD-exosomes carry high levels of sumoylated CSN5 (sumo-CSN5) andthat the delivery of the sumo-CSN5 to immature myeloid promotes the degradation of Jak3 a process that isessential for differentiation of the myeloid cells. This pinpointed the production of the sumo-CSN5 as a criticalpathogenic step in exosomes mediated Induction of inflammation cytokines. In hepatocyte cells ErK1/2 kinaseis activated by a soluble factor(s) from the supernatant of liver extracts of high fat-fed mice and causes thedisassociation of Senp1 which acts as a suppressor of sumoylation of CSN5 thereby promoting the productionof sumo-CSN5. This process is inhibited by curcumin which is known to inhibit ErK1/2 activation. Thereforewe hypothesize that a high-fat diet promotes the production of exosomes with high levels of sumo-CSN5 byhepatocyte cells; that these exosomes are taken up by immature myeloid cells resulting in sumo-CSN5-mediated immunosuppression by enhancing degradation of Jak3 and thus the promotion of tumor growth. Wefurther hypothesize that curcumin treatment leads to the inhibition of processing of sumoylation of CSN5 in thehepatocyte cells from mice fed a high-fat diet by inhibition of ErK1/2. These hypotheses will be tested in vitroand in vivo to determine whether: (1) Sumoylated CSN5 in high-fat hepatocyte exosomes is essential foraccumulation of activated iMCs and promotion of liver tumor progression; (2) The ErK1/2 signaling pathwaydetermines the balance of desumoylation vs. sumoylation of CSN5 in hepatocyte cells and is promoted by ahigh-fat diet; and (3) the high-fat diet-induced hepatocyte exosome-mediated promotion of liver tumor growth isreversible by using novel edible fruit exosomes as a delivery vehicle for targetable delivery of an anti-inflammatory agent to inflammatory cells for treatment of cancer. Clinical Relevance. The data generatedshould identify a novel mechanism that links a high-fat diet to inflammatory and immunosuppressive responsesassociated with tumor development and thereby identify molecular targets for chemotherapy orchemoprevention. Demonstration of the safety of fruit exosomes-based delivery of curcumin and its targeting toinflammatory cells would be a significant step forward in the treatment of this debilitating disease.

project_terms:
Acceleration;Address;Anti-Inflammatory Agents;Binding Sites;C57BL/6 Mouse;COPS5 gene;Cells;Centers of Research Excellence;Chemoprevention;Chronic;Curcumin;Data;Development;Diet;Diethylnitrosamine;Disease;Elements;Enzymes;Equilibrium;Fatty acid glycerol esters;Fruit;Goals;Growth;Hepatic;Hepatocyte;High Fat Diet;Human;ITGAM gene;Immunosuppression;Immunosuppressive Agents;In Vitro;Individual;Inflammation;Inflammatory;Inflammatory Response;Lead;Link;Liver;Liver Extract;Liver neoplasms;MAPK3 gene;Malignant Neoplasms;Malignant neoplasm of liver;Mediating;Membrane;Modeling;Molecular Target;Mus;Mutation;Myelogenous;Myeloid Cells;Natural Killer Cells;Obese Mice;Obesity;Pathogenicity;Pathway interactions;Phosphorylation Site;Phosphotransferases;Play;Prevention;Process;Production;Property;Role;Safety;Signal Pathway;Signal Transduction;Site;Small Interfering RNA;T-Lymphocyte;Technology;Testing;Toxicology;Tumor Promotion;Vesicle;base;cancer therapy;cell growth;chemotherapy;clinically relevant;cytokine;exosome;in vitro testing;in vivo;knock-down;liver development;macrophage;mouse model;nanoparticle;neoplastic cell;novel;peripheral blood;prevent;response;targeted delivery;tumor;tumor growth;tumor progression;tumorigenesis


application_id: 9673155
project_number: 5P20GM113226-04
project_title: Pathogenic role of PDE4 in hepatic stellate cell activation and TGF signaling
administering_ic: NIGMS
award_notice_date: 2019-04-01
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6173
contact_pi_person_id: 11058066
contact_pi: GOBEJISHVILI, LEILA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-04-01
budget_end_date: 2020-03-31
project_abstract:
Liver injury of different etiologies leads to a wound healing process involving activation of hepatic stellate cells(HSCs). However an ongoing hepatocyte injury and inflammation results in an uncontrolled activation andproliferation of HSCs and development of hepatic fibrosis leading to cirrhosis and even hepatocellular cancer.Despite the advances made gaps remain in our understanding of the mechanisms involved in the process ofHSC transformation from quiescent to activated phenotype. Recently we discovered that thephosphodiesterase 4 (PDE4) subfamily of enzymes play a pathogenic role in the development of cholestaticliver injury and fibrosis. Notably PDE4s are not present in quiescent HSCs and are rapidly induced uponactivation in vitro. Further the PDE4 specific inhibitor rolipram effectively attenuates SMA collagenexpression and accompanying morphological changes in HSCs. PDE4 is the largest sub-family among cAMP-hydrolyzing PDEs which tightly regulate the levels of cellular cAMP. cAMP through its effector moleculesprotein kinase A (PKA) and Exchange Protein directly Activated by cAMP (EPAC) has been shown to down-regulate cytokine induced fibrogenic genes in non-hepatic cells. Hence we hypothesize that induction of PDE4expression and activity plays a causal role in HSC activation by decreasing cAMP-PKA/EPAC activities andpromoting fibrogenic signaling. We postulate that during HSC activation promoter associated epigeneticchanges and post-translational modifications play a significant role in the regulation of PDE4 expression andactivity. We also postulate that PDE4 inhibition will restore PKA/EPAC activities and attenuate TGF-Smadsignaling through: (i) inactivation of relevant MAPKs; and (ii) de-repressing PPAR leading to decreasedexpression of SMA and Col1A1. Importantly inhibition of PDE4 activity may be a significant therapeuticapproach for liver fibrosis. The specific aims of this proposal are to: 1) Determine the role of PDE4 in theregulation of fibrogenic signaling in HSCs; 2) Determine promoter-associated epigenetic modificationscontributing to the induction of PDE4 isoforms during HSC activation; and 3) Determine the post-translationalmodifications (PTMs) relevant for PDE4 isoform function during HSC activation. Importantly the results of thisCOBRE-funded project will provide proof-of-principle and mechanistic rationale for in vivo translational studies(R01) to examine PDE4 targeted strategies for prevention and treatment of hepatic fibrosis.

project_terms:
Address;Attenuated;Centers of Research Excellence;Cirrhosis;Collagen;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;DNA Modification Process;Development;Enzymes;Epigenetic Process;Etiology;FDA approved;Family;Fibrosis;Funding;Genes;Genetic Transcription;Hepatic Stellate Cell;Hepatocyte;In Vitro;Inflammation;Injury;Knockout Mice;Liver Fibrosis;MAP Kinase Gene;Mass Spectrum Analysis;Mediating;Modeling;Modification;Morphology;Myofibroblast;PDE4B;PPAR gamma;Pathogenicity;Phenotype;Phosphorylation;Play;Post-Translational Protein Processing;Prevention strategy;Primary carcinoma of the liver cells;Process;Promoter Regions;Protein Isoforms;Proteins;Proteomics;Rattus;Regulation;Role;Rolipram;Second Messenger Systems;Signal Transduction;Therapeutic;Toxicology;Transcriptional Activation;Transforming Growth Factor beta;Wound Healing;base;cell transformation;cytokine;experimental analysis;histone modification;in vivo;inhibitor/antagonist;liver injury;member;phosphodiesterase IV;promoter;translational study


application_id: 9673154
project_number: 5P20GM113226-04
project_title: Role of oxidized linoleic acid metabolites in the pathogenesis of alcoholic liver disease
administering_ic: NIGMS
award_notice_date: 2019-04-01
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6172
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA A.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-04-01
budget_end_date: 2020-03-31
project_abstract:
Alcoholic liver disease (ALD) ranks among the major causes of morbidity and mortality in the world andaffects millions of patients worldwide each year. Despite the progress made on ALD pathogenesis the specificmechanism(s) responsible for ALD development and progression remain poorly understood. Importantly thereis no FDA approved therapy for any stage of ALD. Recent studies from our laboratory and others havedemonstrated that dietary unsaturated fat specifically rich in linoleic acid (LA) exacerbated alcohol-mediatedliver and intestinal injury in an experimental animal model of ALD. Our preliminary data show elevated levels ofcirculating oxidized LA metabolites specifically 9- and 13-hydroxy-octadecadienoic acids (9-and 13-HODEs) inparallel with the up-regulation of hepatic 12/15 lipoxygenase (12/15-LO) a key enzyme involved in theoxidation of LA. These findings have led us to postulate that specific oxidized LA metabolites (OXLAMs) mayplay a significant role in ALD. OXLAMs are natural ligands to the transient receptor potential vanilloid 1(TRPV1) a ligand-gated non-selective cation channel with high permeability for Ca2+. Recent studiesdemonstrate a critical role for Ca2+ release in inflammasome activation which are key signaling platforms forstressor-induced pathogenesis and which upon activation trigger the release of highly pro-inflammatorycytokines interleukin-1 (IL-1) and interleukin-18 (IL-18). IL-1 release is thought to be a critical mediator ofinflammation and thus serves as a potential therapeutic target for treating hepatic inflammation in ALD. Basedon our own and other published findings our CENTRAL HYPOTHESIS is that OXLAMs play a significantrole in the development and progression of ALD. We hypothesize that OXLAMs contribute to the EtOH-induced hepatic inflammation and injury via two mechanisms: 1) OXLAMs-mediated mitochondrialdysfunction and hepatocyte death; and 2) OXLAM/TRPV1/Ca2+-mediated inflammasome activation andIL-1 release. The proposed studies will lead to better understanding of molecular mechanisms contributing tothe pathogenesis of alcohol-induced liver inflammation and injury. These studies will also help us to betterunderstand alcohol-diet interactions which may lead to identification of new therapeutic targets and potentialdietary interventions for treating ALD as well as help to explain why only some people who drink heavilydevelop clinically important ALD. A combination of in vitro in-vivo animal (knockouts and chimeric mousemodels) and human studies will be employed.

project_terms:
Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Animals;Arachidonate 15-Lipoxygenase;Attenuated;Cations;Centers of Research Excellence;Cessation of life;Chronic;Clinical;Data;Development;Diet;Dietary Intervention;Enzymes;Ethanol;Experimental Animal Model;FDA approved;Fatty Liver;Heavy Drinking;Hepatic;Hepatocyte;Human;In Vitro;Inflammasome;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Interleukin-1 beta;Interleukin-18;Intestines;Knock-out;Knockout Mice;Kupffer Cells;Laboratories;Lead;Ligands;Linoleic Acids;Liver;Mediating;Molecular;Morbidity - disease rate;Mus;Oxides;Pathogenesis;Pathway interactions;Patients;Permeability;Pharmacology;Plasma;Play;Production;Publishing;Role;Signal Pathway;Signal Transduction;Testing;Toxicology;Translating;Unsaturated Fats;Up-Regulation;Vanilloid;Whole Blood;base;cytokine;human study;in vitro testing;in vivo;liver inflammation;liver injury;macrophage;mitochondrial dysfunction;monocyte;mortality;mouse model;new therapeutic target;octadecadienoic acid;oxidation;peripheral blood;receptor;stressor;therapeutic target


application_id: 9672939
project_number: 5P42ES023716-03
project_title: Characterizing Urban- and Finer-Scale Spatial Variability for Select VOC Superfund Compounds
administering_ic: NIEHS
award_notice_date: 2019-04-01
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5123
contact_pi_person_id: 10828196
contact_pi: TURNER, JAY ROBERT
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: 2019-04-01
budget_end_date: 2020-03-31
project_abstract:
SUMMARY  Project 4 Hazardous volatile organic compounds (VOC) have adverse impacts on human health.These compounds likely exhibit high spatial variability in urban areas because of the numerousemission sources (e.g. industrial commercial residential traffic) and complex dispersionpatterns. Thus tools are needed to characterize the small-area variation of intra-urban VOCconcentrations. Land use regression (LUR) modeling is a powerful tool for assessing spatialvariability. It relies upon ambient measurements at a large number of sites and has beenextensively used for pollutants such as nitrogen dioxide and particulate matter. Howeverrelatively few studies have built LUR models for VOCs and in most cases the focus was trafficrelated emissions of benzene and other compounds emitted by vehicles. Mobile platformmeasurements have recently been used to collect air quality data for LUR model-building.However mobile monitoring of VOCs has not been used in LUR modeling because ofmeasurement challenges. This project will develop a portable VOC monitor suitable for mobileplatform measurements. Field studies will be conducted at urban- and neighborhood scales andthe VOC data will be used for LUR model-building. LUR results will be used by another Centerproject to evaluate relationships between ambient VOCs and cardiometabolic disease. LURresults will also be used to examine relationships between VOC air quality and proximity togreen space which might be an effective VOC remediation strategy. New tools will bedeveloped to use mobile platform measurements to identify the location and strength ofemission sources. This project is closely coupled to the Centers primary objective to examinecardiometabolic effects of exposure to VOC Superfund chemicals. It will also have broaderimpacts on air quality monitoring and exposure assessment.

project_terms:
Air;Automobile Driving;Benzene;Categories;Complex;Coupled;Data;Data Analyses;Data Quality;Development;Disease;Disease Progression;Ecology;Environment;Environmental Engineering technology;Environmental Exposure;Equipment and supply inventories;Etiology;Exhibits;Exposure to;Future;Gases;Geography;Goals;Green space;Health;Heart;Housing;Human;Industrialization;Location;Measurement;Modeling;Monitor;Neighborhoods;Nitrogen Dioxide;Participant;Particulate Matter;Pattern;Proxy;Research Project Grants;Resolution;Route;Sampling;Scheme;Seasons;Site;Small-Area Variations;Source;Superfund;Testing;Time;Variant;Work;cardiometabolism;density;design;design and construction;field study;insight;land use;metropolitan;miniaturize;mobile computing;model building;novel;pollutant;portability;remediation;sample collection;spatial relationship;study population;superfund chemical;tool;urban area;urinary;volatile organic compound

public_health_relevance:
RELEVANCE  Project 4This environmental science and engineering research project will develop a novel portablevolatile organic compound (VOC) monitor suitable for mobile platform measurements andconduct monitoring for land use regression model-building. The project will determine the small-scale variation of intra-urban VOC concentrations which will be used by another Center projectto examine the impact of VOCs on cardiometabolic disease. Relationships between VOCconcentrations and proximity to green space will be examined towards evaluating whethergreening could be an effective remediation strategy. Tools will be developed to use mobilemonitoring data to identify emission sources of ambient VOCs.


application_id: 9672937
project_number: 5P42ES023716-03
project_title: Molecular and Cellular Mechanisms of Cardiometabolic Toxicity of VOCs
administering_ic: NIEHS
award_notice_date: 2019-04-01
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5121
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
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: 2019-04-01
budget_end_date: 2020-03-31
project_abstract:
SUMMARYExposure to toxicants has been linked to the development or exacerbation of chronic disease. While the healthof effects of ubiquitous environmental substances such as tobacco smoke and particulate matter are morewell-studied less is known about how volatile organic chemicals (VOC)a class of toxicants associated withhigher prevalence of type 2 diabetes (T2D) and strokepromote the development of cardiometabolic disease(CMD). Understanding how VOC affect CMD is important because obesity and T2D are rapidly growing globalhealth crises. Accordingly the overarching goals of this Superfund project are to determine the mechanisms bywhich VOCs negatively impact cardiovascular health and metabolism identify biomarkers for VOC exposureand vascular injury and test therapeutic strategies to minimize VOC-induced CMD. Our preliminary datasuggest that VOC such as acrolein promote endoplasmic reticulum (ER) stress and trigger the unfolded proteinresponse (UPR) in endothelial cells resulting in insulin resistance. In addition we find that individuals exposedto VOC such a vinyl chloride develop symptoms of CMD that could be instigated at the molecular level byVOC-induced ER stress. Specifically we hypothesize that aldehyde metabolites of VOC which are generallymore toxic than their parent compound diminish insulin sensitivity in vascular tissues by inducing ER stresswhich triggers metabolic changes that accelerate ectopic lipid deposition and promote cardiometabolicdysfunction. To test this hypothesis we will: (1) examine the effects of VOC exposure on endothelial functionand insulin resistance; (2) delineate the contribution of endothelial UPR to the cardiometabolic toxicity of VOC;and (3) elucidate the role of VOC-derived aldehydes in exacerbating CMD. The design of these studiesincludes molecular and pharmacological interventions designed to detoxify or quench the reactiveintermediates evoked by VOC exposure as well as studies that could lead to the identification of novelsensitive and robust biomarkers of both VOC exposure and vascular injury. These studies were designed tosynergize with and provide biological plausibility for the associations identified in Project 1. Successfulcompletion of this project will lead to identification of the underlying cellular and molecular mechanisms bywhich VOC affect insulin sensitivity and cardiometabolic function and provide insights into how VOC toxicitycould be prevented or therapeutically minimized by targeting aldehydes or protein-folding pathways.

project_terms:
ATF6 gene;Acids;Acrolein;Adipose tissue;Adult;Affect;Aldehydes;Apoptosis;Atherosclerosis;Attenuated;Benzene;Biochemical Pathway;Biological;Biological Markers;Blood Vessels;Body Burden;Butyric Acids;Cardiovascular Diseases;Cardiovascular system;Carnosine;Cell Respiration;Chemical Exposure;Chemical Injury;Chemicals;Chronic Disease;Data;Deposition;Development;Diabetes Mellitus;Diet;Disease;Disease Resistance;Dyslipidemias;Endoplasmic Reticulum;Endothelial Cells;Endothelium;Environmental Exposure;Environmental Impact;Enzymes;Exposure to;Fatty Liver;Fatty acid glycerol esters;Functional disorder;Goals;Hazardous Chemicals;Hazardous Substances;Health;Hepatic;High Prevalence;Individual;Inflammatory;Injury;Insulin Resistance;Investigation;Lead;Link;Lipids;Measures;Mediator of activation protein;Metabolic;Metabolism;Molecular;Molecular Chaperones;Mus;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Nutritional status;Obesity;Organic Chemicals;Oxidative Stress;Parents;Particulate;Particulate Matter;Pathway interactions;Pharmacology;Phase;Plants;Plasma;Poison;Polyvinyl Chloride;Process;Production;Proteins;Protocols documentation;Reporting;Risk;Role;Series;Signal Transduction;Stress;Stroke;Superfund;Surveys;Symptoms;Testing;Therapeutic;Tissues;Tobacco smoke;Toxic effect;Vinyl Chloride;Work;aldehyde dehydrogenases;ambient air pollution;cardiometabolism;cardiovascular disorder risk;cardiovascular health;design;endoplasmic reticulum stress;global health;insight;insulin sensitivity;metabolomics;mouse model;novel;overexpression;oxidized lipid;prevent;protein folding;response;superfund site;tauroursodeoxycholic acid;therapeutic evaluation;therapy design;toxicant;urinary;vascular inflammation;volatile organic compound;western diet

public_health_relevance:
PROJECT NARRATIVEExposure to hazardous substances has been linked to the development or worsening of chronic disease. Thepurposes of this Superfund project are to understand how a particular class of compounds i.e. volatile organiccompounds affect cardiovascular health and the onset or progression of insulin resistance obesity anddiabetes as well as to develop therapeutic strategies to minimize these affect after exposure to toxiccompounds.


application_id: 9672936
project_number: 5P42ES023716-03
project_title: Environmental Exposure and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2019-04-01
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5120
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: 2019-04-01
budget_end_date: 2020-03-31
project_abstract:
The overall goal of this project is to examine whether exposure to environmental pollutants specifically volatileorganic compounds (VOCs) induces/exacerbates cardiometabolic disease (CMD) by causing systemic insulinresistance and low grade inflammation. Insulin is a master regulator of metabolism and energy disposition anddysregulation of insulin signaling is associated with the development of obesity and Type 2 diabetes (T2D)which are robust contributors to atherogenesis and heart disease. Recent research has identified a pathogeniccontinuum between the development of insulin resistance hepatic steatosis dyslipidemia and cardiovasculardisease. We postulate that environmental pollutants/toxins can either directly cause CMD or interact withobesity and poor nutrition to cause/exacerbate CMD. We have published initial experimental human/rodentdata to support this concept and further preliminary animal data are presented in Project #2. Here we presentimportant human preliminary results from a unique database/specimen bank of plant workers exposed to highlevels of certain VOCs especially vinyl chloride. The Toxicology Specimen and Databank provides theopportunity for a novel cross-sectional study evaluating the effects of vinyl chloride and other VOCs on thedevelopment of insulin resistance and fatty liver (Aim 1a). We will examine our death certificate data toevaluate the effects of VOC exposure on all cause and cardiac deaths (Aim 1b). We will also perform aretrospective/prospective study using samples obtained over a ~40-year period of time to correlate thedevelopment of insulin resistance with outcome measures of the CMD and predictors of risk (includingoccupational exposure personal exposure and novel markers of metabolic injury that we have developedAim 1c). We will also be able to enroll residents from VOC "hot spots" including the Lees Lane superfund sitein a prospective longitudinal evaluation of the impact of lower levels of exposure and the impact ofobesity/nutrition on the progression of CMD (Aim 2). We are able to perform these studies because of anestablished database continued linkages with industry for nearly 40 years and ongoing interactions withcommunity leaders and residents which provide a highly-novel opportunity to assess the cardiometaboliceffects of VOCs over a range of exposures.

project_terms:
Air;Area;Arsenic;Attention;Benzene;Biochemical Pathway;Biological Markers;Blood;Blood Coagulation Factor;Blood Platelets;Cardiac Death;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell physiology;Cessation of life;Chronic;Clinical;Collaborations;Communities;Controlled Study;Cross-Sectional Studies;Cytokeratin 18;Data;Databases;Death Certificates;Development;Disease;Disease Progression;Dyslipidemias;Endocrine Disruptors;Endothelial Cells;Endothelium;Enrollment;Environment;Environmental Exposure;Environmental Pollutants;Environmental Risk Factor;Event;Exposure to;Fatty Liver;Geography;Glucose Intolerance;Goals;Heart;Heart Diseases;Hot Spot;Human;Hydroxyeicosatetraenoic Acids;Impact evaluation;Individual;Industrialization;Industry;Inflammation;Injury;Insulin;Insulin Resistance;Lipids;Liver diseases;Longitudinal prospective study;Measures;Medical;Medical History;Metabolic;Metabolic Marker;Metabolism;Modeling;Monitor;Non obese;Non-Insulin-Dependent Diabetes Mellitus;Nutritional status;Obesity;Occupational;Occupational Exposure;Outcome Measure;Participant;Particulate;Pathogenicity;Pathway interactions;Plants;Plasma;Population;Prevalence;Process;Prospective Studies;Publishing;Research;Resources;Retrospective Studies;Risk;Rodent;Role;Sampling;Serum;Severities;Specimen;Stem cells;Superfund;Testing;Time;Toxicology;Toxin;Urine;Vinyl Chloride;Work;adipokines;animal data;atherogenesis;base;biobank;blood glucose regulation;cardiometabolism;cardiovascular disorder risk;cardiovascular injury;cohort;cytokine;data management;data warehouse;endoplasmic reticulum stress;endothelial dysfunction;exposed human population;insulin signaling;monocyte;novel;novel marker;nutrition;obesity development;pollutant;primary outcome;prospective;superfund chemical;superfund site;translational study;urinary;volatile organic compound

public_health_relevance:
The overall goal of this project is to examine whether exposure to environmental pollutants particularly volatileorganic compounds (VOCs) causes or makes worse a group of disease processes known as cardiometabolicdisease (CMD). These processes include type 2 diabetes cardiovascular disease and fatty liver disease. Allof these conditions seem to be regulated through insulin resistance. We hypothesize that environmentalpollutants/toxins can either directly cause CMD or interact with obesity and poor nutrition to cause CMD ormake it worse. In this project we will investigate subjects from two ongoing studiesOccupational ToxicologyData and Specimen Bank and the Louisville Healthy Heart Studyto determine if exposure to pollutants leadsto insulin resistance and subsequent CMD. We are able to perform these studies because of an establisheddatabase continued linkages with industry for nearly 40 years and ongoing interactions with communityleaders and residents which provide a highly-novel opportunity to assess the effects of pollutants in bothworkers and a residential population from the same West Louisville area.


application_id: 9672935
project_number: 5P42ES023716-03
project_title: Sample and Data Management Core
administering_ic: NIEHS
award_notice_date: 2019-04-01
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5119
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: 2019-04-01
budget_end_date: 2020-03-31
project_abstract:
ABSTRACTThe primary objective of the Sample and Data Management Core (SDMC) is to provide support to each of thefour projects of the Louisville Superfund Center. The functions of the Core are matched to the needs of eachproject and cover a full range of services from collaboration and routine service to protocol preparation toprocedural review and oversight. The Core will provide two main services: it will establish a repository for thelong-term storage and archiving of samples and data; and it will assist Center investigators in the statisticalanalysis of their results. The core will assure the authenticity and quality of these specimens and it will preparethese samples for long-term storage or dispense samples as needed. The Core will also provide scientificallyvalid and rigorous statistical analysis of data and support the development of innovative methods to enhance thebasic and translational research efforts of Center investigators. The Core will provide state-of-the-art biostatisticsand bioinformatics expertise and analytical support. Core biostatisticians will also develop new statisticalmethods such as quantitative risk assessment models for estimating cardiometabolic disease risk in exposedpopulations and for the analysis and evaluation of exposures and health consequences. In addition the corewill develop novel methods for the analysis of multi-pollutant exposures as they relate to health outcomes. Thecore will serve as a unique educational resource for training graduate students post-doctoral fellows residentsand junior faculty and in collaboration with the Training and Administration Cores. This Core will allow Centerinvestigators easy access to high quality centralized data management and statistical services and thereby willstrengthen the organizational cohesion of the Center. This comprehensive and integrated service permits oneor more biostatisticians to be involved from the initial planning stage of a project (when statistical consultation ismost beneficial) throughout its implementation analysis and completion. The Core will provide a stable andcollegial environment that fosters long-term working relationships between biostatisticians and investigators andcontinues to promote sophisticated approaches to experimental design and analysis. The biostatisticians of thisCore are knowledgeable about clinical research and have broad expertise in statistical applications forepidemiological investigations clinical trials pre-clinical studies and prevention and control research. Theirinterdisciplinary interactions with basic scientists and clinical investigators will add a new dimension to theinterpretation of experimental results one that is only possible when collaborators share a mutual appreciationof problems and issues.

project_terms:
Animals;Annual Reports;Archives;Basic Science;Bioinformatics;Biological;Biometry;Biostatistical Methods;Cataloging;Catalogs;Clinical Investigator;Clinical Research;Clinical Trials;Collaborations;Collection;Communities;Consultations;Continuing Education;Data;Data Analyses;Development;Dimensions;Disease;Educational workshop;Elements;Ensure;Environment;Environmental Exposure;Evaluation;Experimental Designs;Exposure to;Faculty;Fostering;Future;Goals;Hazardous Chemicals;Hazardous Substances;Health;Human Resources;Individual;Journals;Metabolism;Methods;Modeling;Outcome;Population Analysis;Postdoctoral Fellow;Preparation;Prevention;Procedures;Productivity;Protocols documentation;Publications;Records;Reproducibility;Research;Research Activity;Research Design;Research Personnel;Resources;Risk;Risk Assessment;Sampling;Scientist;Services;Signal Recognition Particle;Source;Specimen;Statistical Data Interpretation;Statistical Methods;Students;Superfund;System;Technology;Testing;Tissues;Toxic effect;Training;Translational Research;Universities;Work;base;biobank;cardiometabolism;career development;cohesion;cohort;data archive;data management;design;disorder risk;education resources;efficacy testing;epidemiology study;experience;experimental analysis;graduate student;innovation;meetings;member;novel;operation;pollutant;preclinical study;programs;quality assurance;radio frequency;repository;statistical service;tool;usability

public_health_relevance:
RELEVANCEBy ensuring proper study designs and supporting appropriate data analysis the core will help in theunderstanding of risk sources and cardiometabolic disease risk estimation due to exposure to hazardouschemicals. Long-term storage and archiving of data and samples within the Core will facilitate future studies.


application_id: 9672933
project_number: 5P42ES023716-03
project_title: Research Translation Core
administering_ic: NIEHS
award_notice_date: 2019-04-01
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5117
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-04-01
budget_end_date: 2020-03-31
project_abstract:
ABSTRACTThe overall goal of the Research Translation Core (RTC) is to disseminate scientific knowledge acquired fromthe Louisville Superfund Basic Research Program (SBRP) in a timely manner to key constituencies in formsthat are targeted and useful to our audience. Our primary target audience are: (a) our local community andcommunity-based groups involved in protecting human health and the environment; (b) scientists and publichealth professionals working at other academic institutions and at local and federal agencies including theNIEHS itself and the broader SBRP community; (c) local state and federal policy makers and non-governmental organizations that contribute to the development of environmental regulations and policies; and(d) local media and press. We will tailor messages to appropriate audiences and use conventional andinnovative tools such as social media blogs and tweets to communicate with our audience aboutenvironmental issues of mutual interest. Our intent is to cultivate an informed participatory audience as well asto enhance awareness and understanding of our Superfund team of environmental issues of interest andconcern to both local and national stakeholders. Serving as a multi-directional bridge the RTC will facilitatemaximize and optimize interactions between our Superfund team and its wider audience. This arrangementwill ensure that environmental issues particularly those related to VOC exposure and cardiometabolic healthinform our research activities and that the findings of our research are appropriately disseminated. It will alsoensure that knowledge generated by our program contributes substantially to practices and policies relevant toenvironmental health across Kentucky and the nation. The RTC will serve as bidirectional bridge between thecommunity and the Louisville Superfund Program and develop effective and contextually appropriatecommunication strategies and tools. The core personnel will communicate routinely with policy makers andpublic health organizations and assist Center investigators in their efforts in disseminating research findingsand facilitate intellectual and technology transfer of promising scientific and engineering applications topromote timely application of research. The RTC will working closely with the Community Engagement Core tofurnish educational information to be incorporated in their community and trainee education activities andprovide a venue for Training Core participants to experience and learn research translation and regulatoryscience. The Core will also evaluate its effectiveness in facilitating communication between the program andits broad audience and in facilitating technology transfer and enabling educational activities.

project_terms:
Administrator;Affect;Area;Awareness;Basic Science;Cardiovascular Diseases;Chemical Exposure;Chemicals;Collaborations;Communication;Communities;Consequentialism;Data;Decision Making;Detection;Development;Devices;Diabetes Mellitus;Disease;Education;Educational Activities;Educational Materials;Educational Technology;Effectiveness;Emergency response;Engineering;Ensure;Environment;Environmental Exposure;Environmental Health;Evaluation;Exposure to;Federal Government;General Population;Goals;Government;Government Agencies;Government Officials;Health;Health Policy;Health Professional;Human;Human Resources;Information Dissemination;Institution;Intellectual Property;Kentucky;Knowledge;Learning;Link;Liver diseases;Local Government;Medical emergency;Methods;National Institute of Environmental Health Sciences;Newsletter;Nongovernmental Organizations;Organic Chemicals;Participant;Pathway interactions;Policies;Policy Maker;Population;Process;Public Health;Regulation;Research;Research Activity;Research Personnel;Risk Estimate;Science;Scientist;State Government;Students;Superfund;Technology;Technology Transfer;Time;Training;Translating;Translational Research;Work;base;cardiometabolism;effectiveness research;experience;federal policy;health organization;innovation;interest;meetings;member;news;novel;programs;public health relevance;social media;superfund chemical;superfund site;symposium;tailored messaging;tool;web site;webinar

public_health_relevance:
Project Narrative:The Research Translational Core (RTC) will provide a communication pathway linking the community atSuperfund site and other areas of high exposure to volatile organic chemicals (VOCs) with investigators at theLouisville Superfund Center (LSC). Working with both the Community Engagement Core and theAdministrative Core the RTC will organize Town Hall Meeting symposia informal meeting round tablediscussions between the community residents and leaders subject matter experts LSC researchers membersof governmental agencies and other stakeholders. The Core will develop communication strategies to targetspecific audiences and disseminate research findings and environmental health relevant information incontextually appropriate formats. Core personnel will communicate regularly with governmental organizationsand other interested parties to Louisville Superfund Center to provide assessments and risk estimates of VOCexposure in affected communities. The RTC will strive to identify the barriers to communication betweenresearchers and policy makers and work toward eliminating or ameliorating those barriers. The Core will alsofacilitate transfer of intellectual property and technology to ensure that the research and technology developedby LSC members finds appropriate and timely application. In collaboration with the Community EngagementCore and the Training Core the RTC will develop educational material for community forums and for traineesand students. The Core will gather data on its effectiveness in enabling communication between the programand its broad audience and provide an evaluation of its activities.Public Health RelevanceLittle is known about the health effects of volatile organic chemicals (VOCs) an important class of SuperfundChemicals on cardiovascular disease liver disease or diabetes. The Core will assist in understanding theimpact of these chemicals in affected populations facilitate the dissemination of this information and translatethis knowledge into formats that would be readily accessible to policy makers and regulators. During thisprocess the Core will ensure that the technologies and research developed by LSC researcher finds timelyapplications and that the activities of the Center are fully understood by its participants trainees governmentagencies and the general public.


application_id: 9672932
project_number: 5P42ES023716-03
project_title: Community Engagement Core
administering_ic: NIEHS
award_notice_date: 2019-04-01
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5116
contact_pi_person_id: 11775218
contact_pi: HEBERLE, LAUREN
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: 2019-04-01
budget_end_date: 2020-03-31
project_abstract:
Abstract: Residents of Kentucky suffer disproportionately from many chronic diseases and exposure to toxics in theirenvironment. Dangerously high rates of obesity hypertension diabetes and cancer in Kentucky have beenwell documented. Our areas of focus are West Louisville encompassing six zip codes within the larger Metroarea. In West Louisville neighborhoods 61.1% of residents are black/African Americans and 55% of childrenunder age 18 live in poverty. Our preliminary assessments suggest that residents living near the Lees Lanelandfill in West Louisville Rubbertown a heavily industrialized residential area and Oakdale a neighborhoodnear Churchill Downs have high in VOC exposures. The Louisville medical community has a long history of bi-directional interactions with active communityinvolvement in health care delivery and research. These interactions date back to the creation of the MarineHospital in 1823 to treat riverboat workers continues in the 1970s with partnerships with industries to establishthe ongoing surveillance program of workers with hepatic hemeangiosarcoma associated with their exposureto vinyl chloride and more recently is highlighted by the partnership between Louisville Metro Department ofPublic Health and Wellness along with UofL and other community partners to fight obesity and chronic diseaseunder the CDC Communities Putting Prevention To Work (CPPW) grant and to mitigate the effects of airpollution exposure by planting trees under the Funders Network for Smart Growth and Livable CommunitiesPartner-for-Places grant. The overarching goal of the CEC is to support community and academicscientists/educators in transdisciplinary research that incorporates best practices in community engagement byfacilitating beneficial and bidirectional interactions between residents industry policy makers and SuperfundCenter interdisciplinary investigators. We will achieve this through the following Specific Aims: 1. Augment community and investigator capacity for transdisciplinary research focused on exposure to Superfund contaminants through facilitating Community Environmental Quality Resource Exchange Sessions (CEQRES) and establishing a Sustainable InstitutionalizedCollaborative Framework through the Louisville Superfund Center Community Advisory Board (LSC-CAB). 2. Support and facilitate project- and core-specific community engagement activities 3. Support a community project aimed at mitigating the effects of exposures to Superfund VOCs 4. Assess change in perception and knowledge of community participants and investigators as a result of engaging in specific Superfund Center activities.Through regular public forums and board meetings support of specific Superfund research projects andtraining community engaged intervention assessment of community and investigator perceptions andknowledge and substantive interactions with other project Cores particularly the Research Translation Core(RTC) the CEC will provide content and structural support necessary for ongoing community engagedresearch aimed at evaluating the health effects of pollutant exposure and reducing exposures to and negativeimpacts of Superfund toxic emissions.

project_terms:
Address;Adult;Affect;African American;Age;Air;Air Pollution;Area;Awareness;Back;Belief;Centers for Disease Control and Prevention (U.S.);Child;Chronic;Chronic Disease;Code;Communities;Dangerousness;Data;Death Rate;Development;Diabetes Mellitus;Disease;Elements;Ensure;Environment;Environmental Exposure;Environmental Health;Equipment;Evaluation;Exposure to;Fatty Liver;Feedback;Future;Goals;Government;Grant;Green space;Growth;Health;Health Food;Health Sciences;Heart Diseases;Hepatic;Home environment;Hospitals;Hot Spot;Housing;Hypertension;Industrialization;Industry;Intervention;Kentucky;Knowledge;Liver diseases;Love;Malignant Neoplasms;Marines;Measures;Medical;Monitor;Natural Sciences;Neighborhoods;Obesity;Participant;Patient Recruitments;Perception;Plants;Play;Policy Maker;Population;Poverty;Prevention;Preventive Intervention;Process;Public Health;Recording of previous events;Research;Research Personnel;Research Project Grants;Resources;Risk;Role;Scientist;Social Sciences;Source;Structure;Superfund;Surveillance Program;Syndrome;Testing;Toxic effect;Training;Transcend;Translational Research;Transportation;Trees;Vinyl Chloride;Work;attributable mortality;biological systems;cardiometabolism;community center;community involvement;fighting;health care delivery;health disparity;landfill;meetings;member;pollutant;public health relevance;racial disparity;social;superfund site;therapy design;toxicant

public_health_relevance:
Project Narrative:Residents of Kentucky are disproportionately affected by many chronic diseases and exposure to toxics in theirenvironment. Dangerously high rates of obesity hypertension diabetes and cancer in Kentucky have beenwell documented. Health disparities by race and class persist across Louisville Metro. Our areas of focus areWest Louisville neighborhoods where 61% of the population is black/African American. This area includesboth the Lees Lane Superfund site and Rubbertown. A nearby neighborhood Oakdale also is a hot spot.All of these areas have excessive exposure to Superfund VOCs. Within the West Louisville neighborhoods thepercentage of children under age 18 who live in poverty is 55% and the rates of deaths attributable to povertyfor adults over 25 are 4%-24% higher than in other Louisville Metro neighborhoods. West Louisville is alsohome to a very high number of industries (located very near residential areas) that are major sources of toxicair emissions numerous brownfields and a superfund designated land-fill. In addition area residents strugglewith poor access to greenspace inadequate transportation lack of affordable safe housing and limited accessto healthy food options. The CEC goal is to support transdisciplinary research that incorporates best practicesin community engagement by facilitating beneficial bi-directional interactions between residents industrypolicy makers and Superfund Center interdisciplinary investigators building all stakeholders capacities tocollaboratively understand reduce exposure to and address the negative impacts of contaminants initiallyfocused on VOCs from Superfund sites and industrial activities in West Louisville.Public Health Relevance:We are beginning to understand that exposure to toxicants can initiate/exacerbate multiple health problemsespecially cardiometabolic diseases. Kentuckians are disproportionately affected by many chronic diseasesincluding obesity hypertension heart disease diabetes fatty liver disease etc. which are all aspects of thecardiometabolic syndrome. Certain communities are more highly impacted than others and it is critical tounderstand why. It is our hypothesis that exposure to toxics specifically VOCs initiates/exacerbates theseconditions. It is fundamental to our understanding of the effects of these toxics to engage the communitiesmost deeply affected by exposure to these pollutants and to try to mitigate the effects of these exposures.Thus determining the influence of pollutant exposure on the development/progression of these chronicconditions is vital.


application_id: 9672517
project_number: 5R01HL056652-20
project_title: Molecular Mechanism of Platelet Exocytosis
administering_ic: NHLBI
award_notice_date: 2019-04-03
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 056652
program_official: SARKAR, RITA
project_start_date: 1996-07-01
project_end_date: 2020-03-31
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
World-wide spurious thrombosis accounts for 1 in 4 non-communicable disease deaths.Normally platelets respond to vascular damage and secrete granule cargo that are essential forrecruiting more platelets their adhesion and thrombosis. This releasate promotes normalsequelae but can also contribute to disease. Do platelets actively control what they release?How much releasate is enough? These are key questions to understand how platelets affecttheir vascular microenvironments. Membrane proteins (v- and t-SNAREs) fuse granule andplasma membranes to allow cargo release. In platelets VAMPs SNAP-23 and Syntaxin-11form a membrane-spanning complex that mediates fusion. Formation of this complex requirespost-translational modifications and a host of SNARE-regulators. This controls the complexity ofthe platelet release reaction: its rate extent and content. We hypothesize that bymanipulating the platelet secretory machinery we can modulate thrombosis with onlymodest effects on hemostasis. We propose three Aims: 1) Determine how alterations inplatelet exocytosis affect thrombosis and hemostasis. Using our unique collection oftransgenic mice we will genetically titrate platelet secretory machinery to determine how muchsecretion is needed for thrombosis and hemostasis. 2) Determine if platelet exocytosis canbe controlled by targeting post-translational modifications of t-SNAREs. We will examinetwo post-translational modifications: SNAP-23 phosphorylation by IB kinase and t-SNAREacylation. We will test inhibitors to determine if they can be repurposed as anti-thrombotics. t-SNARE acylation is highly dynamic in platelets. We will alter its cycling with acyl transferase andthioesterase inhibitors to define its importance to secretion and whether acylation can betargeted to affect platelet exocytosis. 3) Determine the roles of new elements of the plateletexocytosis machinery. We will probe the roles of two novel secretory elements: -synucleinand RalA/B. Our proposal expands our knowledge of the molecular requirements and thesequence of protein-protein interactions controlling platelet exocytosis. Our work is significantbecause it provides the needed mechanistic insights to identify potential targets for therapeuticintervention and to evaluate the relevance of the increasing volume of gene/risk associations.

project_terms:
Acylation;Address;Adhesions;Affect;Agonist;Amino Acid Sequence;Biochemical;Biological Assay;Blood Coagulation Disorders;Blood Platelets;Blood Vessels;Cell membrane;Cessation of life;Clinical;Coagulation Process;Collection;Communicable Diseases;Complex;Cytoplasmic Granules;Data;Defect;Disease;Elements;Equilibrium;Event;Exocytosis;Fatty Acids;Funding;Goals;Health;Hemorrhage;Hemostatic function;Hyperactive behavior;Kinetics;Knowledge;Mediating;Membrane;Membrane Fusion;Membrane Proteins;Molecular;Mus;Myocardial Infarction;Pathology;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Physicians;Post-Translational Protein Processing;Process;Proteins;Public Health;Reaction;Risk Factors;Role;S-nitro-N-acetylpenicillamine;SNAP receptor;Serine;Stroke;Testing;Therapeutic;Therapeutic Intervention;Thrombosis;Transferase;Transgenic Animals;Transgenic Mice;Transmembrane Domain;Work;active control;alpha synuclein;alpha-SNAP;base;design;experimental study;genetic analysis;genetic manipulation;genetic regulatory protein;in vivo;inhibitor/antagonist;insight;kinase inhibitor;novel;platelet function;protein protein interaction;recruit;response;risk variant;syntaxin 11;target SNARE proteins;targeted treatment;therapeutic target;vesicle-associated membrane protein;vesicular SNARE proteins

public_health_relevance:
NarrativeRelevance of the Project to Public Health:Worldwide thrombotic events e.g. strokes and heart attacks account for 1 of 4 deaths not caused bycommunicable diseases. Platelet secretion is essential for clot formation and thus is a target forcontrolling thrombosis; however we need to know more about the process before we can manipulate it.This proposal will yield the knowledge necessary to understand the process of platelet secretion andwill identify strategies to control it.


application_id: 9672489
project_number: 5R01ES019217-07
project_title: Endothelial Progenitor Cells and Particulate Air Pollution
administering_ic: NIEHS
award_notice_date: 2019-03-21
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 019217
program_official: NADADUR, SRIKANTH
project_start_date: 2011-09-23
project_end_date: 2023-03-31
study_section: Special Emphasis Panel[ZRG1-CVRS-C(02)]
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: BHATNAGAR, ARUNI ;POPE, ARDEN
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Adult;Adverse effects;Affect;Age;Air Pollution;Angiogenesis Inhibition;Animal Model;Antioxidants;Arrhythmia;Arteries;Atherosclerosis;Attenuated;Automobile Exhaust;Biological Markers;Blood Vessels;Bone Marrow;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Carnosine;Cell physiology;Cells;Characteristics;Chronic;Clinical Trials;Coal;Defect;Development;Dipeptides;Double-Blind Method;Endothelium;Enrollment;Ethnic Origin;Event;Exposure to;Fossil Fuels;Functional disorder;Grant;Growth Factor;Guidelines;Health;Heart Arrest;Heart failure;Hematopoiesis;Human;Impairment;Individual;Industrialization;Inflammation;Inflammatory Response;Injury;Insulin Resistance;Intervention;Lead;Link;Lipid Peroxidation;Measures;Mediating;Mediator of activation protein;Mus;Myocardial Infarction;Myocardial Ischemia;Organic Chemicals;Oxidative Stress;Participant;Particulate;Particulate Matter;Peripheral;Placebos;Population;Populations at Risk;Predisposing Factor;Predisposition;Reactive Oxygen Species;Reporting;Risk;Risk Factors;Smoke;Socioeconomic Status;Stem cells;Stroke;Testing;Therapeutic Intervention;Thrombosis;Toxic effect;Vascular Diseases;Wood material;Work;adverse outcome;ambient particle;arterial stiffness;atherogenesis;base;biological adaptation to stress;burden of illness;cardiovascular disorder risk;cardiovascular injury;cohort;cytokine;design;epidemiology study;experimental study;fine particles;indexing;mortality;novel;oral supplementation;pollutant;prevent;randomized trial;repaired;sex;sudden cardiac death


application_id: 9672414
project_number: 5P30ES026529-03
project_title: Pilot Project Program
administering_ic: NIEHS
award_notice_date: 2019-04-30
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: 7095
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-04-01
budget_end_date: 2020-03-31
project_abstract:
PROJECT SUMMARY  Pilot Project ProgramThe overall goal of the pilot program of the University of Kentucky Center for Appalachian Research andEnvironmental Science (UK-CARES) is to provide new opportunities and resources to support highlyinnovative and collaborative research studies that will enhance the ability to identify and capitalize on emergingenvironmental issues. This will be accomplished by providing developmental and pilot funds for innovativetime-sensitive pilot studies that improve our understanding of the relationships among environmentalexposures human biology and disease. Specifically the goals of the UK-CARES Pilot Program are to:1. Expand the research mission of UK-CARES by supporting new and novel areas of investigation in promising transdisciplinary areas of environmental health research and environmental medicine.2. Provide research support for early career faculty to establish competitive research programs in environmental health science and environmental medicine.3. Provide support for faculty to explore new and innovative directions representing a significant departure from ongoing funded research into the environmental health sciences discipline.4. Enhance the interactions and expand the critical mass of investigators with expertise and experience in transdisciplinary translational environmental health and environmental medicine research on the UKcampus.5. Foster opportunities that meet goals and research interest areas relevant to NIEHS.The pilot program will contribute to creating synergy across the proposed UK-CARES Projects enhancing theeducational component as well as initiating interactions among UK-CARES investigators and otherresearchers at the University of Kentucky. The Pilot Program will actively facilitate research support newlyemerging technologies and focus on the development of the next generation of environmental healthscientists.

project_terms:
Advertisements;Advertising;Appalachian Region;Area;Award;Budgets;Categories;Clinical Sciences;Collaborations;Communities;Data;Development;Dimensions;Discipline;Disease;Ecology;Electronic Mail;Emerging Technologies;Ensure;Environmental Exposure;Environmental Health;Environmental Medicine;Evaluation;Faculty;Fostering;Funding;Funding Opportunities;Generations;Goals;Grant;Human Biology;IACUC;Institutional Review Boards;Investigation;Kentucky;Leadership;Legal patent;Manuscripts;Mission;Monitor;National Institute of Environmental Health Sciences;Pilot Projects;Publishing;Research;Research Personnel;Research Support;Resources;Scientist;Supervision;System;Time;Translational Research;United States National Institutes of Health;Universities;Work;career;community organizations;design;early-career faculty;electronic data;experience;faculty support;health science research;high risk;improved;innovation;interest;meetings;new technology;next generation;novel;off-patent;programs;research study;success;synergism;web site


application_id: 9672413
project_number: 5P30ES026529-03
project_title: Community Outreach and Engagement Core
administering_ic: NIEHS
award_notice_date: 2019-04-30
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: 2019-04-01
budget_end_date: 2020-03-31
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;research data dissemination;self reliance;social media;success;water quality;web site;working group


application_id: 9672411
project_number: 5P30ES026529-03
project_title: Analytical Services Core
administering_ic: NIEHS
award_notice_date: 2019-04-30
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: 2019-04-01
budget_end_date: 2020-03-31
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;analytical method;cost effectiveness;data archive;design;disorder risk;experience;improved;in vitro Model;instrument;instrumentation;member;metabolomics;method development;outreach;pollutant;programs;quality assurance;small molecule;stable isotope;statistics;validation studies


application_id: 9672410
project_number: 5P30ES026529-03
project_title: Integrative Health Sciences Facility Core
administering_ic: NIEHS
award_notice_date: 2019-04-30
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: 2019-04-01
budget_end_date: 2020-03-31
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 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: 9672408
project_number: 5P30ES026529-03
project_title: Center for Appalachian Research in Environmental Sciences
administering_ic: NIEHS
award_notice_date: 2019-04-30
opportunity_number: RFA-ES-16-001
application_type: 5
activity_code: P30
ic: ES
serial_number: 026529
program_official: THOMPSON, CLAUDIA L
project_start_date: 2017-05-01
project_end_date: 2022-03-31
study_section: Environmental Health Sciences Review Committee[EHS(P3)-1]
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN J
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Air;Analytical Chemistry;Appalachian Region;Area;Arsenic;Asthma;Atherosclerosis;Awareness;Bioinformatics;Chemicals;Child Health;Chromium;Chronic Disease;Chronic Obstructive Airway Disease;Clinical;Collaborations;Colorectal Cancer;Communication;Communities;Community Outreach;Complex;Computational Biology;Core Facility;Development;Diabetes Mellitus;Disease;Ecology;Environment;Environmental Health;Environmental Risk Factor;Exposure to;Fostering;Foundations;Funding;Genetic Predisposition to Disease;Goals;Health;Health Professional;Health Sciences;Healthcare;Heart;Heart Diseases;Heavy Metals;Human;Incidence;Individual;Infrastructure;Integrative Medicine;Interest Group;Kentucky;Leadership;Longevity;Malignant Neoplasms;Malignant neoplasm of lung;Medical;Medical center;Mentorship;Metabolic Diseases;Mining;National Institute of Environmental Health Sciences;Nickel;Obesity;Outcome;Particulate;Pilot Projects;Population;Positioning Attribute;Public Health;Pulmonary Heart Disease;Radon;Research;Research Personnel;Resources;Rivers;Rural;Science;Scientist;Stimulus;Structure;Talents;Toxic Environmental Substances;Toxicology;Training;Training Activity;Translations;Universities;Vision;Water;base;career;career development;early life exposure;health science research;innovation;interest;member;metabolomics;neonate;novel;population health;programs;recruit;socioeconomic disadvantage;water quality


application_id: 9671870
project_number: 5R01DC017025-02
project_title: ATP-purinergic mechanisms underlying noise-induced cochlear synaptopathy and hearing loss
administering_ic: NIDCD
award_notice_date: 2019-01-25
opportunity_number: PAR-16-170
application_type: 5
activity_code: R01
ic: DC
serial_number: 017025
program_official: CYR, JANET
project_start_date: 2018-03-22
project_end_date: 2023-02-28
study_section: Special Emphasis Panel[ZRG1-IFCN-Y(56)]
contact_pi_person_id: 8536073
contact_pi: ZHAO, HONG-BO
other_pis: Not Applicable
congressional_district: 06
department: OTOLARYNGOLOGY
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:
Acoustic Nerve;Address;Animals;Apoptosis;Apoptotic;Area;Astrocytes;Auditory system;Brain;CASP3 gene;Cell Death;Cells;Cessation of life;Cochlea;Data;Development;Exhibits;Fiber;Gap Junctions;Gene Family;Generations;Genetic;Goals;Hair Cells;Hearing problem;Homogeneously Staining Region;Human;Injury;Inner Hair Cells;Mediating;Microscopy;Molecular;Mutation;Nerve Degeneration;Nerve Fibers;Neurons;Noise;Noise-Induced Hearing Loss;Optics;P2X-receptor;Pathway interactions;Play;Postsynaptic Membrane;Predisposition;Protein Isoforms;Purinoceptor;Research;Resolution;Risk Factors;Role;Stroke;Synapses;Techniques;Technology;Testing;Therapeutic Intervention;Toxic effect;cochlear synaptopathy;extracellular;hearing impairment;hearing threshold;hidden hearing loss;light microscopy;normal hearing;novel;novel therapeutics;public health relevance;receptor;receptor expression;receptor function;reconstruction;spiral ganglion


application_id: 9671661
project_number: 1R01DA047690-01
project_title: Accelerated Development of Lofexidine for Neonatal Opioid Withdrawal Syndrome
administering_ic: NIDA
award_notice_date: 2018-09-19
opportunity_number: PAR-18-218
application_type: 1
activity_code: R01
ic: DA
serial_number: 047690
program_official: KLINE, RICHARD
project_start_date: 2018-09-30
project_end_date: 2021-06-30
study_section: Special Emphasis Panel[ZDA1 IXN-O (06)]
contact_pi_person_id: 15430214
contact_pi: GULLO, KRISTEN LEANN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 087875626
primary_uei: NKGSYBV5UGN1
duns_number: 087875626
uei: NKGSYBV5UGN1
fips: US
organization_id: 10003722
organization_name: US WORLDMEDS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40241
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY:Over the past decade rates of opioid use among the general population has continued to rise in the UnitedStates. This astounding increase in opioid use has resulted in the government declaring a public healthemergency in 2017. Compounding the problem a concurrent rise in opioid use among pregnant females hasresulted in a massive increase in infants born suffering from opioid withdrawal termed Neonatal OpioidWithdrawal Syndrome (NOWS). The NOWS epidemic has led to significant increases in healthcare costs andburden on the healthcare system due to increased length of hospital stay and level of required care. A normalinfant averages 2.1 days of hospital care post-birth costing $3500 whereas an infant born with NOWS averages16.9 days of inpatient care costing $66700. Currently there are no FDA-approved medications available fortreatment of NOWS. US WorldMeds (USWM) has developed lofexidine in collaboration with NIDA for thetreatment of opioid withdrawal in adults and anticipates possible Food and Drug Administration (FDA) approvalfor this use in May 2018. USWM now proposes to extend this successful co-development program throughinvestigation of the safety and efficacy of lofexidine in NOWS. This application proposes a strategic alliancebetween USWM and the National Institute on Drug Abuse (NIDA) to complete development and registrationprerequisites prior to initiation of clinical assessment of lofexidine in the neonatal patient population.The FDA has requested that USWM develop and establish safety information on lofexidine for neonate patientuse. Initial requirements for registration of lofexidine for pediatric use are clearly defined and agreed upon withthe FDA and include a total of five nonclinical studies in animals seven clinical studies and commitment todeveloping a pediatric specific formulation. The overall goal of this project is to develop a strategic alliance withNIDA and leverage this partnership to accelerate the development of the pediatric lofexidine program withspecific emphasis on the activities relevant for NOWS development. The research strategy in this proposalspecifically targets the FDA requested development of lofexidine for NOWS treatment and will be supported by:1) the development scale up and clinical trial material production of a neonatal-appropriate lofexidineformulation (Specific Aims 1 and 5) 2) completion of pivotal nonclinical studies to establish safety margins innonclinical juvenile rodent models considered appropriate to assess safety related to early brain developmentand general toxicity (Specific Aims 2 3 and 4) and 3) completion of a comparative bioavailability study withadult and pediatric formulations in normal healthy adult volunteers (Specific Aim 6).

project_terms:
Adolescent;Adrenergic Agonists;Adrenergic Receptor;Adult;Animals;Benzodiazepines;Biological Availability;Birth;Blood;Brain;Caring;Childhood;Clinical Research;Clinical Trials;Clinical assessments;Collaborations;Cytoplasmic Granules;Data;Deglutition;Development;Distress;Dosage Forms;Dose;Drug Kinetics;Drug Prescriptions;Drug user;Effectiveness;Ensure;Epidemic;Exposure to;Fees;Female;Formulation;General Population;Goals;Government;Grant;Growth;Health Care Costs;Healthcare Systems;Human;Incidence;Infant;Intervention;Investigation;Label;Length of Stay;Literature;Manufactured Materials;Medical;Metabolism;National Institute of Drug Abuse;Neonatal;Neurologic;Opioid;Patients;Pharmaceutical Preparations;Pharmacology;Pharmacology Study;Phase III Clinical Trials;Production;Program Development;Rattus;Receptor Activation;Reporting;Reproductive system;Research;Rodent Model;Role;Safety;Substance Withdrawal Syndrome;Symptoms;Systems Development;Tablets;Testing;Toxic effect;Toxicokinetics;Toxicology;United Kingdom;United States;United States Food and Drug Administration;Withdrawal;Work;care costs;comparative;cost;human subject;in utero;inpatient service;lofexidine;neonatal brain;neonatal patient;neonate;nervous system development;neurodevelopment;novel therapeutics;opioid abuse;opioid epidemic;opioid use;opioid withdrawal;patient population;pregnant;programs;public health emergency;reconstitution;reproductive development;safety study;scale up;volunteer

public_health_relevance:
PROJECT NARRATIVE:The nations opioid epidemic was declared a public health emergency in 2017 and is marked by high rates ofopioid use and abuse among adults and a correlated rising incidence of Neonatal Opioid Withdrawal Syndrome(NOWS) in infants exposed to opioids in utero. There are no FDA-approved pharmacologic interventions for thetreatment of NOWS resulting in medical reliance on off-label use of medications such as opioids andbenzodiazepines to manage distressing symptoms in withdrawing infants; but these medications are notformulated for pediatric use and therefore are administered with ingredients not recommended for neonateswhich are associated safety concerns and have not been well studied to characterize benefits and dosing forthis use. USWM intends to investigate lofexidine a non-opioid medication which has initially developed foropioid withdrawal in adults as a potential first line-therapy in NOWS patients that could limit administration ofcurrent off label treatments: the initial development steps include formulation of a pediatric-appropriate dosageform completion of nonclinical studies to inform safety and an initial clinical study in adults to compare bloodlevels between the pediatric and adult formulations.


application_id: 9671381
project_number: 5R34DA045563-02
project_title: Social media HIV prevention intervention for rural women drug users
administering_ic: NIDA
award_notice_date: 2019-01-28
opportunity_number: PA-15-268
application_type: 5
activity_code: R34
ic: DA
serial_number: 045563
program_official: JENKINS, RICHARD A
project_start_date: 2018-04-01
project_end_date: 2021-02-28
study_section: Special Emphasis Panel[ZRG1-AARR-G(02)M]
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 application is to adapt and feasibility test an evidence-based intervention for HIVprevention for a high-risk group of rural women in Appalachia. This study has potential to make a significantcontribution to science by advancing knowledge on the use of social media to increase access to preventioninterventions to reduce high-risk substance use and related health disparities among rural women during a timeof emerging and significant public health risk in Appalachia. Successfully accomplishing study aims will respondto a critical and unmet need to increase the reach and scope of prevention interventions using social media aswell as advance knowledge about the high-risk drug use behaviors of this underserved group. Considering theneed for prevention interventions among this high-risk group and the popularity of Facebook the purpose of thisR34 proposal is to adapt an evidence-based HIV prevention intervention for social media delivery and tofeasibility test through a randomized control trial with 60 high-risk rural women drug users. The following aimsguide the proposed study: (1) Adapt the NIDA Standard for HIV prevention for delivery via Facebook; and (2)Examine the feasibility of the adapted intervention with high-risk rural women through a randomized control pilot.The proposed use of Facebook in this study is promising because it is a stable widely used cost-efficientplatform that could be leveraged to increase access to critically needed HIV prevention education. This studypresents an exciting opportunity to examine the use of Facebook as a technique to expand the reach of evidence-based preventions interventions for high-risk drug users who are not likely to engage in formal treatment.Findings from this study will inform development of the larger R01 which would allow examination of theeffectiveness and sustainability of this HIV prevention intervention in understudied high risk populations.

project_terms:
AIDS prevention;Address;Affect;Alcohol or Other Drugs use;Appalachian Region;Area;Attention;Cessation of life;Communicable Diseases;Consent;Country;County;Coupled;Development;Disease Outbreaks;Documentation;Drug user;Education;Effectiveness;Effectiveness of Interventions;Epidemic;Evidence based intervention;Facebook;Feedback;Focus Groups;Frequencies;Funding;HIV;Health;Hepatitis C;Human immunodeficiency virus test;Impairment;Imprisonment;Indiana;Infection;Injections;Intervention;Interview;Jail;Kentucky;Knowledge;Link;Media Intervention;Methods;Morbidity - disease rate;National Institute of Drug Abuse;Needle Sharing;Participant;Pharmaceutical Preparations;Pilot Projects;Prevalence;Prevention;Prevention education;Preventive Intervention;Public Health;Publications;Quality of life;Randomized;Reporting;Research;Resources;Risk;Risk Behaviors;Rural;Rural Community;Science;Services;Techniques;Testing;Time;Underserved Population;United States National Institutes of Health;Virus Diseases;Vulnerable Populations;Woman;Work;behavioral health;community reentry;control trial;cost efficient;disability;disease transmission;drug use behavior;evidence base;health disparity;high risk;high risk behavior;high risk population;improved;injection drug use;innovation;men;opioid epidemic;pilot trial;prevention service;primary outcome;public health research;recruit;rural area;rural underserved;social media;testing services;transmission process;trend

public_health_relevance:
PROJECT NARRATIVEThe overall aim of this R34 application is to adapt and feasibility test an evidence-based HIV preventioneducation for high-risk underserved rural women in Appalachia. This study has potential to make a significantcontribution to science by advancing knowledge on the use of social media to increase access to preventioninterventions to reduce high-risk substance use and related health disparities among rural women during a timeof emerging and significant public health risk in Appalachia. Successfully accomplishing study aims will respondto a critical and unmet need to increase access to prevention interventions using social media as well asadvance knowledge about the high-risk drug use behaviors among vulnerable populations.


application_id: 9670867
project_number: 5R01NS097781-03
project_title: Altered Motor Function & Force Feedback After Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2019-03-15
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 097781
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2017-04-01
project_end_date: 2022-03-31
study_section: Special Emphasis Panel[ZRG1-BDCN-N(91)S]
contact_pi_person_id: 1904515
contact_pi: HOWLAND, DENA R.
other_pis: NICHOLS, T. RICHARD
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Extensor muscles of the hind limbs are actively involved in weight support and walking activities.These muscles are extensively linked by inhibitory force dependent pathways which contributeto the successful execution of a range of functional behaviors including locomotion. Thesereflex pathways are thought to arise from Golgi tendon organs and are believed to regulate limbstiffness and promote inter-joint coordination during movements. Weightings of these linkagesvary across control decerebrate animals when quiescent but obey a proximal to distal gradientduring stepping on a treadmill. This finding indicates the strength and distribution of these reflexpathways are subject to modulation in a task-dependent manner. Our preliminary data inanimals suggest that spinal cord hemisection alters the normal distribution and a dominantdistal-to-proximal inhibitory gradient emerges. Animals with this lesion do not exhibit clasp-knifeinhibition a phenomenon mediated by receptors other than Golgi tendon organs and that resultsfrom bilateral injury to the dorsal half of the spinal cord. Changes in the strength and distributionof force feedback that we have observed is correlated with diminished limb stiffness and poorweight acceptance during locomotor tasks  both of which are problems seen in humans withspinal cord injuries (SCIs). These findings provide new insight into potential mechanismscontributing to disruption of motor function following injury. Our guiding hypothesis is: SCI-induced force-feedback dysregulation results in strong inhibition directed towardproximal muscles and contributes to inadequate limb stiffness during weight supportphases of movement. The current application has evolved from collaborative work across twoestablished laboratories bringing together expertise in SCI plasticity force feedback and motorcontrol. The proposed studies are designed to understand and map changes in force feedbackcontrol following SCI characterize associated changes in gait subphases where inhibitory forcefeedback is thought to be most active across diverse locomotor tasks and determine whichwhite matter tracts may modulate spinal circuitry responsible for force feedback. Datagenerated in the proposed projects will be compared with an existing laboratory databasecontaining force feedback findings from control decerebrate preparations. Overall findings fromthese studies will explicate the impact of disrupting this intralimb control system onperformance provide critical mechanistic insight likely to be essential for design of the mosteffective rehabilitation programs for those with SCIs and other neurological disorders and laygroundwork for development of a new method for testing force feedback in humans

project_terms:
Acute;Animals;Area;Behavior;Bilateral;Chest;Data;Data Collection;Databases;Decerebrate State;Decerebration procedure;Development;Distal;Dorsal;Extensor;Feedback;Felis catus;Gait;Goals;Golgi Targeting;Golgi Tendon Organs;Human;Immunohistochemistry;Injury;Joints;Laboratories;Lateral;Leg;Lesion;Limb structure;Link;Locomotion;Maps;Mediating;Methods;Modeling;Motor;Movement;Muscle;Normal Statistical Distribution;Pathway interactions;Pattern;Performance;Phase;Preparation;Procedures;Production;Publishing;Recovery;Reflex action;Rehabilitation therapy;Research;Silver;Spinal;Spinal Cord;Spinal cord injury;Stains;System;Testing;Time;Walking;Weight;Work;base;design;experimental study;gait examination;gait rehabilitation;injured;innovation;insight;kinematics;locomotor tasks;motor control;motor disorder;nervous system disorder;novel;preservation;programs;receptor;relating to nervous system;response;spinal tract;treadmill;white matter

public_health_relevance:
NarrativeCoordination of muscles in each leg and appropriate limb stiffness are critical for weight supportand walking. Even though it is not directly damaged the basic system responsible which liespartially in the muscle becomes dysfunctional following spinal cord injury. This study willassess this change and why it occurs with the long term goal of enhancing recovery for thosewith spinal cord injuries.


application_id: 9669484
project_number: 1R21AA026787-01A1
project_title: PD-L1 and Ethanol-enhanced Mammary Tumorigenesis
administering_ic: NIAAA
award_notice_date: 2019-01-23
opportunity_number: PA-17-219
application_type: 1
activity_code: R21
ic: AA
serial_number: 026787
suffix: A1
program_official: MURRAY, GARY
project_start_date: 2019-02-01
project_end_date: 2021-01-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 10212779
contact_pi: CHEN, GANG
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Alcohol consumption is a well-known risk factor for human cancer including female breast cancer. Thebiological and epidemiological evidence indicates that alcohol consumption is causally and dose-dependentlyassociated with breast cancer. However the mechanism underlying ethanol-promoted mammarycarcinogenesis is unclear. Cancer is a systemic disease. The immune system monitors the host bodyrecognizing and reacting against newly arising mutated/tumor cells to stop/control tumor formation. A processtermed immunoediting is initiates when the immune system encounters mutated/tumor cells and may result inone of the three outcomes: elimination equilibrium or escape of tumor cells from immune control. Hencetumor formation indicates a compromise of host immunosurveillance. T cells particularly cytotoxic T cellsrepresent a major component of cell-mediated anti-tumor immunity. One of the mechanisms modulating T cellantitumor effector function involves the activation/inhibition receptors on a T cell membrane. Inhibition of T cellantitumor function through the activation of immune checkpoint pathways such as PD-L1/PD-1 pathway hasbeen shown to promote tumor cell immune escape and tumorigenesis. In addition previous reports indicatethat the aberrant activation of STAT3 may up-regulate PD-L1 in many human tumors. The proposed study willtest our hypothesis that ethanol promotes mammary tumorigenesis through STAT3/PD-L1/PD-1-mediatedinhibition of T cell antitumor function.

project_terms:
Alcohol consumption;Binding;Biological;Breast Cancer Model;Breast Epithelial Cells;Cell membrane;Cells;Cellular Structures;Cytotoxic T-Lymphocytes;Data;Dose;Epidemiology;Equilibrium;Ethanol;Female Breast Carcinoma;Foundations;Functional disorder;Genes;Human;Immune;Immune system;Immunologic Monitoring;Immunologic Surveillance;Knowledge;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mammary gland;Mediating;Monitor;Mouse Mammary Tumor Virus;Mus;Mutate;Outcome;PD-1 pathway;PDCD1LG1 gene;Pathway interactions;Process;Receptor Inhibition;Reporting;Risk Factors;Role;SLEB2 gene;STAT3 gene;Signal Transduction;Solid;Systemic disease;T-Lymphocyte;Testing;Tissues;Tumor Escape;Tumor Immunity;Tumorigenicity;Up-Regulation;alcohol exposure;cancer cell;immune activation;immune checkpoint;in vivo;malignant breast neoplasm;mouse model;neoplastic cell;promoter;tumor;tumorigenesis

public_health_relevance:
This proposed study aims to investigate a mechanism for ethanol-promoted mammary tumor formation byusing a mammary tumorigenesis mouse model. Ethanol exposure may compromise host anti-tumor immunitywhich in turn promotes an immune escape of tumor cells from the surveillance of immune system. The ideahas never been investigated before and will provide valuable information for further study the mechanismunderlying ethanol-promoted mammary tumorigenicity.


application_id: 9667552
project_number: 1R01AI140195-01A1
project_title: Innate immunity and inflammatory response of macrophages to Legionella infection
administering_ic: NIAID
award_notice_date: 2018-09-14
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: AI
serial_number: 140195
suffix: A1
program_official: ERNST, NANCY L
project_start_date: 2018-09-14
project_end_date: 2023-08-31
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Adaptor Signaling Protein;Amylases;Animal Model;Anti-inflammatory;Attenuated;Bacterial Infections;Binding;Bypass;Case Study;Communities;Crystallization;Cytosol;Data;Dimensions;Exhibits;Glucose;Glycogen;Glycolysis;Growth;Human;Immune;In Vitro;Infection;Infection Control;Inflammatory;Inflammatory Response;Innate Immune Response;Knowledge;Legionella;Legionella pneumophila;Legionnaires' Disease;Lung;Lysosomes;Macrophage Activation;Mediating;Membrane;Metabolism;Morbidity - disease rate;Mus;Natural Immunity;Pathway interactions;Phenotype;Phosphotyrosine;Pneumonia;Proteins;Role;Side;Signal Transduction;Structure;Surface;Testing;Up-Regulation;Vacuole;aerobic glycolysis;arm;cytokine;diabetic patient;in vivo;macrophage;monocyte;mortality;mutant;novel;pathogen;response


application_id: 9667454
project_number: 5R01HL141081-02
administering_ic: NHLBI
award_notice_date: 2019-02-12
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 141081
program_official: WONG, RENEE P
project_start_date: 2018-04-01
project_end_date: 2023-02-28
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 12204790
contact_pi: MOORE IV, JOSEPH B
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
budget_start_date: 2019-03-01
project_terms:
Affect;Azacitidine;Biological;Bone Marrow;Cardiac;Cardiovascular system;Cell Lineage;Cell Survival;Cell Therapy;Cell Transplantation;Cell Transplants;Cells;Characteristics;Chronic;Clinical Trials;Competence;Congestive Heart Failure;Dependence;Development;Exhibits;Future;GATA4 gene;Genetic;Goals;Heart;Heart failure;Human;In Vitro;Infarction;Injections;Injury;Left Ventricular Function;Light;Link;Mediating;Mediator of activation protein;Mesenchymal;Methods;Modality;Modeling;Modification;Muscle Cells;Myocardial Infarction;Nude Rats;Paracrine Communication;Pathway interactions;Patients;Pharmacology;Phase;Population;Production;Rattus;Research;Role;Signal Transduction;Stem cells;Structure;Testing;Therapeutic;Tissues;Treatment Efficacy;Variant;Ventricular;Ventricular Remodeling;Work;arteriole;cardiac regeneration;cardiac repair;cell type;cytokine;extracellular vesicles;heart function;improved;neovascularization;novel;pre-clinical;release factor;repaired;retention rate;transcription factor


application_id: 9666626
project_number: 1K01DK116923-01A1
project_title: Social Network Analysis and Social Support Intervention for Rural Dwelling Older Adults with T2DM
administering_ic: NIDDK
award_notice_date: 2018-12-14
opportunity_number: PAR-18-418
application_type: 1
activity_code: K01
ic: DK
serial_number: 116923
suffix: A1
program_official: SPAIN, LISA M
project_start_date: 2019-01-01
project_end_date: 2023-12-31
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 11808527
contact_pi: SMALLS, BRITTANY L.
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: ORGANIZED RESEARCH UNITS
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Adherence;Adult;Affect;Age;Aging;Attention;Behavior;Blindness;Blood Pressure;Clinical;Communities;Community Health Aides;Complications of Diabetes Mellitus;Coronary Arteriosclerosis;County;Decision Making;Diabetes Mellitus;Diagnosis;Disease;Education;Effectiveness;Elderly;Epidemic;Exposure to;Foundations;Geriatrics;Glycosylated hemoglobin A;Health Communication;Health Food;Health Personnel;Health behavior;High Prevalence;Individual;Influentials;Intervention;Interview;Kentucky;Kidney Diseases;Knowledge;Life Expectancy;Maps;Medical Records;Methods;Morbidity - disease rate;Neighborhoods;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Pathway Analysis;Play;Population;Positioning Attribute;Poverty;Prevalence;Quality of life;Regimen;Research;Research Personnel;Risk;Role;Rural Appalachia;Rural Community;Self Care;Social Environment;Social Network;Social support;Source;Stress;Stroke;Structure;Surveys;Syndrome;Testing;Training;United States National Institutes of Health;aging population;base;blood lipid;cognitive function;diabetes management;disease transmission;empowerment;experience;fall risk;frailty;glycemic control;health care service;health literacy;improved;individual patient;innovation;member;negative affect;post intervention;premature;programs;recruit;rural area;rural dwellers;rural residence;sarcopenia;social;statistics


application_id: 9662079
project_number: 1R01HL141103-01A1
administering_ic: NHLBI
award_notice_date: 2019-01-10
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: HL
serial_number: 141103
suffix: A1
program_official: OH, YOUNGSUK
project_start_date: 2019-01-15
project_end_date: 2022-10-31
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: GUO, ZHENHENG
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
ARNTL gene;Affect;Agonist;Blood Pressure;Calories;Cardiovascular Diseases;Cardiovascular system;Circadian Rhythms;Data;Diabetes Mellitus;Diabetic Angiopathies;Diabetic mouse;Eating;Event;Excretory function;Food;Functional disorder;Future;GLP-I receptor;Genes;Glucagon;Goals;Health;High Fat Diet;Human;Incidence;Injury;Intake;Kidney;Knockout Mice;Life;Light;Link;Liver;Macronutrients Nutrition;Metabolism;Monitor;Mus;Muscle function;Norepinephrine;Nuclear;Obesity;Organ;Outcome;Peptides;Pharmacology;Prevalence;Receptor Activation;Regimen;Regulation;Renal function;Reporting;Rho-associated kinase;Role;Severities;Signal Transduction;Smooth Muscle;Smooth Muscle Myocytes;Sympathetic Nervous System;Testing;Time;Time-restricted feeding;Type 2 diabetic;Variant;Vascular Smooth Muscle;circadian;db/db mouse;diabetic;diabetic patient;fasudil;feeding;gender difference;glucagon-like peptide 1;improved;indexing;inhibitor/antagonist;mouse model;neurotensin mimic 1;novel;novel strategies;novel therapeutics;outcome forecast;pre-clinical;prevent;protective effect;urinary


application_id: 9661572
project_number: 1R01AI121281-01A1
administering_ic: NIAID
award_notice_date: 2018-11-05
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: AI
serial_number: 121281
suffix: A1
program_official: KEHN, PATRICIA J
project_start_date: 2018-11-05
project_end_date: 2023-10-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_title:
A novel immunomodulatory approach to overcome innate and adaptive immune barriers to islet transplantation

project_abstract:
PROJECT SUMMARYType I diabetes is a chronic autoimmune that affects 3 million children and adults in the US with healthcarecosts exceeding $14.9 billion annually. Currently there is no cure for type 1 diabetes representing a criticalunmet medical need. Transplantation of allogeneic islets is a reliable method of achieving durable glucosehomeostasis and preventing the devastating complications of type 1 diabetes. However there are four majorbarriers to allogeneic islet transplantation; i) ineffective engraftment ii) rejection iii) adverse effects ofimmunosuppression used to control rejection and iv) shortage of cadaveric donor islets. Therefore there is asignificant need for strategies that overcome these limitations of islet transplantation for a broader clinical practice.This R01 application aims to develop an innovative and highly translational immunomodulatory protocol toovercome the limitations of islet transplantation for sustained long-term graft survival in the absence ofchronic use of immunosuppression. Infusion of islets into the liver via portal vein the only route of transplantation in clinical use instantlyexposes the graft to blood and initiates an immediate blood-mediated inflammatory reaction (IBMIR). IBMIR ismediated by thrombotic and inflammatory reactions and is responsible for the destruction of 50-80% isletsimmediate post-transplantation. The remaining islets are then subject to rejection by the slower but potentadaptive immune responses. Significant early islet loss requires transplantation from 2-3 donors perrecipients which further contribute to the shortage of cadaveric donors. The goal of this proposal is todevelop powerful yet focused therapies to simultaneously target the immediate inflammatoryreactions and adaptive immune response to prevent early and late graft loss. This will be accomplishedby generating novel recombinant proteins with robust inhibitory functions on prothrombotic proinflammatoryand adaptive immune reactions. These proteins will be engineered on pancreatic islets before transplantationfor localized modulation of thrombotic and inflammatory responses to enhance engraftment and achieveindefinite graft survival without the chronic use of debilitating immunosuppression that is currently standard.This concept will be tested in three different allogeneic islet transplantation settings for efficacy andmechanisms; chemically diabetic BALB/c-to-C57BL/6 mice spontaneously diabetic C57BL/6-to-NOD miceand human islets into humanized mice. These models will generate critical data relevant to the human setting.Furthermore proof-of-efficacy and the elucidation of the immune mechanisms regulating effective outcomeswill expedite further refinement of this immunomodulatory concept and its eventual translation to nonhumanprimates as a prelude to clinical trials for the treatment of type 1 diabetes.

project_terms:
Adult;Adverse effects;Affect;Allogenic;Antigens;Apoptosis;Autoimmune Diseases;Autoimmune Process;Biological Response Modifiers;Blood;C57BL/6 Mouse;CD47 gene;Cadaver;Cells;Cessation of life;Chemicals;Child;Chronic;Clinical;Clinical Treatment;Clinical Trials;Coagulation Process;Complement;Data;Development;Diabetic mouse;Eating;Engineering;Engraftment;Eragrostis;FOXP3 gene;Goals;Graft Rejection;Graft Survival;Health Care Costs;Homologous Transplantation;Human;IL2RA gene;Immune;Immunity;Immunosuppression;Inbred BALB C Mice;Inbred NOD Mice;Infiltration;Inflammatory;Inflammatory Response;Infusion procedures;Innate Immune Response;Insulin;Insulin-Dependent Diabetes Mellitus;Islets of Langerhans;Islets of Langerhans Transplantation;Leukocytes;Liver;Mediating;Medical;Methods;Modeling;Natural Immunity;Outcome;Pancreas;Pathway interactions;Phagocytes;Phagocytosis;Platelet Activation;Play;Population;Portal vein structure;Prevention;Proteins;Prothrombin;Protocols documentation;Reaction;Recombinant Proteins;Regimen;Regulatory T-Lymphocyte;Role;Route;SHPS-1 protein;Signal Transduction;Stimulus;Streptavidin;Structure of beta Cell of islet;Surface;Testing;Therapeutic;Thrombin;Thrombomodulin;Thromboplastin;To autoantigen;Translating;Translations;Transplantation;Treatment Protocols;Work;adaptive immune response;adaptive immunity;allograft rejection;blood glucose regulation;chronic autoimmune disease;clinical practice;design;diabetic;graft function;humanized mouse;immunoreaction;immunoregulation;innovation;islet;monocyte;mouse model;neutrophil;new technology;nonhuman primate;novel;novel strategies;post-transplant;prevent;response;standard care;transplant model

public_health_relevance:
PROJECT NARRATIVEType 1 diabetes (T1D) is a chronic autoimmune disorder that affects more than 1% of population worldwide.Insulin as a standard treatment has major long-term complications; therefore the development of novelapproaches to prevent and treat T1D is a significant therapeutic goal. The primary objective of this proposal isto develop an immunomodulatory protocol that prevents the rejection of pancreatic allogeneic islets for thetreatment of T1D. If effective this approach will have immediate and important implications for the use ofallogeneic islets for the treatment of T1D in humans.


application_id: 9661438
project_number: 1R01CA223164-01A1
project_title: Integrin alpha6beta4 regulation of cancer epigenetics
administering_ic: NCI
award_notice_date: 2018-12-27
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: CA
serial_number: 223164
suffix: A1
program_official: AULT, GRACE S
project_start_date: 2019-01-01
project_end_date: 2023-12-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Actins;Apoptosis;Base Excision Repairs;Basement membrane;Bioinformatics;Biometry;Breast;Carcinoma;Cell Nucleus;Cells;Chromatin;Clinical;Complex;Cytokeratin;Cytoskeleton;Cytosol;DNA;DNA Methylation;DNA Repair;DNA Sequence Alteration;Data;Enhancers;Environment;Epigenetic Process;Event;Fostering;Funding;GADD45A gene;Gene Expression Regulation;Genes;Genetic;Genome;Genomics;Heterogeneity;Histones;Integrin Binding;Integrin alpha6beta4;Integrin beta4;Integrins;Intermediate Filaments;Investigation;Keratin;Laboratories;Laminin;Link;Literature;Malignant Neoplasms;Mediating;Methodology;Methylation;Modeling;Modification;Molecular;Mutation;Neoplasm Metastasis;Nuclear;Nuclear Translocation;Oncogenic;Pathology;Pathway interactions;Phenotype;Post-Translational Protein Processing;Process;Property;Regulation;Research;Resistance;Role;Signal Transduction;Site;Solid;Specificity;Testing;Therapeutic;Therapeutic Intervention;Tumor Biology;Tumor Cell Invasion;Untranslated RNA;Vimentin;Work;base;cell motility;demethylation;emerin;epigenome;falls;genome-wide;innovation;insight;laminin A;leukemia/lymphoma;mechanotransduction;migration;next generation sequencing;novel;plectin;prevent;promoter;recruit;repair enzyme;sensor;transcriptome;transcriptomics;triple-negative invasive breast carcinoma;tumor;tumor microenvironment


application_id: 9660342
project_number: 5R01HL125877-03
project_title: A novel mechanism of stromal cell-derived factor 1 protection against diabetic cardiomyopathy
administering_ic: NHLBI
award_notice_date: 2019-02-28
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 125877
program_official: BUXTON, DENIS B
project_start_date: 2017-05-01
project_end_date: 2022-02-28
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 12101586
contact_pi: TAN, YI
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Diabetic cardiomyopathy (DCM) is one of the major chronic complications in diabetic patients. Conventionaltherapies for treatment of DCM include glycemic control management of hypertension lowering lipid andlife-style management. However there are no treatment strategies available that specifically target thepathogenesis of DCM. Greater understanding of the pathogenic mechanism of DCM is needed to developimproved therapeutic strategies.Stromal cell-derived factor-1 (SDF-1) belongs to C-X-C motif chemokine family. It controls diverse cellfunctions by interacting with its receptors CXCR4 and CXCR7. Myocardial SDF-1 is transiently up-regulatedduring ischemia or after infarction and can attract stem cells to the injury site contributing to cardiacregeneration and angiogenesis. Exogenous SDF-1 can help prevent myocardial infarction andischemia/reperfusion injury through stem cell-dependent and -independent mechanisms. However the roleand mechanism of the SDF-1-CXCR4/CXCR7 system in DCM has not been established.Accumulating evidence indicates that diabetes-induced deficiency of growth factors such as SDF-1 isassociated with diabetic cardiovascular complications. In a preliminary study the PI showed that theexpression of SDF-1 is notably down-regulated in the cardiac tissue of mice with type 1 and type 2 diabeteswhile the receptor expression levels are unaffected. The PI considered that lack of cardiac SDF-1 maycontribute to DCM and supplementary SDF-1 may provide direct cardiomyocyte protection. As an initial testcultured cardiac cells were exposed to palmitate-mimicked diabetic lipotoxicity with SDF-1 pretreatment.These studies showed that SDF-1 protected against palmitate-induced cell death via CXCR7- but notCXCR4- mediated AMP-activated protein kinase (AMPK) activation. The results are of great significancesince they demonstrate SDF-1 can provide direct protection against diabetic cardiac cell death independentof stem cells. Therefore it is critical to determine if in vivo protection involves the same direct actions bySDF-1 identified on isolated cardiomyocytes. Based on the critical role of CXCR4 and CXCR7 incardiovascular diseases it is hypothesized that SDF-1 treatment of diabetic mice directly protects againstdiabetes-induced cardiomyocyte death and cardiac remodeling via CXCR7-mediated activation of AMPKand that SDF-1 treatment can ultimately prevent DCM.This hypothesis will be tested through three specific aims: (1) to determine the direct cardiomyocyte effectsof SDF-1 in protection against DCM; (2) to determine whether SDF-1 signaling through CXCR7 mediatesprotection against DCM independently of CXCR4; (3) to determine whether AMPK mediates SDF-1/CXCR7protection against DCM.This project will provide fundamental evidence for the interaction of SDF-1-CXCR4 and/or -CXCR7 at thecardiomyocyte as a new therapeutic target for the prevention of DCM in future clinical investigations.

project_terms:
5'-AMP-activated protein kinase;Adhesions;Apoptosis;Bone Marrow;CXCR4 Receptors;CXCR4 gene;Cardiac;Cardiac Myocytes;Cardiovascular Diseases;Cardiovascular system;Catalytic Domain;Cell Death;Cell physiology;Cells;Cessation of life;Chemotaxis;Chronic;Cytoskeletal Modeling;Data;Development;Diabetes Mellitus;Diabetic Angiopathies;Diabetic mouse;Dysplasia;Exposure to;Family;Future;GTP-Binding Proteins;Genes;Growth Factor;Heart;High Fat Diet;In Vitro;Infarction;Injections;Injury;Insulin-Dependent Diabetes Mellitus;Interleukin-6;Ischemia;Knock-out;Knockout Mice;Life Style;Lipids;MAP Kinase Gene;MAPK14 gene;Mediating;Modeling;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Non-Insulin-Dependent Diabetes Mellitus;Oxidative Stress;Palmitates;Paper;Pathogenesis;Pathogenicity;Pathologic;Pathology;Phosphorylation;Phosphotransferases;Prevention;Process;Production;Protein Kinase;Reperfusion Injury;Role;Signal Pathway;Signal Transduction;Site;Stem cells;Streptozocin;Stromal Cell-Derived Factor 1;System;Testing;Therapeutic;Tissues;Transgenes;Transgenic Organisms;Transplantation;Ventricular septum;antioxidant therapy;base;beta-arrestin;cardiac angiogenesis;cardiac regeneration;chemokine;clinical investigation;clinical practice;conventional therapy;diabetic;diabetic cardiomyopathy;diabetic patient;glycemic control;heart damage;hypertension control;improved;in vivo;insight;new therapeutic target;novel;prevent;receptor;receptor expression;treatment strategy

public_health_relevance:
The objective of this study is to test our hypothesis that SDF-1 treatment of diabetic mice directly protectsagainst diabetes-induced cardiomyocyte death and cardiac remodeling via CXCR7-mediated activation ofAMPK and that SDF-1 treatment can ultimately prevent diabetic cardiomyopathy. We will first determine thedirect cardiomyocyte effects of SDF-1 in protection against diabetic cardiomyopathy in type 2 diabetes. Nextwe will determine which receptor mediates SDF-1's cardiomyocyte protection and the specific cell signalingpathway responsible. This project will reveal new insight into the underlying mechanism behind SDF-1protection against diabetic cardiomyopathy as well as provide fundamental evidence supporting the SDF-1/CXCR7 axis as a novel therapeutic target for the prevention of diabetic cardiomyopathy in future clinicalpractice.


application_id: 9659982
project_number: 1R01EY028911-01A1
project_title: Chemical Optimization of c-Cbl Antagonists for Corneal Wound Healing
administering_ic: NEI
award_notice_date: 2019-01-24
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: EY
serial_number: 028911
suffix: A1
program_official: MCKIE, GEORGE ANN
project_start_date: 2019-02-01
project_end_date: 2024-01-31
study_section: Special Emphasis Panel[ZRG1 BDCN-J (81)]
contact_pi_person_id: 1925445
contact_pi: CERESA, BRIAN P.
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:
Address;Advanced Development;Adverse drug effect;Affinity;Anatomy;Animal Model;Antineoplastic Agents;Bacteria;Binding;Biochemical;Biological Assay;Biology;Biomedical Engineering;Blindness;Calorimetry;Cell Proliferation;Cell model;Cetuximab;Chemical Injury;Chemical Structure;Chemicals;Complex;Computer Simulation;Cornea;Corneal Injury;Data;Development;Diabetes Mellitus;Disease;Distress;Drug usage;EGF gene;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Epithelial;Epithelial Cells;Event;Eye;Eye Infections;FDA approved;Generations;Goals;Growth Factor Receptors;Health care facility;Homeostasis;Human;In Vitro;Incidence;Infection;Investigation;Laboratories;Lead;Ligands;Light;Lysosomes;Maintenance;Measures;Mediating;Membrane;Mission;Modeling;Modification;Molecular;Operative Surgical Procedures;Oryctolagus cuniculus;Pain;Patients;Pharmaceutical Preparations;Pharmacology;Prevalence;Primary Health Care;Procedures;Proteins;Public Health;Reagent;Receptor Signaling;Recombinants;Recurrence;Replacement Therapy;Research;Retina;Rodent;Signal Transduction;Stem cells;Structure;Testing;Therapeutic;Therapeutic Agents;Tissue Model;Tissues;Topical application;Trauma;Virus;Vision;Work;Wound Healing;base;cancer type;cell growth;cell motility;corneal epithelial wound healing;corneal epithelium;corneal surgery;cytokine;cytotoxicity;desensitization;drug development;experience;heat injury;improved;in vivo;inhibitor/antagonist;innovation;interest;knock-down;limbal;nanomolar;novel;novel therapeutics;particle;preservation;prevent;receptor;restoration;side effect;tissue culture;trafficking;ubiquitin-protein ligase


application_id: 9659314
project_number: 5R01DK056132-16
project_title: Neural Circuitry in the Dorsal Vagal Complex
administering_ic: NIDDK
award_notice_date: 2019-01-11
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 056132
program_official: COOKE, BRAD
project_start_date: 2001-06-01
project_end_date: 2021-01-31
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Diabetes mellitus is a major health concern affecting nearly 26 million people in the United States. Serious complications resulting from diabetes including include heart disease stroke hypertension blindness nervous system damage and autonomic dysfunction. A major impediment to developing successful diabetes treatments (versus treating symptoms) is the relative knowledge gap regarding the multifaceted and redundant systems that contribute to control of metabolic homeostasis. This proposal investigates disease-related plasticity of central neural circuitry involved in autonomic control including control of blood glucose homeostasis. Experiments utilize murine models of type 1 and type 2 diabetes. Preautonomic neurons of the dorsal vagal complex which contains second-order viscerosensory neurons in the nucleus tractus solitarius (NTS) and preganglionic parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV) are glucosensors and also contribute significantly to autonomic regulation of glucose homeostasis. Vagal motor output is suppressed in diabetes leading to autonomic dysregulation including excess hepatic glucose production and gastric motility dysfunction. Preliminary results show that GABA neurons in the NTS in particular are responsive to elevated glucose. Paradoxically GABAA receptor-mediated responses in the DMV are persistently enhanced in a model of type 1 diabetes in a manner consistent with maintenance of prolonged hyperglycemia. Some but not all of these responses are preserved in a type 2 diabetes model suggesting a form of GABA receptor plasticity that mediates the decreased vagal output seen in diabetes. In addition modulation of GABA receptors in the dorsal vagal complex has a significant effect on blood glucose levels and this effect is hypothesized to be enhanced in diabetic mice versus controls. This proposal aims to determine the causes and underlying features of the recently-discovered diabetes-induced plasticity of the GABAergic system in the vagal complex. Electrophysiological recordings from vagal complex neurons in slices from control and diabetic mice will be used to obtain functional cellular data related to altered GABAergic inhibition changes associated with diabetes development in the streptozotocin-treated mouse a model of type 1 diabetes and the TallyHo mouse a model of type 2 diabetes. Aim 1 will determine insulin- and glucose- dependence of enhanced tonic GABA currents in diabetic mice aim 2 will identify cellular mechanisms contributing to diabetes-associated GABA receptor plasticity in the DMV and aim 3 will determine the effects of GABA receptor modulation in the dorsal vagal complex on systemic glucose homeostasis. Results will guide future studies aimed at disease-modifying therapies from a systemic standpoint based on modulating specific inhibitory neural functions in the brainstem to address diabetes-related autonomic dysregulation in patients.

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

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


application_id: 9658954
project_number: 1R01NS103785-01A1
project_title: Cell-Specific Actions of IL-1 / IL-1R1 Signaling Following Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2018-12-12
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: NS
serial_number: 103785
suffix: A1
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2018-12-15
project_end_date: 2023-11-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
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
project_terms:
Acute;Address;Alzheimer's Disease;Alzheimer's disease related dementia;Attenuated;Blood Vessels;Brain;Cells;Central Nervous System Diseases;Chronic;Clinical;Closed head injuries;Data;Development;Disease;Electrophysiology (science);Endothelial Cells;Endothelium;Extravasation;FDA approved;Failure;Functional disorder;Generations;Genetic;Goals;Immunomodulators;Immunosuppressive Agents;Impaired cognition;Impairment;Inflammation;Inflammatory;Injury;Interleukin Suppression;Interleukin-1;Interleukin-1 Receptors;Knockout Mice;Knowledge;Lead;Learning;LoxP-flanked allele;Memory;Modeling;Molecular;Mus;Nature;Nerve Degeneration;Neurodegenerative Disorders;Neuronal Injury;Outcome;Pathologic;Pathway interactions;Patient-Focused Outcomes;Permeability;Pharmaceutical Preparations;Public Health;Radial;Receptor Signaling;Regulation;Residual state;Risk Factors;Role;Severities;Signal Transduction;Synapses;Synaptic plasticity;Testing;Time;Traumatic Brain Injury;Vascular Diseases;Vascular remodeling;Vertebral column;arm;brain endothelial cell;cell type;central nervous system injury;cerebral atrophy;density;improved;mild traumatic brain injury;mouse model;neuroinflammation;neuroprotection;novel;response;restoration;targeted treatment;water maze


application_id: 9658438
project_number: 5F32AR071753-03
project_title: Fusion-Independent Roles of Satellite Cells in Muscle Adaptation
administering_ic: NIAMS
award_notice_date: 2019-02-27
opportunity_number: PA-16-307
application_type: 5
activity_code: F32
ic: AR
serial_number: 071753
program_official: BOYCE, AMANDA T
project_start_date: 2017-03-01
project_end_date: 2020-02-29
study_section: Special Emphasis Panel[ZRG1-F10B-B(20)L]
contact_pi_person_id: 14386396
contact_pi: MURACH, KEVIN
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/ABSTRACTThe loss of skeletal muscle mass is characteristic of inactivity- disease- and age-related conditions andnegatively affects whole muscle function and quality of life. Consequently understanding the mechanisms ofmuscle fiber size maintenance and growth is important for guiding interventions and therapeutics. In responseto short-term loading (two weeks) muscle stem cells (satellite cells) are not necessary for hypertrophy in adultmice. However after long-term loading (eight weeks) the absence of satellite cells results in robust expansionof the cytosolic area that myonuclei govern (myonuclear domain) excessive extracellular matrix depositionand blunted muscle fiber growth. Whether compromised growth is a consequence of fibrosis or a lack ofmyonuclear addition mediated by the loss of satellite cells is presently uncertain. To understand the role ofsatellite cells during prolonged muscle hypertrophy our laboratory recently developed the Pax7-N-WASpmouse. Inducible depletion of N-WASp specifically in satellite cells inhibits their ability to fuse into a musclefiber and contribute a nucleus during hypertrophy. However their presence and activation during growth canregulate extracellular matrix accumulation. This mouse model will elucidate whether limiting fibrosispromotes muscle fiber growth in the absence of myonuclear accretion. Furthermore the ability toprevent satellite cell fusion in vivo will allow for exploration into whether satellite cells communicatewith muscle fibers in the absence of fusion. The findings from this proposal will provide fundamentalinformation on the necessity of satellite cells during adult skeletal muscle hypertrophy and potentially definenew roles for satellite cells independent from fusion into muscle fibers.

project_terms:
Ablation;Address;Adult;Affect;Apoptotic;Area;Cell Culture Techniques;Cell Density;Cell Nucleus;Cell Proliferation;Cell Separation;Cell fusion;Cell physiology;Cells;Characteristics;Collagen Gene;Communication;Cytoplasm;Data;Deposition;Development;Disease;Environment;Extracellular Matrix;Fiber;Fibroblasts;Fibrosis;Gene Expression;Genetic Recombination;Growth;Hypertrophy;Immunohistochemistry;In Vitro;Intervention;Knock-out;Knockout Mice;Label;Laboratories;Limb structure;Maintenance;Measures;Mechanics;Mediating;Methodology;MicroRNAs;Modeling;Molecular Biology Techniques;Mus;Muscle;Muscle Fibers;Muscle function;Muscle satellite cell;Operative Surgical Procedures;PAX7 gene;Phenotype;Physiological;Plantaris muscle;Quality of life;Regulation;Reporter;Repression;Rest;Role;Scientist;Skeletal Muscle;Stem cells;System;Tamoxifen;Techniques;Testing;Therapeutic;Transgenic Mice;Transgenic Organisms;Wasps;Weight;age related;density;exosome;experience;experimental study;extracellular;in vivo;inhibitor/antagonist;knock-down;mouse model;muscle form;muscle hypertrophy;negative affect;novel;novel therapeutic intervention;prevent;response;satellite cell;skeletal muscle growth;skeletal muscle wasting;training opportunity

public_health_relevance:
PROJECT NARRATIVESatellite cells are the primary stem cells in skeletal muscle and are important for muscle hypertrophy but theirrole(s) are incompletely defined. Using a novel transgenic mouse model this project will elucidate whethersatellite cell-mediated regulation of the muscle extracellular environment or contribution to muscle fibers isnecessary to sustain prolonged muscle fiber growth and whether satellite cells can communicate to musclefibers without fusing. Understanding how satellite cells participate in muscle growth during loading will guidefuture research regarding the therapeutic potential of these cells.


application_id: 9658365
project_number: 5R01CA131075-09
project_title: Defining the contribution of ATR to MC1R-enhanced DNA repair in melanocytes
administering_ic: NCI
award_notice_date: 2019-03-28
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 131075
program_official: JOHNSON, RONALD L
project_start_date: 2010-07-01
project_end_date: 2021-03-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN A
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Melanoma the most lethal skin malignancy is a significant cause of cancer mortality often affecting men and women in their prime. The melanocyte-stimulating hormone (MSH)-melanocortin-1 receptor (MC1R) signaling axis is an inducible cutaneous pathway that regulates ultraviolet (UV) responses in melanocytes. Loss-of- function polymorphisms of MC1R signaling affecting millions in the United States alone more than double lifetime melanoma risk . Signaling through the MC1R a Gs-coupled membrane receptor leads to activation of adenylyl cyclase production of cAMP and enhancement of the ability of melanocytes to repair UV-damaged DNA that if left unrepaired causes "UV signature" mutations that fuel progression of melanocytes into melanoma. As a result MC1R-defective individuals with blunted DNA repair responses accumulate more mutations after UV exposure and are predisposed to melanoma. Our laboratory identified a critical molecular pathway linking MC1R/cAMP signaling to nucleotide excision repair (NER) the genome maintenance pathway responsible for removing UV-damaged bases from DNA. Activated by MC1R signaling and cAMP generation cAMP-dependent protein kinase (PKA) phosphorylates the ataxia and rad3 related (ATR) protein on the S435 residue. This post-translational modification causes ATR to associate with the NER factor xeroderma pigmentosum A (XPA) accelerating its interaction with nuclear photodamage and enhancing DNA repair. Compelling findings during the previous funding cycle indicate that A-kinase anchoring protein 12 (AKAP12) integrates PKA-ATR-XPA interactions. We hypothesize that through AKAP-regulated PKA-mediated ATR phosphorylation MC1R signaling protects melanocytes from UV mutagenesis by enhancing NER. The overall goal of this project is to determine how the PKA-ATR-XPA DNA repair axis is regulated and to understand how it impacts NER. Experiments proposed in the first Aim will determine how AKAP12 regulates MC1R-enhanced NER in melanocytes using co-localization kinase assays proximity ligation assay (PLA) proteomics and a UV-inducible mouse melanoma model. Studies proposed in the second Aim will identify how pS435 ATR impacts NER by focusing on mechanisms of DNA binding and strand incision using co-immunoprecipitation PLA fluorescent strand incision assay and oligonucleotide retrieval assay (ORA) as a functional measure of NER. Finally since we have determined that dysregulated pS435 signal profoundly sensitizes cells to genotoxic agents the third aim will define how p-S435 ATR is inactivated in melanocytes focusing on the role of PP2A phosphatase in pS435 ATR inactivation and determining how persistent pS435 ATR sensitizes melanoma cells to DNA damaging agents. Together these studies will define how MC1R signaling promotes NER and UV resistance and will serve as a platform for the development of rational melanoma-preventive strategies among high-risk MC1R-defective populations.

project_terms:
A kinase anchoring protein;ATR gene;Address;Adenylate Cyclase;Affect;American;Ataxia;Binding;Biological Assay;Cancer Etiology;Cells;Cessation of life;Co-Immunoprecipitations;Complex;Coupled;Coupling;Cutaneous;Cyclic AMP;Cyclic AMP Receptors;Cyclic AMP-Dependent Protein Kinases;DNA;DNA Binding;DNA Damage;DNA Repair;Defect;Development;Diagnosis;ERCC1 gene;Event;Funding;GTP-Binding Protein alpha Subunits Gs;Generations;Genetic Polymorphism;Genome;Goals;Gravin;Incidence;Individual;Inherited;Laboratories;Left;Ligation;Link;Maintenance;Malignant Neoplasms;Measures;Mediating;Melanins;Melanocortin 1 Receptor;Melanocyte stimulating hormone;Melanoma Cell;Membrane;Modeling;Molecular;Mus;Mutagenesis;Mutagens;Mutation;Nuclear;Nucleotide Excision Repair;Oligonucleotides;Pathway interactions;Pharmacology;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Pigmentation physiologic function;Population;Positioning Attribute;Post-Translational Protein Processing;Prevention strategy;Preventive therapy;Production;Protein Kinase;Protein Phosphatase 2A Regulatory Subunit PR53;Proteomics;Public Health;Radiation therapy;Receptor Signaling;Regulation;Repair Complex;Reporting;Resistance;Retrieval;Risk;Risk Factors;Role;Seminal;Signal Transduction;Skin;Skin Cancer;Surface;Surgical incisions;Time;Tissues;UV Radiation Exposure;UV response;Ultraviolet Rays;United States;Woman;Xeroderma Pigmentosum;anti-cancer;base;cell type;chemotherapy;defined contribution;design;experimental study;high risk;loss of function;melanocyte;melanoma;men;mortality;prevent;receptor;recruit;repaired;response;therapy development;ultraviolet;ultraviolet damage

public_health_relevance:
PUBLIC HEALTH RELEVANCEL: Melanoma the deadliest form of skin cancer affects nearly 80000 individuals in the United States each year. The proposed study focuses on the role of a receptor known as the melanocortin 1 receptor (MC1R) that is important in normal pigmentation. Inherited defects in MC1R affect millions of Americans who are at elevated risk from ultraviolet light damage and mutations and as a result have a high risk for melanoma. By discovering how MC1R protects against melanoma formation our goal is to develop therapies to prevent melanoma.


application_id: 9658119
project_number: 1R21AI142576-01
project_title: Endothelial JAK3 expression and inflammatory lung injury in sepsis
administering_ic: NIAID
award_notice_date: 2019-01-31
opportunity_number: PA-18-489
application_type: 1
activity_code: R21
ic: AI
serial_number: 142576
program_official: MINNICOZZI, MICHAEL
project_start_date: 2019-02-01
project_end_date: 2021-01-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8693493
contact_pi: FU, JIAN
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 SummarySepsis remains a major cause of death in critically ill patients. New therapeutic strategies areneeded to treat this devastating disease. Excessive inflammatory responses which lead toinflammatory tissue injury contribute to the pathogenesis of multiple organ failure in sepsis.Recent studies have demonstrated that JAK3 is a promising target against various inflammatorydiseases. However the regulation and function of JAK3 in sepsis have not been studied. In ourpreliminary studies we demonstrated that JAK3 expression is highly up-regulated during sepsis.Selective JAK3 inhibition by JAK3 inhibitors including a FDA-approved inhibitor Tofacitinibblocked endothelial inflammatory signaling and inflammatory lung injury during sepsis.Furthermore we demonstrated that JAK3 expression is controlled by HDAC6 a histonedeacetylase that modulates nuclear and non-nuclear protein function through deacetylation.HDAC6 knockdown or inhibition prevented TNF- induced endothelial JAK3 expression STAT1activation and leukocyte adhesion molecule ICAM-1 expression. In a mouse model ofpolymicrobial sepsis HDAC6 inhibition blocked sepsis-induced JAK3 expression. In the proposedstudies we will conduct a serial of experiments to assess the therapeutic potential of JAK3inhibition against sepsis-induced inflammatory lung injury and to investigate the regulation ofJAK3 by HDAC6 during sepsis.

project_terms:
Bacterial Infections;Blood Vessels;Cause of Death;Chronic;Clinical;Clinical Trials;Critical Illness;Cytokine Receptors;Data;Deacetylation;Disease;Endothelial Cells;Endothelium;FDA approved;Family;Future;Gene Expression;HDAC4 gene;HDAC6 gene;Inflammatory;Inflammatory Response;Injury;Intercellular adhesion molecule 1;JAK3 gene;Janus kinase;Lead;Leukocyte Adhesion Molecules;Lung;Mediating;Multiple Organ Failure;Nuclear;Nuclear Protein;Pathogenesis;Pathway interactions;Patients;Phase III Clinical Trials;Play;Regulation;Reporting;Rheumatoid Arthritis;Role;STAT1 gene;STAT1 protein;Sepsis;Signal Pathway;Signal Transduction;Structure of parenchyma of lung;Systemic Inflammatory Response Syndrome;TNF gene;Testing;Therapeutic;Therapeutic Effect;Tissues;Up-Regulation;antitumor effect;experimental study;inhibitor/antagonist;knock-down;lung injury;member;mouse model;novel;novel therapeutic intervention;novel therapeutics;polymicrobial sepsis;prevent;protein function;transcription factor

public_health_relevance:
Project NarrativeSuccessful completion of the proposed studies will reveal a novel role of JAK3 in sepsis-inducedinflammatory signaling. The studies will validate the therapeutic potential of JAK3 inhibition againstinflammatory injury in sepsis. The proposed studies will provide important information for futureclinical trials.


application_id: 9657799
project_number: 5P20GM125504-02
administering_ic: NIGMS
award_notice_date: 2019-02-20
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
study_section: ZGM1-RCB-3
subproject_number: 8247
contact_pi_person_id: 10329001
contact_pi: STEINBACH-RANKINS, JILL
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: 2019-03-01
budget_end_date: 2020-02-29
funding_mechanism: Research Centers
project_title:
Understanding the Host-Microbiome-Therapeutic Triad: Implications for Designing Alternative Intravaginal

project_abstract:
ABSTRACTBacterial vaginosis (BV) is a prominent dysbiotic condition resulting from the disruption of the diverse microbialcommunities that maintain host homeostasis and innate defense in the female reproductive tract. BV infection and recurrenceaffects over 30% of women imparting detrimental effects to female reproductive health by increasing the susceptibility toadverse pregnancy outcomes postsurgical infections and sexually transmitted infections (STIs). Current treatment optionsprimarily comprised of orally- or topically-applied antibiotics are initially efficacious; however frequent relapse isprevalent contributing to recurrent BV infections and adverse side effects. New therapeutic options including prebiotics(e.g. lactic acid glycogen) and probiotics have been utilized to recruit and stabilize indigenous normal Lactobacilli tocounterbalance the predominant BV-associated bacterial pathogen Gardnerella vaginalis (G.v.). However significant gapsremain in our understanding of host-microbiome-therapeutic interactions contributing to the difficulty in attaining a long-term effective method of protection and treatment. These widespread pandemic effects underscore the urgent need todevelop more effective BV treatment strategies and to improve our understanding of host-microbiome-therapeuticinteractions that contribute to efficacy.In this project we seek to develop new therapies to alter BV pathogenesis while advancing the understanding of host-microbiome-therapeutic interactions. To achieve these goals we will optimize the design of a novel delivery platformcomprised of core-shell polymeric electrospun fibers (EFs) that deliver pre- and probiotics test their efficacy in vitro andassess the effectiveness of these fibers in a murine model of BV infection. These studies will provide the foundation forimproved therapeutic outcomes while providing new insight into the effects of combined pre- and probiotic fibers on thevaginal microbiome host inflammatory response and BV disease markers and progression. While we will initially applythis delivery approach to target and understand the implications to BV pathogenesis we envision the research outcomeswill have a significant impact on the development of future multipurpose platforms to prevent and treat broader morecomplex interactions between bacterial and viral pathogens in the female reproductive tract.

project_terms:
Adherence;Affect;Antibiotics;Atopobium vaginae;Bacterial Infections;Bacterial Vaginosis;Chronic;Coculture Techniques;Complex;Cream;Development;Disease Marker;Disease Progression;Dosage Forms;Ecosystem;Effectiveness;Encapsulated;Epithelial;Female;Fiber;Formulation;Foundations;Future;Gardnerella vaginalis;Glycogen;Glycolates;Goals;HIV-1;Homeostasis;Human Herpesvirus 2;In Vitro;Indigenous;Infection;Inflammation;Inflammatory Response;Lactic acid;Lactobacillus;Measures;Mediating;Methods;Microbial Biofilms;Modeling;Mucous Membrane;Mus;Oral;Outcome Study;Outcomes Research;Pathogenesis;Pathogenicity;Patients;Physiological;Polymers;Predisposition;Probiotics;Recurrence;Regimen;Relapse;Reproductive Health;Sexually Transmitted Diseases;System;Tablets;Testing;Therapeutic;Time;Tissue Model;Topical application;Treatment Efficacy;Triad Acrylic Resin;Vagina;Viral;Woman;Work;adverse pregnancy outcome;antimicrobial;base;chemokine;cytokine;design;dysbiosis;host microbiome;improved;in vivo;insight;microbial community;microbiome;microbiome alteration;microbiome research;microbiome therapeutics;mouse model;nanoparticle;novel;novel therapeutics;oral biofilm;pandemic disease;pathogen;pathogenic bacteria;pathogenic virus;prebiotics;prevent;recruit;reproductive tract;residence;response;scaffold;side effect;success;therapy outcome;treatment strategy;vaginal microbiome;vaginal microbiota


application_id: 9657798
project_number: 5P20GM125504-02
project_title: Modulation of respiratory melioidosis inflammation
administering_ic: NIGMS
award_notice_date: 2019-02-20
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
study_section: ZGM1-RCB-3
subproject_number: 8246
contact_pi_person_id: 10426217
contact_pi: WARAWA, JONATHAN MARK
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: 2019-03-01
budget_end_date: 2020-02-29
project_abstract:
Burkholderia pseudomallei (Bp) is an antibiotic resistant Select Agent bacterial pathogen and the causativeagent of the disease melioidosis with endemicity in tropical regions worldwide. Bp is infectious by several routesof entry into a host with inhalation representing an important route of entry and furthermore Bp exhibit a stronglung tropism regardless of the route of entry. Respiratory melioidosis is an acute inflammatory disease of thelung which progresses into a fatal systemic disease involving all major organs. Bp is a facultative intracellularpathogen which employs the Type 3 Secretion System cluster 3 (T3SS3) to mediate vacuolar escape of Bp fromphagocytes allowing for subsequent outgrowth of the bacteria in the host cytoplasm. Importantly the specifichost cells which support the intracellular lifestyle of Bp have not been well characterized.A critical gap in our understanding of Bp pathogenesis is the identification of which host cell types facilitate areplicative niche for Bp. Identification of these host environments will further provide key insights into which hostcells mount an inflammatory response against Bp. It is furthermore poorly understood as to whether the cytokinestorm mounted as a response to respiratory melioidosis contributes to morbidity as recent evidence suggeststhat excessive neutrophil recruitment is associated with reduced host survival. This suggests thatimmunomodulation of the innate immune response may represent an excellent method of providing noveltherapeutics for a disease which has no licensed vaccine and minimal treatment options due to inherentgenome-encoded antibiotic resistance. We provide preliminary data which demonstrate the therapeutic efficacyof inhaled slow-release IL-12 particles to provide full protection against a lethal Bp respiratory challengeOur central hypothesis is that the host innate immune response to lethal respiratory melioidosis is driven by apoorly-controlled intracellular bacterial proliferation where immunomodulation represents an effective method ofcombating disease. In Specific Aim 1 we will identify the replicative niche of Bp in the lung. We hypothesize thatspread of Bp to secondary phagocytes is the leading cause of sepsis/death associated with respiratorymelioidosis. In Specific Aim 2 we will determine the contribution of host innate immune cells to inflammation. Wehypothesize that the late-arriving myeloid component causes lethality via the inflammatory mediators theyproduce. In Specific Aim 3 we will determine the mechanism of microparticulate IL-12 therapeutic efficacy ofrespiratory melioidosis.Modification of the state of inflammation of respiratory melioidosis may provide effective control of disease byeither encouraging early clearance of pathogen through promoting early inflammation or by improving outcomethrough modulating late inflammation.

project_terms:
Acute;Antibiotic Resistance;Bacteria;Burkholderia pseudomallei;Cells;Cessation of life;Cytoplasm;Data;Disease;Environment;Exhibits;Genome;Immune;Inflammation;Inflammation Mediators;Inflammatory Response;Inhalation;Innate Immune Response;Interleukin-12;Life Style;Lung;Mediating;Melioidosis;Methods;Modification;Morbidity - disease rate;Myelogenous;Neutrophil Infiltration;Organ;Pathogenesis;Pathogenicity;Phagocytes;Route;Secondary to;Sepsis;System;Systemic disease;Treatment Efficacy;Tropism;Vaccines;cell type;combat;cytokine release syndrome;disorder control;immunoregulation;improved outcome;inflammatory lung disease;insight;microbiome research;novel therapeutics;particle;pathogen;pathogenic bacteria;respiratory;response


application_id: 9657797
project_number: 5P20GM125504-02
project_title: Pathogenesis of Yersinia pestis infection during intracellular infection
administering_ic: NIGMS
award_notice_date: 2019-02-20
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
study_section: ZGM1-RCB-3
subproject_number: 8245
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
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: 2019-03-01
budget_end_date: 2020-02-29
project_abstract:
PROJECT SUMMARY/ABSTRACT: Yersinia pestis is a facultative intracellular pathogen that causes the human disease known as plague. Growingevidence indicates that intracellular growth in macrophages is important for Y. pestis virulence. Uponphagocytosis Y. pestis alters the maturation of the phagosome to generate a protective compartment within thecell known as the Yersinia containing vacuole (YCV). Key steps in the generation of the YCV include inhibitionof YCV acidification expansion into a spacious vacuole and acquisition of the autophagic markers. Howeverthe mechanisms used by the bacterium to subvert the normal phagosome maturation process and generate theYCV have not been defined. Our long term goals are to elucidate the mechanisms by which Y. pestis evadesmacrophage killing and define the contribution of intracellular survival to Y. pestis virulence. Recently wediscovered that Y. pestis manipulates the host endocytic recycling pathway to survive in macrophages.Moreover we have demonstrated that Y. pestis recruits Rab1 Rab4 and Rab11 to the YCV. Importantly wealso discovered that Y. pestis manipulation of Rab11b disrupts global endocytic recycling in the macrophage.Together these data suggest the hypothesis that Y. pestis specifically targets and recruits Rab11 to the YCV toavoid phagolysosome maturation and generate a replicative niche within macrophages. Furthermore wehypothesize that disruption of cellular trafficking during the YCV biogenesis process also disrupts TLR-4trafficking and immune signaling during intracellular infection. Here we propose to expand on these initial findingsto further define how Y. pestis manipulates Rab11 and the host recycling machinery to generate the YCV.Specifically we will answer two key questions. First how does Y. pestis recruit Rab11 to the YCV (Aim 1)?Second how does Rab11 recruitment impact the remodeling of the YCV (Aim 2)? Specifically what othercomponents of the recycling pathway does Rab11 recruit to the YCV and do these components directly contributeto YCV biogenesis and intracellular survival? Furthermore as TLR-4 recruitment to the phagosome is dependenton Rab11 how does YCV biogenesis and Rab11 manipulation by Y. pestis impact TRL-4 trafficking andinflammatory signaling? Answering these questions will fill a critical gap in our understanding of how Y. pestis isable to subvert normal phagosome maturation and survive within this intracellular niche. Furthermore throughunderstanding how Y. pestis manipulates the host recycling and inflammatory pathways we can gain novelinsight into the interactions between these pathways in the context of normal cell biology.

project_terms:
Bacteria;Biogenesis;Bubonic Plague;Cells;Cellular biology;Data;Development;Fleas;Generations;Goals;Growth;Immune signaling;Infection;Inflammation;Inflammatory;Inflammatory Response;Innate Immune Response;Integration Host Factors;Link;Mediating;Molecular;Normal Cell;Pathogenesis;Pathogenicity;Pathway interactions;Phagocytosis;Phagolysosome;Phagosomes;Pharmacology;Plague;Process;Proteins;RNA interference screen;Recycling;Research Personnel;Signal Transduction;Testing;Vacuole;Virulence;Yersinia;Yersinia pestis;base;defined contribution;human disease;insight;macrophage;microbiome research;novel;overexpression;pathogen;recruit;response;trafficking;transmission process


application_id: 9657796
project_number: 5P20GM125504-02
project_title: SGK1 and the Control of Periodontal Inflammation
administering_ic: NIGMS
award_notice_date: 2019-02-20
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
study_section: ZGM1-RCB-3
subproject_number: 8244
contact_pi_person_id: 16064057
contact_pi: WANG, HUIZHI
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: 2019-03-01
budget_end_date: 2020-02-29
project_abstract:
Host inflammatory immune responses to oral microbiota are tightly regulated by multiple pro-inflammatory andanti-inflammatory mechanisms. The balance of there two activities ensures a state of immune homeostasiswhich is critical for protecting against microbial invasion and avoiding subsequent collateral tissue damages. Tolimit the ferocity of inflammation a number of established pathways exist that dampen the innate immuneresponse. Our recent publication has demonstrated a novel role for serum- and glucocorticoid- inducible kinase1 (SGK1) a serine/threonine kinase associated with the PI3K pathway in restraining the production of E. coilLPS-mediated pro-inflammatory cytokine production in human monocytes. Preliminary data for this applicationshow that SGK1 is phospho-activated in human monocytes in response to challenge with multiple oral bacteria.Using P. gingivalis and F. nucleatum well-established model oral organisms for the investigation of host-pathogen interactions in the periodontium we show that inhibition of SGK1 robustly enhances the production ofpro-inflammatory cytokines (TNF IL-12 IL-6 IL-1 IL-8) a result also confirmed by using Cre-loxP-mediatedSGK1 knockout mice. Moreover combination of Pg and Fn exhibits synergistic effects on the production of pro-inflammatory cytokine production in human monocytes. In addition the anti-inflammatory role for SGK1 wasvalidated by our preliminary in vivo evidence showing that systemic administration of the SGK1 inhibitorEMD638683 elevated infiltration of neutrophils and macrophages into the gingival tissues and aggravated theseverity of alveolar bone resorption in mice orally infected with P. gingivalis. These data strongly suggest thatSGK1 is critical for limiting the magnitude of the pro-inflammatory response to oral bacterial communities andin the absence of SGK1 destructive inflammatory responses are exacerbated. Thus we propose that stimulationof this endogenous anti-inflammatory pathway in the host will help limit or prevent oral bacteria-induced tissuedestruction. The specific hypothesis to be tested in this application is that in the context of P. gingivalis and/orF. nucleatum challenge SGK1 constrains the production of pro-inflammatory cytokines; down-regulatesrecruitment of inflammatory cells to the periodontium; and in turn protects against alveolar bone lossthrough downstream modification of inflammatory signaling molecules including Nedd4-2 MKP-1 andTAK1 which ultimately converge on NF-B. We will challenge this hypothesis with three specific Aims: (i) Tocharacterize SGK1 as an innate immune suppressor of inflammatory responses in vitro; (ii) To elucidate thesignaling mechanisms by which SGK1 controls host inflammatory responses; and (iii) To establish the in vivorelevance of SGK1 in the control of host inflammation using mouse subcutaneous chamber and alveolar boneloss models. Successful completion of these studies will characterize for the first time the anti-inflammatoryfunction of SGK1 in host inflammatory responses to oral bacteria and elucidate the novel anti-inflammatorysignaling network mediated by the SGK1-MKP1 module in the control of the inflammation progression.

project_terms:
Acute;Adopted;Alveolar Bone Loss;Anti-inflammatory;Bacteria;Bone Resorption;Cells;Centers of Research Excellence;Communities;Coronary Arteriosclerosis;Data;Disease;Ensure;Equilibrium;Exhibits;Fusobacterium nucleatum;Gingiva;Glucocorticoids;Gnotobiotic;Goals;Gram-Negative Bacteria;Homeostasis;Human;IL8 gene;Immune;Immune response;In Vitro;Infection;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Innate Immune Response;Interleukin-1;Interleukin-12;Interleukin-6;Investigation;Knockout Mice;MAP3K7 gene;MAPK phosphatase;Mediating;Modeling;Modification;Molecular;Mus;Natural Immunity;Neutrophil Infiltration;Oral;Oral cavity;Organism;Outcome;Pathogenicity;Pathway interactions;Periodontitis;Periodontium;Phosphorylation;Phosphotransferases;Porphyromonas gingivalis;Predisposition;Production;Protein-Serine-Threonine Kinases;Publications;Role;Serum;Severities;Signal Pathway;Signal Transduction;Signaling Molecule;TNF gene;Testing;Time;Tissues;alveolar bone;bacterial community;bone loss;cytokine;dysbiosis;host microbiome;in vivo;inhibitor/antagonist;insight;macrophage;microbial;microbial community;microbiome research;monocyte;novel;novel therapeutic intervention;oral bacteria;oral infection;oral microbial community;oral microbiome;oral tissue;p65;pathogen;prevent;recruit;response;subcutaneous;therapeutic target


application_id: 9657794
project_number: 5P20GM125504-02
project_title: Novel synthetic analogue of microbial metabolite Urolithin A mitigates inflammatory bowel diseases
administering_ic: NIGMS
award_notice_date: 2019-02-20
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
study_section: ZGM1-RCB-3
subproject_number: 8243
contact_pi_person_id: 9246960
contact_pi: JALA, VENKATAKRISHNA RAO
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: 2019-03-01
budget_end_date: 2020-02-29
project_abstract:
Project Summary/Abstract Inflammatory Bowel Diseases (IBDs) which include f ulcerative colitis and Crohns disease affect asmany as 1.4 million people in the USA. Chronic inflammation and microbial dysbiosis are major features of IBDs.Beneficial effects rendered by healthy dietary practices are not uniform among individuals and are attributed tovariations in gut microbiota and their active metabolites. To overcome the challenge of inter-individual differencesin gut microbiota their metabolites and poor bioavailability here we propose direct usage of microbialmetabolites to maintain gut immune homeostasis to mitigate IBDs. Urolithin A (UroA) is one of such beneficialmicrobial metabolite derived from ellagic acid and ellagitannins major polyphenolic components of berries andpomegranate. Based on UroA structure we developed novel potent structural analogue UAS03 which exhibitedincreased anti-inflammatory and gut barrier functional activities compared to parent UroA compound. Thecurrent proposal investigates the molecular and cellular mechanisms of UAS03 and its therapeutic efficacies inIBD pre-clinical models. Our preliminary results showed that the oral administration of UAS03 mitigated colitis in dextran sodiumsulphate (DSS)- or 246-Trinitrobenzenesulfonic acid (TNBS) induced murine colitis even at 10 fold lower dosecompared to UroA. UAS03 significantly inhibited lipopolysaccharide (LPS)-induced increase in inflammatorymediators in immune cells and epithelial cells with 10 fold higher efficacy than UroA. Further treatment withUAS03 reduced intestinal permeability by up-regulating junctional proteins through activation of nuclear factor(erythroid-derived 2)-like 2 (Nrf2)-hemoxygenase (HO1) pathways in epithelial cells. Based on these results wepropose two-pronged beneficial activities of UAS03 and UroA where these compounds protect the host fromexternal challenges by protecting gut barrier function and dampening inflammatory activities. In this proposal wewill test the hypothesis that treatment with UAS03 an effective analogue of a microbial metabolite protectsfrom IBD development by reducing barrier dysfunction and inflammation. In Aim 1 we will investigate howUSA03/UroA increase gut barrier function in a Nrf2-dependent manner by upregulating junctional proteins aswell as molecular events involved anti-inflammatory activities of UAS03. In Aim 2 therapeutic efficacies ofUAS03 and UroA will be examined in acute chronic and spontaneous IBD pre-clinical models. In Aim 3 wepropose to identify the bacteria responsible for UroA production and test their pro-biotic activities in colitis models.The successful completion of proposed studies will allow understanding of UAS03 and UroA mechanisms ofactions and establishes the basis for therapeutic usage in IBDs.

project_terms:
Acids;Acute;Affect;Anti-inflammatory;Bacteria;Benzopyrans;Berry;Biological;Biological Availability;Cells;Chemopreventive Agent;Chronic;Clinical;Colitis;Crohn's disease;Data;Development;Diet;Dietary Intervention;Dietary Practices;Disease;Disease model;Dose;Down-Regulation;Ellagi-Tannins;Ellagic Acid;Epithelial;Epithelial Cells;Erythroid;Event;Exhibits;Functional disorder;Glycols;Goals;Heme;Homeostasis;Human;Ileitis;Immune;In Vitro;Indigenous;Individual;Individual Differences;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Bowel Diseases;Interleukin-1;Interleukin-6;Intestinal permeability;Lipopolysaccharides;Measures;Mediating;Modeling;Molecular;Mus;Nuclear;Oral Administration;Oxygenases;Parents;Pathogenicity;Pathway interactions;Phenotype;Phytochemical;Pilot Projects;Pomegranate;Pre-Clinical Model;Probiotics;Production;Proteins;Risk;Role;Sampling;Sodium Dextran Sulfate;Structure;T-Lymphocyte;TNF gene;Testing;Therapeutic;Therapeutic Uses;Tight Junctions;Time;Treatment Efficacy;Trinitrobenzenesulfonic Acid;Ulcerative Colitis;Variant;analog;bacterial metabolism;base;chemokine;comparative efficacy;dysbiosis;gut bacteria;gut microbiota;in vivo;in vivo Model;inter-individual variation;microbial;microbiome research;microbiota metabolites;molecular targeted therapies;novel;preservation;protective effect


application_id: 9657793
project_number: 5P20GM125504-02
project_title: Functional Microbiomics Core-Bodduluri
administering_ic: NIGMS
award_notice_date: 2019-02-20
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
study_section: ZGM1-RCB-3
subproject_number: 8242
contact_pi_person_id: 6074575
contact_pi: BODDULURI, HARIBABU
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: 2019-03-01
budget_end_date: 2020-02-29
project_abstract:
Biomedical research areas including the study of metagenomics inflammation and pathogenesis are resourceand technology intense. All COBRE-supported investigators require state of-the-art resources to successfullycompete with investigators from other resource-rich institutions for NIH support. The primary goal of theFunctional Microbiomics Core (FMC) is to establish an integrated service center that functions as a criticalresource for all Microbiome Inflammation and Pathogenicity COBRE investigators. Since all the COBRE projectsutilize mouse models to explore the inter-relationships between inflammation and pathogenesis and thecontribution of microbiota to this process the development of a facility to house and maintain germ-free andgnotobiotic mice is crucial to the FMC. An anaerobic culture facility will support research on gnotobiotic mice thatrequires specific colonization with fecal transplants or defined anaerobic bacteria. Further in Aim 2 we proposeto establish an integrated metagenomics center for microbiota. This facility will prepare genomic DNA followingunified protocols and generate 16S rRNA gene amplicon sequences and provide bioinformatics support for allmicrobiota analysis. The FMC will also support all COBRE projects with analysis of their biological samples forinflammatory markers as well as histopathological examination of tissue sections. Education and training of juniorinvestigators and the university wide research community in microbiota research is an important goal of the FMC.Towards this goal the FMC will organize seminars as well as informal meetings that will serve as a forum forhighlighting the scientific and technical advances in the field. Finally the FMC plans to become an independentservice center at UofL to support the needs of all researchers in this area of research

project_terms:
Address;Adopted;Anaerobic Bacteria;Area;Attention;Award;Bioinformatics;Biological;Biomedical Research;Centers of Research Excellence;Clinical;Communities;Continuing Education;Core Facility;Data Analyses;Development;Dietary Intervention;Disease;Equipment;Extramural Activities;Fee-for-Service Plans;Fostering;Funding;Generations;Genomic DNA;Genomics;Germ-Free;Gnotobiotic;Goals;Health;Housing;Human Resources;Incubators;Individual;Infection;Inflammation;Inflammation Mediators;Institution;Kentucky;Laboratories;Mentors;Metagenomics;Methodology;Mission;Mus;Outcome;Pathogenesis;Pathogenicity;Phase;Pilot Projects;Process;Protocols documentation;Research;Research Personnel;Research Support;Resources;Ribosomal RNA;Sampling;Services;Sterility;Techniques;Technology;Tissues;Training;Training and Education;Translational Research;United States National Institutes of Health;Universities;Work;animal facility;base;biosafety level 3 facility;experimental study;fecal transplantation;histopathological examination;inflammatory marker;innovation;interest;investigator training;meetings;member;metabolomics;microbial;microbiome;microbiome research;microbiota;mouse model;pathogen;programs;protocol development;rRNA Genes;social health determinants;success;tool


application_id: 9657792
project_number: 5P20GM125504-02
project_title: COBRE-Administrative Core
administering_ic: NIGMS
award_notice_date: 2019-02-20
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
study_section: ZGM1-RCB-3
subproject_number: 8241
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-03-01
budget_end_date: 2020-02-29
project_abstract:
The University of Louisville (UofL) COBRE in Functional Microbiomics Inflammation and Pathogenicitycomprises a multidisciplinary group of investigators addressing thematic aspects of microbiome inflammationand pathogenicity studies. The UofL is uniquely poised to investigate these problems in a coordinated andefficient fashion and the COBRE is horizontally integrated with a number of UofL funded initiatives and grantapplications in related areas. The departments of Oral Immunology and Infectious Diseases Microbiology andImmunology and Bioengineering all contribute to the cross-disciplinary nature of the center. These units haveestablished records of federal funding mentoring junior faculty graduate student training and collaborativeinteractions across campus. This application is led by well-qualified and well-funded Center Directors. There arefive outstanding PI-mentees with senior established funded mentoring teams. Our proposed COBRE will havea major positive impact on research throughout UofL and will help recruit and retain faculty. The germ freeanimal facility to be established will be one of only a few in the country. Many of the projects address chronicinflammatory diseases that occur at disproportionately high incidence in minority communities. Other projectsinvolving plague and melioidosis have national and international significance. The Administrative Core willprovide overall governance and will ensure that the COBRE projects and cores work together in a cohesive andcoordinated manner. All projects and cores will utilize the Administrative Core. The Specific Aims are: to providea formal governance structure to allow coordination direction and prioritization of activities including budgetissues ensuring the quality of all functions; to evaluate progress; to resolve any conflicts as they arise; to providea formalized process for mentoring junior faculty; to provide a mechanism to replace mentees as they becomeindependent; to provide a mechanism to replace any key individuals who may leave; to provide pilot funding forjunior faculty to ensure a pipeline of investigators; to provide biostatistical and bioimaging support; and todisseminate pertinent information resulting from the COBRE activities.

project_terms:
Acute;Address;Applications Grants;Area;Biological Warfare;Biomedical Engineering;Biometry;Bubonic Plague;Budgets;Burkholderia pseudomallei;Centers of Research Excellence;Chronic;Communicable Diseases;Communities;Conflict (Psychology);Country;Disease;Disease Outcome;Ensure;Faculty;Funding;Germ-Free;Goals;Guidelines;Health;Human;Human Microbiome;Immunology;Incidence;Individual;Inflammation;Inflammatory;Inflammatory Response;Interdisciplinary Study;International;Location;Melioidosis;Mentors;Microbiology;Minority;Modality;Natural Immunity;Pathogenicity;Plague;Play;Population;Process;Records;Regulation;Research;Research Personnel;Role;Structure;Universities;Work;Yersinia pestis;animal facility;bioimaging;cohesion;graduate student;host-microbe interactions;immune system function;microbiome;microbiome research;microbiota;minority communities;multidisciplinary;nature center;new technology;new therapeutic target;oral immunology;oral infection;pathogen;recruit;student training


application_id: 9657790
project_number: 5P20GM125504-02
project_title: Functional Microbiomics Inflammation and Pathogenicity
administering_ic: NIGMS
award_notice_date: 2019-02-20
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
program_official: CUPIT, PAULINE
project_start_date: 2018-03-01
project_end_date: 2023-02-28
study_section: ZGM1-RCB-3(C1)
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Anaerobic Bacteria;Anti-inflammatory;Area;Autoimmune Diseases;Basic Science;Bioinformatics;Biological Assay;Biometry;Centers of Research Excellence;Chronic;Colorectal Cancer;Communities;Complex;Dentistry;Development;Disease;Distant;Ecology;Education;Engineering;Ensure;Environment;Equilibrium;Evaluation;Extramural Activities;Faculty;Funding;Germ-Free;Goals;Health;Health Sciences;Homeostasis;Human;Human Microbiome;Immune response;Immune system;Immunologist;Immunology;Indigenous;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Infrastructure;Interdisciplinary Study;International;Lead;Location;Mentors;Methods;Microbe;Microbiology;Monitor;Mucous Membrane;Natural Immunity;Normal tissue morphology;Outcomes Research;Parkinson Disease;Pathogenicity;Pathology;Pathway interactions;Periodontitis;Physiology;Pilot Projects;Play;Positioning Attribute;Postdoctoral Fellow;Process;Recovery;Renaissance;Research;Research Infrastructure;Research Personnel;Research Priority;Research Project Grants;Resources;Rheumatoid Arthritis;Role;Scientist;Services;Shapes;Site;Specificity;Structure;Surface;System;Talents;Teacher Professional Development;Therapeutic Agents;Time;Tissues;Training;Universities;animal facility;autism spectrum disorder;bioimaging;career development;chronic infection;dysbiosis;graduate student;host-microbe interactions;immune system function;inflammatory marker;intercellular communication;medical schools;microbial;microbial community;microbiome;microbiome research;microbiome sequencing;microbiota;multidisciplinary;nervous system disorder;novel;novel therapeutics;pathogen;programs;recruit;response;tool


application_id: 9657647
project_number: 5R01AR070313-03
project_title: Macrophage phenotype orchestrates mammalian tissue regeneration
administering_ic: NIAMS
award_notice_date: 2019-02-12
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AR
serial_number: 070313
program_official: BELKIN, ALEXEY
project_start_date: 2017-03-13
project_end_date: 2022-02-28
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 10345749
contact_pi: SEIFERT, ASHLEY WINN
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_abstract:
ABSTRACT/PROJECT SUMMARYDespite clinical advances the fact remains that humans cannot regenerate injured tissue. Instead tissuetrauma stimulates inflammation which in turn induces fibrosis and ultimately the formation of scar tissue.Trauma-induced inflammation is primarily regulated by macrophages; key regulators of fibrosis. Althoughcurrent therapies to control human fibrotic diseases include agents that target macrophages new data indicatethese treatments negatively impact regenerative ability. This outcome results from our lack of knowledge abouthow macrophages regulate endogenous tissue regeneration. A mammalian model of tissue regeneration isnecessary to directly study how macrophages regulate the injury response to fill this knowledge gap. Thediscovery that African spiny mice (Acomys) can regenerate complex tissues of the external ear including skinhair follicles nerves muscle and cartilage provides such a model. Furthermore because laboratory miceproduce scar tissue in response to an identical injury this comparative system provides a unique opportunity todirectly study how macrophage phenotypes regulate regeneration and scarring. The long-term goal is todevelop clinical interventions that stimulate regeneration and inhibit fibrosis. The objective of this proposal is toidentify macrophage subtypes that regulate regeneration and manipulate inflammation to stimulateregeneration in response to injury. This proposal tests the central hypothesis that specific macrophagesubtypes stimulate a regenerative extracellular environment and that phenotype switching from one state toanother is critical to the outcome of injury. This hypothesis is based upon published and preliminary studiesindicating general macrophage phenotypes are associated with regeneration that Acomys and Mus exhibitdifferent cytokine and inflammatory gene profiles and that production of a regenerative or scarring extracellularenvironment corresponds to specific macrophage phenotypes observed in Acomys or Mus. Guided by strongpreliminary data this hypothesis will be tested by pursuing the following two specific aims: (1) identify specificmacrophage phenotypes that regulate tissue regeneration and scarring in Acomys and Mus. Parallel in vivoand in vitro studies will integrate the timing and extracellular influence of macrophage subtypes andmacrophage origin using newly developed regeneration assays; and (2) test the role of macrophage-producedarginase on tissue regeneration through the use of a newly identified immunomodulatory agent and geneticallyengineered mice with macrophages that lack arginase. The approach is innovative in the applicant's opinionbecause it departs from the status quo of investigating wound healing and instead focuses on understandingendogenous tissue regeneration in a unique model of mammalian tissue regeneration. The proposed researchis significant because it is expected to provide new and fundamental insight into how macrophages coordinatethe inflammatory and immune reaction to stimulate a regenerative response to injury.

project_terms:
Acomys;Address;African;Azithromycin;Biological Assay;Cartilage;Cicatrix;Clinical;Complex;Data;Disease;Ear;Environment;Exhibits;External Ear;Extracellular Matrix;Fibroblasts;Fibrosis;Genes;Genetic Transcription;Genetically Engineered Mouse;Genomics;Goals;Granulation Tissue;Hair follicle structure;Human;Immunomodulators;In Vitro;Inflammation;Inflammatory;Injury;Intervention;Knowledge;Laboratory mice;Mammals;Medicine;Modeling;Molecular;Mus;Muscle;Musculoskeletal;Natural regeneration;Nerve;Outcome;Pathology;Phenotype;Process;Production;Proteomics;Public Health;Publishing;Regenerative response;Research;Role;Skin;Structure;System;Testing;Time;Tissue Model;Tissues;Trauma;Work;Wound Healing;arginase;base;comparative;cytokine;disability;extracellular;healing;immunoreaction;improved functioning;in vivo;inhibitor/antagonist;injured;injury and repair;innovation;insight;macrophage;novel;organ regeneration;recruit;regenerative;response;response to injury;stem;targeted agent;tissue regeneration;tissue trauma

public_health_relevance:
PROJECT NARRATIVEAlthough humans cannot regenerate damaged tissue the African spiny mouse can naturally regenerate skinhair follicles nerves muscle and cartilage. Thus the proposed research is relevant to public health becausestudying the cellular mechanisms that regulate endogenous regeneration is expected to generate novel clinicalapproaches to restore damaged tissue. Stimulating natural tissue regeneration greatly improves thefunctionality of injured tissue and will help reduce the burden human disability.


application_id: 9657247
project_number: 2R56DK084045-05A1
project_title: The insulin/IGF axis in diabetic osteopathy
administering_ic: NIDDK
award_notice_date: 2018-03-15
opportunity_number: PA-16-160
application_type: 2
activity_code: R56
ic: DK
serial_number: 084045
suffix: A1
program_official: MALOZOWSKI, SAUL N
project_start_date: 2012-05-23
project_end_date: 2020-03-31
study_section: Special Emphasis Panel[ZRG1-MOSS-K(02)M]
contact_pi_person_id: 6741266
contact_pi: FOWLKES, JOHN L
other_pis: NYMAN, JEFFRY STEPHEN
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Type 1 diabetes mellitus (T1D) in humans is associated with several disorders of skeletalhealth including decreased bone mineral density (BMD) and an increased risk for osteoporosisand fragility fractures. These features are the primary clinical characteristics of diabetic bonedisease (DBD). Evidence suggests that DBD occurs early in the progression of T1D involvesimpaired bone formation includes micro-architectural abnormalities and poor bone quality andeventually may lead to abnormal bone turnover. Despite what is known clinically the pathogenicmechanisms behind these findings are not well understood. Translational studies in rodentmodels of T1D DBD have begun to unravel how a compromised skeleton can arise in thediabetic state what are the mechanisms involved in the process and what therapeutics mightbe most appropriate to prevent or treat DBD. Studies in mouse models supported by humanstudies suggest that impairment in insulin and insulin-like growth factor-I (IGF-I) production andaction may be central events in promoting DBD. Recent data from our laboratory and othershave demonstrated that: 1) severe deficits in bone formation occur in the context of insulin-deficiency in mouse models of T1D; 2) insulin therapy can improve both cancellous and corticalbone thereby increasing fracture resistance; 3) normalization of systemic insulin levelsstimulates bone formation through RUNX2 and RUNX2 target genes in diabetic animals; and 4)insulin and IGF-I may signal via similar down-stream pathways to promote osteoblastogenesis.Nonetheless overlap and compensation between each ligand for the other has not beenestablished in the diabetic state nor have the downstream mediators or critical signalingpathways been identified. To clarify the mechanisms by which insulin and/or IGF-I modulateosteogenesis and to understand how deficiencies of impaired signaling of each may contributeto DBD we will carry out studies to 1) determine how insulin and IGF-1 deficiencies contributeto DBD and 2) how each may perform overlapping and independent effects through specificdownstream signaling pathways to prevent diabetic bone disease and/or reverse DBD.

project_terms:
Address;Affect;Animals;Architecture;Basic Science;Biomechanics;Bone Density;Bone Development;Bone Diseases;Bone structure;Characteristics;Clinical;Data;Development;Diabetes Mellitus;Diabetic mouse;Event;FOXO1A gene;Female;Financial compensation;Fracture;Fracture Healing;Gene Targeting;Genetic;Glucose;Growth Factor Receptors;Health;Homeostasis;Homologous Gene;Human;Impairment;Insulin;Insulin Receptor;Insulin deficiency;Insulin-Dependent Diabetes Mellitus;Insulin-Like Growth Factor I;Insulin-Like Growth Factor Receptor;Knock-out;Knockout Mice;Laboratories;Lead;Ligands;Mediator of activation protein;Modeling;Molecular;Mus;Osteoblasts;Osteocalcin;Osteocytes;Osteogenesis;Osteopathic Medicine;Osteoporosis;Outcome;Pathogenicity;Pathway interactions;Personal Satisfaction;Persons;Phenotype;Play;Prevention;Process;Production;Receptor Activation;Receptor Signaling;Reporting;Reproducibility;Resistance;Risk;Rodent Model;Role;Signal Pathway;Signal Transduction;Skeleton;Streptozocin;Structure;Therapeutic;Tissues;Transgenic Organisms;Translational Research;bone;bone quality;bone turnover;cortical bone;diabetic;fracture risk;fragility fracture;improved;male;mouse model;osteoprogenitor cell;prevent;skeletal;skeletal disorder;substantia spongiosa;translational study

public_health_relevance:
PROJECT NARRATIVEHumans with Type 1 diabetes (T1D) are susceptible to diabetic bone disease and are atincreased risk for fracture. Despite this well-recognized increased risk of osteoporosis fractureand poor fracture healing in persons with diabetes it is still not well understood how insulinitself or its homolog insulin-like growth factor 1 (IGF-I) directly affects skeletal well-being. Thestudies described in this proposal are intended to better define the relative contributions ofinsulin and IGF-I to the molecular cellular and tissue-level events involved in the developmentof diabetic bone disease as well as to explore the therapeutic potential of insulin and IGF-I inpreventing diabetic bone disease.


application_id: 9656958
project_number: 5R01CA217255-03
project_title: Studies to understand and exploit 10-membered enediyne biosynthesis
administering_ic: NCI
award_notice_date: 2019-01-31
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 217255
program_official: FU, YALI
project_start_date: 2017-03-01
project_end_date: 2022-02-28
study_section: Special Emphasis Panel[ZRG1-BCMB-U(02)M]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: PHILLIPS, GEORGE NEAL;VAN LANEN, STEVEN GARY
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:
ABSTRACTThe 10-membered enediynes [exemplified by calicheamicin (CLM) esperamicin (ESP) and dynemicins (DYN)]are arguably among the most renowned natural products (NPs) discovered to date by virtue of theirunprecedented complex molecular architectures notable anticancer and anti-infective potencies and in the caseof CLM demonstrated clinical utility. The current study builds on a longstanding collaborative effort ofachievement and discovery relating to key aspects of 10-membered enediyne biosynthesis as well as parallelinnovative efforts to co-opt key biosynthetic catalysts for synthetic applications. The studies put forth will takeadvantage of this strong foundation and a powerful combination of genetic biochemical chemical and proteinstructural tools to elucidate the remaining unusual biosynthetic transformations and to exploit select catalysts forenediyne non-native modification. Specifically aims 1 and 2 will focus on extending our understanding of thefundamental steps of enediyne core biosynthesis common to CLM/DYN/ESP DYN anthraquinone biosynthesisand a selected set of unique tailoring reactions (CLM/ESP thiosugar sulfur installation and aminopentose N-alkylation ESP C6-hydroxylation and O-glycosylation). In parallel aim 3 will focus on tactical structural studiesto augment both aims 1 and 2 and the structural study of unknowns to facilitate functional annotation. Additionalstudies in aim 2 with key catalysts and corresponding non-native substrates are designed to assess the potentialfor strategic installation of chemoselective handles to enable novel approaches for facile mild bioconjugation ofCLM to tumor-targeting mAbs (in collaboration with Pfizer).

project_terms:
Achievement;Alkylation;Amines;Anabolism;Anthraquinones;Anti-Infective Agents;Antibodies;Antitumor Natural Products;Architecture;Biochemical;Biogenesis;Bioinformatics;Biotin;Chemical Structure;Chemistry;Clinical;Collaborations;Complement;Complex;Crystallization;Cyclization;Development;Dynemicin;Enzymatic Biochemistry;Enzymes;Family member;Foundations;Genetic;Hybrids;Hydroxylation;Iodination reaction;Ligands;Mixed Function Oxygenases;Modality;Modification;Molecular;Monoclonal Antibodies;Natural Products;Nucleotides;Polyenes;Proteins;Reaction;Reagent;Route;Series;Structural Protein;Structure;Sulfur;Trisaccharides;analog;anti-cancer;base;cancer therapy;catalyst;chemical genetics;clinical development;design;enzyme pathway;glycosylation;glycosyltransferase;innovation;insight;non-Native;novel;novel strategies;oxidation;polyketide synthase;protein structure;prototype;structural biology;structural genomics;sugar;targeted agent;thiosugar;tool;tumor

public_health_relevance:
PROJECT NARRATIVEThis proposal seeks to study a prioritized set of highly unique enzyme-catalyzed transformations involved inthe biosynthesis of antitumor natural products (10-membered enediynes) and develop new strategies toconjugate 10-membered enediynes to tumor-targeting agents. The proposed studies will advance ourfundamental understanding of natural product biosynthesis and provide strategies for enhancing the clinicalutility of enediynes in the treatment of cancer.


application_id: 9656919
project_number: 5R01AA024405-05
project_title: SAM Deficiency Mediated Epigenetic Mechanisms in Alcohol induced Immunosuppression
administering_ic: NIAAA
award_notice_date: 2019-06-19
opportunity_number: PA-14-077
application_type: 5
activity_code: R01
ic: AA
serial_number: 024405
program_official: WANG, JOE
project_start_date: 2015-03-10
project_end_date: 2021-02-28
study_section: ZAA1-GG(50)P
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
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:
CD4+ T cell depletion is a major component of the multiple detrimental effects of chronic alcoholconsumption on the immune system. Chronic alcohol abuse leads to abnormal S-adenosylmethionine (SAM)metabolism and decreased hepatic SAM levels. Our earlier work in CD4+ T cells has demonstrated thatethanol significantly decreases lymphocytic methionine adenosyltransferase (MAT II) expression and activitywith resultant SAM deficiency and also increases activation-induced Fas-mediated apoptotic death. Notablyexogenous SAM supplementation restored intracellular SAM and prevented apoptotic signaling and death inethanol treated CD4+ T cells. These data not only showed a causal role for SAM deficiency in ethanolmediated apoptotic death but also provided the proof-of-concept for SAM therapy in preventing alcoholinduced CD4+ T cell depletion and immune suppression. SAM functions as the critical methyl donor duringepigenetic regulation leading to enzymatic modification of histones and DNA cytosine residues. Our recentwork on ethanol treated primary human CD4+ T cells in vitro as well as CD4+ T cells obtained from alcoholicpatients has provided convincing preliminary data showing that ethanol exposure can cause transcriptionallypermissive modifications in histones associated with the FasL promoter. These histone modificationsenhance transcriptional activation of the FasL promoter resulting in increased mRNA expression apoptoticsignaling and cell death. The overall objective of this proposal is to systematically examine genome wide aswell as gene specific (promoter associated) histone and DNA modifications involved in alcohol-mediatedapoptotic signaling and death in CD4+ T cells. We expect that the results of our study will provide criticalmolecular insights in the alcohol-induced immunotoxicity of CD4+ T cells. We predict that results from thisresearch will also provide important insights into immune dysfunction/CD4+ T cell loss in alcohol consumingHIV-infected patients. The specific aims of this translational proposal investigating the epigeneticmechanisms involved in aberrant apoptotic signaling and cell death of CD4+ T lymphocytes in alcoholicpatients are: Aim 1: Examine the effects of alcohol on cellular SAM levels global histone and DNAmodifications and apoptotic cell death in CD4+ T cells. Aim 2: Determine the gene specific (promoterassociated) histone and DNA modifications occurring in response to alcohol-mediated SAM deficiency thatimpact the expression of apoptotic genes relevant to CD4+ T cell survival.RELEVANCE (See instructions):Alcohol abuse continues to be a significant burden on the US healthcare system. The studies proposed herewill examine epigenetic modifications involved in alcohol-induced depletion of CD4+ T lymphocytes usingboth a genome-wide approach as well as a hypothesis-based candidate gene approach. The data obtainedfrom these studies will yield mechanistic insights underlying alcohol induced immune suppression and howalcohol may further depress immune function in HIV-infected patients.

project_terms:
Alcohol abuse;Alcohol consumption;Alcohols;Apoptotic;CD4 Positive T Lymphocytes;Candidate Disease Gene;Cell Death;Cell Survival;Cessation of life;Chronic;Clinical;Cytosine;DNA;DNA Modification Process;Data;Epigenetic Process;Ethanol;Gene Expression;Genes;Genetic Transcription;HIV;Healthcare Systems;Hepatic;Histones;Human;Immune System Diseases;Immune system;Immunosuppression;In Vitro;Instruction;Lymphocyte;Mass Spectrum Analysis;Mediating;Metabolism;Modification;Molecular;Patients;Proteomics;Research;Role;S-Adenosylmethionine;Signal Transduction;Supplementation;T-Cell Depletion;Transcriptional Activation;Work;alcohol abuser;alcohol effect;alcohol exposure;alcohol prevention;alcohol response;base;chronic alcohol ingestion;epigenetic regulation;genome-wide;histone modification;immune function;immunotoxicity;insight;mRNA Expression;methionine adenosyltransferase;prevent;problem drinker;promoter


application_id: 9656260
project_number: 3R01GM113087-04S1
project_title: Supplement to Deciphering the molecular mechanisms underlying active scaffolding
administering_ic: NIGMS
award_notice_date: 2018-08-21
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: GM
serial_number: 113087
suffix: S1
program_official: KODURI, SAILAJA
project_start_date: 2015-08-01
project_end_date: 2020-05-31
study_section: Molecular and Integrative Signal Transduction Study Section[MIST]
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
project_abstract:
The extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway plays an essential role inseveral critical steps of embryonic development and tumor progression. It also controls critical cellularfunctions such as apoptosis motility and differentiation. Kinases and phosphatases of this pathway have beenextensively studied and targeted therapeutically. However the mechanisms that determine the signalspecificity and orchestrate the diverse biological outcomes of ERK1/2 signaling are still poorly understood.Scaffold proteins are key players in the ERK1/2 signaling pathway that are thought to integrate incomingsignals and deliver signaling specificity and yet their role in signal propagation and the mechanisms of theiraction are still unknown. The long-term goal of our research is to reveal how scaffold proteins are involved inthe biological processes regulated by the ERK1/2 cascade. In this way new therapeutic strategies can bedeveloped to more specifically target this cascade without affecting other essential biological functions. The objective of this proposal is to determine the mechanisms underlying the ability of the key scaffoldprotein Shoc2 to regulate ERK1/2-mediated cell motility. Shoc2 is essential for embryonic development and acritical regulator of ERK1/2 activity. We have shown that depletion of Shoc2 in zebrafish results in defects inhematopoiesis. We also found that Shoc2 integrates endocytic and ubiquitin machineries to regulate ERK1/2signaling. Based on this preliminary data the central hypothesis of this proposal is that Shoc2 creates asignaling hub that regulates ERK's developmental signals in a spatio-temporal manner. Our hypothesis will be tested by pursuing three specific aims: Aim 1 will determine the spatio-temporalorganization and dynamics of Shoc2 scaffold complexes. Aim 2 will reveal the molecular mechanism by whichthe E3 ligase HUWE1 controls Shoc2 function and assembly of the Shoc2 scaffold complexes. Aim 3 willdetermine the signaling events mediated through the Shoc2 scaffold complexes that control embryonicdevelopment. The proposed Aims therefore are expected to provide a detailed understanding of how Shoc2 isinvolved in determining the specificity of ERK1/2 signaling outcomes. These studies will employ state-of-the-artinnovative microscopy genetic molecular and cellular techniques and will provide critical insights into ourunderstanding of the spatial-temporal control of signaling by scaffold proteins. This research has significancefor contributing to the advancement of novel therapeutic strategies and biomarker innovations fordevelopmental disorders and cancer progression. Thus the proposed studies are relevant to the NIH's missionto increase understanding of biological processes and to lay the foundation for advances in disease diagnosistreatment and prevention.

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

public_health_relevance:
PUBLIC HEALTH. Deregulation of the MAPK signaling cascade is found in 30% of all tumors and multiplecardiac abnormalities and virtually every component of the cascade is target for therapeutic development. Theeffective targeting of this pathway in disease relies upon a clear understanding of all the intricacies inmodulating numerous signaling components. Understanding the molecular mechanisms underlying the role ofShoc2 in MAPK signaling propagation potentially may lead to the development of specific prognostic markersand will enhance the effectiveness of targeted treatment.


application_id: 9654736
project_number: 5R21DC015759-02
administering_ic: NIDCD
award_notice_date: 2019-02-15
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: DC
serial_number: 015759
program_official: SULLIVAN, SUSAN L
project_start_date: 2018-03-01
project_end_date: 2021-02-28
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 2239737
contact_pi: LUNDY, ROBERT F
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
budget_start_date: 2019-03-01
project_title:
Behavioral Function of Forebrain Projections to Brainstem Gustatory Nuclei Revealed By Optogenetic Control of Cell-Type/Target-Specific Pathways

project_abstract:
The gustatory region of the nucleus of the solitary tract (NST) and parabrachial nucleus (PBN) play distinctroles in the control of taste-guided behaviors and are densely innervated by numerous ventral forebrainstructures including the central nucleus of the amygdala (CeA). The extent to which such neuromodulatorycircuits shape the distinct functional roles of the NST and PBN is unknown. This project is aimed at developingan experimental model system new to the field of gustatory research for addressing long-standing questionsregarding the function of specific neural pathways in various aspects of taste-guided behavior. Specifically wewill use existing virus technologies to design an experimental platform that will enable isolation andmanipulation of cell-type/target-specific circuits of the gustatory system. Study of the interactions betweenforebrain and brainstem gustatory circuits that participate in dietary selection is particularly relevant to ourunderstanding of factors that contribute to overconsumption and obesity. We will use mice that express Cre-recombinase in somatostatin (Sst) neurons combined with viruses that infect axonal terminals and areretrogradely-transported back to the parent cell body (Herpes Simplex Virus (HSV)). The viruses containfloxed stop sequences (DIO) and encode: 1) enhanced yellow fluorescent protein (EYFP) and an excitatorylight-activated ion channel (ChR2) or 2) EYFP and an inhibitory light-activated ion channel (eNpHR3.0). Thisensures specific expression of transgenes in Sst-expressing neurons. Specific aim 1 will inject HSV-DIO-ChR2-EYFP and HSV-DIO-eNpHR3.0-EYFP into the NST or PBN. In vivo extracellular recording of CeAneurons will be made before during and after delivery of light pulses at various temporal frequencies.These experiments will demonstrate the utility of retrograde gene transfer techniques for bidirectional control ofcell-type/target-specific gustatory pathways. Specific aim 2 will inject the same viruses bilaterally into the NSTor PBN combined with bilateral optic fiber cannula implantation above the CeA to determine the effects ofactivation and inactivation of Sst-CeA neurons on: 1) concentration-dependent intake of quinine and sucroseand 2) conditioned taste aversion acquisition. These experiments will test the validity of our central premisethat specific pathways carry particular gustatory-related functions as opposed to particular neuron types.Successful completion of the proposed experiments will represent a significant advance within the field bypermitting selective manipulation of taste circuits and characterization of their behavioral function. This modelsystem also will be broadly-useful to the fields of behavioral neuroscience and optogenetic-assisted circuitmapping.

project_terms:
Address;Affective;Amygdaloid structure;Area;Back;Behavior;Behavioral;Bilateral;Biological Models;Brain;Brain Stem;Cannulas;Cell Nucleus;Cells;Chemical Stimulation;Corticotropin-Releasing Hormone;D Cells;Diet;Electric Stimulation;Ensure;Enterobacteria phage P1 Cre recombinase;Experimental Designs;Experimental Models;Fiber Optics;Frequencies;Gene Transfer;Gene Transfer Techniques;Genes;Genetic Recombination;Heterogeneity;Imagery;In Vitro;Injections;Intake;Ion Channel;Label;Light;Link;LoxP-flanked allele;Mediating;Mus;Neural Pathways;Neurons;Neurosciences;Nucleus solitarius;Obesity;Parents;Pathway interactions;Pattern;Physiologic pulse;Play;Population;Presynaptic Terminals;Prosencephalon;Proteins;Quinine;Research;Resolution;Role;Shapes;Simplexvirus;Somatostatin;Source;Stimulus;Structure;Sucrose;System;Taste Perception;Taste aversion;Techniques;Technology;Testing;Virus;cell type;experimental study;extracellular;gamma-Aminobutyric Acid;implantation;in vivo;nerve supply;neural circuit;neurochemistry;neuroregulation;optogenetics;parabrachial nucleus;relating to nervous system;retrograde transport;taste system;tool;transgene expression

public_health_relevance:
A key function of the gustatory system is to promote favorable dietary selection as part of ahealthy nutritive system. Central gustatory pathways play an important role in this decision bytransmitting information about intensity quality and affective value. This project is aimed atdeveloping a new model system for addressing long-standing questions regarding the functionof specific neuronal pathways in various aspects of taste-guided behavior.


application_id: 9654733
project_number: 5R01DA043519-03
administering_ic: NIDA
award_notice_date: 2019-02-13
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DA
serial_number: 043519
program_official: HIGHSMITH, KEISHER S
project_start_date: 2017-05-01
project_end_date: 2022-02-28
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 3100162
contact_pi: BADA, HENRIETTA S.
other_pis: LEGGAS, MARKOS
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-03-01
project_abstract:
ABSTRACTThe number of newborns that develop the constellation of drug withdrawal symptoms or Neonatal AbstinenceSyndrome (NAS) in the US has increased to epidemic proportions. The pharmacologic treatment of NAS withmorphine or methadone is highly concerning as it corresponds with a timeframe of rapid postnatal brain development. The negative effects of opioids on the developing brain include decreased neurogenesis synaptogenesis and corticogenesis decreased brain size and decreased brain volumes in older children with prenatalopiate exposure. Furthermore response of neonates to treatment is highly variable and limited pharmacogenetic and metabolic activity data which can be used to optimize therapy in this population pose additionalchallenges in using any drug to treat NAS. Collectively these issues present a critical need to evaluate andoptimize the use of a non-opioid drug for treatment of NAS. The long term goals of our research is to establishthe best pharmacological treatment for NAS and determine how pharmacologic treatment of NAS affects long-term developmental outcomes. The objective of this application is to evaluate the effectiveness of clonidine an2 adrenergic receptor agonist as a treatment for neonates with NAS in a randomized clinical trial. Our central hypothesis is that clonidine will effectively treat drug withdrawal manifestations in neonates. Preliminaryclinical evidence supports this hypothesis. Clonidine has previously been reported by us and others as a singledrug therapy for NAS in small number of infants with relief of withdrawal symptoms and as an effective adjunctive treatment when giving chloral hydrate or morphine. The rationale for the proposed research is that oncewe understand how clonidine can be used optimally in the clinic to treat NAS a safe medication will be available and it could potentially minimize complications associated increased length-of-stay in the hospitalhealthcare costs and the deleterious opiate assaults on the developing brain that continue with postnatal opiateadministration. To test our central hypothesis and accomplish the objective of this application we plan to pursue the following three specific aims: 1) To determine whether the treatment of NAS with a non-opiate medication clonidine will be more effective than morphine. 2) To determine whether treatment of NAS with clonidinewill result in better early childhood outcomes than those treated with morphine. 3) To determine how infantswith NAS metabolize morphine and clonidine. With respect to expected outcomes this proposal will provideprospective evidence: a) regarding the potential of clonidine treatment to treat NAS; b) regarding how opioidand non-opioid exposure affect early childhood development; c) regarding factors that influence response totreatment. These results are expected to have an important positive impact because they have the potential toprovide fundamental information regarding the metabolic ontogeny of infants exposed to opioid drugs andmost importantly to improve the long-term outcomes of children born to addicted mothers.

project_terms:
Abstinence;Adrenergic Agonists;Affect;Aftercare;Age;Analgesics;Brain;Cells;Child;Child Behavior Checklist;Chloral Hydrate;Chronic;Clinic;Clinical;Clonidine;Cognitive;Collaborations;Data;Development;Drug Kinetics;Drug Withdrawal Symptoms;Effectiveness;Epidemic;Exposure to;Genetic;Goals;Growth;Health;Health Care Costs;Hospitals;Infant;Informal Social Control;Injury;Laboratory Study;Language;Length of Stay;Life;Metabolic;Methadone;Mission;Modeling;Morphine;Mothers;Motor;Narcotics;Neonatal;Neonatal Abstinence Syndrome;Neurons;Newborn Infant;Norepinephrine;Opioid;Opioid Receptor;Outcome;Performance;Pharmaceutical Preparations;Pharmacogenetics;Pharmacological Treatment;Pharmacology;Pharmacotherapy;Pilot Projects;Population;Pregnancy;Problem behavior;Property;Public Health;Randomized Clinical Trials;Reflex action;Reporting;Research;Stress;Testing;Time;United States National Institutes of Health;Withdrawal;Withdrawal Symptom;assault;brain size;brain volume;cost;drug withdrawal;early childhood;fetal opioid exposure;heroin use;improved;individual response;neonate;neurobehavioral;neurogenesis;non-opioid analgesic;noradrenergic;opioid exposure;opioid use;pharmacodynamic model;postnatal;prevent;prospective;response;standard of care;synaptogenesis;treatment duration;treatment optimization;treatment response

public_health_relevance:
PROJECT NARRATIVEThe proposed research is relevant to public health because it will investigate the treatment of newborn drugwithdrawal or neonatal abstinence syndrome afflicting infants born to mothers who used heroin or opioid painkillers (prescribed or non-prescribed) during pregnancy. Instead of treating infants with opioids to alleviateintense drug withdrawal symptoms the project will test the effectiveness of a non-opioid medication and inaccompanying laboratory studies it will determine how genetics and metabolic maturity of neonates affectindividual response to treatment. This study is relevant to NIH's mission because it has the potential to improvethe short- and long-term health outcomes of these neonates.


application_id: 9652914
project_number: 1R01HL146832-01
administering_ic: NHLBI
award_notice_date: 2018-12-21
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: HL
serial_number: 146832
program_official: OCHOCINSKA, MARGARET J
project_start_date: 2019-05-01
project_end_date: 2019-08-15
study_section: Special Emphasis Panel[ZRG1 MDCN-M (91)]
contact_pi_person_id: 6869069
contact_pi: LOMINADZE, DAVID
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-05-01
project_title:
Mechanisms of neurodegeneration by a fibrinogen-containing protein complex during traumatic brain injury

project_abstract:
Project SummaryThis application addresses problems related to vascular cognition impairment (VCI). Particularly it aims to definemechanisms of vasculo-astrocyte functional connectivity that results in cognitive decline after inflammatorypathologies e.g. traumatic brain injury (TBI). It is known that increased vascular permeability is involved inpathological alterations in neurovascular network such as accumulation of fibrinogen (Fg) and cellular prion protein(PrPC) leading to neuronal dysfunction and degeneration. However critical factors that initiate these effects are notknown. Our preliminary data indicated that TBI-induced an increase in blood level of Fg called hyperfibrinogenemia(HFg) and enhanced cerebrovascular permeability to proteins mainly via caveolar transcytosis. This effect causeda greater deposition of Fg and increased formation of Fg and PrPC complex in vasculo-astrocyte interface resultingin vasculo-astrocyte physical uncoupling and astrocyte activation leading to neuronal degeneration viaoverexpression of neurotrophic tyrosine receptor kinase B (TrkB) and formation of reactive oxygen species (ROS).These effects were associated with neuronal degeneration and reduction in short-term memory (STM) in mice afterTBI. Importantly treatment of mice with siRNA against caveolae membrane protein caveolin-1 (Cav-1) amelioratedTBI-induced memory reduction. Based on these data we propose a novel hypothesis that TBI-mediatedinflammation increases the blood level of Fg which via binding to endothelial ICAM-1 activates caveolar proteintranscytosis resulting in enhanced Fg deposition and formation of Fg-PrPC complex which cause astrocyteactivation vasculo-astrocyte uncoupling and subsequent neuronal degeneration (via TrkB-ROS pathway) resultingin STM reduction. This compelling hypothesis provides the crucial link between vascular dysfunction and neuronaldegeneration leading to cognition impairment during various cerebrovascular pathologies. The present studyshould reveal the fundamental previously unknown mechanism for vasculo-astrocyte uncoupling (alteredfunctional and physical connectivity) leading to neuronal degeneration and memory reduction after TBI. Thehypothesis will be tested with three specific aims: (1) To define whether the HFg-mediated caveolar proteintranscytosis enhances Fg deposition and Fg-PrPC complex formation in brain extravascular space during TBI. (2)To define whether the Fg-PrPC complex formation in vasculo-astrocyte interface causes vasculo-astrocyteuncoupling and neuronal degeneration leading to reduction in STM during TBI. (3) To define if diminishing caveolaeformation in vascular endothelium and Fg-PrPC complex formation can ameliorate neuronal degeneration and STMreduction during TBI. Specific mechanisms of TBI-induced vasculo-astrocyte uncoupling and memory impairmenti.e. VCI will be studied using cultured endothelial cells and astrocytes and C57BL/6J wild type and transgenic HFgmice. Fg-PrPC complex and ROS formations levels of TrkB astrocyte activation and neuronal degenerationassessed by NeuN will be evaluated by immunohistochemistry and Western blot. STM will be assessed by novelobject recognition test Barnes maze and Y-maze tests.

project_terms:
Address;Animals;Antisense Oligonucleotides;Astrocytes;Binding;Blood;Blood Proteins;Blood Vessels;Brain;Caveolae;Cognition;Complex;Data;Deposition;Disease;Endothelial Cells;Endothelium;Female;Fibrinogen;Hippocampus (Brain);Immunohistochemistry;Impaired cognition;Impairment;In Vitro;Inflammation;Inflammatory;Intercellular adhesion molecule 1;Link;Mediating;Membrane Proteins;Memory;Memory impairment;Morbidity - disease rate;Mus;Nerve Degeneration;Neuronal Dysfunction;Pathogenicity;Pathologic;Pathology;Pathway interactions;Patients;Permeability;Phosphorylation;PrP;Process;Proteins;Reactive Oxygen Species;Receptor Protein-Tyrosine Kinases;Research Priority;Resistance;Short-Term Memory;Signal Transduction;Small Interfering RNA;Stains;Stimulus;Testing;Transgenic Organisms;Traumatic Brain Injury;United States National Institutes of Health;Vascular Cognitive Impairment;Vascular Diseases;Vascular Endothelium;Vascular Permeabilities;Western Blotting;base;caveolin 1;cell motility;cerebral microvasculature;cerebrovascular;cerebrovascular pathology;controlled cortical impact;design;fluoro jade;in vivo;loss of function;male;mortality;neurovascular;novel;object recognition;overexpression;protein complex;transcytosis

public_health_relevance:
Project NarrativeIncreased cerebrovascular permeability is a major contributing factor to the morbidity and mortalityduring inflammatory diseases (e.g. traumatic brain injury (TBI)) that are accompanied with increasedblood content of fibrinogen (Fg). The latter increases cerebrovascular permeability deposits inextravascular space and by forming degradation resistant complex with cellular prion protein (PrPC)detaches astrocyte endfeet from vessels leading to reduction in short-term memory (STM). As weaddress mechanisms of this process the proposed study will reveal a novel pathogenic causalrelationship in TBI-induced vasculo-neuronal dysfunction and STM impairment.


application_id: 9652816
project_number: 5R25CA203637-03
project_title: Training in Interprofessional Education for Palliative Care in Oncology
administering_ic: NCI
award_notice_date: 2019-02-27
opportunity_number: PAR-15-151
application_type: 5
activity_code: R25
ic: CA
serial_number: 203637
program_official: RADAEV, SERGEY
project_start_date: 2017-03-14
project_end_date: 2022-02-28
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 8126973
contact_pi: PFEIFER, MARK P
other_pis: HEAD, BARBARA A
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/Abstract Excellent oncology care requires the close collaboration of numerous professionals. Extending andenhancing interdisciplinary care will require interprofessional education (IPE)for students which develops theirunderstanding of the strengths capabilities skills roles and cultures of other professionals and teaches thecommunication and collaboration skills essential for effective teamwork. Integration of palliative care is nowrecommended at the time of a cancer diagnosisregardless of prognosisand palliative care by its verynature requires interdisciplinary patient-centered care to meet the complex needs of oncology patients. Thisproject will develop a critical mass of competent equipped oncology educators skilled in the development andimplementation of IPE for palliative oncology care. Through faculty development webinars and materials atrain-the-trainer workshop ongoing educational activities and mentoring by experienced interprofessionaleducators 160 health science educators (representing the fields of medicine nursing social work andchaplaincy) from 35-50 institutions will develop the skills knowledge and resources to overcome barriers toIPE and teach oncology palliative care and teamwork to students of multiple disciplines. Guided by thisprojects faculty the trainees will work in interprofessional faculty teams to develop a plan for implementing anIPE curriculum in palliative oncology at their site. Trainee and institutional outcomes will be evaluated usingvalidated instruments and a pre/post-test design. A national summit on interdisciplinary palliative oncologyeducation will be held at the completion of the project; sites will share their experiences and other interestededucators will be invited to attend and present their own initiatives.

project_terms:
Accreditation;Address;Cancer Patient;Caring;Collaborations;Communication;Complex;Crowding;Development;Diagnosis;Discipline;Discipline of Nursing;Education;Educational Activities;Educational Curriculum;Educational workshop;Faculty;Future;Goals;Health Sciences;Infrastructure;Institution;Knowledge;Lead;Learning Skill;Length;Logistics;Malignant Neoplasms;Medicine;Mentors;Modeling;Nature;Nurses;Outcome;Palliative Care;Patient Care;Patient-Centered Care;Patients;Physicians;Pre-Post Tests;Program Sustainability;Quality of life;Resources;Role;Site;Social Work;Social Workers;Students;Teacher Professional Development;Time;Trainers Training;Training;Training Programs;Work;base;cancer care;cancer diagnosis;cancer education;cancer palliative treatment;design;experience;health care service utilization;improved;instrument;interest;method development;oncology;outcome forecast;palliative;patient oriented;pedagogy;practice setting;programs;science teacher;skills;student training;success;symposium;webinar

public_health_relevance:
Project Narrative (Relevance)Excellent care of patients diagnosed with cancer requires the integration of palliative care and the closecollaboration of professionals from many disciplines including physicians nurses chaplains and socialworkers. Through faculty development webinars online modules and a train-the- trainer program this projectwill train 160 health science educators to provide interprofessional education in oncology palliative care at 35-50 institutions across the nation. As a result students of the health sciences at these institutions will learn theskills and knowledge essential for providing effective team-based patient-centered palliative oncology care.


application_id: 9651537
project_number: 1R21AI142590-01
administering_ic: NIAID
award_notice_date: 2018-11-15
opportunity_number: PA-18-489
application_type: 1
activity_code: R21
ic: AI
serial_number: 142590
program_official: FERGUSON, STACY E
project_start_date: 2018-11-15
project_end_date: 2020-10-31
study_section: Genetics of Health and Disease Study Section[GHD]
contact_pi_person_id: 10517640
contact_pi: WATSON, COREY TAYLOR
other_pis: MARASCO, WAYNE A.
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-11-15
project_title:
Population level characterization of human immunoglobulin heavy chain germline variants with impacts on variability in the Ab repertoire of healthy adults

project_abstract:
Project Summary AbstractAntibodies (Abs) are a diverse family of proteins expressed by B cells and are critical components of theadaptive immune system. They are encoded by hundreds of genes at three primary immunoglobulin (IG) generegions: the IG heavy chain (IGH) locus and two light chain loci IG kappa (IGK) and IG lambda (IGL). TheIGH locus in particular has been demonstrated by us and others to exhibit extreme genetic variability at boththe individual and population levels. This extreme variation is characterized by the occurrence of singlenucleotide polymorphisms (SNPs) as well as large insertions deletions and duplications spanning tens ofthousands of kilobases and resulting in losses or gains of functional genes (copy number variants CNVs).Given its inherent locus sequence complexity and extreme genetic diversity IGH remains a difficult genomicregion to study thus little is known about the effects of IGH genetic polymorphism on the function of Abs andthe associated effects on disease pathologies and treatment outcomes. However with the advent of high-throughput sequencing approaches for profiling the expressed Ab repertoire it has become increasingly clearthat IGH genetic variants including coding and non-coding SNPs as well as CNVs likely play a role in thedeveloping Ab response and may contribute to Ab biases observed in many disease contexts. This includesexamples in cancer autoimmunity infectious disease and vaccine responsiveness. These data stronglysupport the idea that not all individuals are poised to mount the same Ab response and that this at least inpart can be attributed to IGH genetic determinants. With this in mind we propose that the integration of locus-wide IGH population genetic data can inform our understanding of the functional B cell response in diseaseprocesses and help direct better clinical care such as the design of more effective therapeutic andprophylactic strategies. However no study to date has sought to comprehensively survey IGH variants locus-wide and identify key polymorphisms contributing to variability in the expressed Ab repertoires of healthyadults. Critically for such an approach to be successful new genomic tools are required that are capable ofovercoming pitfalls associated with current approaches and that allow for the comprehensive assaying of IGHvariants locus-wide. The proposed project will seek to demonstrate the utility of novel IGH genotyping methodsto comprehensively characterize for the first time associations between germline IGH haplotype variation andsignatures in expressed antibody repertoires of healthy adult subjects. This project will yield basic insights intothe effects of IGH polymorphisms on inter-individual Ab repertoire variation with implications for the discoveryof novel genomic factors and molecular mechanisms influencing Ab repertoire development and diversity. Inaddition this work will lay a foundation for the future integration of IGH genomics into immunological studiesseeking to more fully characterize the Ab response in disease and clinical phenotypes.

project_terms:
Adaptive Immune System;Adult;Age;Alleles;Antibodies;Antibody Repertoire;Antibody Response;Antigens;Autoimmunity;B-Lymphocytes;Bioinformatics;Biological Assay;Code;Collection;Communicable Diseases;Complex;Copy Number Polymorphism;Data;Data Set;Development;Disease;Exhibits;Foundations;Frequencies;Future;Gene Dosage;Genes;Genetic;Genetic Determinism;Genetic Polymorphism;Genetic Recombination;Genetic Variation;Genome;Genomic Segment;Genomics;Genotype;Goals;Haplotypes;Health Status;Heavy-Chain Immunoglobulins;Heritability;High-Throughput Nucleotide Sequencing;Human;Human Genome;IGH@ gene cluster;IgE;Immune response;Immunogenetics;Immunoglobulin A;Immunoglobulin Class Switching;Immunoglobulin D;Immunoglobulin G;Immunoglobulin Genes;Immunoglobulin M;Immunoglobulin Somatic Hypermutation;Immunoglobulins;Immunologics;Immunology;Individual;Knowledge;Light;Malignant Neoplasms;Mediating;Methods;Mind;Molecular;Nucleic Acid Regulatory Sequences;Outcome;Pathology;Pattern;Play;Population;Population Genetics;Process;Protein Family;Proteins;Protocols documentation;Publishing;Recording of previous events;Regulatory Element;Resolution;Role;Single Nucleotide Polymorphism;Structure;Surveys;Technology;Time;Treatment Efficacy;Treatment outcome;Twin Multiple Birth;Untranslated RNA;Vaccines;Variant;Work;analysis pipeline;base;clinical care;clinical phenotype;cohort;complementarity-determining region 3;design;disease phenotype;functional gain;genetic association;genetic variant;genomic tools;improved;insertion/deletion mutation;insight;inter-individual variation;interest;kappa-Chain Immunoglobulins;novel;personalized medicine;population based;prophylactic;response;statistics

public_health_relevance:
Individual immune responses are known to track with signatures in the expressed antibody (Ab) repertoirewhich we and others have recently demonstrated robustly associate with genetic variants in theimmunoglobulin heavy chain locus (IGH); we propose that such findings have broad implications. Here weapply novel genomic tools to leverage long-read sequencing for comprehensive IGH genotyping which we useto characterize IGH variants with impacts on Ab repertoire variability in a multi-ethnic healthy adult population.This project will have outcomes with transformative impacts on B cell immunology and immunogenetics.


application_id: 9650404
project_number: 5R01HD075829-05
project_title: The development of emotion processing in infancy
administering_ic: NICHD
award_notice_date: 2019-02-11
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HD
serial_number: 075829
program_official: ESPOSITO, LAYLA E
project_start_date: 2015-04-01
project_end_date: 2021-02-28
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 8534513
contact_pi: BHATT, RAMESH S
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Emotion processing is a critical component of social functioning. Adults derive a considerable amount of emotion information from body posture and movement. In some circumstances bodies are better sources of emotion cues than faces. Yet virtually nothing is known about the development of emotion processing from body gestures. This is in contrast to a great number of studies that have examined facial emotion processing. The proposed studies are aimed at filling this gap. They will examine predictions from models of body knowledge development emotion processing and action understanding while documenting the nature of development in early infancy and examining mechanisms that drive development. Slaughter and Heron's model of body knowledge development proposes that visuospatial body knowledge is minimal early in life and slow to develop in comparison to facial knowledge. In contrast other models of body knowledge development and theories of action understanding and emotion processing envision early development of knowledge about bodies and emotions signaled by them. One set of studies will contrast these predictions. Another set of studies will address a significant debate in the emotion literature concerning whether knowledge about basic categories of emotions is available early in life. A third set of proposed studies will test the hypothesis that visual exploration capacities contribute to the development of body emotion knowledge. Another group of studies will examine the proposition that motor experience and development are associated with body emotion knowledge development. The fifth set of proposed studies originates from empirical findings and theoretical propositions suggesting that learning plays a significant role in the development of object and social perception. We will test the hypothesis that body emotion knowledge development is facilitated by learning induced by observing exemplars of emotional behavior and correlations between bodily facial and vocal emotional expressions. Thus the proposed studies will document the development of body emotion knowledge in infancy examine the role of visual exploration as an underlying mechanism of development and investigate whether motor development and observational learning contribute to this development. Many developmental disorders such as Autism are at least in part based on deficits in emotion processing. The proposed research will contribute to the analyses and treatment of such disorders by documenting the nature of emotion processing from body information in infancy and the manner in which it normally develops early in life.

project_terms:
Address;Adult;Affect;Age-Months;Age-Years;Anger;Awareness;Behavior;Categories;Conduct Disorder;Cues;Development;Disease;Emotional;Emotions;Exposure to;Face;Face Processing;Feeling;Fright;Gestures;Human;Human body;Infant;Infant Development;Intention;Knowledge;Learning;Life;Literature;Mental disorders;Modality;Modeling;Motor;Movement;Nature;Organism;Perception;Perceptual learning;Persons;Play;Posture;Psychopathology;Research;Role;Scanning;Signal Transduction;Social Functioning;Social Interaction;Social Perception;Source;Testing;Visual;Visuospatial;Walkers;Work;autism spectrum disorder;base;cognitive function;developmental disease;emotional behavior;experience;infancy;negative affect;object perception;predictive modeling;public health relevance;research study;showing emotion;social engagement;theories;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Many disorders such as Autism Spectrum Disorder and Conduct Disorder are at least in part based on deficits in emotion processing. Some of these disorders manifest themselves quite early in life while the psychopathology associated with others may be caused by developmental deficits. It is thus important to understand the development of emotion processing. The proposed research will contribute to the analysis and treatment of psychological disorders by documenting the nature of emotion processing from body information in infancy and the manner in which it normally develops early in life.


application_id: 9649377
project_number: 4R00HL129193-03
project_title: Protein S Anticoagulant Activity: Biochemical Mechanisms and Structural Studies
administering_ic: NHLBI
award_notice_date: 2018-03-22
opportunity_number: PA-14-042
application_type: 4
activity_code: R00
ic: HL
serial_number: 129193
program_official: SARKAR, RITA
project_start_date: 2015-09-15
project_end_date: 2021-03-31
study_section: NSS
contact_pi_person_id: 9231243
contact_pi: WOOD, JEREMY P
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Project Summary/Abstract Thrombosis is a leading cause of death in the United States. It is caused by excessive production of the blood clotting factor thrombin. During normal hemostasis thrombin generation is tightly regulated by several anticoagulant proteins including protein S (PS). PS is an important anticoagulant protein in humans with total deficiency producing severe life-threatening thrombosis at birth. However the biochemical mechanism(s) by which PS mediates its anticoagulant activity are poorly understood. PS is a cofactor for two other endogenous anticoagulants tissue factor pathway inhibitor alpha (TFPIa) and activated protein C (APC). PS/TFPIa inhibits coagulation factor Xa (FXa) while PS/APC proteolytically inactivates factor Va (FVa). FVa and FXa combine to form prothrombinase the powerful enzymatic complex that converts prothrombin to thrombin. Prothrombinase is resistant to inactivation by either PS/APC or PS/TFPIa during the propagation phase of blood clotting yet its activity is clearly regulated because thrombi do not spread throughout the entire vasculature during normal hemostasis. PS promotes the inactivation of both protein components of prothrombinase FVa (as an APC cofactor) and FXa (as a TFPIa cofactor) suggesting that it may modulate prothrombinase activity. We hypothesize that coordinated action of the PS/TFPIa and PS/APC anticoagulant systems will produce efficient inhibition of prothrombinase. This hypothesis will be tested via complimentary biochemical and structural studies. The K99 will focus on biochemical studies using assays established during my post-doctoral research. They will further define the mechanism by which PS enhances TFPIa inhibitory activity (Specific Aim 1.1) and determine how FXa inhibition by PS/TFPIa alters the ability of PS/APC to proteolytically inactivate FVa and vice versa (Specific Aim 1.2). The R00 will extend this work further by assessing the contribution of different physiologic membrane surfaces to the regulation of thrombin generation (Specific Aim 1.3). These functional studies will be correlated with structural studies. The K99 will focus on development of molecular models of the PS/TFPIa and PS/APC complexes (Specific Aim 2.1). The R00 will extend this work by producing crystal structures of individual domains of PS TFPIa and APC separately and in complex (Specific Aims 2.2 and 2.3). These studies will coincide with career development training which will include a focus on training in structural biology through a combination of courses and work in the laboratory of Dr. Stephen Everse. This will differentiate my work from that of my mentor and enable me to establish an independent research career studying the biochemistry of hemostatic proteins.

project_terms:
Amino Acids;Anticoagulants;Binding;Biochemical;Biochemistry;Biological;Biological Assay;Birth;Blood Coagulation Disorders;Blood Coagulation Factor;Blood Platelets;Blood Proteins;Blood coagulation;Cause of Death;Coagulation Process;Complex;Crystallization;Data;Development;Disease;Endothelial Cells;Factor Va;Factor Xa;Generations;Hemophilia A;Hemorrhage;Hemostatic Agents;Hemostatic function;Human;Individual;Injury;Laboratories;Length;Life;Lipoproteins;Mediating;Membrane;Mentors;Modeling;Molecular Conformation;Myocardial Infarction;Patients;Phase;Physiological;Plasma;Postdoctoral Fellow;Production;Property;Protein S;Proteins;Prothrombin;Regulation;Research;Resistance;Risk;Site;Stroke;Structure;Surface;System;TFPI;Testing;Thrombin;Thromboplastin;Thrombosis;Thrombus;Training;United States;Work;X-Ray Crystallography;activated Protein C;base;career;career development;cofactor;design;inhibitor/antagonist;innovation;molecular modeling;prevent;protein protein interaction;structural biology;tubulin-specific chaperone C

public_health_relevance:
Project NarrativeBlood clots are a leading cause of death in the United States every year. Protein S keeps blood from clottingbut we don't understand how it works. This project is designed to determine how protein S interacts with otherblood proteins to prevent clotting and the results will have applications for the treatment of patients withbleeding or clotting disorders.


application_id: 9648865
project_number: 1R21AG061551-01
project_title: Novel misfolded proteins in ADRD: proteomics genetics and clinical-pathological correlations
administering_ic: NIA
award_notice_date: 2019-04-02
opportunity_number: PA-18-489
application_type: 1
activity_code: R21
ic: AG
serial_number: 061551
program_official: PETANCESKA, SUZANA
project_start_date: 2019-04-15
project_end_date: 2021-01-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
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:
The heterogeneous pathologies of Alzheimer's disease and related dementias (ADRD) are stillincompletely understood. There is no perfect animal model to study these diseases. Four known aberrantlymisfolded proteins are commonly detected via neuropathologic examination of brains with ADRD: A TauTDP-43 and/or -Synuclein. Our preliminary data indicate that there are more pathogenic proteinspecies awaiting identification. Characterization of these proteins may be relevant to the development ofboth diagnostic and therapeutic strategies for ADRD. The goals of this research project are to identifypreviously uncharacterized misfolded and aberrantly processed proteins in ADRD; to resolve gene variantsthat modulate the severity and heterogeneity of dementia through the novel misfolded proteins; and toperform clinical-pathological correlation focusing on these novel proteins to identify new disease-associatedpathologic biomarkers. We will leverage the resources of the University of Kentucky AD Center (UK-ADC)biobank and the University of Kentucky Proteomics Core Facility to execute the following Specific Aims:Specific Aim 1. Analyse detergent-insoluble protein extracts from human amygdala (snap-frozenat autopsy) to investigate whether as yet uncharacterized misfolded proteins are detectable in ADRD.Polypeptides from the detergent-insoluble urea-soluble protein fractions of amygdala will be interrogatedusing mass spectrometry. We have on-hand amygdalae from 40 UK-ADC subjects which incorporate aspectrum of clinical and pathologic features. Immunohistochemistry and biochemical studies will beperformed to determine the best candidate proteins for additional studies (Aims 2 and 3). Specific Aim 2. Construct a robust and harmonized database with exonic sequencing to localizegenetic regions associated with novel misfolded proteins in ADRD. We will test the association betweendementia and rare exonic (`mis-sense') genetic variants in genes that encode candidate misfolded proteins(Aim 1). Genetics data augmented with rich neuropathologic endophenotypes and longitudinal clinical data willenable insights into novel mechanisms that drive dementia. Large-scale datasets (NACC ADGC ADSP) willbe aggregated and harmonized to test the genetic drivers of clinical and neuropathology-basedendophenotypes focusing on novel candidate genes. Candidate target genes have already been identified. Specific Aim 3. Establish the clinical-pathologic correlation for the novel misfoldedproteinopathies in ADRD. We will test the association between the potential novel proteinopathies (fromAim 1) with cognitive impairment factoring in known markers A tau -Synuclein and TDP-43 as well ascerebrovascular pathologies. We have 370 samples available for analyses (both sexes) from the UK-ADCwhich should be statistically powered to test our hypothesis that the presence and severity of novelmisfolding protein pathologies are associated with cognitive impairment.

project_terms:
Age;Alzheimer's disease related dementia;Amygdaloid structure;Amyloid beta-Protein;Animal Model;Automobile Driving;Autopsy;Biochemical;Biochemistry;Biological Markers;Brain;Brain Diseases;Candidate Disease Gene;Cessation of life;Chromosome Mapping;Clinical;Clinical Data;Core Facility;Correlation Studies;Data;Data Set;Databases;Dementia;Detergents;Development;Diagnostic;Disease;Education;Elderly;Electrospray Ionization;Freezing;Funding Mechanisms;Future;Genes;Genetic;Genetic study;Genie;Genomics;Goals;Hand;Heterogeneity;Human;Image;Immunohistochemistry;Impaired cognition;Impairment;Individual;Kentucky;Knowledge;Liquid Chromatography;Mass Spectrum Analysis;Mutation;Neurodegenerative Disorders;Neurofibrillary Tangles;Pathogenicity;Pathologic;Pathology;Persons;Process;Proteins;Proteome;Proteomics;Public Health;Reporting;Research;Research Project Grants;Sampling;Seasons;Series;Severities;Statistical Data Interpretation;Statistical Models;Testing;Therapeutic;Universities;University resources;Urea;Work;aged;aging brain;alpha synuclein;base;biobank;cerebrovascular pathology;clinical Diagnosis;cohort;demented;endophenotype;frontotemporal lobar dementia-amyotrophic lateral sclerosis;genetic risk factor;genetic variant;insight;misfolded protein;multidisciplinary;neuropathology;novel;polypeptide;protein TDP-43;protein misfolding;sex;synuclein;tandem mass spectrometry;tau Proteins

public_health_relevance:
Project NarrativeAlzheimer's disease and related dementias are an enormous public health problem. Itis challenging to develop optimal diagnostic or therapeutic strategies because we havenot yet identified the full spectrum of misfolded proteins that commonly underlie theclinical state of dementia. Here we plan to perform a study that identifies a list ofmisfolded proteins in dementia that is more comprehensive than ever before as anecessary prerequisite for future work aimed at finding cures.


application_id: 9648153
project_number: 5R01EY012716-20
project_title: Circuit Assembly in the developing thalamus
administering_ic: NEI
award_notice_date: 2019-04-02
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: EY
serial_number: 012716
program_official: GREENWELL, THOMAS
project_start_date: 2001-05-01
project_end_date: 2022-02-28
study_section: Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section[SPC]
contact_pi_person_id: 1864719
contact_pi: GUIDO, WILLIAM
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractThe thalamic reticular nucleus (TRN) is a shell like structure that surrounds the dorsal thalamus and serves asa key inhibitory interface for the bidirectional signaling between thalamus and the neocortex. Together withinputs from thalamus cortex and cholinergic nuclei of brainstem and basal forebrain the TRN regulates manyaspects of sensory motor and cognitive processing. When the connections between these structures aredisrupted by disease degeneration or trauma they have devastating consequences. In fact many adult andchildhood neurological disorders have at their core a disturbance in TRN signaling and circuitry. Despite itskey role in thalamocortical function remarkably little is known about how reticular circuitry emerges duringdevelopment and becomes operational. To address this substantive gap in knowledge we developed a robustmouse model as an experimental platform to visualize manipulate and dissect emergent and developingreticular circuitry. We plan to conduct anatomical electrophysiological and optogenetic experiments ingenetically modified mice that allow for the visualization and experimental manipulation of specific cell typesarising from the TRN first-order thalamic sensory nuclei layer VI of cortex and cholinergic nuclei of brainstemand basal forebrain. The goals of this proposal focus on three unanswered questions about TRN development.First how are the sensory sectors of TRN established; do inputs from primary sensory thalamic nuclei andcorresponding regions of cortex innervate TRN diffusely and then segregate to form modality specificdomains? Second what is the sequence and pattern of driver and modulator innervation of TRN; do driver-likeinputs from sensory thalamic nuclei such as the dorsal lateral geniculate nucleus arrive prior to modulatoryinput from cortex or brainstem and basal forebrain? Third how and when do feed-forward and feedbackcircuits linking TRN to thalamus and cortex emerge during development to control thalamocortical signaling?Finally for each of these questions we plan to take a loss of function approach to assess whether the absenceof sensory input (vision) affects the development form and function of reticular circuitry. These studies willprovide valuable information about the organizing principles that guide the emergence of reticular circuitry inthe neonatal brain and perhaps reveal a new understanding into childhood disorders that result from abnormalpatterns of connectivity.

project_terms:
Acute;Address;Adult;Affect;Anatomy;Area;Attention;Attention Deficit Disorder;Axon;Biological Models;Brain;Brain Stem;CRH gene;Cell Differentiation process;Cell Nucleus;Childhood;Childhood Neurological Disorder;Cognitive;Conscious;Deafferentation procedure;Decision Making;Development;Development Plans;Diffuse;Disease;Dorsal;Electrophysiology (science);Epilepsy;Failure;Feedback;Gap Junctions;Generations;Genetic;Glutamates;Goals;Imagery;In Vitro;Injections;Knowledge;Lateral Geniculate Body;Light;Link;Modality;Motor;Mus;Nature;Neocortex;Neurons;Pathway interactions;Pattern;Play;Preparation;Reporter;Retinal Ganglion Cells;Role;Schizophrenia;Sensory;Series;Signal Transduction;Sleep;Sleep Disorders;Slice;Source;Structure;Synapses;Testing;Thalamic Nuclei;Thalamic structure;Tomatoes;Trauma;Viral;Vision;Visual;Visual Cortex;Wakefulness;autism spectrum disorder;awake;basal forebrain;basal forebrain cholinergic neurons;cell type;cellular development;cholinergic;cognitive function;developmental disease;experimental study;in vivo;insight;loss of function;mouse model;mutant;neonatal brain;nerve supply;nervous system disorder;optogenetics;postnatal;postsynaptic;response;retinogeniculate;sensory input

public_health_relevance:
NarrativeThe TRN is a critical nexus between thalamus and cortex and the connections betweenthese structures are essential for many aspects of sensory and motor processing as wellas the generation of synchronous rhythms that define different levels of consciousness.When these connections are disrupted by a developmental anomaly disease or traumathey have devastating consequences and lie at the core of many childhood and adultdisorders including epilepsy sleep disorders schizophrenia autism and attention deficitdisorders. Thus these studies will provide valuable information about how thedeveloping brain forms precise patterns of connections and offer further insight into thestudy and treatment of developmental and neurological disorders that result from theformation of abnormal patterns of connectivity.


application_id: 9646307
project_number: 5R01AG034389-10
project_title: Function of ceramide in neurodegenerative disease
administering_ic: NIA
award_notice_date: 2019-02-14
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AG
serial_number: 034389
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2010-09-01
project_end_date: 2021-02-28
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:
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized by progressive neurodegeneration and build-up of A peptides amyloid plaques and neurofibrillary tau tangles. Current strategies to prevent A formation or secretion are not successful. Preventing A build-up while enhancing A uptake and clearance is an alternative approach to minimize the effect of A peptides. A critical barrier to progress in the development of novel drugs that prevent A build-up and improve clearance is the lack of a thorough understanding of how A amyloid plaques are nucleated and proliferate instead of A being taken up and cleared by glial cells. Our goal is to interrupt amyloid plaque nucleation and propagation to enhance A clearance and delay the onset and reduce neurodegeneration in AD. Our central hypothesis is that ceramide-enriched exosomes secreted by astrocytes form complexes with A (A/Exos) that function as "seeds" to catalyze nucleation and propagation of neurotoxic plaques instead of facilitating A transport and clearance by microglia. Secretion aggregation and neurotoxicity of A/Exos is enhanced by elevation of ceramide levels in particular by neutral sphingomyelinase 2 (nSMase2) an enzyme generating ceramide when activated by A. Drug (e.g. nSMase2 inhibitor)-induced reduction of ceramide will prevent A/Exo build-up/spreading and protect neurons which is a novel treatment option for AD. Our objectives are to 1) test key regulatory factors that control secretion of exosomes and their association with A; 2) test a novel molecular mechanism by which A/Exos induce plaque formation tau hyperphosphorylation and neuronal cell death; 3) test pharmacological drugs that prevent exosome secretion A/Exo-induced plaque formation tau hyperphosphorylation and neuronal cell death in vitro and in vivo; and 4) test if A/Exos in serum and cerebrospinal fluid from AD model mice and AD patients can be used as a novel diagnostic tool for monitoring plaque and tangle build-up and treatment success. Our expected outcomes include 1) determining an exosome composition that induces association with A plaque nucleation and propagation tau hyperphosphorylation and neuronal cell death; 2) identifying ceramide- modulating drugs that prevent A/Exo-induced plaque formation tau hyperphosphorylation and neuronal cell death; and 3) defining a level of A/Exos in serum that indicates severity of AD and success of treatment. The impact of this project on public health will include knowledge needed for the development of new strategies and treatments that could delay and reduce the onset of progressive neurodegeneration in AD. We will test by which mechanism ceramide promotes association and aggregation of A42 (Aim 1) how A42/Exos induce plaque formation and neurodegeneration (Aim 2) and which treatment prevents exosome-induced amyloid aggregation plaque formation and AD pathology (Aim 3).

project_terms:
Alzheimer's Disease;Alzheimer's disease model;Amyloid;Amyloid beta-Protein;Apoptosis;Apoptotic;Astrocytes;Behavior;Binding;Brain;Brain Diseases;Ceramides;Cerebrospinal Fluid;Cholesterol;Complex;Development;Disease Progression;Enzymes;Genetic;Goals;Impaired cognition;In Vitro;Interruption;Knowledge;Lipids;Mediating;Microglia;Molecular;Monitor;Nerve Degeneration;Neurodegenerative Disorders;Neurofibrillary Tangles;Neuroglia;Neurons;Outcome;PAWR protein;Pathology;Patients;Peptides;Pharmaceutical Preparations;Pharmacology;Proliferating;Prostate;Public Health;Seeds;Senile Plaques;Serum;Severities;Sphingomyelinase;Testing;Vesicle;amyloid peptide;exosome;improved;in vivo;inhibitor/antagonist;mouse model;neurofibrillary tangle formation;neuron loss;neurotoxic;neurotoxicity;novel;novel diagnostics;novel marker;novel therapeutics;prevent;progressive neurodegeneration;public health relevance;response;small molecule;success;tau Proteins;tau aggregation;tau phosphorylation;tool;treatment strategy;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Development of novel drugs to treat Alzheimer's disease (AD) by preventing amyloid plaque formation and neurodegeneration is being impeded by lack of knowledge of how neurotoxic plaques are nucleated and propagated. Our goal is to interrupt amyloid plaque nucleation and propagation to enhance amyloid peptide clearance and delay the onset and reduce neurodegeneration in AD. The impact of this project on public health will include knowledge needed for the development of new strategies and treatments that could delay and/or reduce the onset of progressive neurodegeneration in Alzheimer's disease.


application_id: 9646047
project_number: 1K99DE028346-01
project_title: Polymicrobial Synergy between Treponema denticola and Porphyromonas gingivalis
administering_ic: NIDCR
award_notice_date: 2018-09-17
opportunity_number: PA-18-398
application_type: 1
activity_code: K99
ic: DE
serial_number: 028346
program_official: FRIEDEN, LESLIE A
project_start_date: 2018-09-17
project_end_date: 2020-08-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 11206459
contact_pi: MILLER, DANIEL PATRICK
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryPolymicrobial communities that exhibit synergistic pathogenicity cause periodontal disease one of the mostcommon infections of humans. As a model system for the study of polymicrobial synergy we are investigatingthe interactions of Treponema denticola and Porphyromonas gingivalis. Heterotypic communities develop asphysiologically compatible organisms modulate their own and their partners physiology resulting in enhancedfitness and virulence. Synergistic metabolism can reduce the nutrient requirements of the entire communitythereby increasing the pathogenic potential. T. denticola and P. ginigvalis display metabolic cross-feeding toenhance the growth of both bacteria. Additional bacterial members of the subgingival plaque community areknown to cooperate in metabolic exchanges. However the molecular details of metabolic cross-feeding and howit functions to drive pathogenicity are understudied. The overall premise of this study is to characterize themetabolic interactions between T. denticola and P. gingivalis to better understand the pathogenic potential of thecommunity. Aim 1 will evaluate how glycine is acquired and utilized as a carbon and energy source. Aim 2 willcharacterize the response of T. denticola to mutualistic metabolism by enhancing biofilm development andinvasion into gingival epithelial cells. Aim 3 will demonstrate that metabolic cross-feeding enhances thepathogenicity of T. denticola. Our overall long-term goal is to translate these novel molecular mechanisms intothe development of future therapeutic approaches targeting polymicrobial pathogenic communities. Thecandidate Dr. Miller has a longstanding interest in the microbiology of periodontal diseases. After completingthe mentored (K99) phase his goal is to become an assistant professor at a leading research university wherehe plans to continue his research on interbacterial interactions that promote periodontal diseases. This K99/R00proposal is designed to complement Dr. Millers previous research expertise and provide him with the opportunityto develop the necessary skills and experiences to become an independent research scientist. Dr. Miller willreceive additional training under the guidance of the primary mentor Dr. Richard Lamont and co-mentor Dr.David Scott. Both mentors were carefully selected for as they each contribute diverse yet complementaryexpertise for the successful completion of this research program. Additionally Dr. Miller has assembled acommittee of scientists with various backgrounds who will provide oversight and advise his scientific and careerdevelopment during his transition to independence.

project_terms:
Adherence;Alveolar Bone Loss;Bacteria;Biological Models;Carbon;Catabolism;Cell model;Cells;Chemotaxis;Communication;Communities;Community Developments;Complement;Complex;Development;Disease;Disease model;Energy-Generating Resources;Environment;Epithelial Cells;Exhibits;Future;Gingiva;Glycine;Goals;Growth;Human;Immune response;Infection;Inflammatory;Investigation;Link;Mediating;Mentors;Metabolic;Metabolism;Microbial Biofilms;Microbiology;Modeling;Molecular;Movement;Mus;Nutritional Requirements;Organism;Outcome;Pathogenicity;Periodontal Diseases;Periodontitis;Phase;Phenotype;Physiological;Physiological Processes;Physiology;Porphyromonas gingivalis;Research;Rodent Model;Role;Scientist;Signal Transduction;Signal Transduction Pathway;Source;Symbiosis;System;Therapeutic;Training;Translating;Treponema denticola;Universities;Virulence;bone loss;career development;cell motility;design;dysbiosis;experience;feeding;fitness;improved;in vivo;insight;interest;member;microbial community;novel;novel strategies;novel therapeutics;pathogen;polymicrobial disease;prevent;professor;programs;response;skills;synergism;uptake

public_health_relevance:
Project NarrativePeriodontal diseases are one of the most common infections of humans and are the result of several compatiblebacterial species working synergistically to cause more severe disease. The goal of this study is to examinecooperative metabolism between two periodontal pathogens that promotes synergistic pathogenicity.Understanding polymicrobial metabolic communication and signaling is critical to development of noveltherapeutics or approaches to prevent polymicrobial diseases.


application_id: 9645642
project_number: 5R21HD091118-02
project_title: A Low-cost Compact Diffuse Speckle Contrast Flow-oximeter for Neonatal Brain Monitoring
administering_ic: NICHD
award_notice_date: 2019-01-28
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: HD
serial_number: 091118
program_official: WALSH, MICHELE CATHERINE
project_start_date: 2018-02-10
project_end_date: 2022-01-31
study_section: Special Emphasis Panel[ZRG1-SBIB-H(82)]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
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: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTAlthough significant progress has been made in neonatal intensive care units preterm infants continue to sufferfrom significant morbidities and comorbidities such as hypoxia-ischemia intraventricular hemorrhage and whitematter injury/periventricular leukomalacia. For example 65-85% of extreme preterm infants ( 28 weeks ofgestational age) have patent ductus arteriosus (PDA) at first week of life which leads to shunting of bloodbetween the systemic and the pulmonary circulations. Because of many complications associated with PDA themajority of extreme preterm infants receive medical or surgical therapy in an attempt to close the PDA. HoweverPDA and associated treatment procedures may cause large perturbations in cerebral hemodynamics andmetabolism thus impacting neonatal brain health. Currently there is no clinically accepted quantitative monitorfor continuous bedside assessment of neonatal brain health. We propose to develop and test a near-infrareddiffuse speckle contrast flow-oximeter (DSCFO) which will enable simultaneous quantification of cerebral bloodflow (CBF) cerebral blood oxygen saturation (StO2) and cerebral metabolic rate of tissue oxygen consumption(CMRO2) in infants' brains. The DSCFO uses two small laser diodes at different wavelengths (690 nm and 830nm) and a tiny bare complementary metal-oxide semiconductor (CMOS) sensor chip with no lenses to rapidlyquantify spatial diffuse speckle fluctuations resulting from moving red blood cells for CBF measurements inrelatively deep tissues (up to 8 mm). Alternative measurements of light intensity changes at the two wavelengthswill enable quantification of StO2 variations. Knowing CBF and StO2 together will allow for the derivation ofCMRO2. Compared to conventional near-infrared diffuse optical technologies DSCFO is an innovative designwith significantly lower cost (<$2500) a faster sampling rate (milliseconds) more detection channels on the high-resolution CMOS pixel array and a smaller probe (25 mm x 15 mm) which is particularly applicable to cerebralmonitoring in the small heads of newborn infants. In Specific Aim 1 the proposed DSCFO device will beconstructed and calibrated in head-simulating tissue phantoms and adults' forearms against other establishedstandards. In Specific Aim 2 the calibrated DSCFO device will be further examined in clinic to measure CBFStO2 and CMRO2 in preterm infants with PDA undergoing indomethacin treatment. We hypothesize thatneonatal cerebral hemodynamics/metabolism altered by the PDA and treatment can be detected by the DSCFOwhich should reasonably correlate with other physiological measures and clinical outcomes. The measurementof multiple cerebral hemodynamic/metabolic variables together (i.e. CBF StO2 and CMRO2) is expected toprovide better assessment of neonatal brain health than a single parameter alone which may help optimizepatient care and reduce adverse cerebral impacts. Furthermore the DSCFO has the potential to be used forcerebral diagnosis and therapeutic monitoring of many other diseases in infants (e.g. hypoxic/ischemic injuryshock/hypotension intermittent hypoxemia).

project_terms:
Adult;Affect;Algorithms;Anemia;Biological Markers;Blood;Blood Pressure;Blood gas;Brain;Brain Hypoxia-Ischemia;Cerebrovascular Circulation;Cerebrum;Charge;Child;Clinic;Clinical;Comorbidity;Coupled;Critical Illness;Data;Derivation procedure;Detection;Development;Devices;Diagnosis;Diffuse;Disease;Dose;Echocardiography;Erythrocytes;Flowmeters;Forearm;Forehead;Gestational Age;Head;Hemoglobin;Heterogeneity;Hour;Hybrids;Hypotension;Hypoxemia;Hypoxia;Impairment;Indomethacin;Infant;Infusion procedures;Injury;Intravenous;Laboratories;Lasers;Life;Measurement;Measures;Medical;Metabolic;Metabolism;Methods;Monitor;Morbidity - disease rate;Morphologic artifacts;Near-Infrared Spectroscopy;Neonatal;Neonatal Intensive Care Units;Nervous System Trauma;Neurologic;Neurons;Newborn Infant;Operative Surgical Procedures;Optics;Outcome;Oxygen;Oxygen Consumption;Patent Ductus Arteriosus;Patient Care;Patients;Periventricular Leukomalacia;Periventricular white matter injury;Pharmacological Treatment;Physiological;Premature Infant;Procedures;Process;Pulmonary Circulation;Research;Resolution;Risk;Sampling;Scalp structure;Semiconductors;Shock;Spectrum Analysis;Structure;Techniques;Technology;Testing;Therapeutic;Tissues;Variant;blood flow measurement;brain health;cerebral hemodynamics;clinical practice;cost;design;hemodynamics;high risk;in vivo;innovation;interest;interpatient variability;intraventricular hemorrhage;lens;light intensity;metabolic rate;metal oxide;middle cerebral artery;millisecond;neonatal brain;novel;portability;premature;sensor;tissue oxygenation;tissue phantom;treatment effect

public_health_relevance:
PROJECT NARRATIVEThe objective of this project is to develop and test a noninvasive low-cost fast continuous and portable near-infrared diffuse speckle contrast flow-oximeter (DSCFO) device which will enable simultaneous quantification ofcerebral blood flow (CBF) cerebral blood oxygen saturation (StO2) and cerebral metabolic rate of tissue oxygenconsumption (CMRO2) in the infant' brain. This device will be examined in the neonatal intensive care unit forthe continuous monitoring of cerebral hemodynamic and metabolic variations in preterm infants with patentductus arteriosus undergoing indomethacin treatment. This pilot research will provide key information to validatethe DSCFO device for clinical use and demonstrate its potential to provide prompt biomarkers for evaluatingneuronal brain health and subsequent management of critically ill infants who are at highest risk for developingneurological morbidities.


application_id: 9645119
project_number: 5P40OD019794-05
project_title: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2019-01-29
opportunity_number: PAR-14-005
application_type: 5
activity_code: P40
ic: OD
serial_number: 019794
program_official: CONTRERAS, MIGUEL A
project_start_date: 2015-03-01
project_end_date: 2020-02-29
study_section: Special Emphasis Panel[ZRG1-BBBP-Y(45)R]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application seeks support to continue operations of the Ambystoma Genetic Stock Center (AGSC) at the University of Kentucky. The AGSC maintains a historically significant collection of Mexican axolotls (Ambystoma mexicanum) an endangered species that provides living materials in support of biomedical research nationally and internationally. Most notably axolotls are studied because they are unique among vertebrates in being able to regenerate numerous tissues and body parts. These include the spinal cord limbs jaw retina brain heart and tail all of which can be regenerated at any poit during embryonic larval and adult life. Also axolotls are used by researchers that work in many additional areas including neurobiology ecotoxicology development physiology cell biology genetics genomics and evolution. Over the next 5 years the AGSC will implement a new resource management plan to better ensure long-term sustainability of axolotl stocks and move each year towards greater self- sufficiency. This will be accomplished by providing high quality stocks that the community has come to depend upon increasing production and distribution of axolotls and offering new products and services. In particular the AGSC will offer a microinjection service to assist investigators in the creation of transgenic axolotls. The AGSC will continue to serve as an informatics hub where investigators obtain information about the collection technical procedures potential collaborators and research findings. Overall the project will ensure distribution and long-term sustainability of axolotl resources to NIH-funded investigators.

project_terms:
Adolescent;Adult;Advisory Committees;Ambystoma;Ambystoma mexicanum;Applied Research;Area;Behavior;Biological;Biomedical Research;Body part;Brain;Breeding;Cells;Cellular biology;Collection;Communities;Community Services;Computers;Custom;Data;Development;Embryo;Embryonic Development;Ensure;Equipment;Evolution;Funding;Genes;Genetic;Genome;Genomics;Health;Heart;Hour;Human;IACUC;Informatics;Infrastructure;Injections;Institution;International;Jaw;Kentucky;Knock-in;Life;Limb structure;Methods;Microinjections;Mission;Modeling;Monitor;Natural regeneration;Neurobiology;Organ Model;Organism;Physiology;Population;Preparation;Procedures;Production;Protocols documentation;Research;Research Personnel;Research Support;Resources;Retina;Services;Site;Site-Directed Mutagenesis;Speed;Spinal Cord;System;Tail;Time;Tissues;Transgenic Organisms;Translating;United States National Institutes of Health;Universities;Vertebrates;Visit;Work;animal resource;base;experience;gene function;innovation;knowledge base;learning strategy;meetings;operation;organ regeneration;public health relevance;tissue repair;transcription activator-like effector nucleases;web site

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Living stock resources are needed for the Mexican axolotl so that biomedical investigators can translate biological information to humans. The Mexican axolotl is a primary vertebrate model for organ regeneration tissue repair and post--- embryonic development.


application_id: 9645050
project_number: 5R21CA216447-02
project_title: Investigation of a lectibody targeting tumor-associated oligomannose glycans
administering_ic: NCI
award_notice_date: 2019-01-15
opportunity_number: PAR-16-176
application_type: 5
activity_code: R21
ic: CA
serial_number: 216447
program_official: HARRIS, RAYMOND D
project_start_date: 2018-02-08
project_end_date: 2022-01-31
study_section: ZCA1-RTRB-U(J1)
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThe major goal of this NCI Clinical and Translational R21 application is to reveal the cancer therapeutic anddiagnostic potentials of a novel antibody-like chimeric fusion protein Avaren-Fc lectibody (AvFc) in mousetumor models. AvFc consists of the high mannose glycan (HMG)-specific lectin Avaren and the fragmentcrystallizable (Fc) region of human immunoglobulin (Ig)G1. Recent studies have revealed that HMGs areelevated on the cell surface glycome of various tumors. In normal cells these glycans are processed into morecomplex forms in the endomembrane system and therefore rarely found on cell surface. Hence HMGs mayprovide a new target for cancer therapy and/or diagnosis. However there is currently no agent selectivelytargeting tumor-associated HMGs.Our preliminary data showed that AvFc is capable of binding to a broad spectrum of cancer cell lines includingleukemia melanoma and lung breast colon and cervical cancers but not to noncancerous human cells.Additionally AvFc exhibited strong antibody-dependent cell-mediated cytotoxicity activity against variouscancer cells tested. AvFc showed good safety profiles in mice upon repeated systemic administration. LastlyAvFc is efficiently bioproduced in tobacco plants using a plant virus vector. Given these promisingdevelopability profile we hypothesize that AvFc could be developed as a first-in-class cancer therapeuticand/or diagnostic agent targeting tumor-associated HMGs.To prove this hypothesis we propose two specific aims in this application. In Aim 1 we will investigate AvFc'santi-tumor activity in murine tumor challenge models. We will use well-established syngeneic and human tumorxenograft models to determine the effectiveness of AvFc. In Aim 2 we will employ dynamic positron emissiontomography scan and radiolabeled AvFc to determine their in vivo biodistribution and tumor specificity in mice.Additionally we will attempt to isolate and identify tumor cell-surface glycoproteins targeted by AvFc using aproteomics approach. Results generated in this project will provide a compelling preclinical data package forthe development of AvFc as a novel therapeutic and/or diagnostic agent targeting tumor-associated HMGs.Additionally our data will provide a new basis and a unique tool to investigate the as-yet-unknown roles andmechanisms of elevated HMGs in tumors.

project_terms:
Affinity;Affinity Chromatography;Antibodies;Binding;Biochemical;Biodistribution;Biological Assay;Biological Markers;Cancer Detection;Cancer cell line;Carbohydrates;Cell surface;Cells;Chimeric Proteins;Clinical;Colon Carcinoma;Complement 1q;Complex;Data;Development;Diagnosis;Diagnostic;Effectiveness;Emission-Computed Tomography;Exhibits;Glycocalyx;Glycoproteins;Goals;Human;ITGAM gene;IgG1;Immunoglobulins;In Vitro;Investigation;Label;Laboratories;Lectin;Lesion;Link;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Mannose;Mass Spectrum Analysis;Mediating;Melanoma Cell;Membrane Glycoproteins;Modeling;Molecular;Mus;Mutation;Normal Cell;Oligosaccharides;Pattern;Plant Viruses;Plants;Polysaccharides;Positron-Emission Tomography;Process;Proteomics;Radiolabeled;Recombinant Proteins;Research;Role;SCID Mice;Safety;Series;System;Techniques;Testing;Therapeutic;Therapeutic Effect;Tobacco;Toxic effect;Transplantation;Tumor Burden;Tumor-Associated Carbohydrate Antigens;Variant;Wild Type Mouse;X-Ray Computed Tomography;Xenograft Model;anti-cancer;anti-cancer therapeutic;antibody-dependent cell cytotoxicity;anticancer activity;base;bioimaging;cancer cell;glycosylation;imaging potential;imaging probe;in vivo;leukemia;malignant breast neoplasm;manufacturability;melanoma;microPET;mouse model;mutant;nanomolar;neoplastic cell;novel;novel therapeutics;pre-clinical;targeted agent;targeted cancer therapy;tool;tumor;tumor specificity;tumor xenograft;vector

public_health_relevance:
NARRATIVEThe goal of this project is to investigate the therapeutic and diagnostic potential of a novel recombinant proteinAvaren-Fc which targets a unique carbohydrate biomarker found on a broad spectrum of cancer cells. We willemploy preclinical mouse tumor challnege models in vivo bioimaging techniques and biochemical assays toreveal Avaren-Fc's anti-cancer activity and tumor specificity.


