# projects

application_id: 10417277
project_number: 1S10OD032256-01
project_title: SARRP with Cone Beam CT and bioluminescence imaging guidance
administering_ic: OD
award_notice_date: 2022-07-21
opportunity_number: PAR-21-126
application_type: 1
activity_code: S10
ic: OD
serial_number: 032256
program_official: LI, XIANG-NING
project_start_date: 2022-08-01
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZRG1 SBIB-A (31)]
contact_pi_person_id: 15707821
contact_pi: CHEEK, DENNIS ALLEN
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
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 title: SARRP with Cone Beam CT and bioluminescence imaging guidanceProject Summary/AbstractThe proposed acquisition of the Xstrahl Life Sciences 200 Small Animal Radiation Instrument a small animalradiation research platform (SARRP) will provide new capabilities for 3D bioluminescent optical imaging at theUniversity of Kentucky to meet the needs of 16 NIH-funded investigators whose research programs have acritical need for instrumentation that is capable of delivering highly conformal radiation from multiple angles topreclinical small animal models with image guidance for a dose distribution mimicking clinical radiotherapy.The SARRP system from Xstrahl is able to provide precise irradiation to a small animal from multiple non-coplanar angles. In addition features such as integrated computed tomography (CT) as well as bioluminescenttomography (BLT) provide precise geometric and biological information about the tumor allowing basicscientists to better model delivery of radiation therapy that is used clinically as well as to monitor the effects ofradiation therapy non-invasively. The instrument offers high precision in preclinical radiation therapy treatmentwhich enables a higher dose to the tumor with lower dose to organs at risk with demonstrated high localcontrol less toxicity and the potential to translate advanced new high-precision findings to increased overallsurvival in clinical practice. This instrument platform to be housed in a shared use facility in the University ofKentuckys Department of Toxicology and Cancer Biology addresses a strong need for cancer biologyresearchers to mimic clinical radiotherapy treatment and will support 23 active grants (21 funded by the NIH)all of which involve the use of radiation. Importantly the new instrument capabilities offered by the SARRP willreplace two aging radio-isotopic (Cesium) based irradiators that are at the end of their useful life stage and thatpose a security risk. These systems lack an effective means for targeted radiation delivery. Thus the newinstrument will provide superior precision beam targeting for significantly enhanced research results. Theuniversity also has a kV x-ray boxed system for radiation research. However this system is completelyinadequate for modern research discovery as it lacks the capability to deliver an angled beam and hastherefore been used primarily for cell irradiation. The addition of this Xstrahl instrument will greatly enhancecancer biology research within the University of Kentuckys National Cancer Institute-designated CancerCenter which encompasses large numbers of members with expertise in cancer biology and radiationresearch. Thirteen major users with 19 R01 or equivalent grants and three minor users will form the initial userbase for the SARRP. Detailed outreach plans will also be established to attract more researchers to use thisinstrument. University of Kentucky has made a significant institutional commitment to ensure the successfuluse of the device after its installation thereby ensuring operational continuity of high-end cancer research andthe latest technology in small animal irradiation.

project_terms:
3-Dimensional;Address;Aging;Animal Model;Animals;Biological;Biological Sciences;Cancer Biology;Cancer Center;Cells;Cesium;Clinical;Conformal Radiotherapy;Devices;Dose;Ensure;Funding;Grant;Isotopes;Kentucky;Life;Minor;Modeling;Modernization;Monitor;National Cancer Institute;Organ;Radiation;Radiation therapy;Radio;Research;Research Personnel;Risk;Roentgen Rays;Scientist;Security;System;Technology;Toxic effect;Toxicology;Translating;United States National Institutes of Health;Universities;X-Ray Computed Tomography;anticancer research;base;bioluminescence imaging;clinical practice;cone-beam computed tomography;image guided;instrument;instrumentation;irradiation;member;optical imaging;outreach;pre-clinical;programs;radiation delivery;radiation effect;tomography;tumor

public_health_relevance:
Precise delivery of radiation dose under image guidance have shown a much-improved local control andoverall survival in clinical treatment. The preclinical radiation research thus requires an image-guidedirradiator that can mimic clinical dose distributions to make their result more relevant to clinical practice. TheSARRP with CBCT and BLT guidance will help a large group of researchers at our institution to design animalirradiation experiments that can best replicate clinical radiation therapy and bring their findings closer toclinical translation.


application_id: 10417246
project_number: 5R21AI155824-02
project_title: Dissemination of intracellular and extracellular Listeria from the gut
administering_ic: NIAID
award_notice_date: 2022-05-17
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AI
serial_number: 155824
program_official: BAQAR, SHAHIDA
project_start_date: 2021-06-04
project_end_date: 2025-05-31
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 2545336
contact_pi: D'ORAZIO, SARAH E. F.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Foodborne transmission of the facultative intracellular bacterial pathogen Listeria monocytogenes (Lm)results in human disease that ranges in severity from mild gastroenteritis to life-threatening septicemia ormeningoencephalitis. The host and bacterial factors that determine disease severity are not well definedand our understanding of the intestinal phase of listeriosis in particular is severely limited. To address thisknowledge gap we developed a mouse model of foodborne Lm infection that closely mimics all phases ofthe human disease. In preliminary studies we found that the majority of Lm in the gut were extracellularand that Lm was not able to replicate in many of the mononuclear phagocyte subsets present in the intestinallamina propria. This was an unexpected result because intracellular growth and spread from cell-to-cellwithout encountering the extracellular milieu are generally regarded as the primary virulence strategies forLm. The overall hypothesis of this proposal is that foodborne Lm can use one of three distinct pathways todisseminate from the intestinal lamina propria to the mesenteric lymph nodes (MLN): 1) Lm hitch a rideattached to migratory inflammatory Ly6Chi monocytes which they cannot efficiently invade; 2) Lm invadeconventional dendritic cells (cDC) which serve as a Trojan horse to deliver non-replicating but intracellularbacteria to the MLN; and 3) extracellular Lm traffic free-flowing through lymphatic vessels to the subcapsularsinus of the MLN. We propose that these three pathways are likely to be redundant during in vivo infectionbut may be influenced by the route used by Lm to invade the intestinal epithelium. In Aim 1 the role of cell-associated vs. free-flowing extracellular bacteria in promoting dissemination to the MLN that drain either theileum or the colon will be determined. In Aim 2 we will determine how the dissemination pathway used byLm affects the ability of the bacteria to survive and replicate in the MLN and to promote further systemicspread. These exploratory studies will advance the field by defining the mechanisms used by Lm to avoidclearance in the MLN a critical bottleneck to avoid systemic spread of orally acquired pathogens.

project_terms:
Address;Affect;Anatomy;Antibodies;Antibody Therapy;Antigens;Area;Bacteria;Binding;Blood;Body part;Brain;Bypass;CCL21 gene;Cardiovascular system;Cells;Colon;Confocal Microscopy;Cytosol;Data;Death Rate;Dendritic Cells;Disease;Disease Outbreaks;E-Cadherin;Elderly;Enterocytes;Epithelial;Epithelial Cells;Equus caballus;FLT3 gene;Feces;Food;Food Contamination;Food Supply;Foundations;Gastroenteritis;Gastrointestinal tract structure;Goals;Growth;Gut Mucosa;Hospitalization;Human;Immune;Immune system;In Vitro;Incidence;Individual;Infection;Inflammatory;Ingestion;Intestines;Intravenous;Invaded;Knowledge;Lamina Propria;Lead;Life;Listeria;Listeria monocytogenes;Listeriosis;Lymph Node Subcapsular Sinus;M cell;Macrophage Colony-Stimulating Factor;Mediating;Membrane Proteins;Meningoencephalitis;Microscopic;Minor;Modeling;Mononuclear;Oral;Output;PTPRC gene;Pathway interactions;Persons;Phagocytes;Phase;Process;Resistance;Role;Route;Sepsis;Septicemia;Severities;Severity of illness;Small Intestines;Symptoms;Systemic infection;T-Lymphocyte;Therapeutic Intervention;Time;Vascular Endothelial Growth Factor Receptor-3;Virulence;Work;adaptive immunity;base;cell type;draining lymph node;enteric infection;experience;extracellular;foodborne;foodborne infection;human disease;ileum;in vivo;intestinal epithelium;lymphatic vessel;macrophage;mesenteric lymph node;migration;monocyte;mortality;mouse model;mutant;neonate;pathogen;pathogenic bacteria;podoplanin;prevent;transmission process;uptake

public_health_relevance:
Ingestion of food that is contaminated with the bacterium Listeria monocytogenes causes a wide spectrumof disease in humans ranging from mild gastroenteritis to life-threatening infections of the blood and brain.The goal of this proposal is to understand how the bacteria are able to spread from the gastrointestinal tractto other parts of the body. A better understanding of this process could lead to new strategies to prevent themore severe systemic forms of the infection which can have a 25-30% death rate in susceptible individualssuch as neonates and the elderly.


application_id: 10417194
project_number: 5R01CA218068-06
project_title: Randomized Trial of a Social Media-Delivered Intervention Targeting Indoor Tanning Users
administering_ic: NCI
award_notice_date: 2022-06-09
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 218068
program_official: PERNA, FRANK
project_start_date: 2017-07-15
project_end_date: 2025-05-31
study_section: Psychosocial Risk and Disease Prevention Study Section[PRDP]
contact_pi_person_id: 10885868
contact_pi: STAPLETON, JEROD L
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThe number of U.S. adults treated annually for melanoma the most deadly form of skin cancer has nearlydoubled in the past 15 years and the incidence rate is projected to again double by 2030. This growth is partlyattributed to the popularity of artificial ultraviolet-emitting indoor tanning beds. Despite recognition by numerousnational and international health organizations as being carcinogenic to humans nearly 10 million Americansuse indoor tanning beds each year. An estimated 1 in 10 of all new U.S. cases of melanoma and 400000annual cases of non-melanoma skin cancer are directly attributable to indoor tanning. Most concerning nearly1 in 5 young adult white females engage in high-risk indoor tanning defined as using indoor tanning beds atleast ten times a year which is associated with a substantially increased risk of melanoma. As indoor tanninggained popularity among young women over the past two decades melanoma has recently become one of themost common cancers among this population. The 2014 Surgeon General's Call to Action to Prevent SkinCancer identified a critical research gap related to an absence of interventions that target high risk indoortanners and address underlying motives for tanning including the desire to look attractive and healthy and toconform to societal beauty standards. The purpose of this application is to implement and test an interventiondesigned to encourage indoor tanning cessation among high-risk tanners. The intervention is unique in usingpersuasive techniques and content to reduce perceived pressure to be tan reduce the value placed on tanningand promote positive body image rather than focusing on information about the risks of tanning. Theintervention will be delivered via the social media site Facebook through the secret groups feature. The useof Facebook groups will allow group-based interactions among participants which can facilitate strongerchanges in attitudes and behaviors and provides a platform to embed the intervention into individuals' normalroutines. The first proposed aim is to refine the existing intervention content from our preliminary interventionstudies with user-generated feedback. The second aim is to conduct a randomized controlled trial of theintervention in a sample of 400 young women engaged in high-risk tanning. Our primary hypothesis is thatparticipants who receive the intervention will report less indoor tanning at a 6-month follow-up compared tothose who participate in a control Facebook group. Our third aim will examine hypothesized psychosocialmediators of the intervention effects. The intervention has strong potential for cost-effective widespreaddissemination and targets a group at high-risk for future cancer development. If effective the intervention hasthe potential to significantly reduce the growing burden of melanoma and other skin cancers.

project_terms:
Address;Adopted;Adult;American;Appearance;Attitude;Beauty;Behavior;Behavior Therapy;Belief;Body Image;Cognitive Dissonance;Collaborations;Conflict (Psychology);Control Groups;Development;Eating Behavior;Eating Disorders;Facebook;Facebook delivery;Feedback;Female;Funding;Future;Grant;Growth;Human;Incidence;Individual;Intervention;Intervention Studies;Intervention Trial;Lead;Malignant Neoplasms;Mediating;Mediator of activation protein;Participant;Population;Process;Randomized Controlled Trials;Recording of previous events;Reporting;Research;Research Personnel;Risk;Sampling;Site;Skin;Skin Cancer;Skin Carcinoma;Skin tanning;Surgeon;Techniques;Testing;Time;Treatment Efficacy;Woman;Work;base;behavior change;body dissatisfaction;carcinogenicity;college;cost effective;design;eHealth;efficacy evaluation;experience;follow-up;high risk;implementation intervention;implementation study;innovation;international health organization;intervention effect;melanoma;novel;pressure;primary outcome;programs;psychosocial;randomized trial;skin cancer prevention;social culture;social media;success;tanning booths;theories;therapy design;trend;ultraviolet;usability;web site;young adult;young woman

public_health_relevance:
PROJECT NARRATIVEThe use of artificial ultraviolet indoor tanning beds is associated with an increased risk of skin cancer includingthe deadly melanoma. This project involves developing and testing a novel behavioral intervention deliveredvia the social media site Facebook that is designed to reduce high-risk indoor tanning behaviors among youngadult women. If effective the intervention may be widely disseminated and has the potential to help reverseconcerning melanoma trends observed among young women.


application_id: 10417173
project_number: 5R01AG060056-05
project_title: APOE and the PPP: Glucose Metabolism and Oxidative Stress in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2022-06-28
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 060056
program_official: BARRETT, PAUL JOHN
project_start_date: 2018-08-15
project_end_date: 2023-11-30
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 11146000
contact_pi: JOHNSON, LANCE ALLEN
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:
ABSTRACTMetabolic dysfunction may contribute to the development of several age-related diseases includingAlzheimer's disease (AD). The gene Apolipoprotein E (APOE) encodes three major isoforms in the humanpopulation: E2 E3 and E4. E4 is the most significant genetic risk factor for sporadic AD while E2 isprotective. An understudied hallmark of AD patients  and of cognitively normal E4 individuals  is cerebralglucose hypometabolism. E4-associated reductions in glucose uptake begin decades prior to cognitiveimpairment however the mechanism by which it occurs and its relevance to AD risk remain unknown. Thebrain predominantly metabolizes glucose a substantial amount of which is shunted to the pentose phosphatepathway (PPP) in both neurons and astrocytes. The PPP generates antioxidant reducing factors such asNADPH and glutathione and decreased PPP activity increases oxidative stress and cell death. Interestinglyour novel preliminary data describe a murine model with human apoE that recapitulates an E4-associateddecrease in glucose metabolism and also documents decreases in multiple PPP metabolites. Thus the centralhypothesis of this proposal is that APOE influences neuronal function and survival through isoform-specificchanges in glucose metabolism. Specifically we hypothesize that E4 contributes to cognitive impairmentthrough metabolic reprogramming in which glucose uptake is decreased and redox management via the PPPis reduced. Our preliminary data in mice show a stepwise decrease in brain glucose uptake (E2>E3>E4) andin vitro results suggest these differences are due to changes in astrocytic uptake via GLUT-1. Therefore in thefirst Aim we will test the hypothesis that E4 decreases cerebral glucose uptake through downregulation of theastrocytic glucose transporter GLUT-1 using a scintillation proximity assay with targeted manipulation of apoEisoforms total protein concentrations and glucose transporters. To test the hypothesis that E4 decreasesglucose entry into the PPP we will quantitatively track glucose entry and metabolism in the cell through theunique precursor-product tracing afforded by Stable Isotope Resolved Metabolomics (SIRM) and translateour results through analysis of human brain tissue. Finally we will test the hypothesis that E4 exacerbatesoxidative damage and cell death due to a reduction in PPP-mediated management of oxidative stress. This willbe accomplished in vitro through pharmacological manipulation of PPP enzymes and in vivo by assessingcognitive function AD pathology and oxidative damage using redox proteomics analysis of brain tissue fromhuman apoE mice treated with a PPP stimulant. If successful this proposal will provide novel therapeutictargets to normalize glucose metabolism in high-risk individuals. Enhancing cerebral metabolism by increasingglucose uptake and entry into the PPP could have great impact in preventing or delaying the onset of AD.

project_terms:
Affect;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease pathology;Alzheimer's disease patient;Alzheimer's disease risk;Antioxidants;Apolipoprotein E;Astrocytes;Autopsy;Biological Assay;Brain;Cell Death;Cell Survival;Cells;Cerebrum;Coculture Techniques;Cognitive;Consensus;Data;Development;Disease;Down-Regulation;Enzymes;Genes;Genetic;Genotype;Glucose;Glucose Transporter;Glucosephosphate Dehydrogenase;Glutathione;Glutathione Disulfide;Glycolysis;Human;Impaired cognition;In Vitro;Individual;Knowledge;Late Onset Alzheimer Disease;Link;Longevity;Measures;Mediating;Metabolic;Metabolic Pathway;Metabolic dysfunction;Metabolism;Mus;NADP;Neurons;Oxidation-Reduction;Oxidative Stress;Pattern;Pentosephosphate Pathway;Pharmacology;Population;Protein Isoforms;Proteins;Proteomics;Radiolabeled;Reduced Glutathione;SLC2A1 gene;Sampling;Small Interfering RNA;Stimulant;Testing;Time;Tissues;Translating;age related;aged;base;brain tissue;cell type;cognitive function;enzyme pathway;genetic risk factor;glucose metabolism;glucose uptake;high risk;human tissue;in vivo;inhibitor;innovation;knock-down;metabolomics;mouse model;neuronal survival;new therapeutic target;novel;overexpression;oxidative damage;prevent;response;stable isotope;therapeutic target;uptake

public_health_relevance:
Project NarrativeAPOE*4 (E4) is the strongest genetic risk factor for late-onset Alzheimer's disease. This proposal aims tostudy how E4 negatively influences neuronal survival by studying a metabolic pathway that links glucosemetabolism and oxidative stress. If successful this will provide new therapeutic targets to normalize glucosemetabolism and potentially prevent or delay the onset of AD.


application_id: 10417159
project_number: 5R01GM070559-15
project_title: Epigenetic regulation of hormone action in Tribolium and Aedes
administering_ic: NIGMS
award_notice_date: 2022-03-30
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: GM
serial_number: 070559
program_official: PHILLIPS, ANDRE W
project_start_date: 2005-02-01
project_end_date: 2025-03-31
study_section: Vector Biology Study Section[VB]
contact_pi_person_id: 7355989
contact_pi: PALLI, SUBBA R
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThere has been a continuous demand for development of insect control methods that are target-specific.Juvenile hormone (JH) and ecdysteroids (20-hydroxyecdysone 20E is the most active form) are the majorhormones that regulate many physiological and developmental processes in insects. Since these hormonesare not present in vertebrates they represent attractive targets for development of insect control methods.Hindering this effort is the lack of understanding on the molecular basis of action of these hormones. There hasbeen excellent recent progress in understanding the molecular basis of 20E and JH action. Key playersincluding receptors co-activators response elements and target genes involved in the action of thesehormones have been identified. Non-steroidal ecdysone agonists and JH analogs have been discovered andcommercialized for the control of pests and disease vectors. Research supported by this program showed thatepigenetic modifications especially acetylation levels of histones regulated by histone acetyltransferases(HAT) and histone deacetylases (HDAC) modulate JH and 20E action. Hormone action requires multiple layersof regulation because the same circulating levels of hormones exert diverse functions in different tissues andunder different physiological conditions. Based on the published literature and preliminary data included in thisapplication we hypothesize that epigenetic regulators HDACs HATs histone lysine methyltransferases(HKMT) and histone demethylases (HDM) modulate JH and 20E action in the regulation of postembryonicdevelopment and reproduction. The main goal of this proposal to test this hypothesis by studying themechanisms of action of epigenetic modifiers in JH and 20E action using T. castaneum TcA cells Ae. aegyptiand Aag2 cells as model systems. The two Specific Aims of the proposal are 1. To identify and characterizeepigenetic modifiers required for 20E and JH regulation of postembryonic development and femalereproduction and 2. To study mechanisms of action of epigenetic modifiers required for 20E and JH regulationof postembryonic development and female reproduction. In the first Specific Aim RNAi CRISPR/Cas9genome editing methods RNA sequencing bioinformatics RT-qPCR enzyme assays and cell cultureapproaches will be used to identify and characterize HATs HDACs HKMTs and HDMs required forpostembryonic development and female reproduction in T. castaneum and Ae. aegypti. In the second SpecificAim the mechanisms of action of 10-12 epigenetic modifiers will be studied using western blots and ChIPreporter Two-hybrid and pull-down assays and mass spectrometry approaches. Results from the proposedresearch will impact medicine by providing information for the development of vector control methods. Thisinformation could help in understanding epigenetics of human diseases such as cancer. The results from theproposed research may help to transform our understanding of endocrinology of disease vectors.

project_terms:
Acetylation;Adult;Aedes;Agonist;Animals;Antibodies;Binding;Bioinformatics;Biological Assay;Biological Metamorphosis;Biological Models;CRISPR/Cas technology;Cell Culture Techniques;Cells;Complex;Culicidae;Data;Deacetylation;Development;Developmental Process;Disease;Disease Vectors;Ecdysone;Ecdysteroids;Ecdysterone;Endocrinology;Ensure;Enzymes;Epigenetic Process;Female;Food;Genes;Genome;Goals;Growth and Development function;Histone Deacetylase;Histone-Lysine N-Methyltransferase;Histones;Homologous Gene;Hormone Receptor;Hormones;Human;Insect Control;Insect Hormones;Insecta;Insecticides;Juvenile Hormones;Knowledge;Laboratories;Life;Ligands;Literature;Livestock;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Medicine;Methods;Methoprene;Methylation;Modeling;Modification;Molecular;Pathway interactions;Pest Control;Physiological;Physiological Processes;Plants;Play;Principal Investigator;Process;Proteins;Publishing;RNA Interference;Regulation;Reporter;Reproduction;Reproductive Process;Research;Research Support;Response Elements;Role;Steroid Receptors;Testing;Tissues;Tribolium;Vertebrates;Western Blotting;base;chromatin immunoprecipitation;demethylation;ecdysone receptor;enzyme activity;epigenetic regulation;experimental study;gene product;genome editing;histone acetyltransferase;histone demethylase;histone modification;hormone analog;hormone regulation;hormone response element;human disease;insect disease vector;mass spectrometer;programs;promoter;receptor;receptor binding;response;success;transcription factor;transcriptome sequencing;vector control;yeast two hybrid system

public_health_relevance:
Project Narrative Mosquitoes transmit deadly diseases. The research proposed in this application will provideinformation of potential importance for development of insecticides for vector control. The proposed studieswill reveal functions and mechanisms of action of epigenetic marks which will help in understandingepigenetics of human diseases such as cancer.


application_id: 10413643
project_number: 3R01HL135158-05S1
project_title: Effect of early life stress on obesity-induced hypertension in mice
administering_ic: NHLBI
award_notice_date: 2021-12-15
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: HL
serial_number: 135158
suffix: S1
program_official: MCDONALD, CHERYL
project_start_date: 2017-12-01
project_end_date: 2023-11-30
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 10353675
contact_pi: LORIA, ANALIA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Abstract/ scope of work proposedObesity promotes hypertension a major risk factor for cardiovascular disease. Epidemiologicalstudies have linked early life stress as a modifiable risk factor for increased body mass indexand blood pressure. Using an advantageous mouse model of early life stress that combinespostnatal maternal separation and early weaning (MSEW) with a high fat diet we haveidentified two potential adipose tissue-derived targets implicated in the pathways by whichthese mice display exacerbated obesity-induced hypertension. Our preliminary findingssupport the novel central hypothesis that postnatal MSEW aggravates obesity-induced HT inadult life by stimulating adipose afferent reflex (AAR)-mediated sympathetic activation andadipose tissue-derived angiotensinogen (AGT) secretion. We will test key predictions in twomultilevel specific aims: (1) To test the hypothesis that MSEW heightens obesity-inducedhypertension by stimulating adipose tissue excitatory signals to increase AAR reflex. In thisaim the applicant will contribute to determine the different neurons that are activated inresponse to MSEW mice fed a high fat diet and test the afferent reflex in vivo in female mice;and (2) To test the hypothesis that MSEW exacerbates obesity-induced hypertension byincreasing AGT secretion in adipose tissue. The applicant will contribute to determinewhether changes in circulating angiotensin II influence the activation of the circuventricularorgans (CVO).

project_terms:
Acute;Adipose tissue;Administrative Supplement;Adult;Affect;Afferent Neurons;American;Angiotensin II;Angiotensinogen;Autonomic ganglion;Baroreflex;Biological Assay;Birth;Blood Pressure;Body mass index;Brain;Capsaicin;Cardiovascular Diseases;Catecholamines;Child;Diet;Dose;Exposure to;Fatty acid glycerol esters;Feedback;Female;Gene Expression;Generations;Glomerular Filtration Rate;Glucocorticoids;Health;High Fat Diet;Homeostasis;Hormones;Hypertension;Hypothalamic structure;Immediate-Early Genes;Kidney;Knockout Mice;Leptin;Life;Link;Lipolysis;Longevity;Mediating;Mediator of activation protein;Metabolic;Microinjections;Modeling;Morbidity - disease rate;Mus;Myocardial Ischemia;Nerve;Neuraxis;Neurons;Nociceptors;Norepinephrine;Obesity;Organ;Pathway interactions;Personal Satisfaction;Plasma;Procedures;Reflex action;Renal Hypertension;Renin-Angiotensin System;Resiniferatoxin;Risk Factors;Scheme;Sensory;Signal Transduction;Source;Stimulus;Sympathetic Nervous System;Tamoxifen;Testing;Therapeutic Intervention;Time;Tissues;Visceral;Weaning;Work;abuse neglect;analog;base;blood pressure elevation;blood pressure reduction;blood pressure regulation;cardiovascular risk factor;chromatin immunoprecipitation;comorbidity;diet-induced obesity;early life stress;epidemiologic data;epidemiology study;experimental study;hypertension prevention;in vivo;indexing;kidney dysfunction;leptin receptor;male;maternal obesity;maternal separation;modifiable risk;molecular marker;mortality;mouse model;neglect;neonate;neurotransmission;next generation;novel;paraventricular nucleus;postnatal;prevent;promoter;response;somatosensory;stressor;urinary

public_health_relevance:
Project NarrativeObesity promotes hypertension a major risk factor for cardiovascular disease. Under this administrativesupplement the candidate will study the fat-brain-lipolysis axis mouse model of early life stress during diet-induced hypertension.


application_id: 10412967
project_number: 5R01CA243529-03
administering_ic: NCI
award_notice_date: 2022-06-28
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: CA
serial_number: 243529
program_official: CHEN, WEIWEI
project_start_date: 2020-06-01
project_end_date: 2025-05-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 9351620
contact_pi: TSODIKOV, OLEG V
other_pis: LEGGAS, MARKOS ;ROHR, JURGEN T
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: 2022-06-01
project_title:
Mechanistic and pharmacologic studies of selective mithramycin analogues targeting EWS-FLI1 in Ewing sarcoma

project_abstract:
Ewing sarcoma family of tumors (ESFT) is a family of resilient devastating cancers of bone and soft tissueaffecting primarily children and young adults. Current highly cytotoxic combination therapy of five drugs providesonly 30% overall survival. The aberrant transcription factor EWS-FLI1 present only in tumor cells is the oncogenicdriver of EWS. However transcription factors were believed to be undruggable until a recent NCI screeningfound mithramycin (MTM) to act as a potent EWS-FLI1 antagonist. MTM has proven to be too toxic with a narrowtherapeutic window and poor pharmacokinetic (PK) properties. Here we propose mechanistic and pharmacologystudies of novel MTM analogues (MTM-SA) with significantly reduced toxicity increased target specificity andgreatly improved PK properties. In contrast to other analogues reported elsewhere which still suffer from poorPK properties the MTM-SA analogs display superior kinetics and reduced toxicity. The goal of this project is togain molecular insights into the mode of action of MTM via structural biochemical and pharmacological studiesto generate a highly efficacious and selective anti-ESFT treatment. To aid synthetic efforts in Aim1 and identifyanalogues with clinical potential we will perform molecular structure-function level studies in Aim 2 to determinehow transcription factor EWS-FLI1 interacts with DNA microsatellite repeats and transcription factor Runx2 (eacha necessary interaction for oncogenesis) and how these oncogenic functions are disrupted by MTM-SA. In Aim3 will assess the in vitro cytotoxicity and target selectivity to identify analogues that will be evaluated inpharmacologic studies that will assess toxicity in humanized liver mice PK and metabolism as well as efficacyin xenograft and PDx models of Ewing Sarcoma. The project will be carried out by a team with an establishedcollaboration who have extensive experience in fragment-based drug design and semi-synthetic routes of naturalproducts X-ray crystallographic biophysical and molecular biology studies and pharmacological evaluations.We expect that these structure-function studies will identify a lead-candidate that could enter a clinical trial forthe treatment of ESFT.

project_terms:
Affect;Animal Model;Antineoplastic Agents;Binding;Biochemical;Biological;Biological Assay;Biophysics;Bone Tissue;Cell model;Cells;Child;Clinical;Clinical Treatment;Clinical Trials;Collaborations;Combined Modality Therapy;Complement;Complex;Crystallization;DNA;DNA Binding;DNA Binding Domain;DNA Sequence;Data;Development;Drug Design;Drug Kinetics;EWS-FLI1 fusion protein;Elements;Enhancers;Evaluation;Ewings sarcoma;FLI1 gene;Family;Foundations;Genetic Transcription;Goals;Higher Order Chromatin Structure;Human;In Vitro;Investigational Therapies;Kinetics;Liver;Malignant Bone Neoplasm;Metabolism;Microsatellite Repeats;Modeling;Molecular;Molecular Biology;Molecular Structure;Mus;Natural Products;Oncogenic;Patients;Pharmaceutical Preparations;Pharmacology;Pharmacology Study;Phase I/II Clinical Trial;Plasma;Plicamycin;Preclinical Testing;Property;Proteins;Public Health;Reporter;Reporting;Roentgen Rays;Route;Shunt Device;Side;Site;Specificity;Structure;Testing;Therapeutic;Toxic effect;Translating;Tube;Xenograft Model;analog;antagonist;base;cancer cell;cancer diagnosis;cytotoxic;cytotoxicity;design;drug candidate;drug clearance;effective therapy;experience;improved;inhibitor;insight;lead candidate;mouse model;neoplastic cell;novel;patient derived xenograft model;programs;screening;soft tissue;transcription factor;transcriptional reprogramming;tumor;tumorigenesis;young adult

public_health_relevance:
Ewing sarcoma and other Ewing family tumors are poorly treatable bone and soft tissue cancers diagnosedpredominantly in children and young adults. This project is relevant to public health because it aims to developselective chemotherapeutics to treat Ewing sarcoma through investigating oncogenic mechanisms of thecausative agent of Ewing sarcoma transcription factor EWS-FLI1. This mechanistic inquiry will becomplemented by pharmacological studies and aid the development of selective anti-Ewing sarcomatherapeutics.


application_id: 10412123
project_number: 5R21AI163561-02
project_title: Molecular mode of action of Juvenile hormone analogs
administering_ic: NIAID
award_notice_date: 2022-05-11
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AI
serial_number: 163561
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2021-06-01
project_end_date: 2025-05-31
study_section: Vector Biology Study Section[VB]
contact_pi_person_id: 7355989
contact_pi: PALLI, SUBBA R
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryAdult mosquitoes transmit pathogens that cause deadly diseases in humans. Therefore preventing adultemergence has been used as a strategy to block transmission of pathogens. Juvenile hormones (JH) preventmetamorphosis and adult emergence; juvenile hormone analogs (JHA) such as methoprene hydroprene andpyriproxyfen have been commercialized for controlling mosquitoes and other disease vectors. However themolecular mode of action of JHAs in killing mosquitoes and other insects remains poorly understood. JHAs arethought to act by preventing larval-pupal metamorphosis. This is precisely how these compounds work in mostlepidopteran insects. However in dipteran insects such as the yellow fever mosquito Aedes aegypti JHAapplication does not prevent larval-pupal metamorphosis; the treated larvae undergo pupal ecdysis and dieduring the pupal stage. Preliminary studies showed that the pupae developed from methoprene treated larvaedie due to the persistence of larval tissues. A transgenic CRISPR/Cas9 genome editing method was employedto knockout Ae. aegypti ortholog of the gene coding for ecdysone induced protein 93F (E93) which is known toregulate programmed cell death (PCD) of larval tissues. The phenotypes of Ae. aegypti E93 knockout animalsare like that observed in JHA treated larvae suggesting that JHA suppresses E93 expression in preventing thedeath of larval tissues resulting in pupae containing both larval and pupal tissues leading to their death. Thishypothesis will be tested by conducting experiments under two specific aims. In the first specific aim larvaltissues undergoing PCD will be examined to identify similarities and differences between JHA treatment andE93 knockout. The status of PCD in tissues dissected from JHA treated and E93 knockout larvae and pupaewill be studied by staining with apoptosis and autophagy marker dyes. In the second specific aim RNA andATAC sequencing RNAi and reporter assays will be employed to identify genes involved in larval tissueremodeling and mechanisms of regulation of their expression by JHA working through E93. The function ofE93 acting as a pioneer and an activating transcription factor will be studied. Results from the proposedresearch will impact medicine by providing information for the development of vector control methods. Theresults from the proposed studies will answer long-standing questions on JHA action in mosquitoes andincrease our understanding of JH action which could help to develop novel highly active and safe methods tocontrol mosquitoes and other vectors of pathogens that cause diseases in humans.

project_terms:
Adolescent;Adult;Aedes;Affinity;Animals;Apoptosis;Autophagocytosis;Binding;Biological Assay;Biological Metamorphosis;CRISPR/Cas technology;Cells;Cessation of life;Code;Culicidae;Data;Development;Disease;Disease Vectors;Drosophila melanogaster;Dyes;Ecdysone;Electron Microscope;Ensure;Fleas;Fluorescence;Fluorescent Dyes;Genes;Genetic Transcription;Goals;Homologous Gene;Hormone Receptor;Human;Insecta;Insecticides;Juvenile Hormones;Knock-out;Knowledge;Larva;Life;Mediating;Medicine;Methods;Methoprene;Midgut;Molecular;Molting;Mosquito Control;Orthologous Gene;Phenotype;Plants;Proteins;Pupa;RNA;RNA Interference;Regulation;Reporter;Reporting;Research;Resistance;Resistance development;Salivary Glands;Stains;Testing;Tissues;Transgenic Organisms;Whiteflies;Work;XCL1 gene;Yellow Fever;activating transcription factor;analog;base;combat;experimental study;fly;genome editing;hormone analog;human pathogen;insect disease vector;knockout animal;mutant;novel;pathogen;preservation;prevent;response;screening;success;transcription factor;transgenic insect;transmission process;vector;vector control

public_health_relevance:
Project NarrativeInsect juvenile hormone analogs are being used for mosquito control but some mosquitoes are alreadydeveloping resistance to these analogs. The results from these studies will aid in understanding the mode ofaction of JH analogs thus facilitating their judicious use. The genes identified will be useful to developscreening assays to identify new insect disease vector control agents.


application_id: 10412092
project_number: 5R01GM138837-02
project_title: Ex vivo single molecule tools to analyze membrane receptor dynamics
administering_ic: NIGMS
award_notice_date: 2022-05-19
opportunity_number: PAR-19-253
application_type: 5
activity_code: R01
ic: GM
serial_number: 138837
program_official: YEH, ALVIN TIEN-WEI
project_start_date: 2021-06-03
project_end_date: 2025-05-31
study_section: Enabling Bioanalytical and Imaging Technologies Study Section[EBIT]
contact_pi_person_id: 8957529
contact_pi: RICHARDS, CHRISTOPHER I
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Membrane receptors play a crucial role in many physiological processes throughout the body bymediating communication between cells. Single molecule imaging has been used extensively tostudy membrane receptor assembly and stoichiometry in vitro using isolated protein and to alesser extent cell culture. While studies in isolated cellular systems provide insight into manyprocesses they lack the context of the complex environment present in an animal wherecommunication between cell types residing in tissue is critical for receptor activity. Single-molecule imaging of native proteins synthesized in vivo would provide a direct approach tomeasure processes such as receptor dimerization that regulate physiological activity. Howevercurrent methods are not capable of applying single molecule techniques to study the regulationof protein dynamics taking place within the complex environment of an animal. We have maderecent advances in the development of ex vivo single molecule techniques to monitor changes inprotein assembly that occur within specific organs. The goal of this proposal is to develop andvalidate ex vivo single molecule tools that provide new capabilities to monitor the properties ofoligomeric membrane receptor assembly resolve cell type and subcellular region specific singlemembrane receptors and automate single molecule data analysis using a machine learningplatform. This novel ex vivo technology will enable researchers to take a snap shot in time of themembrane receptor dynamics that took place in the mouse and monitor changes in membranereceptor assembly in response to changes in the animal's physiological environment such asdisease and exposure to therapeutics.

project_terms:
Address;Animal Communication;Animal Disease Models;Animal Model;Animals;Biological;Biological Models;Brain;Brain region;Cardiac;Cell Culture Techniques;Cells;Chemicals;Classification;Communication;Complex;Consumption;Data;Data Analyses;Data Set;Development;Dimerization;Disease;Encapsulated;Environment;Exposure to;Future;Goals;Heart;High Performance Computing;Image;In Vitro;Knock-in;Knock-in Mouse;Lead;Machine Learning;Manuals;Measurement;Mediating;Membrane;Membrane Proteins;Methodology;Methods;Monitor;Mus;Organ;Pharmaceutical Preparations;Pharmacotherapy;Physiological;Physiological Processes;Play;Population;Preparation;Process;Process Measure;Property;Protein Dynamics;Proteins;Regulation;Research;Research Methodology;Research Personnel;Role;RyR2;Ryanodine Receptor Calcium Release Channel;Sampling;Signal Transduction;System;Techniques;Technology;Testing;Therapeutic;Time;Tissues;Training;Vesicle;alpha-SNAP;animal tissue;base;cell type;cluster computing;convolutional neural network;design;in vivo;insight;large datasets;molecular imaging;nanoscale;nanovesicle;novel;open source;postsynaptic neurons;presynaptic;prototype;receptor;response;sex;single molecule;stoichiometry;technique development;therapeutic target;tissue preparation;tool;trafficking

public_health_relevance:
Membrane receptors are important therapeutic targets for many diseases and are expressed throughout thebody. Understanding the role of receptor assembly in the complex environment of a live animal is an importantstep in understanding their mechanism of activation and regulation. We will develop ex vivo single-moleculemethods that for the first time will enable quantitative studies of stoichiometry for receptors extracted frommice.


application_id: 10410552
project_number: 5R01AG061065-05
project_title: Role of Gut Microbial Dysbiosis and Aging on HIV-associated neurocognitive and brain dysfunction
administering_ic: NIA
award_notice_date: 2022-04-29
opportunity_number: RFA-AG-18-023
application_type: 5
activity_code: R01
ic: AG
serial_number: 061065
program_official: MARIC, MAJA
project_start_date: 2018-09-30
project_end_date: 2024-05-31
study_section: ZAG1-ZIJ-U(A1)
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: COHEN, RONALD A;COOK, ROBERT L
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Although AIDS-defining illnesses have decreased the prevalence of HIV-associated non-AIDS conditions suchas HIV-Associated Neurocognitive Disorders (HAND) remains high and is estimated to be over 50%particularly in aging individuals with long-standing HIV infection. However the pathophysiology of HAND inaging HIV+ adults remains unresolved. Current evidence and our preliminary data suggest that interactionsof altered gut microbiome (dysbiosis) gut-derived microbial translocation and systemic inflammationcontribute to neurodegenerative processes. It is becoming increasingly evident that in both HIV-1 infection andaging alterations in gut microbiome (dysbiosis) and ensuing increase in intestinal permeability and microbialtranslocation (MT) are major pathogenic drivers of local and systemic inflammation. Importantly aging-associated microbiota changes are shown to be connected to immunosenescence and inflammaging.Preclinical/clinical studies using bacterial 16S ribosomal RNA (rRNA) gene sequencing indicate that microbialdysbiosis associated with HIV-1 infection or aging has several common pathogenic features. However thesestudies were largely hypothesis-generating with limited sample sizes and were not adequately powered toaddress microbiome endpoints after correction for multiple testing and did not reveal the functional potential ofthe microbiota (pathogenic or beneficial) or yield bacterial resolution to species or strain level. The currentproposal will address these limitations by using an adequately powered longitudinal study and will conduct 16SrRNA gene and Whole Genome Shotgun (WGS) metagenomic sequencing that will determine bacterialcomposition and diversity provide identification at the species and strain level and enable the functionalcharacterization of the bacterial genes. Our overarching hypothesis is that the interactive effects of agingand HIV-1 infection at the level of gut dysbiosis and permeability and ensuing local and systemicinflammation play a major pathogenic role in driving HIV infection and aging-associatedneuroinflammation and cognitive dysfunction. To test these hypotheses we will leverage and utilize HIV+and healthy aging populations from ongoing NIH-sponsored longitudinal studies at the Universities of Louisville(UofL) and Florida (UF) with the following specific aims: Aim 1: To assess longitudinal qualitative andquantitative changes in the gut microbiome (dysbiosis) in older persons living with HIV-1 infection.Aim 2: To determine the impact of HIV-1 infection and age associated gut dysbiosis on (A) intestinalpermeability and microbial translocation (MT) and resultant peripheral endotoxemia andinflammation; and (B) multimodal MRI/MRS measures of neuroinflammation and cerebral metabolicdisturbance. Aim 3: To investigate the impact of gut dysbiosis and peripheral and neuroinflammationand cerebral metabolic disturbance on cognitive dysfunction and functional brain abnormalities (FMRI)relative to age and HIV status.

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

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


application_id: 10410169
project_number: 2T35EY026509-06
project_title: Summer Vision Sciences Training Program
administering_ic: NEI
award_notice_date: 2022-05-27
opportunity_number: PA-20-162
application_type: 2
activity_code: T35
ic: EY
serial_number: 026509
program_official: CLAYTON, EDWIN C
project_start_date: 2017-07-01
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZEY1 VSN (06)]
contact_pi_person_id: 1925445
contact_pi: CERESA, BRIAN P.
other_pis: MCCALL, MAUREEN A
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/AbstractThis is a renewal application for a T35 summer medical student training program in vision research withtwo Specific Aims: 1) To provide hands-on training in basic and clinical vision research to medicalstudents in a structured mentored environment and 2) To provide an interactive educational experiencethat introduces medical students the fundamental skills necessary for basic translational and clinicalresearch in vision biology. The co-directors of this program request support for 8 second-year medicalstudents each summer in vision related research laboratories that focus on topics such as visualcircuitry retinal degeneration corneal epithelial homeostasis uveitis ocular drug discovery anddevelopment of the visual system. Trainees will be selected from the first-year class at University ofLouisville School of Medicine. Students will review research projects submitted by 18 faculty funded bythe NEI or vision related foundations. The directors will make a special effort to recruit students who areunderrepresented in science including females ethnic minorities and from disadvantagedbackgrounds. Students will review the available projects and rank their 1st-5th choices allowing matchingof trainees with mentors. Final decisions will be made based on interviews between mentors andTrainees. During the 10-week summer training students work with mentors on their research project inlaboratory settings complete training in the Responsible Conduct of Research including topics such asfabrication and falsification of data plagiarism managing scientific data publication practices andresponsible authorship mentorship stewardship and conflict of interest. Trainees will complete humansubject IRB training and animal care and handling as required by their specific research projects. AllTrainees will attend a 2-hour weekly Vision Sciences Research Training Seminar designed tointroduce clinical/translational research in Ophthalmology led by mentors in this T35 program. Theseminar series will culminate with each Trainee presenting his/her research project to peers andmentors. In addition trainees present the results of their research as posters with peers at a School ofMedicine-wide week-long celebration of research (Research!Louisville) that includes nationallyrecognized physician-scientists as keynote speakers. Trainees will be encouraged to continue researchas part of the Distinction in Research track that is an enrichment program focusing on providingmeaningful and productive research experiences throughout second through fourth years of medicalschool with ongoing presentations by students with mentors and 4+ weeks of research time in thefourth year toward the goal of developing clinician-researchers. Trainees will be tracked to assess theimpact of this T35 program on careers as physician-scientists.

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

public_health_relevance:
Project Narrative:This NEI Short-Term Institutional Training Grant renewal application requests 5 years of support for 8 risingsecond year Medical Student trainees in our Vision Science laboratories for a 10 week research experience.We will focus on recruitment of under-represented trainees into this program to enhance the diversity of ourmedical workforce. The T35 training grant will be used to entice our medical students into our Distinction inResearch Track a program that encourages students to participate in laboratory research in years 2-4 ofmedical school with an eye toward scholarly activities in academic medicine to continue to build a pipeline oftranslational clinician-researchers.


application_id: 10409752
project_number: 5R01GM129532-05
project_title: Visceral fat gamma delta T cells in sepsis pathogenesis
administering_ic: NIGMS
award_notice_date: 2022-06-06
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: GM
serial_number: 129532
program_official: ZHAO, XIAOLI
project_start_date: 2018-09-01
project_end_date: 2023-05-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 10399494
contact_pi: STARR, MARLENE ELENA
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTSepsis pathophysiology involves activation of both pro- and anti-inflammatory responses along with alterationsin thrombotic and metabolic pathways. We previously revealed that genes for several inflammatory andthrombotic mediators are highly expressed in visceral adipose tissues during sepsis; however what causes thefat tissue to be so reactive and whether adipose-derived factors are mediators of sepsis is currently not known.Our preliminary data using both a preclinical mouse model of sepsis as well as patient-derived samplessuggest that visceral fat is the major source of plasminogen activator inhibitor type 1 (PAI-1) a pro-thromboticfactor which is implicated in the pathogenesis of sepsis and multi-organ failure. In addition we recently foundthat gamma delta ()-T cells a subset of innate-like T cells are surprisingly abundant in visceral fat tissue.These findings have led to our hypothesis that these cells are responsible for PAI-1 overproduction by adiposetissues during sepsis and contribute to the development of organ injury. The major goals of this project are (1)to demonstrate that -T cells are key regulators of PAI-1 production in visceral fat tissue and (2) to establishthat visceral fat-derived PAI-1 promotes organ injury during sepsis. To achieve these goals a series of ex vivoadipose explant culture experiments utilizing tissues from several transgenic mouse strains will be performedand visceral fat tissues will be surgically removed or transplanted from wild-type to PAI-1 knockout mice.Completion of this project will establish the concept that overproduction of PAI-1 from visceral fat contributes tothe pathophysiology of sepsis-associated organ injury and reveal key mechanisms for PAI-1 overproduction.This information will aid in the development of future therapeutic strategies to reduce sepsis severity.

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

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


application_id: 10409129
project_number: 3R01AG062550-03S1
project_title: Examining the Effects of the Neuroprotective APOE2 Allele on Peripheral Immunometabolism
administering_ic: NIA
award_notice_date: 2021-07-15
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: AG
serial_number: 062550
suffix: S1
program_official: BARRETT, PAUL JOHN
project_start_date: 2019-04-01
project_end_date: 2024-03-31
contact_pi_person_id: 11146000
contact_pi: JOHNSON, LANCE ALLEN
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:
Examining the Effects of the Neuroprotective APOE2 Allele on Peripheral ImmunometabolismApolipoprotein E (APOE) is an apolipoprotein involved in the transport of cholesterol and phospholipids in thebrain contributing to lipid homeostasis by regulating cholesterol triglycerides and phospholipid metabolism andtransport throughout the body. Three isoforms of APOE exist (E2 E3 and E4) and confer various risks forAlzheimers disease (AD). The APOE4 allele found in approximately 14% of the population provides the largestrisk for AD through mechanisms not completely known. Interestingly the APOE2 allele found in about 8% of thepopulation is neuroprotective. APOE2 is associated with reduced AD risk slower cognitive decline andincreased longevity. The parent grant to support this project focuses on finding novel biomarkers to predict latentdisease and provide new molecular targets for the prevention and treatment of AD. The funded project makesuse of whole-body energy expenditure measured by indirect calorimetry to investigate the underlying metabolicdifferences between APOE isoforms and how they associate with cognitive function. In conjunction with themetabolic changes observed in AD patients and cognitively healthy E4 individuals increased neuroinflammationand abnormal immunological responses have also recently been described. This provides the impetus for thecurrent proposal in which we aim to find meaningful peripheral biomarkers of latent disease with respect toimmunological dysfunctions associated with APOE4 carriage. The goal of this project is to elucidate differencesbetween immune cells known as peripheral blood mononuclear cells (PBMCs) of E2 individuals in comparisonto higher risk E3 and E4. It is well established that innate immune responses invoke metabolic reprogrammingin microglia and our lab has observed metabolic changes between both brain-derived microglia and peripheralmacrophages from the different APOE genotypes. Previous research in our laboratory identified a shift in themetabolic preference of E4 astrocytes from oxidative phosphorylation to aerobic glycolysis a metabolic shift thatcan increase inflammatory mediators like lactate providing further justification to examine immunometabolismin the context of APOE in humans. Using transcriptomic and metabolomics approaches the current project willuse PBMCs isolated from the blood of APOE genotyped study participants to shed light on the mechanisms bywhich E4 individuals respond to inflammatory stimuli with the hypothesis that E4 peripheral immune cells exhibitsimilar pro-inflammatory phenotypes as microglia causing a metabolic shift within the cell toward aerobicglycolysis while E2 cells favor oxidative phosphorylation.

project_terms:
Alleles;Alzheimer's Disease;Alzheimer's disease patient;Alzheimer's disease risk;Apolipoprotein E;Apolipoproteins;Astrocytes;Biological Markers;Blood;Brain;Cells;Cholesterol;Cholesterol Homeostasis;Cognitive;Disease;Energy Metabolism;Exhibits;Funding;Genotype;Goals;Homeostasis;Human;Immune;Immune System Diseases;Immune response;Impaired cognition;Indirect Calorimetry;Individual;Inflammation Mediators;Inflammatory;Innate Immune Response;Laboratories;Light;Lipids;Longevity;Measures;Metabolic;Microglia;Molecular Target;Oxidative Phosphorylation;Participant;Peripheral;Peripheral Blood Mononuclear Cell;Persons;Phenotype;Phospholipid Metabolism;Phospholipids;Population;Prevention;Protein Isoforms;Research;Risk;Stimulus;Triglyceride Metabolism;aerobic glycolysis;cognitive function;high risk;macrophage;metabolomics;neuroinflammation;novel marker;parent grant;preference;protective effect;transcriptomics

public_health_relevance:
Project NarrativeApolipoprotein E (APOE) has three common isoforms that exist in the human population; APOE2 provides aprotective effect against Alzheimers disease (AD) while APOE4 increases the risk and onset. Currently thereare no reliable blood markers for assessing a persons risk for AD. This project aims to study the effects ofAPOE on cells of the blood as an indication of its effects within the brain.


application_id: 10409098
project_number: 3P30CA177558-09S2
project_title: CCSG Supplement: Childhood Cancer Survivors
administering_ic: NCI
award_notice_date: 2021-09-24
opportunity_number: PA-20-272
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S2
program_official: ROBERSON, SONYA
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACTChildhood cancer survivors residing in rural areas many of whom travel to urban-based cancer treatmentcenters may face particular challenges receiving follow-up care when returning to their home communities.Although many rural childhood cancer survivors continue to receive at least some follow-up services fromcancer treatment centers local primary care professionals (PCPs) could play an important role in attenuatingrural/urban disparities in childhood cancer survivors access to follow-up care. Yet we have very littleinformation about the organizational barriers to delivering follow-up care within primary care practices (e.g.organizational support for cancer follow-up care costs and technical support for implementing telehealth forfollow-up care consultations and partnerships with cancer treatment centers). Similarly we have very littleinformation about organizational factors associated with access to follow-up care from the parent perspective(e.g. the acceptability of follow-up services delivered by local or nearby PCPs the acceptability of telehealthvisits with PCPs or cancer treatment centers and the accessibility of local or nearby PCPs). This project will examine rural/urban disparities in childhood cancer survivors organizational barriers tofollow-up care from both the primary care physician (PCP) and parent perspective. We will conduct qualitativeinterviews among a sample of 20 PCPs serving rural areas to evaluate their practices barriers to deliveringfollow-up care to childhood cancer survivors. Simultaneously we will conduct quantitative surveys among asample of 200 parents (100 rural 100 urban) of childhood cancer survivors to evaluate their childrens barriersto follow-up care receipt preferences and experiences. Specific aims are: 1. To investigate PCPs perceivedabilities and experiences organizational barriers and formal and informal policy barriers to delivering follow-upcare for childhood cancer survivors; and 2. To investigate the parent perspective of barriers and facilitatorsto the receipt of follow-up care preferences for a combined cancer treatment center/local or nearby PCPmodel of follow-up care and preferences for telehealth vs. in-person follow-up care. Kentucky provides a unique setting to address these concerns because it has a strong cancer registry andrelatively high childhood cancer incidence rates especially in the rural and highly impoverished Appalachianregion. The findings will inform the potential development implementation or expansion of follow-up servicesfor childhood cancer survivors residing in rural areas including those served by the UK Markey Cancer Center.

project_terms:
Address;Adult;Aftercare;Appalachian Region;Attenuated;Cancer Center;Cancer Center Support Grant;Cancer Patient;Caring;Child;Clinic;Communities;Consultations;Detection;Development;Face;Funding;Health;Health Professional;Health system;Healthcare;Home;Incidence;Insurance;Interview;Kentucky;Longterm Follow-up;Malignant Childhood Neoplasm;Malignant Neoplasms;Modeling;Monitor;Outcome;Parents;Persons;Play;Policies;Policy Maker;Poverty;Primary Care Physician;Primary Health Care;Regional Cancer;Research;Role;Rural;Sampling;Services;Societies;Surveys;Travel;Treatment Side Effects;Universities;Visit;base;cancer recurrence;cancer risk;cancer therapy;care costs;care preference;childhood cancer survivor;experience;follow-up;improved;neoplasm registry;preference;rural area;rural dwellers;satisfaction;survivorship;telehealth;treatment center;urban area;urban disparity

public_health_relevance:
NARRATIVEThis study will provide new information about rural/urban disparities in childhood cancer survivors barriersto follow-up care. Health care professionals health system managers and policy makers may apply thestudy findings to better meet the continued health care needs of childhood cancer survivors residing inrural and urban areas of the U.S.


application_id: 10408992
project_number: 2R24OD010435-20A1
project_title: Research Resources for Model Amphibians
administering_ic: OD
award_notice_date: 2022-03-15
opportunity_number: RFA-OD-19-027
application_type: 2
activity_code: R24
ic: OD
serial_number: 010435
suffix: A1
program_official: CONTRERAS, MIGUEL A
project_start_date: 2001-10-01
project_end_date: 2026-02-28
study_section: Special Emphasis Panel[ZRG1 GGG-G (55)]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: SMITH, JERAMIAH JAMES
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
project_terms:
Achievement;Address;Adult;Ambystoma;Ambystoma mexicanum;Amphibia;Animal Model;Area;Base Sequence;Bioinformatics;Biology;Biomedical Research;Body part;Brain;ChIP-seq;Chromatin;Chromosomes;Communities;Complex;DNA Binding;DNA sequencing;Data;Data Set;Development;Disease model;Embryo;Enhancers;Ensure;Environment;Epigenetic Process;Funding;Gene Expression;Generations;Genes;Genetic;Genetic Transcription;Genetic Variation;Genome;Genomics;Growth;Haploidy;Histones;Human;Hybrids;Laboratories;Limb structure;Methods;Modeling;Molecular;Natural regeneration;Phase;Positioning Attribute;Post-Translational Protein Processing;Protocols documentation;Publishing;Reagent;Recommendation;Regenerative research;Repetitive Sequence;Research;Research Personnel;Resources;Salamander;Sampling;Site;Spinal Cord;System;Tail;Tetrapoda;Tigers;Time;Tissues;Translating;Untranslated RNA;Variant;base;bioinformatics resource;cell type;data dissemination;data sharing networks;design;empowerment;experience;genetic pedigree;genome browser;genome editing;genome resource;genome-wide analysis;genomic data;histone-binding proteins;human tissue;improved;innovation;knowledgebase;limb regeneration;promoter;regeneration model;stem cells;tissue regeneration;user-friendly;web portal


application_id: 10405582
project_number: 5R01DA048876-04
administering_ic: NIDA
award_notice_date: 2022-05-20
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: DA
serial_number: 048876
program_official: LYNCH, SEAN EDWARD WINTERS
project_start_date: 2019-08-01
project_end_date: 2025-05-31
study_section: Community Influences on Health Behavior Study Section[CIHB]
contact_pi_person_id: 6264981
contact_pi: OSER, CARRIE BETH
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
budget_start_date: 2022-06-01
project_title:
DAT18-08 Geographic variation in Opioid Addiction Treatment (GATE) study: Multi-Level Factors Influencing MAT Use Other Treatment & Adverse Outcomes among Re-entering Rural and Urban Prisoners

project_abstract:
ABSTRACT: As outlined in DAT18-08 NIDA has a strong interest in understanding treatment utilization amongpersons with opioid use disorders (POUDs) as they transition from prison to the community because treatingindividuals with opioid use disorder (OUD) simultaneously improves public health and public safety. Kentuckyis in the midst of an opioid crisis with many POUDs cycling through the criminal justice system each year. Whileevidenced-based medications for addiction treatment (MAT) exist for treating OUD MAT is underutilized withinprisons which elevates the risk of relapse and overdose when POUDs are released and re-enter theircommunities. Research is scant regarding the multi-level factors associated with offenders willingness to initiateMAT while in prison and their continued engagement in treatment after release. Furthermore rural and urbanpopulations have not been compared. In response to NIDA DAT18-08 we propose to conduct the high-impactGeographic variation in Addiction Treatment (GATE) study which will address the knowledge gap on multi-levelfactors influencing prison-based extended-release injectable naltrexone (XR-NTX) initiation as well as examinepredictors of post-release MAT use and adverse outcomes (i.e. relapse overdose recidivism) among both ruraland urban POUDs. This mixed methods study employs a social ecological framework to understand individualcharacteristics that influence MAT initiation and adverse outcomes as well as contexts more distal to theindividual including social networks and structural factors. The specific aims of the GATE study are: 1) toidentify the individual personal network and structural factors associated with XR-NTX initiation inprison among rural as compared to urban POUDs and 2) to examine the individual personal networkand structural factors predicting MAT use treatment use and adverse outcomes in the communityamong re-entering rural as compared to urban POUDs over time. A prospective observational longitudinalcohort study will be conducted with 500 POUDs using survey and social network data collected in prison andat 6- and 12-months post-release to explore multi-level rural-urban variation in key outcomes. In-depth guidedqualitative interviews will be conducted with POUDs prison-based treatment staff and social service clinicians.To maximize rigor and reproducibility we will employ a concurrent triangulation strategy whereby qualitativeand quantitative data contribute equally to the analysis and are used for cross-validation. This study is led by aqualified interdisciplinary team and is the first mixed methods study examining the processes of social influencesthat occur in rural and urban social networks as POUDs transition from prison back to geographically diversecounties. The GATE study will enhance our ability to address the opioid epidemic within the correctional contextsof prisons and community supervision by informing process improvement efforts for prison-based MAT initiationand post-release retention in care applying network science findings to improve the re-entry planning processand establishing the foundation for future R-level intervention applications.

project_terms:
Address;Aftercare;Back;Caring;Characteristics;Communities;Continuity of Patient Care;County;Crime;Criminal Justice;Data;Distal;Drug Screening;Drug usage;Economically Deprived Population;Education;Elements;Enrollment;Equipment and supply inventories;Foundations;Future;Geographic Locations;Geography;Goals;Health;Health Services Accessibility;Healthcare;Imprisonment;Individual;Injectable;Intervention;Interview;Kentucky;Knowledge;Literature;Longitudinal cohort study;Measures;Mediating;Medicaid;Mentors;Methods;Naltrexone;National Institute of Drug Abuse;Opiate Addiction;Outcome;Outpatients;Overdose;Persons;Pharmaceutical Preparations;Pilot Projects;Predictive Factor;Prisoner;Prisons;Process;Public Health;Recovery;Relapse;Reproducibility;Research;Resources;Rural;Rural Appalachia;Rural Population;Safety;Sampling;Science;Social Network;Social Work;Structure;Substance abuse problem;Supervision;Support Groups;Surveys;System;Time;Treatment outcome;United States National Institutes of Health;Urban Population;Validation;Variant;Woman;addiction;adverse outcome;base;effective therapy;evidence base;experience;follow-up;geographic difference;improved;interest;offender;opioid epidemic;opioid misuse;opioid use disorder;primary outcome;programs;prospective;recidivism;recruit;relapse risk;response;social;social influence;social structure;uptake;willingness

public_health_relevance:
PROJECT NARRATIVE To improve future treatment interventions for persons with opioid use disorders (POUDs) who areincarcerated this study compares the multi-level factors influencing prison- and community-based initiation ofmedications for addiction treatment (MAT) and associated post-release outcomes under real-world conditionsin rural Appalachian Kentucky an economically-deprived region with limited service availability and moreresource-rich urban counties. This study will make significant contributions to public health and public safetyby examining how rural-urban variation in personal social network characteristics support or impede the effortsof POUDs to access continuing treatment post-release achieve stable recovery and desist from crime duringthe vulnerable re-entry period.


application_id: 10405572
project_number: 5R01DC019054-03
project_title: GIPC3 multifunctional myosin adaptor in mammalian auditory hair cells
administering_ic: NIDCD
award_notice_date: 2022-05-19
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DC
serial_number: 019054
program_official: FREEMAN, NANCY
project_start_date: 2020-06-10
project_end_date: 2025-05-31
study_section: Special Emphasis Panel[ZRG1-IFCN-E(02)M]
contact_pi_person_id: 8360158
contact_pi: FROLENKOV, GREGORY I
other_pis: VANDER KOOI, CRAIG
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:
GIPC3 a member of G-Interacting Protein C-terminus (GIPC) family is known to be essential forhearing. Eleven mutations in GIPC3 spread throughout its three structural domains cause inheritedautosomal recessive hearing loss. However the molecular basis for GIPC3 function in the auditorysystem and the mechanisms by which these human mutations result in hearing loss are unknown. Wehave recently determined the structure of GIPC3 bound to a prototypical receptor and determined themolecular mechanism of GIPC3 activation and its subsequent binding to MYO6 the unconventionalmyosin that is expressed in the auditory hair cells and is essential for hearing. These biochemical andstructural studies allowed us to predict the effects of known deafness-related mutations in GIPC3 on itsactivation and MYO6 binding. We have generated two new mouse models one that is lacking functionalGIPC3 and another one with a W301X point mutation in Gipc3 that corresponds to a mutation with themost severe auditory phenotype in humans. This study will explore the central hypothesis that GIPC3 hasa dual role in the auditory hair cells. We hypothesize that in stereocilia GIPC3 is involved in shapingmechanotransduction and hair bundle structure through its interactions with CDH23/myosin-VIIa andmyosin-XVa respectively. In the cell body GIPC3 is essential for apical endocytosis at the pericuticularneckless region due to its interaction with myosin-VI. All these functions are crucial for normal hearing.However the exact molecular mechanisms that determine the resting tension in the mechanotransduc-tion machinery as well as gradation of stereocilia heights and diameters in the auditory hair cell bundlesare still enigmatic. Likewise very little is known about molecular mechanisms and even the role ofpericuticular neckless endocytosis in the hair cell function. The expected outcomes of this study are touncover (a) the precise mechanism of deafness associated with GIPC3 deficiency and (b) thephysiological role of GIPC3 in hair cell functions especially in mechanotransduction formation of the hairbundle architecture and endocytosis at the pericuticular neckless. Deciphering the function of GIPC3protein and its known mutations is a critical step towards the development of therapies for the treatmentand/or prevention of GIPC3-dependent deafness and hearing loss.

project_terms:
Actins;Adopted;Affect;Age;Age-Months;Ankle;Apical;Architecture;Auditory;Auditory system;Belief;Binding;Biochemical;Biochemistry;C-terminal;CDH23 gene;Cadherin Domain;Caliber;Cell physiology;Cells;Cellular Structures;Complex;Consensus;Coupling;Custom;Data;Development;Dimerization;EPS8 gene;Endocytosis;Family;Family member;Hair;Hair Cells;Hearing;Human;Inherited;Inner Hair Cells;Knowledge;Label;Labyrinth;Link;MYO7A gene;Mechanics;Mediating;Molecular;Motor;Mouse Strains;Mus;Mutation;Myosin ATPase;N-terminal;Outcome Study;Patients;Phenotype;Physiological;Point Mutation;Positioning Attribute;Prevention;Protein Family;Proteins;Receptor Activation;Reporting;Rest;Role;Shapes;Site;Structure;Surface;Synaptic Transmission;Therapeutic;Time;Ubiquitin;Vesicle;WHRN gene;base;cell type;deaf;deafness;dimer;hearing impairment;in vivo;insight;live cell imaging;mechanotransduction;member;mouse model;mutant;myosin VI;myosin XVA;nanobodies;normal hearing;novel;prevent;receptor;receptor binding;response;structural biology;therapy development;trafficking;two-photon;uptake

public_health_relevance:
Advancement in our understanding of molecular mechanisms of key molecules in the inner ear isa prerequisite to developing therapeutic strategies for hearing loss. The studies outlined in thisproposal explore structural and functional effects of all eleven reported patient mutations in GIPC3protein that have been identified to date as a cause of non-syndromic autosomal recessive deafnessDFNB72. In addition since GIPC3 is a previously unexplored molecular partner of other deafnessproteins our study will provide fundamental knowledge into the pathophysiological mechanisms of otherforms of deafness that will help to reduce the burden of human hearing loss.


application_id: 10405425
project_number: 5R01DE022597-09
project_title: Bacterial peptidylarginine deiminase a link between gums and joint disease
administering_ic: NIDCR
award_notice_date: 2022-03-29
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: DE
serial_number: 022597
program_official: MCNEALY, TAMARA L
project_start_date: 2013-02-01
project_end_date: 2024-03-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SummaryPorphyromonas gingivalis a keystone pathogen in chronic periodontitis secretes a large variety of virulencefactors including an enzyme peptidylarginine deiminase (PAD) unique for pathogenic species of thePorphyromonas genus. Alike human endogenous PADs the bacterial enzyme converts arginine residues inproteins to citrulline but it has a strong preference for C-terminal Arg. We postulated that P. gingivalis PAD(PPAD) activity not only contributes to pathogenesis of periodontitis but also it may be involved in thebreakdown of immunotolerance and the development of rheumatoid arthritis (RA) a diseases driven byautoantibodies targeting citrullinated epitopes. This contention is supported by findings that PPAD inconjunction with Arg-specific gingipain proteases (Rgps) can generate a large spectrum of citrullinatedpeptides derived from bacterial and host proteins including fibrinogen and enolase  both acceptedautoantigens in RA. Also citrullinated proteins of P. gingivalis stimulate human gingival fibroblasts (HGF) toproduce prostaglandin E2 (PGE2) one of the most potent mediators of bone resorption implicated in thepathogenesis of PD and RA. Moreover our unpublished data show that both resting and P. gingivaliscitrullinome-stimulated HGFs derived from periodontitis patients produce significantly more PGE2 than cellsfrom healthy donors. Finally we discovered two allelic forms of the ppad gene among P. gingivalis clinicalisolates one encoding a superactive isoform of the enzyme which crystal structure suggests that it bindssubstrates with higher affinity than the other form of PPAD. The tighter substrate binding may contribute toproposed second important function of PPAD as the carrier protein of haptens (bacteria and/or host protein-derived citrullinated peptides) presented to B cell followed by T cell activation and the breakdown ofimmunotolerance in a hapten/carrier mechanism. Based on these findings we postulate that PPAD is directlyresponsible for the breakdown of immunotolerance and subsequent anti-citrullinated protein antibody (ACPA)production - key pathological events preceding clinical onset of RA; and the severity of PD and its link to RA isassociated with the occurrence of a superactive variant of PPAD expressed by subset of P. gingivalis strains.To experimentally verify these hypotheses we propose the following specific aims: (i) investigate the functionalrelevance of citrullinated bacterial proteins in pathological interactions between P. gingivalis and fibroblasts; (ii)determine if PPAD targeting by T cells provides help for the production of ACPA through a hapten/carriermechanism; and (iii) analyse the prevalence of P. gingivalis strains carrying the superactive PPAD gene in thecontext of the severity of PD and relation to associated RA.Successful completion of this project will drive the field forward by providing a novel perspective to theunderstanding the pathogenesis of PD-RA associations thus offering venues to develop novel strategies totreat these debilitating diseases.

project_terms:
Affinity;Alleles;Alveolar Bone Loss;Animal Model;Antibodies;Antibody Formation;Antigens;Arginine deiminase;Autoantibodies;Autoantigens;Autoimmune;B-Lymphocytes;Bacteria;Bacterial Proteins;Binding;Bone Resorption;C-terminal;Carrier Proteins;Cells;Characteristics;Chronic;Citrulline;Clinical;Collaborations;Collagen Arthritis;Communities;Complex;Crystallization;Data;Development;Diagnosis;Dinoprostone;Disease;Enzymes;Epitopes;Etiology;Event;Fibrinogen;Fibroblasts;GTP-Binding Proteins;Genes;Gingiva;Gingival Crevicular Fluid;Grant;HLA-DR4 Antigen;Haptens;Human;Immune response;Immunize;Inbred C3H Mice;Individual;Inflammation;Inflammatory Arthritis;Inflammatory Response;Link;Mammals;Mediator of activation protein;Mucous Membrane;Norway;Pathogenesis;Pathogenicity;Pathologic;Patients;Peptide Hydrolases;Peptides;Periodontal Ligament;Periodontitis;Periodontium;Play;Porphyromonas;Porphyromonas gingivalis;Prevalence;Process;Production;Protein Isoforms;Protein-arginine deiminase;Proteins;Research;Rest;Rheumatoid Arthritis;Role;Saliva;Self Tolerance;Serum;Severities;Site;Solid;Specimen;Structure;Surface;Symptoms;T-Cell Activation;T-Lymphocyte;Testing;Tissues;Universities;Variant;Virulence;Virulence Factors;arthropathies;base;biobank;citrullinated protein;cohort;dysbiosis;enolase;gingipain;joint destruction;mouse model;novel;novel strategies;oral bacteria;pathogen;periodontopathogen;preference;response

public_health_relevance:
NarrativePorphyromonas gingivalis an established periodontal pathogen is able to produce citrullinated proteinsthrough the action of an enzyme (PPAD) unique to this bacterium. Citrullinated bacterial proteins are able toinduce human fibroblasts to produce prostaglandin E2 (PGE2) which can stimulate the bone resorption processimplicated in the pathogenesis in periodontitis and rheumatoid arthritis (RA). PPAD may also directly promotebreakdown of self-tolerance in susceptible individuals to generate autoantibodies against citrullinated self-proteins in the development of RA.


application_id: 10405248
project_number: 2KL2TR001996-05A1
project_title: Institutional Career Development Core
administering_ic: NCATS
award_notice_date: 2021-07-30
opportunity_number: PAR-18-940
application_type: 2
activity_code: KL2
ic: TR
serial_number: 001996
suffix: A1
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2026-06-30
study_section: ZTR1-SRC(99)
contact_pi_person_id: 1901822
contact_pi: KELLY, THOMAS H.
other_pis: SUPINSKI, GERALD S.
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Academy;Address;Arts;Award;Biomedical Research;Career Choice;Characteristics;Clinical;Clinical Research;Clinical Sciences;Clinical and Translational Science Awards;Collection;Communities;Competence;Complex;Dentistry;Development;Discipline;Discipline of Nursing;Educational Curriculum;Educational Technology;Elderly;Engineering;Extramural Activities;Faculty;Fellowship;Fostering;Foundations;Funding;Future;Graduate Education;Growth;Health;Health Sciences;Human;Individual;Institution;Ireland;Kentucky;Leadership;Life;Longevity;Medical Education;Medical Students;Medicine;Mentors;Methods;Modeling;Monitor;Mosses;National Research Council;Nature;Operative Surgical Procedures;Outcome;Pharmacy facility;Physicians;Pilot Projects;Policies;Principal Investigator;Process;Public Health Education;Publishing;Randomized Controlled Trials;Rehabilitation therapy;Reporting;Research;Research Methodology;Research Personnel;Research Training;Residencies;Science;Scientist;Sports;Sum;Time;Training;Training Programs;Training Support;Training and Education;Translational Research;Underrepresented Minority;United States National Academy of Sciences;United States National Institutes of Health;Universities;Washington;Yin;biomedical informatics;career;career development;clinical center;cohort;college;design;education research;empowered;experience;instructor;interest;multidisciplinary;next generation;prenatal;preservation;programs;recruit;research and development;retention rate;skills;student mentoring;undergraduate student;working group


application_id: 10405236
project_number: 2UL1TR001998-05A1
project_title: Kentucky Center for Clinical and Translational Science
administering_ic: NCATS
award_notice_date: 2021-07-30
opportunity_number: PAR-18-940
application_type: 2
activity_code: UL1
ic: TR
serial_number: 001998
suffix: A1
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2026-06-30
study_section: ZTR1-SRC(99)
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Academic Medical Centers;Address;Aging;Agriculture;Appalachian Region;Arts;Award;COVID-19 pandemic;Cardiovascular system;Center for Translational Science Activities;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Clinical and Translational Science Awards;Collaborations;Communities;Complement;Computer software;County;Development;Diabetes Mellitus;Discipline;Distress;Economics;Engineering;Environment;Epidemic;Fostering;Funding;Future;Generations;Grant;Growth;Health;Health Sciences;Health Status;Healthcare;Home;Institutes;Institution;Integrated Health Care Systems;Intervention;Investments;Kentucky;Lead;Leadership;Longevity;Malignant Neoplasms;Medical;Medical center;Minority Access;Mission;Modeling;Neurosciences;Obesity;Participant;Patients;Phase;Policies;Population;Positioning Attribute;Quality of life;Reporting;Research;Research Support;Resources;Rural;Rural Community;Rural Health;Science;Sports;Students;Substance Use Disorder;Substance abuse problem;Translating;Translational Research;Translations;Underserved Population;United States;Universities;West Virginia;Work;austin;clinical center;clinical research site;collaborative environment;college;community based participatory research;diversity and inclusion;health disparity;health equity;health inequalities;improved;innovation;inter-institutional;new technology;opioid abuse;programs;recruit;response;rural area;rural underserved


application_id: 10405101
project_number: 5U01DA051079-03
project_title: Development of a Long-acting Enzyme Therapy for Treatment of Cocaine Abuse
administering_ic: NIDA
award_notice_date: 2022-04-27
opportunity_number: PAR-18-219
application_type: 5
activity_code: U01
ic: DA
serial_number: 051079
program_official: SOUSA, JASON CARLOS
project_start_date: 2020-08-15
project_end_date: 2026-04-30
study_section: ZDA1-IXN-O(11)S
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Cocaine abuse is a major public health problem that directly or indirectly affects most communities andfamilies. There is still no FDA-approved medication specific for treatment of cocaine dependence or overdose.Disastrous medical and social consequences of cocaine abuse have made the development of an anti-cocainemedication a high priority. Accelerating cocaine metabolism that produces biologically inactive metabolites viathe most favorable cocaine-metabolizing pathwaycocaine hydrolysis catalyzed by humanbutyrylcholinesterase (BChE) in plasmais recognized as the most efficient treatment strategy for cocaineoverdose and dependence. Since the catalytic efficiency of wild-type BChE against the naturally occurring (-)-cocaine is low we have designed and discovered a set of BChE mutants known as cocaine hydrolases(CocHs) with at least 1000-fold improved catalytic efficiency against (-)-cocaine compared to wild-type BChE.Preclinical and clinical data for the first one of our previously discovered CocHs has demonstrated the promiseof enzyme therapy approach to the treatment of cocaine dependence. Our more recently designed anddiscovered novel CocH entity denoted as CocH5-Fc(M6) which has not only further improved catalyticefficiency against cocaine but also a considerably prolonged biological half-life. It has been demonstrated thata single dose of CocH5-Fc(M6) can be used to completely block cocaine-induced physiological behavioraland reinforcing effects for a long period of time in animal models. In addition a stable CHO cell line capable ofefficiently expressing CocH5-Fc(M6) and the corresponding master cell bank (MCB) have been developedalong with establishment of the robust upstream and downstream protein production processes ready forlarge-scale CocH5-Fc(M6) protein production. Built on the encouraging progress of our rational designdiscovery and development of the highly efficient long-acting CocH entity CocH5-Fc(M6) the proposed newproject is focused on further development of CocH5-Fc(M6) as a novel therapeutic candidate for cocainedependence treatment including large-scale production of the CocH5-Fc(M6) protein material using thedeveloped MCB and established robust upstream and downstream protein production processesinvestigational new drug (IND)-enabling studies and first-in-human (FIH) clinical trials. The obtained clinicaldata about the safety pharmacokinetics and ex vivo pharmacodynamics of CocH5-Fc(M6) in humans willenable us to rationally design the most appropriate dosage regimen for future further clinical trials to determinethe clinical efficacy of CocH5-Fc(M6) in cocaine-dependent patients. Thus this investigation will move apromising candidate of the highly desired enzyme therapy closer toward FDA approval for cocainedependence treatment.

project_terms:
Affect;Animal Model;Antibodies;Behavioral;Binding;Binding Sites;Biological;Biological Assay;Butyrylcholinesterase;Cell Line;Chinese Hamster Ovary Cell;Clinical Data;Clinical Research;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependence;Communities;Development;Dose;Double-Blind Method;Drug Kinetics;Enzymes;FDA approved;Family;Formulation;Future;Half-Life;Human;Hydrolase;Hydrolysis;Immunoglobulins;Infusion procedures;Intake;Investigation;Investigational Drugs;Legal patent;Medical;Metabolic;Metabolism;Monoclonal Antibodies;Neuraxis;Neurons;Outcome;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phase I Clinical Trials;Phase II Clinical Trials;Phase II/III Trial;Physiological;Placebo Control;Plasma;Process;Production;Proteins;Public Health;Randomized;Rattus;Regimen;Safety;Schedule;Self Administration;Serum Albumin;Time;Vaccines;Work;base;cell bank;clinical efficacy;cocaine overdose;cocaine self-administration;design;dosage;drug of abuse;efficacy testing;enzyme therapy;first-in-human;improved;in vivo;large scale production;mutant;novel;novel therapeutics;placebo controlled study;placebo group;pre-clinical;preclinical safety;rational design;safety testing;small molecule;social;therapeutic candidate;treatment group;treatment strategy

public_health_relevance:
The outcomes of this investigation will enable us to design the most appropriate dosage regimen for futurefurther clinical trials to determine the clinical efficacy of the long-acting cocaine hydrolase in cocaine-dependent patients.


application_id: 10404559
project_number: 5R01AI095032-09
project_title: Cooperation of CD8+ T cells and phagocytes to eliminate Toxoplasma cysts
administering_ic: NIAID
award_notice_date: 2022-05-24
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AI
serial_number: 095032
program_official: PESCE, JOHN T
project_start_date: 2012-01-01
project_end_date: 2024-05-31
study_section: HIV Coinfections and HIV Associated Cancers Study Section[HCAC]
contact_pi_person_id: 1882071
contact_pi: SUZUKI, YASUHIRO
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Chronic infection with Toxoplasma gondii can reactivate and cause life-threatening toxoplasmic encephalitis inAIDS patients and other immunocompromised individuals. The basis of persistence of this chronic infection isthe tissue cyst. Thus eliminating T. gondii cysts from chronically infected individuals before they becomeseverely immunosuppressed will be able to prevent this serious disease. However there are currently nodrugs effective against the cysts. Our recent studies using a murine model uncovered that CD8+ immune Tcells have a potent activity to directly penetrate into the cysts and induce their elimination through perforin-mediated mechanisms. We also identified that the N-terminal region (amino acids 41-152) of dense granuleprotein (GRA) 6 (GRA6Nt) of the parasite presented by the H-2Ld molecule is a key antigen to activate the anti-cyst CD8+ T cells. Our studies also identified that Iba1+ microglia and Ly6C+ macrophages accumulate to thecysts during the T cell-initiated immune process and that these phagocytes kill T. gondii bradyzoites within thecysts at least in part by phagolysosome acidification. Based on these observations the proposed studies aredesigned to obtain the information required for proceeding towards development of a vaccine to activate CD8+T cells capable of targeting T. gondii cysts and eradicate chronic infection with this parasite in humans. Forthis purpose we need to determine whether GRA6Nt activates anti-cyst CD8+ T cells through human MHCclass I molecules since the MHC class I molecules present antigens to activate CD8+ T cells. Aim 1 willaddress this point by employing three transgenic mouse strains expressing either of the three major MHC classI supermotifs that cover 90% of human population. Once the anti-cyst T cells are primed these T cells need tobe recruited to cyst-containing cells and activated not only by recognizing T. gondii antigens but also byappropriate costimulatory molecules expressed on the cyst-containing cells. Our recent studies suggested aninvolvement of CXCL10 chemokine and inducible constimulator ligand (ICOSL) in these processes. Thus Aim2 will determine the roles of CXCL10 and ICOSL in recruitment and activation of anti-cyst CD8+ T cellsrespectively. Another critical but unsolved issue is that small numbers of cysts persist in the brains of infectedmice even in the presence of anti-cyst CD8+ T cells. Our recent study revealed that these persisting cystsexpress significantly greater levels of mRNA for selected GRA and rhoptry (ROP) proteins when compared tothe overall cyst population that exists in the absence of the T cells. Since GRAs and ROPs are secreted fromthe parasite into infected cells upregulated secretion of these selected GRAs and ROPs could play crucialroles in manipulating the functions of cyst-containing cells to prevent the attack by CD8+ T cells. Thus Aim 3focuses to determine whether these GRAs and ROPs play key roles in the evasion of the cysts from the T cellattack. We will also address the molecular mechanisms underlying this evasion process. The information fromthese studies will establish the basis for developing a novel method to eradicate chronic T. gondii infection.

project_terms:
Acquired Immunodeficiency Syndrome;Acute;Address;Amino Acids;Antigens;Brain;CD28 gene;CD8 Antigens;CD8-Positive T-Lymphocytes;CD86 gene;CD8B1 gene;CXCL10 gene;CXCR3 gene;Cell surface;Cells;Chronic;Combined Vaccines;Cyst;Cytoplasmic Granules;Disease;Epitopes;Excision;Funding;HLA-A2 Antigen;Histocompatibility Antigens Class I;Human;Immune;Immune Evasion;Immunity;Immunize;Immunocompromised Host;Immunologics;Individual;Interleukin-2;Knockout Mice;Life;Ligands;MHC Class I Genes;Mediating;Messenger RNA;Methods;Microglia;Molecular;Mouse Strains;Mus;N-terminal;Parasites;Patients;Phagocytes;Phagocytosis;Phagolysosome;Pharmaceutical Preparations;Play;Population;Process;Proteins;Role;System;T-Lymphocyte;Tissues;Toxoplasma;Toxoplasma gondii;Toxoplasmosis;Transgenic Mice;Tumor stage;Vaccines;base;chemokine;chronic infection;design;immunological intervention;immunosuppressed;improved;macrophage;mouse model;novel;pathogen;perforin;prevent;rab GTP-Binding Proteins;recruit;rhoptry;toxoplasmic encephalitis;vaccine development

public_health_relevance:
Toxoplasma gondii establishes a chronic infection by forming tissue cysts preferentiallyin the brain and reactivation of this chronic infection causes life-threatening toxoplasmicencephalitis in immunocompromised individuals such as those with AIDS. The proposedstudies aim to identify T. gondii antigen applicable to a vaccine for activating theprotective immunity capable of eliminating the cysts in humans and to uncover themechanisms that T. gondii employs to escape from the protective immunity. Thecombination of the vaccine and a treatment to block the escape mechanism of thepathogen will allow us to develop a novel method to eradicate this widespread chronicinfection in humans.


application_id: 10403971
project_number: 5R01GM127495-05
project_title: Exercise-enhanced resolution of inflammation
administering_ic: NIGMS
award_notice_date: 2022-05-09
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: GM
serial_number: 127495
program_official: NELSON, SHAKIRA M
project_start_date: 2018-09-01
project_end_date: 2024-05-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 11169883
contact_pi: HELLMANN, JASON L
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract:Frequent physical activity improves cardiovascular health and prolongs life span whereas physical inactivity isassociated with premature mortality and global burden of chronic disease. The salutary effects of exercise have beenextensively documented in the literature. Exercise promotes skeletal muscle growth cardiac hypertrophy and tissueangiogenesis and it improves cardiovascular disease (CVD) risk factor profile. Nevertheless the beneficial effects ofexercise extend beyond reduction in CVD risk factors (blood pressure lipids) involving mechanisms and processes thatremain largely unknown. This lack of mechanistic understanding underlying the salubrious effects of exercise limits itsoptimization in healthy individuals and hinders extension of its benefits to obese and diabetic individuals who thoughare most likely to gain from exercise cannot exercise or remain impervious to its benefits. Some investigators havesuggested that CVD risk factor-independent effects of exercise may relate to a decrease in inflammation. Inflammationis a carefully orchestrated systemic response targeted to degrade offending components clear tissue debris promotehealing and restore homeostasis. While escalation of inflammation leading to inflammatory cell invasion and cytokineproduction has been extensively studied less is known about how inflammation is resolved. Recent work has shownthat resolution of inflammation is mediated by specialized pro-resolving lipid mediators (SPMs) that limit neutrophilextravasation quell inflammatory signaling and promote macrophage phagocytosis. SPMs are necessary and sufficientto resolve inflammation by binding to cognate G-protein coupled receptors (GPCRs). We propose that the beneficialeffects of exercise relate to its ability to promote resolution of inflammation by stimulating the synthesis of pro-resolvingSPMs. Our preliminary data show that exercise-adapted mice display enhanced SPM synthesis accelerated neutrophilclearance and increased macrophage phagocytosis suggesting that exercise exerts beneficial effects on resolution ofinflammation. We also find that catecholamines which are transiently elevated by exercise activate SPM biosynthesisin macrophages and increase 5-lipoxygenase (5-LO) and 12/15-lipoxygenase (15-LO) enzymes that synthesize SPMs.These observations link processes activated by exercise to key components of inflammation-resolution and have led usto formulate the hypothesis that exercise-mediated production of catecholamines increases pro-resolving lipid mediatorsynthesis and enhances resolution of inflammation. The specific aims are: (1) Determine the effect of exercise onresolution; (2) Delineate the contribution of catecholamines in mediating the effect of exercise on resolution ofinflammation; (3) Elucidate the role of SPMs in exercise-enhanced resolution. Results of this project will generate newinsights into how exercise regulates inflammation; which processes mediate the beneficial effects of exercise; and howexercise affects the resolution of acute and chronic inflammation. Collectively these results would generate new knowledgeabout the processes by which exercise improves cardiometabolic health and inflammation-resolution. This knowledge couldlead to the development of new therapeutic interventions to enhance the benefits of exercise or simulate its salutary effectsin individuals resistant or recalcitrant to its beneficial effects or those unable to exercise.

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

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


application_id: 10403757
project_number: 3R44DC018763-02S1
project_title: Plug-And-Play Cochlear Electrode Array
administering_ic: NIDCD
award_notice_date: 2021-05-11
opportunity_number: PA-19-272
application_type: 3
activity_code: R44
ic: DC
serial_number: 018763
suffix: S1
program_official: MILLER, ROGER
project_start_date: 2020-05-01
project_end_date: 2023-04-30
study_section: Special Emphasis Panel[ZRG1-ETTN-G(12)B]
contact_pi_person_id: 11208190
contact_pi: JOHNSON, ANGELIQUE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 969965800
primary_uei: NPHRMGVU99E8
duns_number: 969965800
uei: NPHRMGVU99E8
fips: US
organization_id: 10030414
organization_name: MEMSTIM, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402022654
organization_country: UNITED STATES
project_abstract:
Project Summary/AbstractWorldwide approximately 466 million people suffer from disabling hearing loss. When conventional hearingaids provide no appreciable benefit cochlear implants are a solution. Current cochlear implants whilebeneficial in their use are limited in their capabilities by hand-assembly of wire-bundled electrode arrays. Handassembly is very costly extremely labor-intensive and inadequate in implementing new strategies inOtolaryngology for improving speech recognition and music appreciation.Advanced-manufacturing (microfabrication laser-machining etc.) has been deemed a superior replacement tothe hand-assembly of electrode arrays and many innovations have been made in this area. Howevercommercial suppliers have not adopted them. In large part due to mismatches between the flat 2D bond padsof advanced-manufactured arrays and the 3D feedthrough pins of commercial stimulators. As such theyrequire additional adapters that not only reintroduce hand-assembly but also add to the overall manufacturingcosts and clinical failures.MEMStim LLC proposes a plug-and-play advanced-manufacturing solution that relies heavily on 3D printing.By printing conductive and nonconductive silicones biocompatible pluggable arrays can be printed to any sizelength shape or thickness from several microns to tens of millimeters. Most importantly the integratedconnectors plug readily onto stimulators by way of a novel micro-socket technology. The micro-sockets arecompatible and slide right onto the feedthrough pins. The printer resolution can output pluggable connectorsthat are compatible with pin-to-pin pitches smaller than 100 m (edge-to-edge) allowing for enhancedminiaturization.In phase I work high performing stimulating electrode sites and extension cables were demonstrated.Additionally the feasibility of producing high performing plug-and-play connectors was demonstrated. The goalof this Phase II project is to monolithically integrate all three into the first-ever pluggable cochlear electrodearray. The Aims of the Phase II grant are: (1) Produce an integrated 3D printed plug-and-play cochlear arraythat complies with the functional electrical requirements of cochlear implants; (2) Produce a 3D printed plug-and-play cochlear array that complies with the durability requirements of cochlear implants; and (3) Produce3D printed plug-and-play cochlear array that complies with the biocompatibility and surgical safetyrequirements of cochlear implants. The end result will be the first-ever pluggable cochlear electrode arraywhich is functional and passes all the handling/use/safety tests that are necessary to seek approval from theFDA.

project_terms:
3-Dimensional;3D Print;Acoustic Nerve;Address;Adoption;Area;Cadaver;Charge;Clinical;Clinical Trials;Cochlea;Cochlear Implants;Devices;Drops;Electrodes;Electronics;Failure;Goals;Grant;Hand;Hearing;Hearing Aids;Human;Individual;Infection;Lasers;Length;Letters;Methods;Microfabrication;Miniaturization;Muscle;Music;Operative Surgical Procedures;Otolaryngology;Output;Phase;Play;Printing;Reaction;Reporting;Residual state;Resolution;Safety;Shapes;Silicones;Site;Slide;Specific qualifier value;Spinal Cord;System;Technology;Temporal bone structure;Testing;Thick;Tissues;Torsion;Welding;Work;biomaterial compatibility;cost;cytotoxicity;deep brain stimulator;electric impedance;genotoxicity;hearing impairment;histological studies;implantation;improved;innovation;interest;millimeter;neuroprosthesis;novel;preservation;response;safety testing;speech recognition;success;two-dimensional

public_health_relevance:
Project NarrativeWorldwide approximately 466 million people suffer from disabling hearing loss andCochlear implants are limited in their capabilities by the hand-assembly of wire-bundledelectrode arrays. Advanced-manufacturing (microfabrication laser-machining etc.) hasbeen deemed a superior replacement to the hand-assembly of electrode arrays but areincompatible with commercial stimulators. MEMStim LLC will produce plug-and-play 3Dprinted cochlear electrode arrays that readily compatible with commercial stimulatorsand can be used to implementing new strategies in Otolaryngology for improvingspeech recognition and music appreciation and device miniaturization.


application_id: 10403589
project_number: 5K23AA029198-02
project_title: Lactobacillus rhamnosus: A Novel Probiotic Therapy for treating Alcohol Use Disorder
administering_ic: NIAAA
award_notice_date: 2022-05-10
opportunity_number: PA-20-206
application_type: 5
activity_code: K23
ic: AA
serial_number: 029198
program_official: WANG, JOE
project_start_date: 2021-05-10
project_end_date: 2026-04-30
study_section: Clinical, Treatment and Health Services Research Study Section[AA-3]
contact_pi_person_id: 11616840
contact_pi: VATSALYA, VATSALYA
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abstinence;Adverse effects;Adverse event;Albumins;Alcohol consumption;Alcoholic beverage heavy drinker;Alcohols;Animals;Attenuated;Award;Behavior Therapy;Behavioral;Bilirubin;Biochemical Markers;Biochemistry;Biological Assay;Biological Markers;Blood;Blood Circulation;Brain;Chronic;Clinical;Clinical Research;Complex;Data;Diagnosis;Dietary Fiber;Disease;Disulfiram;Double-Blind Method;Endotoxemia;Enrollment;Equipment and supply inventories;FDA approved;Faculty;Fermentation;Frequencies;Functional disorder;Goals;Grant;Health;Healthcare;Heavy Drinking;Hepatitis;Human;Inflammation;Inflammatory;Intervention;Intestinal permeability;Knowledge;Lactobacillus casei rhamnosus;Lead;Lipopolysaccharides;Liver;Liver diseases;Mediating;Medical;Mentors;Mentorship;Methodology;Naltrexone;National Institute on Alcohol Abuse and Alcoholism;Neurotransmitters;Outcome;Pathway interactions;Patient Outcomes Assessments;Patients;Pharmaceutical Preparations;Pharmacological Treatment;Pilot Projects;Placebos;Positioning Attribute;Probiotics;Prognostic Marker;Psychological reinforcement;Public Health;Publications;Quality of life;Randomized;Regulation;Relapse;Reporting;Research;Research Personnel;Research Project Grants;Resources;Rewards;Role;Severities;Structure;Symptoms;Testing;Therapeutic;Training;United States;Universities;Withdrawal;Woman;Work;Writing;alcohol use disorder;base;bench to bedside;candidate marker;chronic alcohol ingestion;comorbidity;craving;design;drinking;effective therapy;efficacy testing;efficacy validation;eligible participant;experience;gut microbiome;gut microbiota;gut-brain axis;improved;liver development;liver inflammation;liver injury;men;metabolomics;microbiome alteration;neurobehavioral;neuroinflammation;new therapeutic target;novel;organ injury;preventable death;probiotic therapy;programs;response;restoration;skills;success;symptomatic improvement;tenure track;therapeutic target;treatment adherence;treatment comparison;treatment trial


application_id: 10402845
project_number: 5R25HL084695-15
project_title: Summer Undergraduate Experiences in Biomedical Research
administering_ic: NHLBI
award_notice_date: 2022-05-17
opportunity_number: RFA-HL-16-008
application_type: 5
activity_code: R25
ic: HL
serial_number: 084695
program_official: WANG, WAYNE C
project_start_date: 2006-04-07
project_end_date: 2025-03-31
study_section: ZHL1-CSR-M(F2)
contact_pi_person_id: 14636178
contact_pi: FALCONE, JEFFREY C
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractCardiovascular disease is the leading cause of death in the United States and accounts foralmost a third of all reported deaths annually. The proposed cardiovascular sciencesundergraduate training program provides an opportunity for minority and disadvantagedundergraduate students interested in cardiovascular sciences to receive training under theguidance of internationally recognized research mentors. The program will provide exposure tocareers and will enhance student preparedness for biomedical research. This training grant willprovide opportunities in several emphasis areas including cardiac and vascular remodeling;molecular cardiology and stem cell research; cardiovascular toxicity of environmental pollutants;and vascular engineering and microcirculatory control. The goals of this training program will beachieved by a multidisciplinary approach that includes participating centers institutes schoolsand members of the training faculty at the University of Louisville. The faculty will provide criticalresources and expertise to perform cutting-edge basic science and clinical research. We are submitting this proposal for an innovative summer research training program.This will serve as a platform for developing interdisciplinary and integrated approaches toelucidate mechanisms and develop new and innovative treatments for cardiovascular diseases.The proposed training program will support 8 undergraduate trainees for a maximumappointment of two summers each. Students will be recruited nationally but emphasis willcontinue to be placed on recruitment from regional Historically Black Colleges and Universities.The long-term objective of this renewal is to expand its initiatives to increase to 60% the numberof participants entering and completing biomedical majors employment post-baccalaureateprograms and eventually matriculating into professional/graduate programs. This program will address 3 specific aims: Aim 1: To recruit and train annually 8undergraduate students in biomedical research methods through classroom and laboratoryexperiences. Aim 2: To provide innovative enrichment programming and initiatives to prepareunderrepresented and disadvantaged students to successfully obtain a science relatededucation that will lead them to graduate and professional pathways in the health andbiomedical sciences. Aim 3: To increase 40 to 60% the number of program participants enteringinto post-baccalaureate programs or careers in biomedicine and/or health.

project_terms:
Address;Appointment;Area;Basic Science;Biomedical Research;Blood Vessels;Cardiac;Cardiology;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cessation of life;Clinical Research;Clinical Sciences;Degree program;Disadvantaged;Education;Employment;Engineering;Environmental Pollutants;Exposure to;Faculty;Goals;Grant;Health;Health Sciences;Historically Black Colleges and Universities;Institutes;International;Lead;Mentors;Minority;Molecular;National Heart Lung and Blood Institute;Participant;Pathway interactions;Readiness;Reporting;Research;Research Methodology;Research Personnel;Resources;Schools;Science;Stem Cell Research;Students;Teacher Professional Development;Toxic effect;Training;Training Programs;Underrepresented Students;United States;Universities;Vascular remodeling;career;disadvantaged student;experience;innovation;interdisciplinary approach;interest;laboratory experience;member;programs;recruit;summer program;summer research;undergraduate student

public_health_relevance:
Project NarrativeThis summer program provides minority and disadvantaged undergraduate students with aninitial exposure to basic and clinical science researchers and their areas of cardiovascularinterest at the University of Louisville Health Sciences Center. It is anticipated that significantnumber of the undergraduate students will elect to enter into graduate and professionaladvanced degree programs interested in pursuing NHLBI-related basic science and/or clinicalresearch.


application_id: 10402803
project_number: 5F30NS118777-02
administering_ic: NINDS
award_notice_date: 2022-05-06
opportunity_number: PA-20-245
application_type: 5
activity_code: F30
ic: NS
serial_number: 118777
program_official: CORRIVEAU, RODERICK A
project_start_date: 2021-05-01
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1-F01A-F(20)L]
contact_pi_person_id: 15841458
contact_pi: WINDER, ZACHARY
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-05-01
project_title:
Investigating Angiogenic Mediators as Biomarkers and Targets for Rescuing Small Vessel Disease in a Model of VCID

project_abstract:
Project Summary Dementia is a disorder characterized by a significant decline from baseline in one or more cognitivedomains that interferes with independence. Prevalence of dementia worldwide is estimated at 50 million withthat number expected to triple by 2030 coming with a cost of roughly $2 trillion. Vascular Contributions toCognitive Impairment and Dementia (VCID) is the second leading cause of dementia and is the umbrella termused to characterize patients with cognitive dysfunction as a result of cerebrovascular pathology. Small vesseldisease (SVD) is one type of cerebrovascular pathology that is found in roughly 50% of patients with VCID.Common neuropathological findings associated with SVD include microinfarctions microhemorrhages andarteriolosclerosis. While MRI identifies larger infarctions and microbleeds it is limited by resolution of the scan.Therefore identification of these pathologies has proven difficult outside of post-mortem evaluation. White matterhyperintensities (WMH) on MRI have become the standard used to evaluate SVD; but are limited by their costand lack of targetable mechanisms for preventing progression of the disease. In this proposal we explore therole of angiogenic mediators as modifiable fluid biomarkers which can be used to evaluate SVD and potentiallyaltered to decrease progression of SVD. We focus on placental growth factor (PLGF) due to its upregulation inhypoxic environments which is found in arteriolosclerosis. Our preliminary data suggests that patients with VCIDhave increased PLGF concentrations compared to controls. Additionally previous studies have shown that PLGFinduces degradation of the extracellular matrix and the blood brain barrier which are initiating steps in formationof microhemorrhages. This proposal first seeks to evaluate whether plasma PLGF is upregulated in patients withincreased levels of SVD pathology as measured in post-mortem neuropathological evaluation (Aim 1a) andwhether PLGF has a tight spatial co-localization with SVD pathology in human tissue (Aim 1b). This willdemonstrate the viability of PLGF as a fluid biomarker for SVD pathology. Secondly we will use a diet to inducea well-established model of VCID in PLGF-KO transgenic mice to evaluate the role of PLGF on development ofmicrohemorrhages (Aim 2). This aim will help support our hypothesis that reducing availability of PLGF willreduce the burden of microhemorrhages in patients with SVD. This mechanism can then be used to developnovel therapeutics in order to halt the progression of VCID. Through this proposal and under the mentorship ofDr. Wilcock and Dr. Jicha at the Sanders-Brown Center on Aging the applicant will investigate the utility of PLGFas a modifiable fluid biomarker for SVD. In doing so the applicant will be trained in immunoassay-basedbiomarker discovery statistical linear modeling clinical patient evaluation immunohistochemistry pathologicalhistology evaluation and oral and written scientific communications for a future career as an independentphysician-scientist.

project_terms:
Aging;Alzheimer's Disease;Analysis of Covariance;Animal Model;Autopsy;Biological Markers;Blood - brain barrier anatomy;Blood Vessels;Brain;Cells;Cerebrovascular Disorders;Clinical;Cognitive;Communication;Data;Dementia;Development;Diagnosis;Diet;Disease;Disease Progression;Environment;Evaluation;Extracellular Matrix;Extracellular Matrix Degradation;Future;Genotype;Hematoxylin and Eosin Staining Method;Histology;Human;Hyperhomocysteinemia;Hypoxia;Immunoassay;Immunohistochemistry;Impaired cognition;Infarction;Linear Models;Link;Liquid substance;Magnetic Resonance Imaging;Measures;Mediation;Mediator of activation protein;Mentorship;Microvascular Dysfunction;Modeling;Monitor;Mus;Neurocognitive;Neurosciences;Oral;Outcome;PGF gene;Pathologic;Pathology;Patients;Physicians;Plasma;Play;Pre-Clinical Model;Prevalence;Recording of previous events;Resolution;Role;Scanning;Scientist;Sensitivity and Specificity;Statistical Models;Technology;Testing;Tissue Sample;Tissues;Training;Transgenic Mice;Up-Regulation;White Matter Hyperintensity;Work;angiogenesis;base;biomarker discovery;brain tissue;burden of illness;candidate marker;career;cerebrovascular pathology;cohort;cost;cost effective;digital;histological stains;human tissue;imaging modality;in vivo;magnetic resonance imaging biomarker;mouse model;nano-string;neuroimaging;neuropathology;novel therapeutics;prevent;protein expression;response;targeted treatment;therapeutic target;tool;vascular cognitive impairment and dementia

public_health_relevance:
Project Narrative Current imaging methods using MRI for evaluating small vessel disease (SVD) in patients with vascularcontributions to cognitive impairment and dementia (VCID) lack appropriate resolution to identify much of theneuropathology associated with the disease. Fluid biomarkers that correlate to SVD pathology may be usefulas a lower cost alternative to MRI for monitoring its progression and act as a therapeutic target for delayingthe progression of SVD. This project investigates the role of placental growth factor (PLGF) as a biomarker forSVD using human tissue samples and as a target for rescuing SVD in a mouse model of VCID.


application_id: 10401633
project_number: 3RF1NS118558-01S1
project_title: Inflammatory contributions of astrocytic RelA in comorbid VCID/AD
administering_ic: NINDS
award_notice_date: 2021-09-25
opportunity_number: PA-20-272
application_type: 3
activity_code: RF1
ic: NS
serial_number: 118558
suffix: S1
program_official: CORRIVEAU, RODERICK A
project_start_date: 2021-09-01
project_end_date: 2022-08-31
contact_pi_person_id: 10594155
contact_pi: MORGANTI, JOSH
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:
PROJECT SUMMARY/ABSTRACTMultiple lines of evidence in both humans and animal models suggest that neuroinflammation mediated viareactive gliosis plays a critical role associated with the initiation and progression of vascular contributions tocognitive impairment and dementia (VCID) and Alzheimers disease (AD) potentially suggesting convergentpathophysiological mechanisms. In particular several of these neuroinflammatory hallmarks in comorbidVCID/AD animal models have been linked with the dysfunctional responses of reactive astrocytes. In thehealthy brain it is well known that astrocytes play a critical role in maintaining a variety of homeostaticmechanisms. However as a response to injury or disease astrocytes are able to rapidly respond in ageneralized description referred as astrogliosis with a variety of neuroinflammatory modalities which recentevidence suggests may cause dysfunctional responses of neurons. Sleep disturbances/circadian disruption isa key clinical issue in dementia patients. Between 40 and 70% of older adults suffer from sleep disturbances ordisorders which are especially prevalent among patients with Alzheimer's Disease and Alzheimers DiseaseRelated Dementias (AD/ADRD) such as VCID. The purpose of this one-year administrative supplement is tofacilitate new collaborative research between the Morganti and Duncan labs to better understand the bi-directional relationship between chronic sleep disturbances/circadian disruption and VCID pathogenesis in thecontext of inflammatory mechanisms of astrocytes. This proposal will examine 2 focused specific aims whichare extensions of our ongoing projects in the parent grant RF1NS118558: 1. Determine the extent to which chronic sleep fragmentation drives astrocyte-specific inflammatory heterogeneity in the context of VCID and whether removal astrocytic-RelA disrupts these transcriptional and morphological phenotypes. 2. Determine the extent to which chronic sleep fragmentation alters cognitive function and whether removal astrocytic-RelA disrupts these phenotypes.

project_terms:
Administrative Supplement;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease related dementia;Amyloid beta-Protein;Animal Disease Models;Animal Model;Astrocytes;Automobile Driving;Award;Blood Vessels;Brain;Cells;Cerebrovascular Circulation;Cerebrovascular Disorders;Chronic;Circadian Dysregulation;Clinical;Coupling;Data;Degenerative Disorder;Dementia;Deposition;Development;Disease;Disease model;Elderly;Excision;Exposure to;FDA approved;Functional disorder;Future;Genetic Transcription;Gliosis;Healthcare;Heterogeneity;Human;Impaired cognition;Individual;Inflammatory;Inflammatory Response;Ischemia;Knowledge;Label;Lead;Link;Mediating;Medical;Microglia;Modality;Modeling;Morphology;Multiple Sclerosis;Neuroglia;Neurological outcome;Neuronal Dysfunction;Neurons;Parents;Pathogenesis;Pathologic;Pathology;Pathway interactions;Patients;Phenotype;Play;Population;Publishing;Recording of previous events;Recovery of Function;Research;Risk;Role;Senile Plaques;Signal Pathway;Signal Transduction;Sleep Disorders;Sleep Fragmentations;Sleep disturbances;Spinal cord injury;Synapses;Testing;Tissues;Work;abeta deposition;aged;astrogliosis;base;blood-brain barrier permeabilization;cerebrovascular;cognitive function;comorbidity;conditional knockout;human model;innovation;neuroinflammation;new therapeutic target;novel;parent grant;response;response to injury;restraint;therapeutic target;vascular cognitive impairment and dementia;vascular contributions;vascular injury;vascular risk factor

public_health_relevance:
PROJECT NARRATIVE (FROM AWARDED PARENT APPLICATION)Growing evidence suggests that pure Alzheimers disease is rare among the human population butstrikingly a significant proportion of individuals with Alzheimers present with vascular comorbidities intandem with plaque deposition. Both Alzheimers and VCID are a major unment medical need withno FDA approved therapy. Defining the role of abberant astrocyte inflammatory response in theseconditions and whether RelA is a factor in these responses will enable new lines of development forfuture therapeutic targeting of these pathways to either restrain or enhance critical facets of astrocyteresponse to the comorbid disease milieu.


application_id: 10401441
project_number: 5R01HL147856-04
project_title: Mechanisms underlying metal nanoparticle-induced lung injury and fibrosis
administering_ic: NHLBI
award_notice_date: 2022-05-11
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: HL
serial_number: 147856
program_official: VUGA, LOUIS J
project_start_date: 2019-06-01
project_end_date: 2025-05-31
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 8567542
contact_pi: ZHANG, QUNWEI
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Metal nanoparticles have been widely used in cosmetics medicine electronics and industry and occupationalor non-occupational exposure to metal nanoparticles is growing. In this proposal we have selected severaltransition metal nanoparticles (Nano-Co Nano-Ni and Nano-TiO2) as `model' metal nanoparticles to examinetheir ability to induce pulmonary injury and fibrosis and the potential underlying mechanisms involved. Aninflammasome is a multiprotein complex that serves as a platform for caspase-1-dependent proteolyticmaturation and secretion of interleukin-1 (IL-1). The central component of an inflammasome is a member ofthe NLRP family and this protein associates with the adaptor protein ASC which in turn recruits pro-inflammatorycaspase precursors (such as procaspase-1). Among a number of inflammasomes the NLRP3 inflammasome isthe most extensively studied. Our working hypothesis is that exposure to metal nanoparticles will causeactivation and/or dysregulation of the inflammasome and IL-1 secretion in alveolar macrophages (AMs)lung epithelial cells and lung fibroblasts which will cause dysregulation of matrix metalloproteinases(MMPs) and tissue inhibitors of metalloproteinases (TIMPs) initiating and promoting metal nanoparticle-induced pulmonary injury and fibrosis. This project will use both in vitro and in vivo systems to address thefollowing specific aims: (1) Determine the role of inflammasome activation in IL-1 secretion induced bymetal nanoparticles in vitro and in vivo. We will identify whether activation of the inflammasome is involvedin metal nanoparticle-induced IL-1 secretion in alveolar macrophages (AMs) lung epithelial cells and lungfibroblasts by: (1) using ac-YVAD-cmk a particular inhibitor of caspase-1; (2) knocking-down one of theinflammasome components such as NLRP3 ASC or caspase-1 by using CRISPR/Cas9 technology; and (3)using NLRP3 or ASC knock-out mice. We will then determine whether NADPH oxidase- and/or mitochondria-dependent ROS generation and potassium efflux are involved in metal nanoparticle-induced inflammasomeactivation and IL-1 secretion. We will also measure IL-1 secretion in mice exposed to metal nanoparticles. (2)Examine the role of IL-1 in the alteration of MMPs and TIMPs expression and activity in lung cellsexposed to metal nanoparticles. While IL-1 is an inducer for MMP-2 and MMP-9 activity it is unclear how itregulates MMPs and TIMPs with exposure to metal nanoparticles. To test the role of the inflammasome and IL-1 in the regulation of MMPs and TIMPs the strategies in Aim 1 will be used to inhibit inflammasome functionand strategies to inhibit IL-1 function will be applied by using: (1) the pharmacologic IL-1 inhibitor; (2) anti-IL-1 antibody; and (3) IL-1RI-/- mice that will not respond to IL-1. After exposure to metal nanoparticles MMP-2MMP-9 and TIMPs expression and activity will be determined. (3) Investigate the role of inflammasomeactivation in metal nanoparticle-induced lung injury and fibrosis in vivo. We will first investigate whetherexposure to metal nanoparticles will cause lung fibroblasts to produce more collagen. Then the role of theinflammasome in metal nanoparticle-induced lung fibrosis will be explored by short- and long-term exposure ofmice to metal nanoparticles. We will use the strategies in Aim 1 and 2 to inhibit inflammasome and IL-1 functionto investigate the role of the inflammasome and IL-1 in metal nanoparticle-induced lung fibrosis.

project_terms:
Adaptor Signaling Protein;Address;Alveolar Macrophages;Antibodies;Apoptosis;Asbestos;Asthma;Attenuated;Biological;Bronchoalveolar Lavage Fluid;CASP1 gene;CRISPR/Cas technology;Caspase;Cells;Collagen;Cosmetics;Development;Electronics;Epithelial Cells;Exposure to;Family;Fibroblasts;Gelatinase A;Gelatinase B;Generations;Health;In Vitro;Industrialization;Industry;Inflammasome;Inflammatory;Interleukin-1;Interleukin-1 Receptors;Interleukin-1 beta;Knockout Mice;Lead;Lesion;Lung;Lung diseases;Malignant neoplasm of lung;Matrix Metalloproteinases;Measures;Medical;Medicine;Metal exposure;Metal fever;Metals;Mitochondria;Modeling;Multiprotein Complexes;Mus;NADPH Oxidase;Normal Range;Occupational;Pharmacology;Play;Potassium;Proteins;Pulmonary Fibrosis;Pulmonary Inflammation;Regulation;Role;Silicon Dioxide;System;Testing;Tissue Inhibitor of Metalloproteinases;Toxic effect;Transition Elements;Wild Type Mouse;anakinra;base;exposed human population;in vivo;inhibitor;interest;interleukin-1beta-converting enzyme inhibitor;knock-down;lung injury;macrophage;member;monocyte;nano;nanomaterials;nanoparticle;particle;recruit;response;titanium dioxide;tool

public_health_relevance:
This project aims to explore how exposure to metal nanoparticles may cause lung diseases. We expect thatour results will provide tools for evaluating other nanomaterials. Successful completion of this project will notonly lead to a better understanding of the mechanisms by which metal nanoparticles induce lung injury butalso provide scientific evidence to reduce their toxicity.


application_id: 10401225
project_number: 3R35NS116824-02S2
project_title: Brain Glycogen - Metabolism Mechanisms and Therapeutic Potential
administering_ic: NINDS
award_notice_date: 2021-09-17
opportunity_number: PA-20-272
application_type: 3
activity_code: R35
ic: NS
serial_number: 116824
suffix: S2
program_official: LEENDERS, MIRIAM
project_start_date: 2020-05-15
project_end_date: 2028-04-30
study_section: ZNS1(12)
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW 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
project_abstract:
This is an Administrative Supplement request in response to NOT-NS-21-040 for Collaborative Activities toPromote Sleep/Circadian Research in ADRD for R35NS116824 entitled Brain Glycogen  MetabolismMechanisms and Therapeutic Potential. The requested funds are to perform metabolomics histology andRNA-sequencing experiments proposed within the scope of R35NS116824 on Alzheimer's disease mousemodels with the addition of including sleep disruption to the methods. The parent grant focuses on defininghow aberrant intracellular glycogen-like aggregates known as polyglucosan bodies (PGBs) impactneurodegeneration. The work is centered on both Alzheimer's disease and the childhood dementia Laforadisease with efforts to define how perturbations in metabolism impact disease progression and test a pre-clinical therapeutic option to ablate PGBs and test the biological outcome. We hypothesize that sleepfragmentation will increase PGB formations and our preliminary data strongly suggests that increased PGBswill negatively impact brain metabolism. A significant strength of this supplement is that it brings together twoprinciple investigators that have non-overlapping and complementary expertise and who have not collaboratedtogether in the past. The supplement will also utilize the wealth of expertise and resources provided by the UKAlzheimer's Disease Center (ADC). In this supplement we will utilize our extensive expertise with PGBs to:Aim 1: Define PGBs metabolic profiles gene expression and AD hallmarks during disrupted sleep.Aim 2: Assess AD hallmarks during disrupted sleep in AD animals treated with VAL-0417.

project_terms:
Administrative Supplement;Alzheimer's Disease;Alzheimer's disease related dementia;Animals;Biological Testing;Brain;Carbohydrates;Cellular Metabolic Process;Childhood;Complex;Comprehension;Data;Dementia;Diagnosis;Disease;Disease Progression;Event;Funding;Gene Expression;Glycogen;Histology;Knowledge;Lafora Disease;Metabolism;Methods;Mus;Nerve Degeneration;Outcome;Research;Research Personnel;Resources;Sleep;Sleep Fragmentations;Sleep disturbances;Testing;Therapeutic;Translating;Work;brain metabolism;circadian;experimental study;glycogen metabolism;insight;metabolic profile;metabolomics;mouse model;parent grant;polyglucosan;pre-clinical;response;transcriptome sequencing

public_health_relevance:
The focus of our work is to determine how sleep disruption and fragmentation will impact carbohydrateaggregates and impact brain metabolism in Alzheimers disease mice while translating this knowledge intotherapies. Our proposal is built on our past discoveries and uses complementary approaches to advance ourunderstanding of the intertwined events of cell metabolism sleep and Alzheimers disease. Completion of thiswork will yield a better comprehension of these complex events and will allow us to translate our insights intodisease mechanisms diagnoses and treatments.


application_id: 10400341
project_number: 3R15DA047610-01A1S1
project_title: Contribution of NMDA NR2B subunit to risky choice and economic demand for cocaine
administering_ic: NIDA
award_notice_date: 2021-05-21
opportunity_number: PA-20-272
application_type: 3
activity_code: R15
ic: DA
serial_number: 047610
suffix: A1S1
program_official: MOORE, HOLLY MARIE
project_start_date: 2019-06-01
project_end_date: 2022-05-31
contact_pi_person_id: 11434612
contact_pi: YATES, JUSTIN RYAN
other_pis: Not Applicable
congressional_district: 04
department: PSYCHOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractRisky choice is one facet of impulsivity that is observed in several psychiatric disorders including substanceuse disorders. Understanding the shared neurobiology of risk-taking behavior and drug abuse is important fordesigning effective pharmacotherapies for individuals that are at risk for developing substance use disorders.The neurotransmitter glutamate is considered to be involved in drug addiction and recent research has shownthat the N-methyl-D-aspartate (NMDA) glutamate receptor is involved in risky choice. Considering NR2B-selective antagonists lack the psychotomimetic side effects observed with NMDA receptor channelblockers (such as MK-801 and ketamine) these drugs may provide a novel therapeutic approach totreating individuals predisposed to engaging in risky behaviors. Using the risky decision task (RDT) inwhich rats choose between a small safe reward and a large risky reward (i.e. paired with foot shock) werecently found that the GluN2B-selective antagonist Ro 63-1908 decreases risky choice but only in male rats.We are currently determining if blocking NR2B-containing NMDA receptors is efficacious in attenuating cocaineself-administration in rats displaying increased risky choice (Specific Aim 2 of grant). Another goal of theproposal is to determine if cocaine exposure differentially alters NR2B subunit distribution (via receptorautoradiography) in high and low risk-taking rats and to determine if Ro 63-1908 can reverse cocaine-inducedalterations in NR2B subunit distribution (Specific Aim 3). Zachary will assist with data collection and dataanalysis. Specifically he will work on research related to Specific Aims 2 and 3 of Dr. Yates R15 grant. BrieflyZachary will learn to handle and weigh rats test rats in a cocaine self-administration paradigm deliversubcutaneous injections record and analyze data and perform animal husbandry. Zachary will read articlesrelated to the research he will be conducting during the internship and he will meet regularly with Dr. Yatesand his other students to discuss this research as well as progress in the experiment. In addition to drug self-administration Zachary will learn to section brains for receptor autoradiography experiments. As requiredZachary will work 40 hours each week for 8 weeks during the summer.

project_terms:
Animal Husbandry;Attenuated;Autoradiography;Behavior;Brain;Cocaine;Data;Data Analyses;Data Collection;Decision Making;Drug Addiction;Drug Targeting;Drug abuse;Economics;Glutamate Receptor;Glutamates;Goals;Grant;Hour;Impulsivity;Individual;Internships;Ketamine;Learning;MK801;Mental disorders;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;N-methyl-D-glutamate;Neurobiology;Neurotransmitters;Pharmaceutical Preparations;Pharmacotherapy;Rattus;Research;Rewards;Risk;Risk Behaviors;Risk-Taking;Role;Self Administration;Shock;Students;Subcutaneous Injections;Substance Use Disorder;Testing;Work;channel blockers;cocaine exposure;cocaine self-administration;comorbidity;design;efficacious treatment;experimental study;foot;male;novel;novel therapeutic intervention;psychostimulant;receptor;side effect

public_health_relevance:
Project NarrativeCurrently there are few treatments that are efficacious in treating individuals with co-morbid impulse-controland substance use disorders. The purpose of this research is to determine the role of the NR2B subunit of theglutamate N-methyl-D-aspartate (NMDA) receptor in risky decision making and psychostimulant reward. Theresults of the current proposal will be important because novel pharmacotherapies (e.g. drugs that target theNR2B subunit of the NMDA receptor) can be used to better treat those that engage in risky behaviors and/orhave substance use disorders.


application_id: 10400230
project_number: 5R01CA133429-15
project_title: The Role of PHLPP in Colon Cancer
administering_ic: NCI
award_notice_date: 2022-04-18
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: CA
serial_number: 133429
program_official: SALNIKOW, KONSTANTIN
project_start_date: 2009-04-01
project_end_date: 2025-04-30
study_section: Molecular Oncogenesis Study Section[MONC]
contact_pi_person_id: 7353657
contact_pi: GAO, TIANYAN
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:
Automobile Driving;Autophagocytosis;Cancer Etiology;Cancer Patient;Cell Death;Cell Proliferation;Cell Survival;Cells;Cellular Stress;Cellular Stress Response;Cessation of life;Chemoresistance;Collaborations;Colon Carcinoma;Colorectal Cancer;Development;Disease;Down-Regulation;Effectiveness;Ensure;Epithelial Cells;Equilibrium;Event;Funding;Grant;HK2 gene;Inflammation;Integrins;Intestines;Knockout Mice;Knowledge;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Metabolic;Metabolism;Mitochondria;Molecular;Oncogenic;Organism;PH Domain;Pathway interactions;Pharmaceutical Preparations;Phosphoric Monoester Hydrolases;Phosphorylation;Physiological;Play;Protein Dephosphorylation;Protein Family;Protein Kinase;Protein phosphatase;Proto-Oncogene Proteins c-akt;Regulation;Resistance;Role;Signal Pathway;Signal Transduction;Stress;Supporting Cell;Testing;Tumor Suppressor Proteins;United States;base;biological adaptation to stress;cancer cell;cancer initiation;cancer survival;cancer type;cell growth regulation;cell motility;chemotherapy;colon tumorigenesis;coping mechanism;endoplasmic reticulum stress;improved;in vivo;insight;leucine-rich repeat protein;mitochondrial autophagy;mortality;mouse model;multicatalytic endopeptidase complex;novel;protein expression;response;sensor;success;tumor initiation;tumor metabolism;tumor progression;tumorigenesis


application_id: 10400103
project_number: 5R01DE011111-29
project_title: P. gingivalis interactions with gingival epithelial cells
administering_ic: NIDCR
award_notice_date: 2022-06-01
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: DE
serial_number: 011111
program_official: MCNEALY, TAMARA L
project_start_date: 1995-04-01
project_end_date: 2024-06-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: 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:
The epithelial layer of host mucosal surfaces presents an initial interface for colonizing microorganisms. Inaddition to constituting a physical barrier to the ingress of organisms epithelial cells can sense and respond tothe presence of bacteria through an elaborate signaling network that can also communicate information to theunderlying immune effector cells in the mucosa. Bacteria that colonize the epithelial surface often engageepithelial cells in a complex molecular dialog which results in significant changes to the host cell transcriptionalprogram and can fundamentally alter epithelial properties. Moreover in vivo bacteria on epithelial surfaces tendto accumulate into polymicrobial communities and communities of organisms can exhibit properties distinct fromindividual constituent species in isolation. Ultimately it is the collective action of the community organisms thatdetermines the impact of the microbial challenge on the host.Our ongoing studies of gingival epithelial cells (GECs) show that the periodontal pathogen Porphyromonasgingivalis can regulate the activity of a number of transcription factors and co-factors which control inflammationcell viability and proliferation. These include -catenin which is proteolytically activated by P. gingivalis andFOXO1 which is activated by site specific dephosphorylation. Activation of -catenin and FOXO1 by P. gingivalisleads to the regulation of ZEB2 a transcription factor pivotal for governing essential epithelial properties andtissue integrity. Moreover ZEB2 can control the maturation of immune cells and the production of inflammatorymediators such as IL-6. We also found that manipulation of the -catenin-FOXO1 axis by P. gingivalis can beantagonized by Streptococcus gordonii and S. oralis but remains unaffected by other common oral streptococci.Hence our hypotheses are that i) the interplay between -catenin and FOXO1 controls ZEB2 expression inresponse to P. gingivalis and impacts epithelial cell characteristics with relevance to the maintenance of tissuehomeostasis; and ii) specific oral community profiles can modulate the influence of P. gingivalis on epithelialsignaling pathways that regulate -catenin and FOXO1 function. The Aims of the project are thus: 1. Tocharacterize the functional integration of -catenin and FOXO1 in the control of ZEB2 by P. gingivalis. 2. Todetermine the functional relevance of site-specific dephosphorylation of FOXO1 by P. gingivalis for the FOXO1transcriptional program and ZEB2 regulation. 3. To characterize the mechanisms by which S. gordonii cansubvert P. gingivalis-induced activation of the -catenin-FOXO1-ZEB2 axis. Successful completion of thisproject will define novel mechanisms for the integration and control of epithelial cell transcription factors andcharacterize modulation of these pathways by P. gingivalis both as a single species infection and in the contextof a community. These studies will increase our understanding of oral diseases that arise from dysbiotic hostresponses such as periodontitis and potentially oral squamous cell carcinoma.

project_terms:
Apoptosis;Bacteria;Binding;Biological;Cell Proliferation;Cell Survival;Cells;Characteristics;Communities;Community Actions;Complex;Disease;Effector Cell;Epithelial;Epithelial Cells;Exhibits;FOXO1A gene;Fusobacterium nucleatum;Genetic Transcription;Gingiva;Grant;Homeostasis;Human;Immune;Immune response;Individual;Infection;Inflammation;Inflammation Mediators;Inflammatory;Interleukin-1 beta;Interleukin-6;Maintenance;Modeling;Molecular;Mouth Diseases;Mucous Membrane;Oral;Organism;Outcome;Pathologic;Pathway interactions;Periodontitis;Physiological;Porphyromonas gingivalis;Post-Translational Protein Processing;Process;Production;Property;Protein Dephosphorylation;Regulation;Role;Serine;Signal Pathway;Signal Transduction;Site;Specificity;Streptococcus;Streptococcus gordonii;Streptococcus oralis;Surface;Tissues;alveolar bone;beta catenin;bone metabolism;dysbiosis;immunological status;in vivo;microbial;microorganism;microorganism interaction;mouth squamous cell carcinoma;novel;oral bacteria;oral streptococci;periodontopathogen;programs;promoter;recruit;response;therapy design;transcription factor;transcriptional reprogramming

public_health_relevance:
Project NarrativeSevere periodontal (gum) diseases occur when there is an imbalance in the interaction between colonizingbacteria and the host response. We will characterize the interface between oral bacteria and human epithelialcells which leads to a disruption in the integrity of periodontal tissue. An understanding of this process couldultimately form the basis of treatments designed to maintain host tissue in a healthy state even in the presenceof disease-causing bacteria.


application_id: 10400083
project_number: 5R35GM141478-02
project_title: Relative adrenal insufficiency as a risk factor and an endotype for sepsis
administering_ic: NIGMS
award_notice_date: 2022-06-16
opportunity_number: PAR-19-367
application_type: 5
activity_code: R35
ic: GM
serial_number: 141478
program_official: ZHAO, XIAOLI
project_start_date: 2021-05-01
project_end_date: 2026-04-30
study_section: Special Emphasis Panel[ZRG1-CB-T(55)R]
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adrenal Glands;Adrenal gland hypofunction;Animal Model;Cessation of life;Corticotropin;Glucocorticoids;Goals;Health;Knockout Mice;Laboratories;Modeling;Mus;Patients;Production;Reporting;Risk Factors;SR-BI receptor;Sepsis;Septic Shock;Stress;Subgroup;Supplementation;Translations;biological adaptation to stress;high density lipoprotein receptor;improved;mortality;precision medicine;protective factors;response;septic;septic patients


application_id: 10399887
project_number: 3P20GM113226-06S1
project_title: Administrative Supplement to Hepatobiology and Toxicology COBRE
administering_ic: NIGMS
award_notice_date: 2021-08-19
opportunity_number: PA-20-272
application_type: 3
activity_code: P20
ic: GM
serial_number: 113226
suffix: S1
program_official: BERNAL, FEDERICO
project_start_date: 2021-04-01
project_end_date: 2022-03-31
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Administrative Supplement;Alcoholic Liver Diseases;Area;Basic Science;Bioinformatics;Biology;Biomedical Research;Centers of Research Excellence;Cirrhosis;Clinical Research;Collaborations;Data Set;Development;Diagnosis;Ensure;Equipment;Funding;Grant;Health Sciences;Hepatitis B;Hepatitis C;Injury;Laboratories;Link;Liver;Liver Failure;Liver diseases;Measures;Mentors;Metabolic syndrome;Molecular;Molecular Target;Pharmaceutical Preparations;Phase;Prevention;Primary carcinoma of the liver cells;Program Sustainability;Proteomics;Protocols documentation;Publications;Research;Research Infrastructure;Research Personnel;Resources;Stable Isotope Labeling;Techniques;Technology;Therapeutic;Toxic Environmental Substances;Toxicant exposure;Toxicology;Training;Translational Research;Universities;base;career development;clinical practice;education research;experience;experimental study;innovation;liver injury;member;metabolomics;multidisciplinary;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;personalized medicine;prevent;programs;success

public_health_relevance:
The University of Louisville (UofL) Hepatobiology and Toxicology COBRE is a unique thematic researchcenter. We have strengthened UofLs biomedical research infrastructure through the establishment of athematic multidisciplinary center in hepatobiology and toxicology to enhance the ability of investigators tocompete for independent funding. This Phase II proposal builds on our Phase I success and extends andstrengthens the scope of the program. The requested equipment will allow us to measure metabolites/substances that are important in the diagnosis/treatment of liver disease.


application_id: 10399834
project_number: 3P20GM103436-21S2
administering_ic: NIGMS
award_notice_date: 2021-08-19
opportunity_number: PA-20-272
application_type: 3
activity_code: P20
ic: GM
serial_number: 103436
suffix: S2
program_official: ZHOU, YANG
project_start_date: 2021-05-01
project_end_date: 2022-04-30
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
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: 2021-05-01
project_title:
KY INBRE Admin Supplement: The Role of Platinum Leaving Ligands in Chemo-immunotherapeutic Resistance in Lung Cancer Models

project_abstract:
Project Summary/AbstractPlatinum chemotherapeutics are the primary treatment for nonsmall cell lung cancer (NSCLC) but due to theprevalence of resistance to these compounds the addition of PD-1 immunotherapy has become the standard ofcare. However chemotherapy has been shown to impact anti-tumor immunity by inducing PD-1 expressionCD8+ T cell priming and infiltration leading to immunogenic cell death. There is an urgent need to understandthe molecular mechanisms by which platinum-based chemotherapeutics impact the immune response inNSCLC. To analyze the paradoxical effects of platinum compounds on the immune system a systemicallydesigned and novel bank of platinum compounds with structural similarities to FDA-approved chemotherapeuticwill be used. Aim 1) In cellular models of lung cancer the cell surface expression patterns of T Cell activatorswill be examined. Both matrix metalloproteases and class I major histocompatibility complex which play a rolein metal sensitivity will be analyzed before and after exposure to the platinum compounds. We hypothesize thatleaving ligand differences of platinum compounds will impact the levels of these factors on the cell surfacecorrelating to the cell-type-specific variances in platinum toxicity. Aim 2) The impact of the novel platinumcompounds on the adenosine dependent pathway through the production of tumor-derived prostaglandin E2(PGE2) and modulation of the cell surface expression of CD73 will be determined. Our hypothesis is thatproduction of adenosine is stimulated by the indirect effects of chemotherapy on M-MDSCs via the followingsteps: (a) chemotherapy induces PGE2 production in tumor cells; (b) the released PGE2 upregulates CD73 ecto-5-nucleotidase enzyme on the surface of M-MDSCs; (c) CD73 catalyzes the production of adenosine from AMP(derived from ATP released by dying cells); and (d) adenosine inhibits the activation of effector CD8+ T cellswithin the tumors. The long-term goal of this proposal is to understand the mechanisms that mediate platinumresistance and toxicity in NSCLC ultimately leading to strategies to block any immunosuppressive effects ofchemotherapy. The study is innovative in both the signaling model proposed for the blockade of the immunesystem and in the design of the platinum compounds that vary only at the leaving ligand.

project_terms:
5'-Nucleotidase;A549;Ablation;Acute;Adenocarcinoma;Adenosine;Apoptosis;Award;Binding;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Etiology;Cancer Model;Cancer Patient;Carboplatin;Cell model;Cell surface;Cells;Centers of Research Excellence;Cessation of life;Cisplatin;Collaborations;DNA;Data;Development;Dinoprostone;Disease Progression;Enzymes;Exposure to;FDA approved;Fluorescence-Activated Cell Sorting;Funding;Generations;Gifts;Goals;Hour;Human;Immune response;Immune system;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Infiltration;Kentucky;Lead;Ligands;Lung Adenocarcinoma;MMP9 gene;Maintenance;Major Histocompatibility Complex;Malignant neoplasm of lung;Mediating;Metalloproteases;Metals;Modeling;Molecular;Mus;Myeloid Cells;Myeloid-derived suppressor cells;National Institute of General Medical Sciences;Non-Small-Cell Lung Carcinoma;Nonmetastatic;Nucleosides;Pathway interactions;Pattern;Pharmaceutical Preparations;Platinum;Platinum Compounds;Play;Prevalence;Production;Prostaglandin Production;Public Health;Resistance;Role;Scheme;Signal Transduction;Structure;Surface;T-Lymphocyte;Testing;Toxic effect;Treatment Failure;Tumor Immunity;Tumor-Derived;United States;Universities;Variant;Work;anti-PD-1;anti-PD1 therapy;base;cancer therapy;cell type;chemotherapeutic agent;chemotherapy;cytotoxic;design;divalent metal;effector T cell;exhaustion;extracellular;graduate student;immunogenic cell death;immunoregulation;improved;innovation;lung cancer cell;monocyte;neoplastic cell;novel;novel strategies;overexpression;oxaliplatin;patient derived xenograft model;programmed cell death ligand 1;programmed cell death protein 1;response;standard of care;therapy resistant;tool;tumor;undergraduate student

public_health_relevance:
Project NarrativeTo improve public health this project seeks to understand the mechanisms by which platinum chemotherapycan lead to resistance and how structural differences in the platinum compound may impact these mechanisms.The regulation of the immune system by platinum compounds will be examined in models of lung cancer byusing a bank of novel platinum compounds with structural similarities to FDA-approved chemotherapeutics.Importantly these funds establish a collaboration between an existing NIGMS-funded Institutional DevelopmentAward and a Center of Biomedical Research Excellence in the state of Kentucky.


application_id: 10399734
project_number: 3P20GM130456-02S1
project_title: Administrative Supplement: COBRE in Pharmaceutical Research and Innovation
administering_ic: NIGMS
award_notice_date: 2021-08-17
opportunity_number: PA-20-272
application_type: 3
activity_code: P20
ic: GM
serial_number: 130456
suffix: S1
program_official: MCGUIRL, MICHELE
project_start_date: 2021-07-01
project_end_date: 2022-06-30
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARY/ABSTRACT OF FUNDED PARENT AWARD (P20 GM130456)The Center of Biomedical Research Excellence in Pharmaceutical Research and Innovation (CPRI) at theUniversity of Kentucky (UK) is a comprehensive multidisciplinary center focused on translational chemicalbiology [the nexus of chemical biology (the application of chemical biology principles to develop validatedprobe/models to advance our understanding of biology) and pharmaceutical science (the application ofpharmaceutical principles to advance leads/materials/devices that address unmet clinical needs)]. This Phase ICOBRE leverages and develops unique translational chemical biology research support infrastructure/expertiseto facilitate junior faculty mentorship and career development innovative biomedical researchprobe/tool/model/materials development and validation and the early advancement of potential translatableassets. Key COBRE infrastructure to be developed and implemented in Phase I includes the CPRI AdministrativeCore and two research support cores (the Translational Core and the Computational Core) and the COBRE willalso further develop and leverage the COBRE for Molecular Medicines Organic Synthesis Core to support CPRIjunior faculty projects/pilots. CPRI currently supports four outstanding junior investigators working in threetherapeutic areas (cancer infectious disease and tissue/bone regeneration). Our overarching hypothesis is that CPRIs translational chemical biology focus presents a distinctly uniqueUK platform to: i) engage integrate and mentor junior faculty from a broad range of fundamental applied andclinical disciplines; ii) facilitate the development of new impactful probes/tools/models and advance innovativetransdisciplinary research; and iii) bridge the gap between basic academic research discoveries andcommercial/clinical application via education mentorship and key support infrastructure. CPRIs distinct focuson translational chemical biology and early translation fills a notable preclinical research gap for many of UKsexceptional research centers strategically focused on understanding treating and preventing the major diseasesthat contribute to Kentuckys disproportionate health challenges. Anticipated COBRE outcomes include anincrease in the number and diversity of UK junior faculty engaged in translational chemical biology research andbetter-prepared to develop and employ innovative biomedical probes/tools/models/materials new sustainableUK translational chemical biology research support infrastructure and capabilities an increase in the number ofUK junior faculty with independent research funding and a boost in the number potentially translatable UKpreclinical assets.

project_terms:
Address;Administrative Supplement;Area;Award;Biology;Biomedical Research;Bone Regeneration;Bone Tissue;Cardiovascular Diseases;Centers of Research Excellence;Chemicals;Clinical;Collaborations;Communicable Diseases;Communication;Core Facility;Development;Devices;Discipline;Disease;Education;Environment;Faculty;Fostering;Funding;Gap Junctions;Goals;Health;Infrastructure;Kentucky;Malignant Neoplasms;Mentors;Mentorship;Modeling;Molecular Medicine;Organic Synthesis;Outcome;Parents;Pharmacologic Substance;Pharmacy facility;Phase;Pilot Projects;Research;Research Personnel;Research Project Grants;Research Support;Science;Scientist;Testing;Therapeutic;Translational Research;Translations;Universities;Validation;career development;clinical application;college;experience;faculty research;innovation;interdisciplinary collaboration;interest;multidisciplinary;pre-clinical;pre-clinical research;prevent;tool

public_health_relevance:
PROJECT NARRATIVE - OVERALLThe University of Kentucky (UK) Center of Biomedical Research Excellence (COBRE) in PharmaceuticalResearch and Innovation (CPRI) will serve as a unique comprehensive translational chemical biology center.The center will support junior faculty career development advance impactful chemical biology andpharmaceutical science research/tools and stimulate transdisciplinary collaboration research innovation andearly preclinical translational research.


application_id: 10399610
project_number: 5R01HL150581-02
project_title: Epidural spinal cord stimulation and respiratory motor function after injury
administering_ic: NHLBI
award_notice_date: 2022-03-02
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: HL
serial_number: 150581
program_official: NATARAJAN, ARUNA R
project_start_date: 2021-05-01
project_end_date: 2026-02-28
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 9348839
contact_pi: OVECHKIN, ALEXANDER VLADIMIROVICH
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Activities of Daily Living;Acute;Blood Pressure;Breathing;COVID-19;Cardiovascular system;Chronic;Clinical;Complication;Data;Development;Effectiveness of Interventions;Electromyography;Electrophysiology (science);Evaluation;Goals;Heart Rate;Human;Individual;Injury;Knowledge;Lead;Lung;Measures;Methods;Modality;Morbidity - disease rate;Motor;Muscle;Neurologic;Neuronal Plasticity;Neurostimulation procedures of spinal cord tissue;Patients;Pattern;Physiological;Population;Property;Protocols documentation;Public Health;Pulmonary function tests;Randomized Controlled Clinical Trials;Rehabilitation therapy;Research;Respiration;Respiration Disorders;Respiratory Muscles;Respiratory physiology;Spinal;Spinal Cord;Spinal Cord Lesions;Spinal cord injury;Surface;Testing;Therapeutic Effect;Time;Training;Work;base;comparative;design;disability;effectiveness evaluation;evidence base;fighting;follow-up;functional outcomes;improved;kinematics;mortality;motor control;neural network;novel therapeutic intervention;preservation;pressure;rehabilitation strategy;respiratory;response;restoration;standard of care;voltage


application_id: 10399503
project_number: 5P20GM103436-22
project_title: Developmental Research Project Program
administering_ic: NIGMS
award_notice_date: 2022-05-09
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1-RCB-9
subproject_number: 7347
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Developmental Research Program (DRPP) - Project Summary The Development Research Project Program provides an array of support programs to develop competitive biomedical research faculty in Kentuckys colleges and universities. The primary assumption underlying this program is that each Kentucky institution needs a critical mass of independent biomedical research faculty in order to provide the highest quality biomedical research training to undergraduate students. Furthermore Kentucky research faculty must be provided with the infrastructure to succeed in their research careers in order to provide first-rate research experiences to undergraduate students which will inspire them to join the biomedical workforce. With the overarching goal of increasing biomedical research capacity in Kentucky the Developmental Research Project Program aims to address the existing low numbers of independent research faculty and existing deficits in infrastructure by enhancing faculty recruitment promoting the research and career development of junior faculty and building a sustainable research network. Based upon our past successes we will focus our efforts on institutions eligible for NIH R15 funding. These institutions are primarily undergraduate institutions (PUIs) so this concentration provides the greatest benefit to undergraduate students. At these institutions we focus our efforts on developing faculty to increase success rates in obtaining R15 funding. In this way we have been successful in increasing the numbers of independent research faculty 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 research experience;undergraduate student


application_id: 10399502
project_number: 5P20GM103436-22
project_title: Electron Microscopy Core
administering_ic: NIGMS
award_notice_date: 2022-05-09
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1-RCB-9
subproject_number: 7346
contact_pi_person_id: 8537263
contact_pi: AEBERSOLD, JULIA WEYER
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Electron Microscopy Core Summary  While methods to image fluorescent molecules have advanced dramatically in recent years the resolution of electron microscopy remains unsurpassed. In the state of Kentucky there are numerous research programs that require the resolution that can only be achieved by the interaction of a beam of electrons with a specimen to distinguish ultrastructural features of tissues cell components viruses or bacteria. However due to declining institutional support for electron microscopy facilities many established Kentucky investigators have utilized facilities and expertise outside the state for their electron microscopic analyses. Furthermore new Kentucky investigators are hesitant to add electron microscopy to their research programs without accessible training and technical support. We propose to address these gaps in infrastructure and education by establishing a statewide electron microscopy core to facilitate equipment sharing provide technical support and offer training.

project_terms:
Address;Adopted;Applications Grants;Bacteria;Biomedical Research;Businesses;Cellular Structures;Collaborations;Cost Sharing;Cost efficiency;Education;Education and Outreach;Educational workshop;Electron Beam;Electron Microscope;Electron Microscopy;Electron Microscopy Facility;Electrons;Ensure;Equipment;Faculty;Fee-for-Service Plans;Fostering;Funding;Health;Infrastructure;Kentucky;Methods;Microscopic;Pilot Projects;Postdoctoral Fellow;Research;Research Personnel;Research Project Grants;Research Training;Resolution;Resources;Site;Specimen;Students;Techniques;Tissues;Training;Universities;Virus;fluorescence imaging;graduate student;outreach;programs;undergraduate student


application_id: 10399501
project_number: 5P20GM103436-22
project_title: Statistics Core
administering_ic: NIGMS
award_notice_date: 2022-05-09
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1-RCB-9
subproject_number: 7345
contact_pi_person_id: 8252047
contact_pi: STROMBERG, ARNOLD JAMES
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
RESEARCH CORES - STATISTICSProject Summary/Abstract:The primary goal of the Statistics Core located at the University of Kentucky is to provide accessto statistics support for experimental design preparation of manuscripts and grant applications. Thecore will also provide statistical training and professional development opportunities for KBRINinvestigators and trainees at UK through regional conferences workshops and seminars and ateach regional university during site visits. We will continue to utilize unique strategies via theApplied Statistics Lab (ASL) to bring in new regional investigators into the KBRIN network andprovide statistical expertise for their research. Some of these endeavors include providing easieraccess to statistical services through video conferences on-site visits and educatinginvestigators about KBRIN statistical resources. ASL faculty students and staff have workedand will work remotely and in person with the regional investigators to supply expertise inexperimental design statistical analysis and data management. Finally with an emphasis onmentorship and training ASL graduate students are partnered with an experienced faculty/staffmember who mentors the graduate student through all stages of a project. Training will be in theareas of data security data management data analysis using SAS and R automatic tablecreation post-hoc analysis and statistical consultation. In summary the Statistics Core willprovide the statistical support to develop a highly skilled workforce in the Commonwealth ofKentucky.

project_terms:
Applications Grants;Appointment;Area;Biological;Biomedical Research;Centers of Research Excellence;Consultations;Data Analyses;Data Security;Department chair;Development;Doctor of Philosophy;Educational workshop;Ensure;Experimental Designs;Faculty;Goals;Grant;Infrastructure;Institution;Kentucky;Laboratories;Lead;Manuscripts;Mentors;Mentorship;Methodology;Methods;Persons;Preparation;Reporting;Research;Research Assistant;Research Personnel;Resources;Site Visit;Statistical Data Interpretation;Students;Training;United States National Institutes of Health;Universities;Videoconferencing;Visit;Work;college;data management;experience;experimental study;graduate student;improved;member;professor;statistical service;statistics;symposium


application_id: 10399500
project_number: 5P20GM103436-22
project_title: Genomics Core
administering_ic: NIGMS
award_notice_date: 2022-05-09
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1-RCB-9
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
project_abstract:
GENOMICS CORE Summary: The thematic research focus of the KBRIN program is functional genomics. This field ofstudy is relevant to all aspects of life health and behavior of humans based on their genetic make-up andinteractions with their individual environment. The study of genes their gene products and their mutualinteractions has become crucial for the development of therapies to combat human diseases to understandthe etiology of such diseases and to narrow in on personalized individual treatment options based ongenetic and genomic information of the patient. Thus functional genomics technologies like thoseimplemented in the UofL Genomics Core will be increasingly essential for the health care of current andfuture populations. Innovative technologies like whole genome DNA and transcriptome RNA sequencing and massivelyparallel gene expression profiling have become technically and economically feasible. However theinfrastructure is best placed in centralized facilities because it is cost-prohibitive for individual researchlaboratories. Thus the instrumental and intellectual research infrastructure provided by the Core representsa critical component for the future overall strategic purpose for biomedical research community in Kentuckywith the potential for a positive state-wide impact for the development of competitive research. This core itsequipment and its staff will serve the UofL and its research base and will also serve the investigators in thenetwork-affiliated institutions in the KBRIN.

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;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;Visualization;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: 10399499
project_number: 5P20GM103436-22
project_title: Bioinformatics Core
administering_ic: NIGMS
award_notice_date: 2022-05-09
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1-RCB-9
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
project_abstract:
Bioinformatics CoreThe Bioinformatics Core based at the University of Louisville Health Science Campus is designed to serve thebioinformatics needs of faculty and students within KBRIN-affiliated institutions. A specific focus is placed onDNA and RNA sequence analysis (i.e. Genomics and Transcriptomics) with an expertise in the field of high-throughput genomic and transcriptomic data resulting from array-based and high-throughput sequencingtechnologies. We have developed the core through recruitment of expert faculty and postdoctoral level researchassociates so as to quickly build a capacity for bioinformatics research as well as to provide service andcollaboration with biomedical research scientists. In addition the core provides multiple levels of student trainingactivities. We will continue to pursue those activities that lead to excellence in this rapidly evolving scientificarena.

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;bioinformatics network;circular RNA;cloud based;computer science;design;experience;member;metagenomic sequencing;novel;recruit;ribosome profiling;student training;transcriptome sequencing;transcriptomics


application_id: 10399498
project_number: 5P20GM103436-22
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2022-05-09
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1-RCB-9
subproject_number: 7342
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Administrative Core Summary The primary purpose of the administrative core is to provide sound management of the INBRE-award on behalf of the network. In addition this core will provide leadership and direction to enable the network to grow in a purposeful and managed way. The administrative core will provide leadership and oversight of the bioinformatics and research cores as well as all other activities adjusting and balancing the commitments and needs of each such that the overall network is productive and impactful. The core will be responsible for tracking and evaluation of all network activities including mentoring and 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 experience;undergraduate student


application_id: 10399497
project_number: 5P20GM103436-22
project_title: IDeA Networks of Biomedical Research Excellence in Kentucky
administering_ic: NIGMS
award_notice_date: 2022-05-09
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
program_official: ZHOU, YANG
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1-RCB-9(IN)
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
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:
Overall SummaryThe overarching goal of the Kentucky Institutional Development Award (IDeA) Network ofBiomedical Research Excellence (KY-INBRE) is to build capacity for health-related andbiomedical research in the Commonwealth of Kentucky. We will build a collaborative researchand research-training community throughout the state. Our primary collaborative network isrepresented by 2 research intensive universities 5 state-supported and one independentprimarily undergraduate institutions (PUIs). We provide outreach activities in support of manyother of our smaller state supported and independent institutions including community technicalcolleges. Overall our activities are designed to build on our established multi-disciplinary researchnetwork with a focus on functional genomics as a means to strengthen research infrastructureof the lead and partner institutions. One aim is to support the development of young researchfaculty investigators to help them become independently competitive for federal research grants.Another aim of our network is to provide a variety of research training opportunities for ourundergraduate and graduate students. These students represent the next generation of the healthcare and/or biomedical research industries and they need to be mentored to develop appropriatescientific research skills..

project_terms:
Award;Biomedical Research;Communities;Development;Educational workshop;Faculty;Goals;Health;Healthcare;Industry;Infrastructure;Institution;Interdisciplinary Study;Kentucky;Knowledge;Lead;Location;Mentors;Network Infrastructure;Osteopathic Medicine;Poa plant;Postdoctoral Fellow;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Schools;Science;Students;Technology;Training;Universities;base;career;college;community college;design;experience;faculty research;functional genomics;graduate student;hazard;higher education;next generation;outreach;performance site;programs;skills;summer research;technical college;training opportunity;undergraduate student

public_health_relevance:
OVERALLProject Narrative:The health relatedness of this project lies with its goal to build capacity for health andbiomedical research throughout the Commonwealth of Kentucky. Moreover one of its primaryconcerns is to train the next generation of workers in the health care and biomedical researchindustries in Kentucky


application_id: 10398946
project_number: 5R01HL152714-03
administering_ic: NHLBI
award_notice_date: 2022-05-05
opportunity_number: PAR-19-274
application_type: 5
activity_code: R01
ic: HL
serial_number: 152714
program_official: BROWN, ALISON GWENDOLYN MARY
project_start_date: 2020-08-01
project_end_date: 2025-04-30
study_section: Dissemination and Implementation Research in Health Study Section[DIRH]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: SPRING, BONNIE
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
budget_start_date: 2022-05-01
project_title:
Implementing an evidence-based mHealth diet and activity intervention: Make Better Choices 2 for rural Appalachians

project_abstract:
ABSTRACT We propose a type 1 hybrid effectiveness-implementation study to test an adapted evidence-basedintervention and explore critical implementation issues including feasibility acceptability and costs thatinfluence scale-up and sustainment. We focus this adaptation effectiveness and implementation study onunderserved rural residents a population that maintains extremely high rates of suboptimal diet and sedentarybehaviors placing them at elevated risk for cardiovascular disease obesity diabetes cancer and otherchronic conditions. Within the vulnerable low socioeconomic status population of rural residents AppalachianKentuckians experience even worse health outcomes including among the highest rates of morbidity andmortality in the nation. Such adversity is exacerbated by and associated with inadequate community resources.Increasingly however Appalachian residents and other vulnerable populations are gaining access tomodalities that may be useful in addressing these health challenges including internet connectivity and nearlyubiquitous cell phone use. Despite this accelerating technology use the evidence base on personaltechnology-associated interventions (mHealth) in a rural high need population remains sparse. We proposefinalizing adaptation and testing an evidence-based multicomponent mHealth intervention Make BetterChoices 2 (MBC2) a behavioral program consisting of personalized health coaching an app accelerometerand financial incentives. In a recent randomized controlled trial among urban adults MBC2 produced largesustained diet and physical activity improvements by leveraging effective behavior change techniquesincluding goal-setting self-monitoring accountability and support. To prepare for the implementation of thissuccessful intervention with a new population marked by extreme health inequities and sparse resources ourteam has engaged in extensive foundational efforts based on the Dynamic Adaptation Process framework.These include: (1) completing focus groups and key informant interviews to assess the feasibility andacceptability for rural Appalachian residents to use the MBC2 program; (2) undertaking a comprehensivecommunity inventory to reveal existing and needed resources; (3) engaging stakeholders in community andacademic team meetings including community forums and CAB meetings; and (4) identifying MBC2programmatic and structural elements in need of adaptation. With this extensive preliminary activity we nowpropose a type 1 hybrid effectiveness-implementation trial in which we: (1) finalize adaptation by wireframe andusability testing MBC2 with local Appalachian residents; (2) conduct a RCT to test the effectiveness of theadapted MBC2 compared to an active control arm; and (3) explore implementation outcomes and contextualfactors with a focus on sustainment. This project aspires to demonstrate that systematic adaptation andimplementation of an evidence-based intervention can lead to meaningful and sustained behavioral changesand to prepare for potential scale-up and sustainment of the intervention to maximize its public health impact.

project_terms:
Accelerometer;Accountability;Address;Adult;Appalachian Region;Behavior;Behavioral;Blood Pressure;Body mass index;Budgets;Cardiovascular Diseases;Cellular Phone;Characteristics;Chronic;Chronic Disease;Clinical;Communities;Consolidated Framework for Implementation Research;Consumption;Data;Devices;Diabetes Mellitus;Diet;Elements;Equipment and supply inventories;Evidence based intervention;Fatty acid glycerol esters;Focus Groups;Foundations;Future;Goals;Health;Influentials;Intake;Internet;Intervention;Interview;Lead;Leisures;Life Style;Lipids;Malignant Neoplasms;Methods;Modality;Monitor;Morbidity - disease rate;Obesity;Outcome;Participant;Physical activity;Population;Process;Public Health;Randomized;Randomized Controlled Trials;Reporting;Research Activity;Resources;Rural;Rural Appalachia;Rural Population;Shapes;Techniques;Technology;Testing;Time;Training Support;Underserved Population;Unhealthy Diet;Vulnerable Populations;acceptability and feasibility;active control;active lifestyle;arm;attentional control;base;behavior change;cardiovascular disorder risk;contextual factors;cost;design;effectiveness evaluation;effectiveness implementation study;effectiveness implementation trial;effectiveness research;effectiveness testing;effectiveness trial;evidence base;experience;financial incentive;fruits and vegetables;good diet;health equity;health inequalities;hybrid type 1 design;implementation evaluation;implementation outcomes;implementation research;implementation science;improved;informant;information gathering;insight;intervention cost;intervention delivery;intervention program;iterative design;knowledge base;low socioeconomic status;mHealth;meetings;mortality;physical inactivity;prevent;primary outcome;programs;rural dwellers;rural underserved;scale up;secondary outcome;sedentary;sedentary lifestyle;smartphone Application;stress management;successful intervention;tool;tv watching;usability;virtual;waist circumference

public_health_relevance:
PROJECT NARRATIVE Rural residents especially Appalachians have among the nations highest rates of cardiovasculardisease (CVD) diabetes and obesity all associated with unhealthy diet and lack of physical activity. Newtools including personal technology offers an opportunity to make long lasting behavioral changes andimprove health. We will test a culturally adapted evidence-based multicomponent mHealth intervention MakeBetter Choices 2 (MBC2) a behavioral program consisting of personalized health coaching an appaccelerometer and financial incentives and explore optimal implementation and sustainment approaches.


application_id: 10398833
project_number: 5R01DA045023-05
project_title: A translational determination of the mechanisms of maladaptive choice in cocaine use disorder
administering_ic: NIDA
award_notice_date: 2022-04-15
opportunity_number: PA-17-111
application_type: 5
activity_code: R01
ic: DA
serial_number: 045023
program_official: FEDOTA, JOHN RAPHAEL
project_start_date: 2018-07-01
project_end_date: 2024-04-30
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: BECKMANN, JOSHUA ;WESLEY, MICHAEL J
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Cocaine use disorder (CUD) is characterized by the decision to use cocaine at the expense of other activities.Lab-based efforts to address this problem have therefore included cocaine choice self-administration proceduresthat incorporate a non-drug alternative to model this defining feature. Studies using these procedures havetypically scheduled competing reinforcers so that the probabilities are certain. However such deterministicoutcomes are not representative of real-world scenarios in which the consequences from drug-related decisionsare often unpredictable. Importantly decision-making in a dynamic uncertain context significantly alters thevalue of choice options and requires continuous updating of option values which engages learning processesand related corticostriatal networks that might be functioning abnormally in CUD. Decision-making in dynamicenvironments has been successfully modeled using probabilistic reinforcement-learning choice (PRLC) tasks.The integration of these tasks with reinforcement-learning (RL) modeling has been used to capture moment-to-moment changes in the mechanisms of dynamic choice and the application of neuroscience techniques hasbegun to identify the underlying neurobiology. This approach has uncovered biologically-based decision-makingabnormalities in multiple brain disorders but has yet to be systematically applied to the experimental study ofCUD The translation of combined RL and neuroscience approaches to CUD is logical considering themaladaptive choice behavior that typifies the disorder the varying reinforcement probabilities in cocaine usersnatural environments and the learning impairments and neuroadaptations that have been documented inindividuals with CUD. Thus there are critical gaps in our understanding of the mechanisms underlying dynamiccocaine use decisions and a strong scientific premise for applying an RL framework to fill these gaps. Thisproject proposes rigorous PRLC tasks RL modeling neuromodulation/fMRI neuroimaging techniques andcomplementary translational study designs in rats and humans to study dynamic choice in CUD. The first set ofcross-species experiments will demonstrate the impact of problematic cocaine use on dynamic decision-makingand reveal the neurobehavioral and neurobiological processes underlying this abnormal task performance. Thesecond set of experiments will use a PRLC task in which intravenous cocaine is available as an alternative tothe non-drug reinforcer to determine the behavioral and neural profile associated with the decision to usecocaine and reduced cocaine choice during treatment. Amphetamine maintenance and non-drug alternativereinforcer treatments reduce cocaine choice which will be leveraged here to uncover behavioral and neuralmechanisms that can be targeted for future treatment development. This project will have a significant impacton the field by establishing the experimental application of reinforcement-learning theory to the study ofmaladaptive dynamic decision-making in CUD.

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

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


application_id: 10398400
project_number: 3P20GM103436-21S1
administering_ic: NIGMS
award_notice_date: 2021-06-28
opportunity_number: PA-18-935
application_type: 3
activity_code: P20
ic: GM
serial_number: 103436
suffix: S1
program_official: ZHOU, YANG
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1(IN)
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
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_title:
KY INBRE NOSI Supplement: Targeted COVID-19 Vaccine Decision Making Support for Sexual and Gender Minorities

project_abstract:
Project Summary/AbstractSince the World Health Organization declared COVID-19 a pandemic 31.6 million Americanshave contracted the SARS-CoV-2 virus and 566000 have died. Effective and safe COVID-19vaccines have been developed tested and deployed in record time and 219 million vaccinedoses have been administered in the US. Racial and ethnic disparities in vaccine uptake havebeen noted but data are not yet available for some other disadvantaged groups. Sexual andGender Minorities (SGMs) are potentially at risk for vaccine hesitancy due to social andhistorical factors affecting vaccination in general and healthcare access specifically. There is acritical need to understand vaccine attitudes and behaviors among SGMs. Our long-term goal isto reduce potential health disparities in COVID-19 among SGMs. The overall objective is todevelop and deploy a decision aid that supports SGM COVID-19 vaccine decision making.Using survey and focus group methods and following accepted international standards fordecision aid development we will develop a tailored decision aid to reduce vaccine decisionalconflict and improve vaccine acceptance.The projects specific aims are to:1. Generate foundational knowledge of COVID-19 vaccine hesitancy among SGMs. Wehypothesize that SGMs overall will be somewhat less accepting of the vaccine than the generalpopulation and among SGMs there will be subgroups with other vaccine hesitancy risk factors(e.g. race gender minority identity political affiliation) who have significantly higher rates ofvaccine hesitancy.2. Produce contextualized understanding of intentions to receive the COVID-19 vaccine. Wehypothesize the reasons for vaccine acceptance or hesitancy will differ among SGM subgroups.Focus group discussions with diverse samples of SGMs who are vaccine-hesitant will identifyknowledge gaps misconceptions perceived barriers negative attitudes such as stigma andmistrust and preferences for decision support. The primary outcome will be determiningdecision support needs for SGM subgroups.3. Create decision aids to reduce decision conflict and improve acceptance of the COVID-19vaccine. We will generate a decision aid or multiple versions of a decision aid to empower theSGM decision maker to compare options for protection against COVID-19 clarify values andsupport efficacy for gathering more information collaborating with a healthcare partner in thedecision-making process and/or obtaining the COVID-19 vaccine. We hypothesize the tailoreddecision aids will reduce decision conflict and improve vaccine acceptance.

project_terms:
2019-nCoV;Affect;African American;American;Attitude;Behavior;Belief;COVID-19;COVID-19 vaccination;COVID-19 vaccine;Categories;Cessation of life;Conflict (Psychology);Contracts;Data;Decision Aid;Decision Making;Development;Disadvantaged;Dose;Ethnic Origin;Focus Groups;Foundations;General Population;Goals;Head;Healthcare;Herd Immunity;Hispanics;Income;Individual;Intention;International;Knowledge;Latinx;Measures;Methods;Motivation;Natural Immunity;Not Hispanic or Latino;Outcome;Pattern;Politics;Population;Prevalence;Process;Race;Recording of previous events;Research;Respiratory distress;Risk;Risk Factors;Sampling;Sex Differentiation;Sexual and Gender Minorities;Subgroup;Surveys;Testing;Time;United States;Vaccinated;Vaccination;Vaccines;Virus;World Health Organization;ethnic minority population;gender minority;health care availability;health disparity;improved;intersectionality;medically underserved;medically underserved population;pandemic disease;preference;primary outcome;protective behavior;psychosocial;racial and ethnic disparities;racial minority;sexual minority;shared decision making;social;social stigma;stem;tool;underserved community;vaccine acceptance;vaccine hesitancy;vaccine trial

public_health_relevance:
Project NarrativeThe proposed research will increase knowledge about COVID-19 vaccine hesitancy amongsexual and gender minorities and their demographic subgroups using a nationallyrepresentative survey examining COVID-19 vaccination history or intention to get vaccinatedand knowledge attitudes and beliefs about the COVID-19 vaccine. Focus groups withsubgroups most at risk of vaccine hesitancy will provide a contextual understanding of thefactors related to SGM vaccination intentions. The data produced will be used to create adecision aid to reduce decision conflict and improve acceptance of the COVID-19 vaccine.


application_id: 10398202
project_number: 5T32DA035200-25
project_title: Research Training in Drug Abuse Behavior
project_terms: Behavior;Drug abuse;Research Training
administering_ic: NIDA
award_notice_date: 2022-04-25
opportunity_number: PA-16-152
application_type: 5
activity_code: T32
ic: DA
serial_number: 035200
program_official: KAUTZ, MARY A
project_start_date: 1998-08-01
project_end_date: 2023-06-30
study_section: ZDA1-SXM-M(01)S
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACT/SUMMARYThis continuation application proposes to support 3 pre-doctoral and 3 post-doctoral trainees with a faculty of20 drawn from six academic and research units of the University of Kentucky. The rich environment providesopportunities for translational and multidisciplinary bio-behavioral research training in facilities such as the: 1)Center on Drug and Alcohol Research/Straus Research Building; 2) Center for Drug and Alcohol ResearchTranslation; 3) Center for Clinical and Translational Science; 4) Laboratory of Human BehavioralPharmacology; and 5) Residential Research Facility.During the most recent five-year funding period we trained 10 pre-doctoral students and 8 post-doctoralfellows. These trainees have authored 237 publications and presented 336 papers at local national orinternational conferences. Seventeen of these trainees remain involved in research or academics. Additionalpre-doctoral trainees (N=2) and post-doctoral fellows (N=3) will be added during the final year of the currentfunding period to keep all 6 training slots filled. Individuals from under-represented racial and ethnic groupsfilled 27 percent of the available training slots.The program is designed to prepare trainees to assume translational and multidisciplinary researchresponsibilities in academic and other scientific organizations concerned with substance-use disorders (SUDs).Pre-doctoral trainees concentrate in translational and interdisciplinary aspects of SUDs as part of a doctoralprogram in a behavioral science discipline (e.g. psychology sociology). Post-doctoral fellows have adoctorate in a behavioral science discipline and are preparing for a research role in SUDs or they are healthprofessionals seeking translational and interdisciplinary training in a behavioral orientation in SUDs research.Basic elements of the program include: (1) training in the basic building blocks of research (e.g. experimentaldesign data analysis) and independent research competence; (2) a translational and interdisciplinaryorientation taking students beyond their basic discipline and providing exposure to key theoretical conceptsand methodological issues of the related behavioral sciences along with a bio-behavioral conceptualization; (3)professional development to support a career in SUDs research; (4) exploration of SUDs topics from amedical-behavioral perspective through courses offered by training faculty; and (5) opportunities for researcharound relevant questions in SUDs constituting a dissertation project for pre-doctoral trainees. The post-doctoral program is individually tailored to the objectives of the fellows and builds on their previous knowledgeand experience while drawing on these core elements. The need for a translational and interdisciplinaryprogram such as the one proposed is greater today than ever before and fills a unique niche in substanceabuse research.

public_health_relevance:
PUBLIC HEALTH RELEVANCE STATEMENTThe purpose of this application is to continue a highly successful 20-year training program in translational andinterdisciplinary research on substance-use disorders and offers translational and interdisciplinary researchtraining on bio-behavioral factors in substance-use disorders at the pre-doctoral and post-doctoral levels.Graduates of this program are actively involved in research teaching publishing articles and becomingindependent substance abuse researchers. We aim to continue this record of success in the next fundingperiod because the need for a translational or interdisciplinary program is greater today than ever before andthe proposed training program fills a unique niche in drug abuse research.


application_id: 10398182
project_number: 5R01AG068215-03
project_title: Sleep Fragmentation and Alzheimers Disease
administering_ic: NIA
award_notice_date: 2022-04-20
opportunity_number: PAR-18-497
application_type: 5
activity_code: R01
ic: AG
serial_number: 068215
program_official: MACKIEWICZ, MIROSLAW
project_start_date: 2020-08-01
project_end_date: 2025-04-30
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 8535896
contact_pi: MURPHY, MICHAEL PAUL
other_pis: BACHSTETTER, ADAM D;DUNCAN, MARILYN J.;O'HARA, BRUCE FREDERICK;SUNDERAM, SRIDHAR
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:
APP-PS1;Abeta clearance;Address;Affect;Aging;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease patient;Alzheimer's disease risk;Amyloid beta-Protein;Anti-Inflammatory Agents;Astrocytes;Attenuated;Biological;Brain;Chronic;Cognition;Cognitive deficits;Correlative Study;Dementia;Demographic Factors;Deposition;Development;Disease;Disease Progression;Exhibits;Family;Frequencies;Human;Impaired cognition;Impairment;Inflammation;Knock-in;Knock-in Mouse;Life;Life Style;Light;Link;Mediating;Mediator of activation protein;Medical History;Microglia;Modeling;Moods;Mus;Nerve Degeneration;Noise;Pathology;Personal Satisfaction;Pharmaceutical Preparations;Pharmacology;Phase;Phase I Clinical Trials;Process;Rest;Risk;Role;Schedule;Sleep;Sleep Deprivation;Sleep Disorders;Sleep Fragmentations;Sleep disturbances;Slow-Wave Sleep;Societies;Synapses;System;Temperature;Testing;Time;Work;abeta accumulation;age related;beta amyloid pathology;circadian;circadian pacemaker;design;improved;middle age;mild cognitive impairment;mouse model;neuroinflammation;neuropathology;neurotoxic;noise exposure;novel;novel strategies;novel therapeutic intervention;pre-clinical;prevent;response;sleep quality;sleep quantity

public_health_relevance:
Age-related dementia is a significant and growing burden on our society  the most well known of which isAlzheimer's disease (AD)  and chronic sleep disruption is a pervasive feature of contemporary life that isassociated with and exacerbated in AD. This project will examine the idea that sleep quality is more importantthan sleep quantity and will investigate the underlying biological mechanisms of this process as well asexplore novel strategies for improving sleep and treating deleterious inflammation in the brain.


application_id: 10396054
project_number: 5R21AG071888-02
project_title: The role of the gut microbiota in sarcopenia
administering_ic: NIA
award_notice_date: 2022-02-02
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AG
serial_number: 071888
program_official: FLORES, ROBERTO L
project_start_date: 2021-05-01
project_end_date: 2025-01-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SummaryA key determinant of geriatric frailty is sarcopenia the age-associated loss of skeletal muscle mass andfunction. Recent estimates indicate that up to one-third of the elderly population may suffer from frailty. Frailtyoften leads to loss of functional independence and is among the leading risk factors for falls in the elderly. Infact as life expectancy continues to increase the maintenance of muscle strength is an important factor thatcontributes to a higher quality of life. Although the etiology of sarcopenia remains to be determined proposedcontributing factors include the loss of innervation and motor unit decline oxidative stress aberrant autophagyand inflammation. There is emerging evidence for the existence of a gut-skeletal muscle axis. On the basis ofthis connection there has been much speculation that dysbiosis of the gut microbiota might have a role in thedevelopment of sarcopenia. While plausible mechanisms have been proposed through which dysbiosis mightcontribute to the development of sarcopenia there remains a paucity of direct evidence to support suchmechanisms. The purpose of this exploratory grant is to test the hypothesis that dysbiosis of the gut microbiotapromotes sarcopenia by inducing a state of anabolic resistance in skeletal muscle through TLR4hyperactivation of mTORC1 signaling. To test this hypothesis the following aims will be pursued: Aim 1:Determine if the gut microbiota from aged mice can induce sarcopenia in adult mice; Aim 2: Determine if thegut microbiota from adult mice can rescue sarcopenia in old mice. If the results of the proposed experimentsprovide evidence to support the hypothesis a future R01 application will seek to rigorously test the proposedmechanism by determining if a skeletal muscle-specific TLR4 knockout prevents sarcopenia despite low-gradesystemic inflammation induced by gut microbiota dysbiosis.

project_terms:
Adult;Age;Age-Months;Aging;Amino Acids;Autophagocytosis;Biological Assay;Cell Count;Cell physiology;Defect;Development;Elderly;Endocrine;Etiology;Exercise;Exhibits;Fiber;Fibrosis;Future;Grant;Impairment;Inflammation;Injury;Interleukin-6;Intestinal permeability;Intestines;Investigation;Knock-out;Life Expectancy;Maintenance;Measures;Metabolic;Motor;Mus;Muscle;Muscle function;Oxidative Stress;Performance;Persons;Phenotype;Polyethylene Glycols;Population;Predisposition;Quality of life;Research;Resistance;Risk Factors;Role;Serum;Signal Transduction;Skeletal Muscle;TLR4 gene;TNF gene;Testing;Woman;aged;dysbiosis;experimental study;falls;fecal microbiota;fluorescein isothiocyanate dextran;frailty;functional independence;functional loss;gut bacteria;gut dysbiosis;gut microbiome;gut microbiota;improved;men;mitochondrial DNA mutation;muscle aging;muscle form;muscle strength;nerve supply;novel;prevent;regeneration following injury;response;sarcopenia;satellite cell;sedentary;skeletal muscle wasting;systemic inflammatory response;therapeutic target

public_health_relevance:
NarrativeA key factor contributing to becoming frail as a person gets older is the loss of skeletal muscle size andstrength. Why people lose muscle as they get older is not known but one possibility is the bacteria in the gutbecome disturbed (dysbiosis). The purpose of the proposed research is to determine if gut dysbiosis causesthe loss of skeletal muscle size and strength associated with aging.


application_id: 10395618
project_number: 5R01DE029650-04
project_title: HPV16 E6 Antibody Detection as an Early Marker for Oropharyngeal Cancer Among Men Living with HIV
administering_ic: NIDCR
award_notice_date: 2022-04-29
opportunity_number: RFA-DE-20-001
application_type: 5
activity_code: R01
ic: DE
serial_number: 029650
program_official: YIN, HONGEN
project_start_date: 2021-02-05
project_end_date: 2025-04-30
study_section: ZDE1-GZ(13)
contact_pi_person_id: 14510566
contact_pi: KUHS, KRYSTLE A.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
People living with HIV (PLWH) have an increased life expectancy due to effective therapies. This has resulted in anincreased incidence of non-AIDS defining cancers (NADCs) in particular cancers caused by human papillomavirus (HPV).The most rapidly increasing HPV-related malignancy in the general US population is HPV-driven oropharyngeal cancer(HPV-OPC) a type of head and neck that has increased in incidence by more than 200% over the past few decades.1 2PLWH are 1.5 to 4 times more likely to develop HPV-OPC than the general population.3 They are also more likely todevelop HPV-OPC at younger ages (51 versus 60)4 and have a less favorable cancer prognoses.5 Unlike cervical cancerwhere the introduction of highly effective screening has significantly reduced the incidence and mortality of cervicalcancer there are no methods for early detection of HPV-OPC. A major barrier for early detection has been the inabilityto identify PLWH at highest risk for HPV-OPC given that a precancerous precursor lesion for OPC has yet to be identified.Recently HPV16 E6 antibody positivity has been identified as a promising early biomarker. Previous work from ourgroup showed that HPV16 E6 antibodies are present in up to 90% of HPV-OPC patients6 and appear more than 10 yearsprior to diagnosis.7-9 Additionally we have shown that HPV16 E6 antibodies are highly specific for HPV-OPC10 and are notstrongly associated with the 5 other cancers caused by HPV.11 The objective of this study is to evaluate the ability of theHPV16 E6 marker to identify a sub-population of PLWH at highest risk for developing HPV-OPC and for which head andneck cancer screening would be most effective. To accomplish this we will conduct a natural history study of the HPV16E6 antibody marker. This study will focus on men aged 40+ living with HIV given that ~85% of HPV-OPC cases occur inmiddle aged men and HIV infection additionally elevates risk by up to 4-fold. Using the Tennessee Center for AIDSResearch (TN-CFAR) Biorepository banked blood samples from men aged 40+ living with HIV (N=3261) will be tested forHPV16 E6 antibodies. All HPV16 E6 seropositives and a subset of HPV16 E6 seronegatives (1:2 ratio) will be invited toparticipate in yearly (4 total) comprehensive head and neck cancer screening exams performed by a Vanderbilt IngramCancer Center (VICC) head and neck surgeon. Cancer screening visits will include: visual inspection of the mouth andpalpation of tonsils ultrasound imaging laryngoscope exam a detailed questionnaire and biospecimen collection. E6seropositive men will be compared to E6 seronegative men in terms of: a) markers of elevated HPV-OPC risk and b)development of HPV-OPC. The specific aims are: (1) Estimate the prevalence of HPV16 E6 antibodies among men aged40+ living with HIV; (2) Determine the association between HPV16 E6 seropositivity and markers of HPV-OPC risk; (3)Estimate the risk of developing: a) precancerous markers of HPV-OPC and/or; b) HPV-OPC by HPV16 E6 serostatus. Wehypothesize that men with HPV16 E6 antibodies will be more likely to have known risk factors associated with HPV-OPCdevelopment [sexual behavior persistent oral HPV infection] and will be more likely to develop HPV-OPC than menwithout HPV16 E6 antibodies. These efforts could help to generate evidence for oral health screening guidelines tailoredto PLWH. This work is particularly impactful given that HPV-OPC disproportionately affects PLWH.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Affect;Age;Antibodies;Behavioral;Biological Markers;Blood;Blood Banks;Blood specimen;Cancer Center;Cancer Etiology;Cancer Prognosis;Clinic;Collection;Comprehensive Health Care;Development;Diagnosis;Early Diagnosis;Eligibility Determination;General Population;HIV;HIV Infections;HIV Seronegativity;HPV oropharyngeal cancer;HPV-High Risk;Head and Neck Cancer;Head and Neck Surgeon;Head and neck structure;High Prevalence;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Incidence;Individual;Laryngoscopes;Lesion;Life Expectancy;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Methods;Natural History;Oncoproteins;Oral cavity;Oral health;Palpation;Patients;Persons;Population;Positioning Attribute;Prevalence;Quality of life;Questionnaires;Research;Resources;Risk;Risk Estimate;Risk Factors;Screening for cancer;Screening procedure;Seroprevalences;Sex Behavior;Surrogate Markers;Tennessee;Testing;Time;Tonsil;Ultrasonography;Visit;Visual;Work;aged;antibody detection;base;biobank;cancer risk;chemoradiation;clinical examination;cohort;early detection biomarkers;effective therapy;high risk;improved;malignant oropharynx neoplasm;men;middle age;mortality;novel;oral HPV;oral HPV infection;premalignant;rapid detection;screening;screening guidelines;seropositive

public_health_relevance:
NARRATIVECases of human papillomavirusdriven oropharyngeal cancer (HPVOPC) now outnumber cervical cancer cases in the US men and people living with HIV (PLWH) are at highest risk. Unlike cervical cancer where the introduction of highlyeffective screening protocols significantly reduced the incidence and mortality due to cervical cancer there are nomethods for early detection of HPVOPC. We are proposing to use HPV16 E6 seropositivity an early biomarker of HPVOPC to develop a cohort of men living with HIV who are at highest risk for OPC to better understand HPV16 E6antibodies as an early marker of HPVOPC and b) to develop new methods of early detection for this rapidly increasingcancer.


application_id: 10395546
project_number: 5R01AG068055-02
project_title: Identifying Associations between Brain Iron Neurocognitive Networks and Protective Factors
administering_ic: NIA
award_notice_date: 2022-02-25
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AG
serial_number: 068055
program_official: WAGSTER, MOLLY V
project_start_date: 2021-05-01
project_end_date: 2026-02-28
study_section: Special Emphasis Panel[ZRG1-BDCN-L(02)M]
contact_pi_person_id: 7993908
contact_pi: GOLD, BRIAN TIMOTHY
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_terms:
Affect;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease risk;Alzheimers disease biomarker;American;Amyloid beta-Protein;Antioxidants;Attenuated;Base of the Brain;Biological Markers;Blood - brain barrier anatomy;Brain;Cerebrospinal Fluid;Cerebrum;Clinical;Cognition;Cognitive;Cognitive aging;Diet;Diffusion Magnetic Resonance Imaging;Disease Progression;Early Diagnosis;Early Intervention;Early identification;Elderly;Episodic memory;Financial compensation;Functional Magnetic Resonance Imaging;Goals;Health;Image;Impaired cognition;Individual;Intake;Iron;Linear Regressions;Liquid substance;MRI Scans;Magnetic Resonance Imaging;Maintenance;Measures;Mediating;Memory;Memory Loss;Modeling;Neurocognitive;Neurocognitive Deficit;Neuropsychology;Participant;Pathologic;Pathology;Pattern;Performance;Plasma;Positron-Emission Tomography;Predisposition;Regression Analysis;Sampling;Scanning;Short-Term Memory;Signal Transduction;System;Testing;Time;age related;base;behavior measurement;cognitive function;cognitive process;cognitive reserve;good diet;improved;in vivo;indexing;inflammatory marker;lifestyle factors;neuroimaging;neuroimaging marker;novel;novel marker;pre-clinical;protective factors;relating to nervous system;support network;tau Proteins;tau-1;white matter


application_id: 10395494
project_number: 5R35GM136295-03
project_title: Mechanisms and functions of Shoc2-transduced cellular signals
administering_ic: NIGMS
award_notice_date: 2022-04-25
opportunity_number: PAR-17-094
application_type: 5
activity_code: R35
ic: GM
serial_number: 136295
program_official: LEWIS, MECHELLE MAYLEBEN
project_start_date: 2020-05-01
project_end_date: 2025-04-30
study_section: Special Emphasis Panel[ZRG1-CB-J(55)R]
contact_pi_person_id: 8586925
contact_pi: GALPERIN, EMILIA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The overall vision of our NIGMS-supported program is to address the molecular mechanisms of theextracellular signal-regulated kinases 1 and 2 (ERK1/2) signal transmission as guided by scaffold proteins.Essential for the normal functioning of the cell the ERK1/2 ability to rewire signaling pathways is a majorproblem for clinical intervention. The rationale for the proposed studies is that a thorough understanding of themechanism by which key regulators such as scaffold protein Shoc2 modify ERK1/2 signaling is essential forunderstanding dysregulated mechanisms in ERK1/2-related diseases and for identifying new drug targets. Ourstudies have raised many exciting questions and the most transformative research will be pursued in the nextfive-year period. Our efforts during the first cycle of NIGMS funding led to the discovery that the ubiquitin machineryregulates the signal transmission of ERK1/2 signals through the Shoc2 scaffolding module and controlsassembly of the proteins in the complex. We identified key enzymes modulating the ability of Shoc2 to transmitERK1/2 signals. We then discovered that organized spatial distribution of the Shoc2 complexes is critical forthe proper transmission of ERK1/2 signals. Our work further revealed a distinct function of the signalstransduced by the Shoc2 scaffold in ERK1/2 in mediating cell adhesion and motility. We also established thatloss of Shoc2 in zebrafish has a systemic effect of on early development recapitulating congenitalmalformations observed in patients with Shoc2 mutations. For MIRA application we propose to define the mechanisms by which endosomal sorting regulates theubiquitin-driven remodeling of the Shoc2 complexes and signaling. The key steps that segregate Shoc2 intothe distinct intracellular sorting pathways will be delineated. The molecular details of how Shoc2-activatedERK1/2 signals promote early developmental stages will be determined. We will use an innovativecomprehensive approach encompassing genetic state-of-the-art microscopy as well as cell-based andbiophysical methodologies. Of note we will use zebrafish as a vertebrate model to investigate the in vivo effectof Shoc2 gene editing on the early stages of development since they offer distinct advantages for studies ofdevelopment including their transparency as well as external and rapid development. The proposed researchis expected to produce an ambitious and comprehensive mechanistic understanding of how Shoc2 is involvedin determining the specificity of ERK1/2 signaling outcomes and has the potential for high impact by laying thegroundwork for future studies on developmental disorders and contributing to the advancement of noveltherapeutic strategies and biomarkers.

project_terms:
Address;Biological Markers;Cell Adhesion;Cell physiology;Cells;Clinical;Complex;Congenital Abnormality;Development;Disease;Enzymes;Funding;Future;Genes;Genetic;Intervention;Lead;MAPK3 gene;Malignant Neoplasms;Mediating;Microscopy;Modeling;Molecular;Mutation;National Institute of General Medical Sciences;Outcome;Pathway interactions;Patients;Proteins;Research;Scaffolding Protein;Signal Pathway;Signal Transduction;Sorting - Cell Movement;Spatial Distribution;Specificity;Syndrome;Ubiquitin;Vision;Work;Zebrafish;base;biophysical techniques;cell motility;developmental disease;in vivo;innovation;new therapeutic target;novel diagnostics;novel therapeutic intervention;programs;public health relevance;scaffold;targeted treatment;therapeutic development;transmission process;tumor;virtual


application_id: 10394525
project_number: 1G20AI167407-01
project_title: Upgrading infectious disease research facilities at University of Louisville RBL
administering_ic: NIAID
award_notice_date: 2021-09-23
opportunity_number: RFA-AI-21-022
application_type: 1
activity_code: G20
ic: AI
serial_number: 167407
program_official: DIAZ SAN SEGUNDO, FAYNA C
project_start_date: 2021-09-23
project_end_date: 2025-02-28
study_section: Special Emphasis Panel[ZAI1 LR-M (S1)]
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Louisville Regional Biocontainment Laboratory (RBL) is an operational unit of the Universitys Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases (CPM). The CPM operates the only Biosafety Level 3 laboratories and animal research facilities available to researchers in the Commonwealth of Kentucky. As such we are a regional resource for two Carnegie Research I (highly research intensive) Universitiesthe University of Louisville and the University of Kentuckyas well as for the local biotechnology industry and other universities and non-profit organizations. The University of Louisville has been an outstanding steward of the RBL paying meticulous attention to the facility needs. However after a decade we have encountered some challenges primarily with obsolescence of control systems and wear and tear on some of the building air handling systems. The necessary HVAC upgrades are already being addressed by the University but we request support from NIAID through this G20 for additional facility related upgrades and modernization of research equipmentSPECIFIC AIMSWe propose to address specific facility operational needs in both the fixed building infrastructure and in upgrading and modernizing our in vivo and in vitro research capabilities. We propose incorporating modern state-of-the-artinstrumentation to build solid foundations for innovations in biodefense and emerging infectious disease research. The building systems upgrades that directly affect operations of the containment space will be scheduled during the annual preventative maintenance shutdown periods to be conducted in November/December 2021 and 2022. Similarly new in vivo and in vitro research equipment shall be installed during the annual shutdown to allow for service professionals to install and commission the equipment without needing to address biosafety training and Select Agent-specific standard operating procedures. Aim 1: Repair renovate and modernize RBL building systems to enhance functions and operations of the existing research facilities. We propose to address specific facility operational needs in the fixed building infrastructure. We shall upgrade critical facility systems that are facing imminent obsolescence and rectify one major facility design defect that placed some inconveniences and limitations on research operations: the BSL-3-ABSL-3 passthrough boxes. The long-term commitment of the CPM is to support basic and translational research that leads to the development of countermeasures for biodefense and emerging infectious agents. These upgrades will secure our ability to maintain our BSL-3 research program and continue to develop innovative countermeasures against biodefense and emerging infectious disease threats. Aim 2: Enhance and modernize the CPM RBL in vivo research capabilities. The COVID-19 pandemic validated the significance and need for ABSL-3 facilities such as we have at the CPM. Over the past 14 months our in vivo research facilities were heavily utilized to support development of novel COVID-19 therapeuticsvaccines and other prophylactic strategies. Until COVID-19 the vast majority of our in vivo research utilized murine models with sporadic use of ferrets for influenza studies. Recently we have made extensive use of the Golden Syrian Hamster (GSH) model. Consequently we have a practical need to expand our caging for medium sized rodent models. Moreover emerging data on post-COVID human pathologies impacting different organ systemslung cardiovascular neural and renal in particularraise the need for more sophisticated tools for assessing physiological function in research models. To this end we propose to elevate our in vivo research facilities by adding Promethion metabolic isocaging systems that record animal metabolic and behavioral data and allow us to integrate research studies with our existing gnotobiotic rodent core. We shall also add telemetry capabilities to precisely record body temperature heart rate and blood pressure metrics. For lung function assessments we will add rodent plethysmography capabilities. These research infrastructure enhancements will build new collaborations with our colleagues in centers of excellence in environmental health cardiovascular disease diabetes and obesity. We will also consolidate existing collaborations with our Functional Microbiomics Inflammation and Pathogenicity COBRE by facilitating use of gnotobiotic animals to assess the impact of microbiome communities in pathogenesis of emerging infectious diseases. In vivo imaging capability is an extremely useful adjunct to physiological and most-mortem pathology assessments. Our existing IVIS optical imaging system is nearing obsolescence and needs upgrading to secure ongoing research studies particularly in Yersinia pestis and Burkholderia pseudomallei infection models.Aim 3: Enhance and modernize the CPM RBL in vitro research capabilities. The CPM RBL is a wellequipped facility but the vast majority of the research instrumentation was installed as the University cost-share contribution to the RBL construction between 2007 and 2010. We have a meticulous equipment maintenance and service program coordinated by Marlene Steffen and funded by the Executive Vice President for Research annual budget to the CPM which has kept all of our equipment fit for purpose. Over the past decade technology Contact PD/PI: PALMER KENNETH EProgram Narrative Page 7for analysis of immune cell function by flow cytometry has become significantly more sophisticated. We propose to enhance and modernize our flow cytometry analytical capabilities by adding a Becton Dickinson FACSymphony analyzer with 4 laser/16 color capabilities and high throughput system that will accommodate 96/384-well plates. This will significantly expand the speed throughput and sophistication of the data acquisition complementing our existing 11-year-old FACSAria II cell sorter. We have existing high throughput screening capabilities in our High Throughput Biology Core. Most of the HTPB equipment is also a decade old. We propose that our biodefense and emerging infectious disease research programs would benefit immensely by acquisition of the Cytation C10 high throughput confocal microscopy instrument that allows rapid collection of high quality and high-resolution quantitative data under normal cell and tissue incubation conditions. Several of our faculty have critical need for this instrument to be located in our RBL BSL-3 laboratories to facilitate their research on emerging viruses and bacterial pathogens.

project_terms:
Area;Chills;Collection;Communicable Diseases;Confocal Microscopy;Data;Disease Outbreaks;Emerging Communicable Diseases;Ensure;Equipment;Flow Cytometry;Goals;Image;In Vitro;Infectious Diseases Research;Kentucky;Laboratories;Laboratory Animal Production and Facilities;Laboratory Research;Lighting;Link;Medicine;Metabolic;Modernization;National Institute of Allergy and Infectious Disease;Normal Cell;Normal tissue morphology;Physiological;Plethysmography;Process;Research;Research Infrastructure;Research Personnel;Research Subjects;Resolution;Seasons;Secure;System;Telemetry;Therapeutic;Treatment Efficacy;Universities;Water;biodefense;biothreat;data acquisition;data complexity;improved;in vivo;infectious disease model;instrument;instrumentation;mouse model;operation;prevent;repaired;research facility;response;vaccine discovery

public_health_relevance:
The University of Louisville Regional Biocontainment Laboratory (RBL) is an operational unit of the Universitys Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases (CPM). The CPM operates the only Biosafety Level 3 laboratories and animal research facilities available to researchers in the Commonwealth of Kentucky. We request support from NIAID through this proposal for additional facility related upgrades and modernization of research equipment. We propose three Specific Aims. First we shall repair renovate and modernize specific RBL building systems to enhance functions of the research facilities. We shall upgrade critical building systemsthe vivarium cage washers; controls for the autoclaves and lighting systems. We shall upgrade the buildings camera video surveillance quality. Replacing piping on the processed chilled water loop is necessary to ensure proper operations of the autoclaves in all seasons. We intend to replace the pass-through boxes between BSL-3 and ABSL-3 spaces that currently require treating the whole BSL-3 and ABSL-3 areas as one space. These building systems upgrades will secure functional biocontainment research facilities that allow us to prevent prepare for and respond to infectious disease outbreaks for the next decade and beyond. Secondly we propose to enhance and modernize the CPM in vivo research facilities and thirdly to enhance and modernize our in vitro research capabilities. We shall achieve our second aim by significantly upgrading our vivarium caging systems through purchasing metabolic isocaging systems that will allow us to derive significantlygreater detail of physiological responses to emerging infectious disease in murine models. We shall augment our in vivo research capabilities with new imaging equipment telemetry systems and plethysmography instrumentation that together allow fine granularity of data acquisition improving our understanding of infectious disease and assisting in discovery of vaccines and therapeutics against biothreats and emerging infectious diseases. This equipment achieves major goals of humane in vivo research: more comprehensive and detailed information about the infectious disease model and effect of therapy closely linked with reduction in the number of research subjects necessary for comprehensive assessment of the treatment efficacy. Upgrades of the in vitro research equipment will be through acquisition of a high throughput spinning disc confocal microscopy instrument that allows rapid collection of high quality and high resolution quantitative data under normal cell and tissue incubation conditions and a flow cytometry analyzer with high throughout capabilities that will significantly expand the throughput and complexity of data acquisition. The equipment upgrades will modernize our research infrastructure enhancing the CPM RBL capabilities to rapidly develop and assist in deployment of countermeasures to mitigate the effects of biothreats and emerging infectious diseases.


application_id: 10394335
project_number: 5R24ES030904-03
administering_ic: NIEHS
award_notice_date: 2022-05-13
opportunity_number: RFA-ES-18-009
application_type: 5
activity_code: R24
ic: ES
serial_number: 030904
program_official: GRAY, KIMBERLY A
project_start_date: 2020-05-06
project_end_date: 2025-04-30
study_section: ZES1-VSM-K(R)
contact_pi_person_id: 7102409
contact_pi: HAYNES, ERIN N
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-05-01
project_title:
Retention Maintenance and Enhancement of the Communities Actively Researching Exposure Study (CARES)

project_abstract:
PROJECT SUMMARYManganese (Mn) plays an essential role in normal growth and development The Communities ActivelyResearching Exposure Study (CARES) was built upon community-engaged research practices. Participantsreside in three communities with the nation's highest levels of ambient Mn: Marietta and East Liverpool Ohioand Southeast Side Chicago Illinois. The CARES cohort consists of over 600 children and their primarycaregiver with two time-points (ages 7-9 years and ages 13-17 years) of extensive neurodevelopmentaloutcomes biomarkers of exposure and home environmental measures. The CARES has been supported bymultiple NIEHS-funded grants and has been instrumental in the training of next generation community-engaged environmental health scientists for over a decade. The cohort has been instrumental in thedevelopment of a lab-on-a-chip sensor for blood metals assessment and is currently exploring the impact ofMn on neuroanatomy function chemistry and physiology through magnetic resonance imaging. Through thisproject the CARES research team will be able to conduct the following: Aim 1) Maintain the integrity of theCARES cohort by implementing community-engaged research strategies to improve participant retention; Aim2) Expand CARES to enhance characterization of critical windows of exposure across the lifespan and assessthe role of caregiver child and community-level psychosocial factors on the etiology of toxicant-inducedneurodevelopmental deficits; and Aim 3) Maintain and enhance biorepository and data managementinfrastructure and develop methods to implement data sharing. The CARES is the only cohort poised toinvestigate ambient exposure to Mn and its relationship to brain function in both a pediatric and adolescentpopulation. The proposed cohort retention enhancement and maintenance plans will accelerate and sustainthe ability of the CARES cohort to investigate the impact of ambient Mn on neurodevelopmental outcomesinform federal polices related to ambient exposure to Mn and serve as a valuable resource for environmentalhealth science trainees and scientists across the globe.

project_terms:
Adolescent;Adult;Age;Air;Anatomy;Applications Grants;Biological;Biological Markers;Blood;Brain;Caregivers;Chemistry;Chicago;Child;Childhood;Cohort Studies;Collaborations;Communities;Community Developments;Data;Data Management Resources;Data Set;Development;Dust;Environmental Epidemiology;Environmental Exposure;Environmental Health;Environmental Impact;Equipment and supply inventories;Etiology;Evaluation;Exposure to;Funding;Grant;Growth and Development function;Hair;Home;Illinois;Infrastructure;Knowledge;Lab-On-A-Chips;Laboratories;Longevity;Magnetic Resonance Imaging;Maintenance;Manganese;Measurement;Measures;Metals;Methods;Motor;National Institute of Environmental Health Sciences;Neuroanatomy;Neurodevelopmental Deficit;Neuropsychology;Ohio;Outcome;Parents;Participant;Pediatric cohort;Pediatric epidemiology;Physiology;Play;Police;Population;Psychosocial Factor;Reporting;Research;Resources;Role;Saliva;Scientific Advances and Accomplishments;Scientist;Serum;Side;Soil;Structure of nail of toe;Time;Training;United States;Urine;Whole Blood;biobank;cohort;community engaged research;data management;data sharing;deciduous tooth;early childhood;improved;innovation;neurodevelopment;next generation;novel;participant retention;patient engagement;point of care;preservation;primary caregiver;research study;sensor;toxicant;water sampling

public_health_relevance:
PROJECT NARRATIVEThe Communities Actively Researching Exposure Study (CARES) is a successful and well-establishedenvironmental pediatric epidemiology cohort study that has reported the impact of environmental manganeseexposure on pediatric brain function. This proposal will retain the over 600 child-parent pairs enhance therobust dataset with ambient and internal exposure characterization during early childhood development andbuild the infrastructure needed to share the unique data within the cohort.


application_id: 10393557
project_number: 5R01ES028268-05
project_title: Effects of Air Pollution on Stem Cell Health
administering_ic: NIEHS
award_notice_date: 2022-05-16
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 028268
program_official: SCHUG, THADDEUS
project_start_date: 2018-08-15
project_end_date: 2024-04-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 11375489
contact_pi: HABERZETTL, PETRA
other_pis: HILL, BRADFORD GUY
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:
ABSTRACTExtensive evidence indicates that exposure to ambient particulate matter (PM) contributes to the global burdenof disease. Worldwide air pollution is linked with seven million premature deaths; and in the US PM isassociated with 200000 deaths per year most of which are due to cardiovascular disease (CVD).Nevertheless the mechanisms by which PM exposure induces cardiovascular injury remain unclear.Understanding such mechanisms is important to develop mechanistically validated biomarkers of PM-inducedsubclinical injury and to develop effective therapeutic interventions. Mechanistic studies in individuals with mildto moderate CVD risk have implicated endothelial dysfunction and inflammation as critical mediators of PM-induced injury; however because these mediators are also key features of CVD it is unclear whether PMdirectly affects endothelial function or whether these changes are secondary to the exacerbation of CVD byPM. We found that in young healthy individuals exposure to elevated levels of fine PM (PM2.5) suppressescirculating levels of endothelial progenitor cells (EPCs). Chronic suppression of EPCs is indicative of earlyendothelial injury and in prospective studies predictive of CVD mortality. Nevertheless the mechanisms bywhich PM2.5 suppress EPC levels remain obscure and it is unclear whether PM2.5 affects EPC function andtheir ability to promote tissue repair and angiogenesis. Our preliminary data show that exposure toconcentrated PM2.5 decreases the metabolic activity of EPCs and reduces their ability to repair vascular tissue.We have also found that the effects of PM2.5 are attenuated by overexpressing extracellular superoxidedismutase in the lung. Based on these observations we propose that upon PM2.5 inhalation pulmonarygeneration of superoxide impairs EPC signaling and metabolism which compromises their ability to maintain ahealthy endothelium and to promote angiogenesis. To test this hypothesis we will determine the effects ofPM2.5 exposure on EPC metabolism; assess the impact of PM2.5 exposure on EPC function; and elucidate themechanisms by which PM2.5 exposure induces metabolic and functional changes in EPCs. Completion of thisproject will not only lead to a better understanding of how PM causes EPC dysfunction but could also identifyselective specific and mechanistically validated biomarkers of PM2.5-induced cardiovascular injury. Overallour results would further a new conceptthat PM2.5-induced cardiovascular injury is due to defective EPCmetabolismand could lead to the development of a novel approach that could be readily tested in futureclinical studies to attenuate PM2.5-induced CVD mortality and morbidity.

project_terms:
Affect;Aging;Air;Air Pollution;Angiogenic Factor;Animal Model;Atherosclerosis;Attenuated;Biological Markers;Blood Vessels;Bone Marrow;Cardiovascular Diseases;Cardiovascular system;Cell Aging;Cells;Cellular Metabolic Process;Cessation of life;Chronic;Clinical;Clinical Research;Competence;Data;Defect;Development;Endothelium;Exposure to;Flow Cytometry;Functional disorder;Future;Generations;Glycolysis;Goals;Health;Hypertension;Impairment;In Vitro;Individual;Inflammation;Inhalation;Injury;Insulin;Intervention;Isotopes;Lead;Link;Lung;Mediator of activation protein;Metabolic;Metabolic dysfunction;Metabolism;Morbidity - disease rate;Mus;Nose;Outcome;Oxidative Phosphorylation;Oxidative Stress;Particulate Matter;Pathologic Processes;Phenotype;Proliferating;Prospective Studies;Research;Resistance;Risk;Secondary to;Signal Pathway;Signal Transduction;Superoxide Dismutase;Superoxides;Techniques;Testing;Therapeutic Intervention;Tissues;Tube;Vascular Endothelial Growth Factors;Work;air filter;angiogenesis;base;burden of illness;cardiovascular disorder risk;cardiovascular injury;endothelial dysfunction;endothelial stem cell;extracellular;fine particles;improved;in vivo;limb ischemia;mortality;novel strategies;overexpression;premature;prevent;repaired;response;stem cell function;stem cells;therapeutically effective;tissue repair

public_health_relevance:
NARRATIVEThe goal of this project is to determine the mechanisms by which air pollution contributes to cardiovasculardisease. In particular the proposed research focuses on how inhalation of particulate matter contributes toprogenitor cell dysfunction and defects in vascular repair.


application_id: 10393516
project_number: 5R01EY031322-03
project_title: Parallel Pulvinar Pathways
administering_ic: NEI
award_notice_date: 2022-05-12
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: EY
serial_number: 031322
program_official: FLANDERS, MARTHA C
project_start_date: 2020-05-01
project_end_date: 2024-04-30
study_section: Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section[SPC]
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: GUIDO, WILLIAM
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 concept of parallel pathways that code different aspects of the visual scene has led to many key insightsregarding the functional organization of the visual system. Inspired by this concept the proposed studies focuson parallel visual pathways from the retina to the superior colliculus (SC) through the pulvinar nucleus (PUL).Projections from the SC to the PUL originate from motion-detecting widefield vertical (WFV) cells and theirsynaptic organization defines two distinct PUL subdivisions: one that receives ipsilateral topographic WFVprojections (specific) and one that is innervated by bilateral convergent WFV projections (diffuse). These twoWFV innervation patterns are correlated with distinct cortical and subcortical connections as well a variety ofhistochemical criteria suggesting that the tectorecipient PUL may be organized into separate visual movementprocessing streams. However we currently lack a functional framework that allows us to test this hypothesis anddecipher the modular organization of the PUL. We plan to address this gap in knowledge by defining PUL celltypes and synaptic inputs in the context of their functional properties. Our guiding hypothesis is that the PUL iscomposed of two distinct modules that coordinate visual perception with body movements or motivational stateto initiate appropriate motor commands. To begin to test this theory with mice as our animal model we will useanatomical intersectional viral vector approaches and in vitro whole cell recordings coupled with dual optogeneticactivation of cortical and WFV synaptic inputs to define circuit mechanisms that can alter firing properties withineach PUL module (Aim 1). We will use in vivo extracellular recordings coupled with optogenetic activation andsilencing of synaptic inputs to determine how circuit interactions within each PUL module adjusts receptive fieldproperties (Aim 2). A key innovation of our experiments is the ability to identify PUL neuron subtypes by theirunique frequency-dependent responses to optogenetic activation of WFV inputs (neuron identification via singleinput dynamics). This new method will allow us to link detailed in vitro circuit dissection techniques with in vivorecording of visual response properties providing a framework of PUL function that has thus far been elusive.By comparing two parallel PUL modules our goal is to understand how visual motion signals are parsed toinitiate appropriate behavioral responses.

project_terms:
Address;Anatomy;Animal Model;Bilateral;Cell Nucleus;Cells;Code;Contralateral;Coupled;Depressed mood;Diffuse;Disease;Dissection;Dorsal;Dyslexia;Environment;Frequencies;Goals;Head;In Vitro;Injections;Ipsilateral;Knowledge;Label;Laboratories;Lateral Geniculate Body;Light;Link;Location;Methods;Motion;Motion Perception;Motivation;Motor;Movement;Mus;Neurons;Opsin;Pathway interactions;Pattern;Property;Pulvinar structure;Retina;Retinal Ganglion Cells;Rewards;Running;Schizophrenia;Sensory;Signal Transduction;Stream;Structure;Synapses;Techniques;Testing;Time;Viral;Viral Vector;Visual;Visual Motion;Visual Pathways;Visual Perception;Visual attention;Visual system structure;Whole-Cell Recordings;Work;area striata;autism spectrum disorder;base;behavioral response;brain circuitry;cell type;experimental study;extracellular;in vivo;innovation;insight;nerve supply;neural circuit;novel;optogenetics;parallel processing;receptive field;response;success;superior colliculus Corpora quadrigemina;theories;visual stimulus

public_health_relevance:
PROJECT NARRATIVEThe results of these experiments will significantly enhance our understanding of the brain circuitry underlyingvisual motion perception thus providing information relevant to the treatment of disorders in which visual motionprocessing is compromised such as dyslexia and schizophrenia. In addition the results of these experimentswill enhance our understanding of subcortical visual pathways which may be altered in autism spectrumdisorder.


application_id: 10392896
project_number: 5R01DK115406-05
project_title: CSN8 regulation of S1P-enriched extracellular vesicles to modulate NAFLD by gut-liver axis
administering_ic: NIDDK
award_notice_date: 2022-04-04
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 115406
program_official: GARCIA, MARTHA
project_start_date: 2018-07-20
project_end_date: 2025-04-30
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 11629370
contact_pi: DENG, ZHONG-BIN
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The overarching theme of this project is to address the mechanisms underlying gut derived extracellular vesicles(EVs)-induced liver inflammation/injury in Non-alcoholic fatty liver disease (NAFLD). We will determine the roleof sphingolipid metabolites specifically; Sphingosine 1-phosphate (S1P)-enriched gut EVs and pathwayCSN8/SphK1 in the development of NAFLD. The current proposal links gut-derived EVs to macrophage-mediated inflammation by proposing that extracellular vesicles from gut recruit macrophages to the liverresulting in liver injury and inflammation. Our recent work has begun to identify intestinal inflammation-inducedalterations in EVs and shows that gut-derived EVs play a critical role in the regulation of NKT cells and Th17cells in the development of liver inflammation and colon cancer via gut-liver axis. Our preliminary data showsthat LPS promotes Intestinal epithelial cells (IECs) release sphingolipid metabolites-enriched pro-inflammatoryEVs including ceramide and S1P. Our preliminary findings also indicate that CSN8/SphK1 signaling pathwayplays a crucial role in the production of S1P-enriched EVs. Chronic high fat diet consumption leads to increasedgut permeability and expose the liver to gut-derived products including EVs of IECs. Increased S1P-enrichedEVs activate its receptor S1P1 on hepatic macrophages which may promote macrophage chemotaxis into theliver. This has led to the central hypothesis that gut microbiota regulate sphingolipid metabolites-enriched EVs biogenesis and release via gut CSN8/SphK1 pathway and gut EVs carrying sphingolipidmetabolites (ceramide and S1P) translocate to liver which in turn attract macrophages into the liverpromoting liver injury in NAFLD. Importantly the proposal also pursues translational studies that examine theefficacy of nutrition-nanoparticles based therapeutic interventions targeted at gut microbiota and SphK1-S1PR1inhibition in mitigating gut-liver axis changes. To address our hypothesis we propose the following specific aims:Aim 1: Determine whether gut-derived EVs-S1P regulate liver inflammation and injury via CSN8/SphK1 pathwayin NAFLD. Aim 2: Determine whether gut-derived EVs-S1P contribute to liver macrophagesrecruitment/activation by S1PR1-STAT3 in NAFLD. Aim 3: Define molecular mechanisms underlying CSN8 andSphK1 reciprocal regulation and modulation of the CSN8/S1P-S1PR1 signal will prevent macrophagesmediated-liver injury in NAFLD. The proposal will provide a better understanding of diet-gut-liver interactions andmolecular mechanisms contributing to the pathogenesis of EVs-S1P-induced liver inflammation and injury. Thestudy will lead to identification of new therapeutic targets and potential dietary interventions for treating NAFLD.

project_terms:
Address;Affect;Biogenesis;Cell physiology;Cells;Ceramides;Chemotaxis;Chronic;Colitis;Colon Carcinoma;Consumption;Data;Development;Diet;Dietary Intervention;Distant;Enzymes;Epithelial Cells;Hepatic;High Fat Diet;Immune;Inflammation;Inflammatory;Injury;Intestinal permeability;Intestines;Kupffer Cells;Link;Lipids;Liver;Macrophage Activation;Mediating;Molecular;Pathogenesis;Pathogenicity;Pathway interactions;Play;Production;Property;Regulation;Role;SPHK1 enzyme;STAT3 gene;Severities;Signal Pathway;Signal Transduction;Sphingolipids;TLR4 gene;Testing;Therapeutic;Therapeutic Intervention;Up-Regulation;Work;base;ceramide 1-phosphate;dietary;edg-1 Protein;efficacy evaluation;exosome;extracellular vesicles;gut inflammation;gut microbiota;gut-liver axis;interest;intestinal epithelium;liver development;liver inflammation;liver injury;lymphocyte trafficking;macrophage;microorganism antigen;nanoparticle;new therapeutic target;non-alcoholic fatty liver disease;nutrition;prevent;recruit;sphingosine 1-phosphate;translational study

public_health_relevance:
Project NarrativeThis proposal underscores the importance of investigating S1P-enriched extracellular vesicles as a critical gut-derived factor for the development of nonalcoholic fatty liver diseases by regulating the recruitment/activation ofhepatic macrophages. We anticipate that we can abrogate their local and/or distant activities by targetingCSN8/SphK1-S1PR1/Stat3 pathway.


application_id: 10390456
project_number: 5R44AA025804-05
project_title: Novel modulators of the dopamine transporter for alcohol and nicotine use disorders
administering_ic: NIAAA
award_notice_date: 2022-04-26
opportunity_number: PA-19-272
application_type: 5
activity_code: R44
ic: AA
serial_number: 025804
program_official: FALK, DANIEL EVAN
project_start_date: 2016-09-22
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZRG1-ETTN-B(18)B]
contact_pi_person_id: 79171237
contact_pi: BURKLOW, CINDY ANN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractSubstance use disorders (SUDs) are at epidemic levels in the US [Mack et al 2017] and this has acceleratedefforts to find effective pharmacotherapies. All SUDs are associated with increased synaptic dopamine in themesolimbic pathway. This makes the dopamine transporter (DAT) a primary molecular target and atypicalDAT inhibitors with low abuse potential are the most promising therapeutic candidates [Reith et al 2015].Lobinaline a complex alkaloid from Lobelia cardinalis is a novel atypical DAT inhibitor [Brown et al 2015] andis a lead for pharmacotherapy of SUDs. However chemical synthesis of lobinaline is challenging so theapplicants used a proprietary technology to optimize this lead in mutant L. cardinalis plant cells [Brown et al2016]. This identified two lobinaline N-oxides that are more water soluble than lobinaline and also modulatethe DAT in a different way. Like lobinaline they are competitive inhibitors of the DAT but paradoxically andunlike lobinaline they also increase DA uptake capacity. This unique combination of actions is ideally suited toreversing effects on synaptic DA associated with SUDs without intrinsic reinforcing effects or precipitatingwithdrawal. Thus lobinaline and its N-oxides are potential therapeutic agents for all SUDs. However inaddition to activity on the DAT lobinaline has partial agonist activity at nicotinic receptors [Brown et al 2015]which suggests specific value in nicotine and alcohol use disorders [Rahman et al 2016]. These are currentlythe most damaging SUDs worldwide [Peacock et al 2018] and smoking cessation is also the most profitablemarket in SUD therapeutics. The potential value of lobinaline and the N-oxides in these SUDs was supportedby activity in simple animal models and this phase IIB SBIR proposal is to begin their development astherapeutics. The aims are; (1) to test lobinaline and the N-oxides for off-target activity and to assess theirsingle dose pharmacokinetics and toxicity in rodents (2) to evaluate them more fully in animal models(including a novel rat model of nicotine plus alcohol self-administration) (3) to scale-up methods forbiosynthesis of lobinaline and its chemical conversion to the N-oxides. The commercial objectives are: (a) toevaluate these novel biosynthetics as potential medications for nicotine and alcohol use disorders and (b) toleverage this into the commercialization of Naprogenix biotechnology as a plant lead discovery platform. Bothobjectives will require partnership with a major pharmaceutical or biotechnology company in phase III.

project_terms:
Agonist;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcohols;Alkaloids;Anabolism;Animal Model;Animals;Biotechnology;Bupropion;Cell Culture Techniques;Cells;Chemicals;Commercial Sectors;Complex;Development;Directed Molecular Evolution;Disclosure;Dopamine;Dose;Drug Addiction;Drug Kinetics;Epidemic;FDA approved;Human;Intention;Lead;Libraries;Lobelia;Methods;Modeling;Molecular Target;Morbidity - disease rate;Mutagenesis;Nicotine;Nicotine Use Disorder;Nicotinic Receptors;Oxides;Parents;Pathway interactions;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Pharmacotherapy;Phase;Plants;Production;Proteins;Rattus;Recording of previous events;Research;Rodent;Self Administration;Small Business Innovation Research Grant;Smoking;Smoking Cessation Intervention;Structure;Substance Use Disorder;Synapses;Technology;Technology Transfer;Testing;Therapeutic;Therapeutic Agents;Therapeutic Human Experimentation;Toxic effect;Water;Withdrawal;Work;abuse liability;alcohol abuse therapy;alcohol use disorder;base;cathinone;chemical synthesis;commercialization;conditioned place preference;cost;cytisine;dopamine transporter;drug discovery;effective therapy;in vitro testing;inhibitor;interest;invention;lead optimization;monoamine;mouse model;mutant;nicotine use;novel;novel therapeutics;product development;receptor;scale up;screening;smoking cessation;social;success;therapeutic candidate;therapeutic target;uptake;varenicline

public_health_relevance:
Project narrativeThe company has used a new biotechnology to discover novel plant drugs that could be effective treatments forall forms of drug dependence. However the way these compounds work suggests that they should be mosteffective against smoking and alcohol abuse so the company will develop them for these uses first. This proposalis to test these plant compounds for their potential as drugs including their ability to reduce alcohol and nicotineself-administration in animals and to begin development of them as medications for alcohol and nicotine usedisorders.


application_id: 10390307
project_number: 5R01NS115895-03
project_title: Long-term effects of wildtype huntingtin lowering in the primate corticostriatal tract and thalamus
administering_ic: NINDS
award_notice_date: 2022-04-18
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 115895
program_official: MILLER, DANIEL L
project_start_date: 2020-04-01
project_end_date: 2024-03-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 8559816
contact_pi: GRONDIN, RICHARD C.
other_pis: BOGER, HEATHER A;KAEMMERER, WILLIAM F
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:
PROJECT SUMMARY / ABSTRACTMost huntingtin-lowering treatments in development or clinical trials are not selective for the mutant allele butalso lower wildtype huntingtin expression. The purpose of this project is to fill critical gaps in our knowledgeabout the effects of wildtype huntingtin lowering in the primate brain over an extended period of time in brainregions relevant to Huntingtons disease (HD) and to the functions of wildtype huntingtin. Data from mousemodels of HD indicate that lowering huntingtin in cortical neurons that are part of the corticostriatal system maybe necessary for optimal therapeutic efficacy.1-3 Although prior research has established that lowering wildtypehuntingtin by 45% in the primate striatum is well-tolerated for six months4 this and other research5 has notlowered wildtype huntingtin in primate corticostriatal neurons whose axons comprise the corticostriatal tract.Huntingtin is involved in the rate of production6 and transport7 of BDNF (brain-derived neurotrophic factor) fromcortical neurons to the striatum on which striatal neurons depend.8 It is unknown whether reduction of wildtypehuntingtin in corticostriatal neurons/tract of the primate brain will adversely affect the survival and functioning ofstriatal neurons. AIM 1 will assess the long-term tolerability of wildtype huntingtin lowering in the corticostriataltract over 9 months by quantitatively measuring the effects of this lowering on locomotor activity BDNF levelsand neurotransmitter systems. As research tools the project uses an shRNA already known to lower huntingtinin the primate4 and a serotype of AAV already known to retrogradely transduce cortical neurons from a striatalpoint of infusion.9 Treatment of the thalamus has been proposed as a means of enhancing vector distribution inthe brain16. However pathologic calcification of the thalamus has been reported in mice 9 months after partialconditional knockout of wildtype huntingtin.10 AIM 2 will determine if reduction of wildtype huntingtin in theprimate thalamus will result in an increased thalamic calcium accumulation whether occurring incidentally fromstriatal infusion of vectors or directly by vector infusion targeting the thalamus. In the proposed studies thirty-two (32) adult rhesus monkeys will be equally divided into four experimental groups (N= 8 animals/group) andrandomly assigned to receive MRI-guided injections of AAV6 encoding a huntingtin-lowering shRNA or acontrol shRNA directly into either the striatum (AIM 1) or thalamus (AIM 2). Monkeys will be assessed byperiodic behavioral and neurological exams. In vivo glutamate signaling in the cortex striatum and thalamuswill be assessed 9 months after AAV administration. Post-mortem analysis will include assessments ofdopamine turnover and BDNF levels in striatal tissue as well as calcium in the thalamus and neuropathologicalevaluations of coronal brain sections including cortex striatum and thalamus. The data obtained by thisproject in the nonhuman primate will provide information that cannot be readily obtained from human clinicaltrials of huntingtin-lowering treatments. This information will be pertinent to any current and future therapies forHD that use non-allele-specific means to lower huntingtin irrespective of the agent or route of delivery.

project_terms:
Address;Adult;Affect;Age;Alleles;Animals;Autopsy;Axon;Behavioral;Biosensor;Blinded;Brain;Brain region;Brain-Derived Neurotrophic Factor;Calcinosis;Calcium;Clinical Treatment;Clinical Trials;Collection;Corpus striatum structure;Data;Deposition;Development;Disease;Dopamine;Evaluation;Future;Future Generations;Genes;Glutamates;Health Status;Health behavior;Histology;Human;Huntington Disease;Huntington gene;Huntington protein;Infusion procedures;Injections;Intervention;Knowledge;Long-Term Effects;Macaca mulatta;Magnetic Resonance Imaging;Measurement;Measures;Methods;Molecular;Monkeys;Motor Activity;Mus;Nature;Neurodegenerative Disorders;Neurologic;Neurological status;Neurons;Neurotransmitters;Participant;Pathology;Patient Monitoring;Patients;Periodicity;Primates;Randomized;Reporting;Research;Resolution;Route;Serotyping;Structure;System;Thalamic structure;Time;Tissues;Treatment Efficacy;brain tissue;calcification;clinically significant;conditional knockout;end stage disease;experimental group;glutamatergic signaling;in vivo;mouse model;mutant;nonhuman primate;protein expression;putamen;retrograde transport;small hairpin RNA;therapeutic target;therapy adverse effect;tool;uptake;vector

public_health_relevance:
PROJECT NARRATIVETreatment of the cortex as well as the striatum may be desirable for optimal efficacy of a huntingtin-loweringtreatment for Huntingtons disease but lowering huntingtin in the cortex may affect underlying neurotransmittersystems and/or reduce the transport of trophic factors from the cortex to the striatum that are necessary for thesurvival and function of striatal neurons. The thalamus is also a potential therapeutic target but reduction ofhuntingtin in the thalamus causes pathologic calcification in mice and it is unknown whether this might alsooccur in the primate brain. The purpose of this project is to fill critical gaps in our scientific knowledgeabout the effects of lowering huntingtin protein expression in the corticostriatal connections and thethalamus of the primate brain to provide useful information for current and future generations of huntingtin-lowering therapies for Huntingtons disease.


application_id: 10389929
project_number: 1F31HL162518-01
project_title: Dynamic Role of Hyaluronan in Ventricular Remodeling
administering_ic: NHLBI
award_notice_date: 2022-01-14
opportunity_number: PA-21-052
application_type: 1
activity_code: F31
ic: HL
serial_number: 162518
program_official: HUANG, LI-SHIN
project_start_date: 2022-02-01
project_end_date: 2025-04-30
study_section: Special Emphasis Panel[ZRG1 F10A-K (20)]
contact_pi_person_id: 15083220
contact_pi: LITTLE, DANIELLE T
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Acute myocardial infarction;Adenoviruses;Advocate;Atomic Force Microscopy;Biomechanics;Cardiac;Cardiac Myocytes;Cells;Chronic;Chronic Phase;Cicatrix;Collaborations;Collagen;Data;Deposition;Development;Disease;Echocardiography;Elements;Embryo;Enterobacteria phage P1 Cre recombinase;Environment;Enzymes;Event;Extracellular Matrix;Family;Fellowship;Fibroblasts;Fibrosis;Future;Goals;HAS2 gene;Health;Heart;Heart failure;Hour;Hyaluronan;Hyaluronidase;Immune;In Vitro;Infarction;Inflammatory;Intervention;Knowledge;Laboratory Research;Lead;Lipids;Literature;Metabolism;Molecular Weight;Mus;Muscle Cells;Mutant Strains Mice;Myocardial Infarction;Myocardium;Organ;Pathology;Phase;Play;Process;Production;Proliferating;Proteins;Regulation;Research;Role;Rupture;Scientist;Techniques;Therapeutic;Tissues;Training;Translating;Ventricular;Ventricular Function;Ventricular Remodeling;acute wound;cell type;disorder risk;heart function;histological stains;in vivo evaluation;innovation;insight;loss of function;novel;novel therapeutic intervention;prevent;tool;training project;wound healing


application_id: 10389514
project_number: 3R01GM138882-02S1
administering_ic: NIGMS
award_notice_date: 2021-08-02
opportunity_number: PA-20-272
application_type: 3
activity_code: R01
ic: GM
serial_number: 138882
suffix: S1
program_official: BARSKI, OLEG
project_start_date: 2020-09-01
project_end_date: 2024-06-30
study_section: Macromolecular Structure and Function A Study Section[MSFA]
contact_pi_person_id: 8085279
contact_pi: GLAZER, EDITH C
other_pis: HEIDARY, DAVID ;RICHARDS, CHRISTOPHER I
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Role of small molecule interactions and multiprotein assemblies in CYP1B1 disease-associated function and dysfunction

project_abstract:
AbstractThe goal of this project is to determine how mutations elevated protein levels and environmentalconditions impact the function and dysfunction of Cytochrome P450 1B1 (CYP1B1). The addition ofinstrumentation is proposed to facilitate characterization of small molecule modulators of CYP1B1 andthe metabolic products of this CYP. Selective inhibition of CYPs is an important goal in medicinalchemistry but these enzymes can chemically modify their inhibitors resulting in deactivation. Therequested High Pressure Liquid Chromatography (HPLC) instrument along with three orthogonaldetection systems will allow for accurate and rapid determination of chemical structures and enzymaticmodifications. This will be accomplished with small amounts of sample as the analytes will come fromcells grown in tissue culture. As CYPs generally increase the polarity of hydrophobic substrates theinstrumentation includes specific modifications that are required for analysis of aqueous mediasolutions. Such solutions are incompatible with most LC mass spectrometers. This equipment will bealso used to evaluate if mutations protein:protein association and environmental conditions alter CYPmetabolic products with implications for tissue-selective metabolism under hypoxia or due to thepresence of signaling molecules.

project_terms:
3-Dimensional;Affect;Aromatase;Aromatase Inhibitors;Basic Science;Binding;Biology;CYP17A1 gene;CYP1B1 gene;Cell Line;Cell physiology;Cells;Chemical Structure;Chemicals;Chemotherapy-Oncologic Procedure;Chimeric Proteins;Cisplatin;Clinical Research;Conflict (Psychology);Cytochrome P450;Data;Disease;Dose;Drug resistance;Environment;Environmental Risk Factor;Enzyme Inhibitor Drugs;Enzymes;Equipment;Functional disorder;Genetic;Genetic Polymorphism;Goals;Half-Life;Heme;Hemeproteins;High Pressure Liquid Chromatography;Homo;Hormones;Hydrophobicity;Hydrophthalmos;Hypoxia;Immune response;In Vitro;Inherited;Iron;Liver;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Medical;Membrane;Metabolic;Metabolism;Modeling;Modification;Molecular Conformation;Mutation;Mycoses;Nucleotides;Paclitaxel;Patients;Pharmaceutical Chemistry;Pharmacology;Phase I Clinical Trials;Phenotype;Photobleaching;Physiologic pulse;Play;Population;Population Distributions;Proteins;Proteolysis;Resistance;Role;Sampling;Scanning;Signaling Molecule;Single Nucleotide Polymorphism;Testing;Thermodynamics;Time;Tissues;Tumor Antigens;Vesicle;Work;aqueous;cancer cell;cancer initiation;chemotherapy;detection platform;enzyme activity;epidemiology study;experimental study;fluorescence lifetime imaging;improved;in vivo;inhibitor/antagonist;instrument;instrumentation;knock-down;malignant breast neoplasm;mass spectrometer;mitochondrial membrane;nanoscale;novel;overexpression;protein degradation;residence;response;single molecule;small molecule;small molecule inhibitor;tissue culture;tumor;tumor progression

public_health_relevance:
Cytochrome P450-1B1 (CYP1B1) is absent or expressed at very low levels in the liver and healthy tissues whilebeing overexpressed in tumors giving it the title of universal tumor antigen. Evidence from basic scienceclinical and epidemiological studies demonstrate that CYP1B1 is involved in cancer initiation progression andresistance to a wide range of chemotherapeutics. This work will define how CYP1B1 subcellular localizationoligomerization degradation and small molecule binding are altered in cancer cells as a function of specificsingle nucleotide polymorphisms (SNPs) and environmental factors facilitating malignant progression and willprovide a new paradigm for small molecule inhibitors of the enzyme that function by inducing CYP1B1 proteindegradation.


application_id: 10389013
project_number: 1R01AA028905-01A1
project_title: Role of Soluble Epoxide Hydrolase in Alcohol-Associated Liver Disease
administering_ic: NIAAA
award_notice_date: 2022-05-20
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AA
serial_number: 028905
suffix: A1
program_official: LIN, LI
project_start_date: 2022-06-01
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZRG1 DKUS-R (04)]
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA 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:
Ablation;Alcohols;Animal Model;Animals;Anti-Inflammatory Agents;Attenuated;Biological Markers;Blood;Blood specimen;CXCL1 gene;Cirrhosis;Dietary Supplementation;Disease;Disease Progression;Enzymes;Epoxide hydrolase;Epoxy Compounds;Ethanol;Etiology;Evaluation;FDA approved;Fatty Acids;Fatty Liver;Fatty acid glycerol esters;Fibrosis;Foundations;Genetic;Glycols;Goals;Health Care Costs;Heavy Drinking;Hepatic;Hepatitis;Hepatocyte;Human;In Vitro;Individual;Infection;Inflammation;Inflammatory;Injury;Kidney;Lipids;Liver;Liver diseases;Lung;Mediating;Mediator of activation protein;Messenger RNA;Metabolic Diseases;Metabolism;Morbidity - disease rate;Mus;N-3 polyunsaturated fatty acid;Names;Neutrophil Infiltration;Obesity;Organ failure;PPAR gamma;Pathogenesis;Pathology;Patients;Pharmacology;Phenotype;Plasma;Play;Prevention;Preventive;Production;Property;Resolution;Role;Severity of illness;Steatohepatitis;Testing;Therapeutic;Transgenic Organisms;Treatment Efficacy;Whole Blood;attenuation;base;chemokine;cytokine;effective therapy;in vivo;inhibitor;liver injury;macrophage;monocyte;mortality;neutrophil;non-alcoholic fatty liver disease;novel;novel therapeutic intervention;novel therapeutics;organ regeneration;peripheral blood;preservation;prevent;receptor;systemic inflammatory response;therapeutic effectiveness;therapeutic evaluation;therapeutic target;therapeutically effective;tissue regeneration


application_id: 10388528
project_number: 1F31AG076282-01
project_title: Apolipoprotein E and immunometabolism in Alzheimer's disease
administering_ic: NIA
award_notice_date: 2022-01-12
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: AG
serial_number: 076282
program_official: BARRETT, PAUL JOHN
project_start_date: 2022-02-13
project_end_date: 2024-02-12
study_section: Special Emphasis Panel[ZRG1 F03A-T (20)]
contact_pi_person_id: 16073908
contact_pi: DEVANNEY, NICHOLAS
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:
Summary: Chronic neuroinflammation and metabolic dysfunction characterize neurodegenerative diseasesincluding Alzheimer's disease (AD). One of the earliest known biomarkers of AD is an altered pattern ofregional glucose metabolism in the brain. Carriers of the 4 allele of apolipoprotein E (APOE) exhibit thispattern of altered cerebral glucose metabolism from a young age and suffer from a dramatically increased riskof acquiring AD. Meanwhile 4 individuals are also considered to have a maladaptive and detrimentalneuroinflammatory phenotype with increased pro-inflammatory signaling in 4 microglia. Additionally it is well-established that microglial inflammatory phenotypes are driven by precise metabolic reprogramming with pro-inflammatory cytokine production requiring increased aerobic glycolysis  a phenomenon known as`immunometabolism'. This proposal aims to investigate whether the neuroinflammatory phenotype in 4microglia could be intrinsically driven by 4s effects on glucose metabolism. Aim 1 will investigate thehypothesis that enhanced pro-glycolytic gene expression drives neuroinflammatory 4 transcriptionalphenotypes by leveraging the power of targeted single-cell RNA sequencing to interrogate gene expression ofa panel of pre-selected metabolic neuroinflammatory and disease-associated genes with results validated atthe protein and post-translational level. Aim 2 will address the hypothesis that 4 microglia show an increasedpro-inflammatory phenotype due to underlying impairments in central carbon metabolism. We will use StableIsotope Resolved Metabolomics (SIRM) with a 13C-glucose tracer to measure metabolic flux in 2 3 and 4primary microglia responding to pro- and anti-inflammatory treatments. We will compare oxidativephosphorylation and glycolytic activity in response to these treatments. These metabolic measures will then belinked to readouts of microglial function by assessing cytokine release and phagocytic activity in parallel. Aim 3will evaluate the efficacy of targeting key metabolic nodes to reprogram the 4 inflammatory response. Wehypothesize that pharmacological inhibition or viral overexpression of specific metabolic enzymes identified inour preliminary data as being perturbed by APOE genotype will rebalance cytokine production in 4 microgliaand improve phagocytosis of amyloid beta peptide. Our ultimate goals for this research are to: (1) understandhow APOE genotype influences the metabolic response to inflammatory stimuli in microglia (2) determinewhether altered metabolic gene expression drives a transcriptional profile that favors neuroinflammation andincreased AD risk and (3) identify immunometabolic pathways altered by APOE genotype that could representavenues to target in the treatment of neurodegenerative disease. This proposal integrates innovativetranscriptomic and metabolomic techniques with functional readouts of microglia to unify our understanding oftwo major facets of 4s risk: metabolic dysfunction and chronic neuroinflammation. Targeting both of theseaspects in tandem may hold greater promise in developing successful therapeutics for the treatment of AD.

project_terms:
Address;Age;Alleles;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease risk;Alzheimers disease biomarker;Amyloid beta-Protein;Amyloidosis;Anti-Inflammatory Agents;Apolipoprotein E;Astrocytes;Brain;Carbon;Cells;Cerebrum;Chronic;Citric Acid Cycle;Data;Deposition;Disease;Enzymes;Exhibits;Gene Expression;Gene Expression Profile;Genes;Genetic Transcription;Genotype;Genus Hippocampus;Glucose;Glycolysis;Goals;Homeostasis;Homozygote;Human;Impairment;In Vitro;Individual;Inflammation;Inflammatory;Inflammatory Response;Innate Immune Response;Knowledge;Late Onset Alzheimer Disease;Link;Measures;Metabolic;Metabolic dysfunction;Metabolism;Microglia;Mitochondria;Modeling;Mus;Nerve Degeneration;Neurodegenerative Disorders;Outcomes Research;Oxidative Phosphorylation;Pathway interactions;Pattern;Phagocytes;Phagocytosis;Pharmacology;Phenotype;Play;Post-Translational Protein Processing;Production;Protein Isoforms;Proteins;Ramp;Research;Respiration;Risk;Role;Senile Plaques;Series;Signal Transduction;Sorting - Cell Movement;Stimulus;Techniques;Testing;Therapeutic;Tracer;Viral;aerobic glycolysis;cytokine;efficacy evaluation;efficacy testing;extracellular;genetic risk factor;genome wide association study;glucose metabolism;improved;innovation;metabolomics;neuroinflammation;overexpression;preference;response;single-cell RNA sequencing;small molecule inhibitor;stable isotope;targeted treatment;therapeutic target;transcriptomics;treatment response

public_health_relevance:
Narrative: Neuroinflammation and metabolic dysfunction are prevalent among neurodegenerative diseasesincluding Alzheimer's disease (AD). Outcomes of this research will elucidate how the strongest genetic riskfactor for late-onset AD the 4 allele of apolipoprotein E may predispose microglia to neuroinflammatoryphenotypes by altering central glucose metabolism. Knowledge gained by the completion of this project willidentify immunometabolic nodes that can be targeted therapeutically to improve microglial function anddampen neuroinflammation in AD.


application_id: 10388180
project_number: 5UM1DA049406-04
project_title: Kentucky CAN HEAL (Communities and Networks Helping End Addiction Long-term)
administering_ic: NIDA
award_notice_date: 2022-04-12
opportunity_number: RFA-DA-19-016
application_type: 5
activity_code: UM1
ic: DA
serial_number: 049406
program_official: HIGHSMITH, KEISHER S
project_start_date: 2019-04-17
project_end_date: 2025-03-31
study_section: ZDA1-TXW-S(16)R
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe Kentucky CAN (Communities and Networks) HEAL (Helping End Addiction Long-term) [KCH] study is alarge-scale community intervention project submitted in response to the HEALing Communities request forproposals to test the immediate impact of implementing an integrated set of evidence-based interventionswith the aim of reducing opioid overdose deaths by 40% in three years. KCH represents a partnership betweenthe University of Kentucky Kentucky State government officials and numerous community organizations. Thisproject will employ an incomplete stepped-wedge cluster randomized design to deploy an integrated set ofevidence-based practices in 17 highly affected counties in Kentucky in two waves of assignment. Highlyaffected counties were identified through an empirical algorithm that incorporated the requisite epidemiologicalcriteria for opioid overdose and structural systems in place to support the deployment of evidence-basedinterventions (EBIs). Prior to randomization a systematic implementation science-based approach will be usedto assess barriers attitudes and assets and to enhance implementation of EBIs. Primary intervention aims areto improve and expand treatment with medications for opioid use disorder (MOUD) by increasing capacityentry and retention expand overdose prevention approaches in the community and reduce opioid supply bydecreasing high risk prescribing and increasing safe drug disposal. Community partners include thoserepresenting behavioral health healthcare public health criminal justice and community coalitions.Interventions will include those focused on 1) development of a Care Navigation network in MOUD treatmentprograms (FQHCs OTPs and OBOT providers) syringe service programs jails and parole and probationoffices to increase the number of individuals screened referred to initiating evidence-based care retained intreatment and receiving ancillary recovery support services; 2) enhancing and expanding the treatmentworkforce through increased DATA 2000 waiver trainings and weekly support through expert telehealthguidance using the ECHO model; 3) increasing overdose education and naloxone distribution in treatmentsettings syringe services programs jails parole and probation; and the community; 4) increasing access tosyringe services programs; 5) reducing risky opioid prescribing and dispensing; and 6) enhancing drugdisposal. By targeting individuals who are at highest risk (e.g. out of treatment reentering the community) anddeploying a community-wide health communication strategy to increase awareness and demand for EBIs wehypothesize that KCH will reduce overdose deaths by 40% in three years. KCH will leverage existing fundingand resources to enhance its effectiveness and the health economics of these interventions will be evaluatedin order to have meaningful and translatable impact on public policy.

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

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


application_id: 10388093
project_number: 5R01CA251478-02
project_title: Local Flavor Policies to Enhance Equity in Tobacco
administering_ic: NCI
award_notice_date: 2022-03-25
opportunity_number: PAR-18-675
application_type: 5
activity_code: R01
ic: CA
serial_number: 251478
program_official: RODITIS, MARIA LEIA
project_start_date: 2021-04-08
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZRG1-RPHB-N(56)R]
contact_pi_person_id: 11156218
contact_pi: ROSE, SHYANIKA W
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_terms:
Address;Advertising;Affect;Area;California;Cigarette;Code;Communities;County;Data;Data Collection;Data Set;Databases;Ecological momentary assessment;Education;Electronic cigarette;Ensure;Ethnic Origin;Exposure to;Goals;Home;Income;Individual;Kentucky;Laws;Link;Longitudinal cohort;Longitudinal trends;Low income;Malignant Neoplasms;Malignant neoplasm of lung;Marketing;Menthol;Modeling;Neighborhoods;Outcome;Participant;Persuasive Communication;Policies;Population;Protocols documentation;Public Policy;Race;Reduce health disparities;Research;Resources;Respondent;Risk;Sales;Smokeless Tobacco;Socioeconomic Status;Statistical Data Interpretation;Structure;Testing;Time;Tobacco;Tobacco use;United States Food and Drug Administration;Universities;Variant;Vulnerable Populations;Youth;attributable mortality;cancer health disparity;cancer risk;cigarette smoking;cigarillos;cohort;cost;demographics;disparity reduction;emerging adult;evidence base;follow-up;health disparity;health equity;implementation framework;innovation;low socioeconomic status;neighborhood disadvantage;people of color;public policy on tobacco;racial difference;reduce tobacco use;theories;tobacco advertising;tobacco exposure;tobacco flavor;tobacco products;tobacco user;trend;vulnerable community;young adult


application_id: 10387711
project_number: 3F32HL149140-01A1S1
project_title: Childcare Supplement request
administering_ic: NHLBI
award_notice_date: 2021-07-26
opportunity_number: PA-20-272
application_type: 3
activity_code: F32
ic: HL
serial_number: 149140
suffix: A1S1
program_official: WANG, WAYNE C
project_start_date: 2021-01-01
project_end_date: 2023-12-31
contact_pi_person_id: 15737705
contact_pi: ABOULEISA, RIHAM RAAFAT ELGHARIB
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:
Myocardial infarction causes irreversible loss of cardiomyocytes (CMs) and often leads to heart failure. Toreplace the lost cells we identified a combination of cell-cycle regulators that induces stable cytokinesis in adultpost-mitotic cells. Overexpression of cyclin-dependent kinase 1 (CDK1) CDK4 cyclin B1 and cyclin D1 (referredto as 4F) promotes cell division in post-mitotic mouse rat and human cardiomyocytes. The high efficiency ofthis protocol in inducing myocyte renewal provides new opportunities for understanding the mechanisms involvedin cardiomyocyte proliferation. One of the most interesting findings related to this discovery was the confirmationof a link between metabolic reprogramming and cardiomyocyte proliferation. Although in proliferating cells thereis a strong correlation between metabolic changes and cellular proliferation it remains unclear how metabolisminfluences the proliferative potential of cardiomyocytes. During the past 2 years in collaboration with Dr. Hillsgroup I have generated preliminary data which indicate that cardiomyocyte proliferation is associated withmarked reprogramming in energy metabolism. In proliferating cardiomyocytes isolated from lineage tracing(MADM) mice RNA-seq data indicate profound downregulation of fatty acid oxidation genes and upregulation ofbiosynthetic pathway enzyme expression; in human iPSC-derived cardiomyocytes (hiPSC-CMs) 4F expressiondecreases mitochondrial respiration and catabolic activities. Using stable isotope-resolved metabolomics(SIRM) we demonstrate that 4F-infected hiPS-CMs show significant elevation in 13C labeled intermediates orend products of the hexosamine biosynthetic pathway (HBP) serine biosynthesis pathway (SBP) and pentosephosphate pathway (PPP). In line with these findings our results also demonstrate that augmenting the carbonavailability for these biosynthetic pathways by overexpressing phosphoenolpyruvate carboxykinase (PCK1 orPCK2) augments the ability of cardiomyocytes to proliferate. These data suggest that higher biosyntheticpathway flux may be required for cardiomyocyte proliferation. Informed by these results we propose the generalhypothesis that activation of ancillary biosynthetic pathways of glucose metabolism are required forcardiomyocyte proliferation. We suggest that higher biosynthetic pathway flux is required for building blocksynthesis and may be important for regulating pro-proliferative gene programs. During this project we willdelineate the importance of each biosynthetic pathway in influencing cardiomyocyte proliferation. First usingpharmacological and virus-based approaches we will determine the specific contribution of the HBP SBP andPPP pathways to myocyte proliferation. In addition we will investigate the influence of increasing the carbon fluxin biosynthetic pathway through overexpression of PCK1 or PCK2 on cardiac function and repair in vivo. Theaims of this project are: Specific Aim 1: Delineate the contribution of each biosynthetic pathway on cardiomyocyteproliferation. Specific Aim 2: Investigate the functional efficacy of increasing carbon flux in biosynthetic pathwayson cardiac repair in vivo.

project_terms:
Adult;Affect;Anabolism;CDC2 gene;CDK4 gene;Carbon;Cardiac Myocytes;Cell Cycle;Cell Cycle Regulation Pathway;Cell Proliferation;Cell division;Cells;Collaborations;Cyclin D1;Cytokinesis;Data;Development;Down-Regulation;Echocardiography;Energy Metabolism;Fetus;Foundations;Genes;Heart;Heart Diseases;Heart failure;Hexosamines;Hip region structure;Histology;Human;Knowledge;Label;Link;Metabolic;Metabolism;Mitochondria;Mitotic;Modeling;Mus;Muscle Cells;Myocardial;Myocardial Infarction;Myocardium;Natural regeneration;Pathway interactions;Patients;Pentosephosphate Pathway;Pharmacology;Phosphoenolpyruvate Carboxylase;Proliferating;Protocols documentation;Rattus;Respiration;Salamander;Serine;Technology;Up-Regulation;Viral;Virus;Zebrafish;base;cardiac repair;cyclin B1;enzyme pathway;fatty acid oxidation;glucose metabolism;heart function;in vivo;induced pluripotent stem cell;metabolomics;mouse model;novel strategies;novel therapeutics;overexpression;programs;stable isotope;transcriptome sequencing

public_health_relevance:
The muscle cells in the adult heart are not able to regenerate themselves which made itdifficult to treat heart disease; however in human fetuses zebrafish and salamanderthe heart muscle is able to regenerate. Here we are using cutting edge technologies tounderstand why the fetuses but not adults are able to regenerate their hearts. Thisunderstanding will allow the development of novel therapies to regenerate the deadheart muscle in heart failure patients.


application_id: 10387632
project_number: 1F31DK130609-01A1
administering_ic: NIDDK
award_notice_date: 2022-04-28
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: DK
serial_number: 130609
suffix: A1
program_official: MARIC-BILKAN, CHRISTINE
project_start_date: 2022-05-01
project_end_date: 2025-04-30
study_section: Special Emphasis Panel[ZDK1 GRB-G (O1)]
contact_pi_person_id: 16133895
contact_pi: ORWICK, ANDREW
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_title:
The role of PGC-1alpha in repeated low-dose cisplatin-induced kidney injury and the progression to chronic kidney disease

project_abstract:
Project Summary:Cisplatin is a first-line chemotherapeutic for many solid organ cancer types but its usages are limited by itsnephrotoxicity. Thirty percent of patients who receive cisplatin develop acute kidney injury (AKI) which increasesthe risk of chronic kidney disease (CKD) and mortality. There are currently no treatment options to prevent ortreat cisplatin-induced kidney injury (CDDP-KI). Cisplatin-induced kidney injury (CDDP-KI) has been extensivelyinvestigated in the past by our lab and many other labs using a single high-dose model. However patients aretypically treated with periodic low doses of cisplatin not a single high dose. Our lab and others have recentlydeveloped a potentially more clinically relevant model utilizing repeated low-dose cisplatin (RLDC) treatment. Inthis new model mice receive 4 weekly doses of low dose cisplatin and are able to survive more than 6-monthspost-treatment. The RLDC model can be broken up into two phases. The repeated low-level injury phase whichconsists of the four weeks of cisplatin treatment and is characterized by a mild decline in kidney functioninsignificant levels of tubule cell death inflammation and development of fibrosis. After the injury phase thereis a progression phase that is characterized by persistent inflammation exacerbated fibrosis and thedevelopment of CKD. The mechanisms involved in both phases of this model remain largely unknown. Thekidneys have the highest density of mitochondria per organ second only to the heart. The majority of thereabsorption performed occurs in the renal proximal tubule epithelial cells (RPTECs). These cells are highlyenriched in mitochondria and rely on fatty acid oxidation (FAO) as their many energy source. Cisplatin has beenshown to disrupt FAO and defective FAO in RPTEC is seen in other models of fibrosis. Our preliminary datasuggest that the RLDC model causes a decrease in renal function mitochondrial content and PGC-1. PGC-1 is a master transcriptional regulator of mitochondrial biogenesis fatty acid oxidation lipogenesisthermogenesis and glucose metabolism. This research proposal will examine the relationship between PGC-1expression and the development of fibrosis/CKD in both phases of the RLDC model. We hypothesize thatincreasing PGC-1 expression during the injury and/ or progression phases of RLDC will protect againstkidney injury and prevent progression to CKD respectively. This hypothesis will be tested with the followingspecific aims: Aim 1: Determine the role of PGC-1 in the injury phase of the RLDC model. We hypothesize thatPGC-1 protects from RLDC-induced kidney injury and initiation of fibrosis. We will test this hypothesis byoverexpressing and knocking out PGC-1 during the injury phase of the RLDC model. Aim 2: Determine the roleof PGC-1 in the progression phase of the RLDC model. We hypothesize that increased PGC-1 expressionfollowing cisplatin dosing will prevent RLDC-induced fibrosis and progression to CKD. We will overexpress andknockout PGC-1 following RLDC dosing.

project_terms:
Acute Renal Failure with Renal Papillary Necrosis;Address;Aftercare;Age-Months;Automobile Driving;Bioenergetics;Biogenesis;Biopsy;Cancer Patient;Carcinoma;Cell Death;Cells;Cellular biology;Chronic Kidney Failure;Cisplatin;Clinic;Data;Development;Dose;Dose-Limiting;Effectiveness;Energy-Generating Resources;Epithelial Cells;Excision;Fibrosis;Generations;Genetic Transcription;Heart;Human;Inflammation;Injury;Injury to Kidney;Kidney;Knock-out;Knowledge;LCN2 gene;Literature;Mediator of activation protein;Medical;Mitochondria;Modeling;Mus;Organ;Oxygen Consumption;Patients;Periodicity;Pharmaceutical Preparations;Phase;Platinum;Prevention;Process;Proximal Kidney Tubules;Publishing;Renal function;Research Proposals;Risk;Rodent Model;Role;Solid;Solid Neoplasm;Testing;Thermogenesis;Time;Tissues;Translations;base;cancer type;clinically relevant;density;fatty acid oxidation;glucose metabolism;innovation;kidney cortex;kidney fibrosis;lipid biosynthesis;metabolomics;mortality;mouse model;nephrotoxicity;new therapeutic target;novel;overexpression;prevent;renal damage;therapeutic target

public_health_relevance:
Project NarrativeCisplatin a highly effective chemotherapeutic used for the treatment of many solid tumors; it has a dose-limitingnephrotoxicity and causes acute kidney injury (AKI) in thirty percent of patients increasing the likelihood fordevelopment of chronic kidney disease (CKD). This proposal examines the role of PGC-1 using a clinicallyrelevant model of cisplatin-induced kidney injury. Successful completion of this project will lead to an increasedunderstanding of the mechanisms driving cisplatin-induced kidney injury for the identification of therapeutictargets for the prevention and treatment of cisplatin-induced kidney injury and progression to chronic kidneydisease.


application_id: 10387235
project_number: 1F31HL162463-01
project_title: Targeting The GLP-1 Receptor As New Chronotherapy Against Nondipping Blood Pressure In Diabetes
administering_ic: NHLBI
award_notice_date: 2021-11-27
opportunity_number: PA-21-052
application_type: 1
activity_code: F31
ic: HL
serial_number: 162463
program_official: NEILSON, KAREN MARY
project_start_date: 2022-01-02
project_end_date: 2024-01-01
study_section: Special Emphasis Panel[ZRG1 F10C-C (20)]
contact_pi_person_id: 16551080
contact_pi: CHACON, AARON
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:
ABSTRACTIn healthy individuals blood pressure (BP) is 10-20% lower during the sleep period than daytime levels.Chronic disruption in this day-night pattern has shown to be an independent risk factor for type 2 diabetes(T2DM) atherosclerosis stroke kidney disease retinopathy and more. These risks increase the less BP dipswith the most severe phenotype being reverse dipping  a pattern characterized by increased BP during thesleep period over daytime levels. Vascular complications are invariably associated with T2DM with prevalencerates of nondipping BP observed as high as 73%. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs)have emerged as effective glucose-lowering therapy with a diverse range of half-lives for type 2 diabetics. Butbecause the GLP-1 receptor (GLP-1R) is widespread GLP-1 RAs have shown to have a multitude of beneficialeffects independent of their glucose-lowering properties. Inhibition of food intake anti-inflammatory propertiesand reduction in BP are among them. My preliminary data demonstrates a clear restoration in BP's rhythm in adiabetic mouse model when the short half-life GLP-1 RA exenatide is administered at the onset of the lightphase and its rhythm exacerbated when administered at the onset of the dark. Coinciding with this is arestoration or worsening in food intake's diurnal rhythm. Currently FDA guidelines consider exenatide'sadministration timing only in the context of glucose-lowering. The goal of this proposal is to investigate if andhow restoration of BP rhythm lends to improvement in vascular contractility and structure. Additionally thelong half-life GLP-1 RA semaglutide will be explored on these parameters. Moreover a novel smooth muscle-specific GLP-1R knockout mouse model will be generated to determine the GLP-1R's role in vascular smoothmuscle hyper-reactivity characteristic in type 2 diabetes. I hypothesize that timed administration of GLP-1 RAswill correct disruptions in circadian rhythm of BP which will lead to healthier vascular functioning in diabeticmice. With a rich history in circadian and vascular research my lab is uniquely positioned to carry out and testeverything proposed. Funding of this proposal will not only provide me with exceptional training in biochemicalmolecular physiological and pharmacological experimentation but also potentially offer a novelchronotherapeutic approach to improve these and other GLP-1 RA's usage in the treatment of T2DM.

project_terms:
Agonist;Anti-Inflammatory Agents;Atherosclerosis;Biochemical;Blood Glucose;Blood Pressure;Blood Vessels;Characteristics;Chronic;Chronotherapy;Circadian Rhythms;Clinical Trials;Data;Diabetes Mellitus;Diabetic mouse;Disease;Diurnal Rhythm;Eating;Food;Functional disorder;Funding;Future;GLP-I receptor;Genes;Glucose;Glycosylated hemoglobin A;Goals;Guidelines;Half-Life;Health;Hour;Impairment;In Situ;Individual;Ingestion;Insulin;Kidney Diseases;Knockout Mice;Lead;Light;Measurement;Measures;Metabolic;Metabolism;Molecular;Monitor;Mus;Muscle Contraction;Non-Insulin-Dependent Diabetes Mellitus;Organ;Outcome;Pancreas;Pattern;Pharmacology;Phase;Phenotype;Physiological;Positioning Attribute;Prevalence;Property;Proteins;Recording of previous events;Reporting;Research;Resistance;Rest;Retinal Diseases;Reverse Transcriptase Polymerase Chain Reaction;Risk;Risk Factors;Role;Satiation;Series;Signal Pathway;Signal Transduction;Sleep;Smooth Muscle;Stroke;Structure;Testing;Time;Training;Type 2 diabetic;Vascular Diseases;Vascular Smooth Muscle;Western Blotting;blood glucose regulation;blood pressure elevation;blood pressure reduction;blood pressure regulation;carbohydrate metabolism;cardioprotection;circadian;db/db mouse;design;diabetic;diabetic patient;exenatide;experimental study;glucagon-like peptide 1;improved;in vivo;indexing;mortality;mouse Cre recombinase;mouse model;novel;pleiotropism;response;restoration

public_health_relevance:
PROJECT NARRATIVENondipping blood pressure (BP) describes a dysfunction in BP's natural healthy day-to-night rhythm and isprevalent in type 2 diabetes (T2DM). GLP-1 receptor agonists (RAs) are effective at lowering blood glucose inT2DM and have also shown to have BP-lowering effects. This proposal seeks to investigate the time-of-administration and half-life differences of GLP-1RAs to correct nondipping BP thereby improving vascularfunction and mortality outcomes in T2DM.


application_id: 10387097
project_number: 3R35GM136295-02S1
project_title: Mechanisms and Functions of Shoc2-Transduced Cellular Signals
administering_ic: NIGMS
award_notice_date: 2021-08-02
opportunity_number: PA-20-272
application_type: 3
activity_code: R35
ic: GM
serial_number: 136295
suffix: S1
program_official: KODURI, SAILAJA
project_start_date: 2020-05-01
project_end_date: 2025-04-30
study_section: Special Emphasis Panel[ZRG1(55)-R]
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_terms:
Address;Biological Markers;Cell Adhesion;Cell physiology;Cells;Clinical;Complex;Congenital Abnormality;Development;Disease;Enzymes;Funding;Future;Genes;Genetic;Intervention;Lead;MAPK3 gene;Malignant Neoplasms;Mediating;Microscopy;Modeling;Molecular;Mutation;National Institute of General Medical Sciences;Outcome;Pathway interactions;Patients;Proteins;Research;Scaffolding Protein;Signal Pathway;Signal Transduction;Sorting - Cell Movement;Spatial Distribution;Specificity;Syndrome;Ubiquitin;Vision;Work;Zebrafish;base;biophysical techniques;cell motility;developmental disease;equipment acquisition;in vivo;innovation;new therapeutic target;novel diagnostics;novel therapeutic intervention;programs;public health relevance;scaffold;targeted treatment;therapeutic development;transmission process;tumor;virtual


application_id: 10386907
project_number: 5P30ES030283-03
project_title: PILOT PROJECT
administering_ic: NIEHS
award_notice_date: 2022-04-01
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
project_start_date: 2020-07-15
project_end_date: 2025-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 6994
contact_pi_person_id: 8957618
contact_pi: LEBLANC, AMANDA JO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Louisville Center for Integrated Environmental Health Science (CIEHS) will promote research toward understanding how lifestyle factors interact with exposure to environmental toxicants in human health and disease. The CIEHS Pilot Project Program will further this overall goal by providing support for short-term projects leading to data collection enabling new external grant applications. In this way the Pilot Project Program will enhance capacity for novel research in environmental health science at the University of Louisville. The Program will publicize the availability of pilot project funds solicit and coordinate the review of pilot project applications make funding recommendations monitor the progress of research projects assess usage of center cores by pilot projects and track deliverables. A mix of investigators will be targeted including new early stage investigators community partners and established researchers who can apply their expertise in novel ways relevant to environmental health. Results obtained through pilot projects will be disseminated via the annual Research!Louisville event that showcases research to the university local and regional communities. Because the ultimate goal is to develop new self-sustaining research projects an emphasis will be placed on facilitating and improving the quality of new grant applications pertaining to environmental exposures/lifestyle factors. Strategies for this include obtaining feedback from CIEHS members regarding pilot project findings and experimental design as well as performing rigorous internal review of grant proposals. Thus the Program will assist investigators throughout the pilot project life cycle from initial idea to extramurally funded project and is expected to generate significant new research funding and enhance the capacity for research in the environmental health sciences at the University of Louisville.

project_terms:
Accountability;Applications Grants;Area;Award;Benchmarking;Categories;Collaborations;Communities;Data Collection;Disease;Environmental Exposure;Environmental Health;Event;Experimental Designs;Exposure to;Extramural Activities;Feedback;Fostering;Funding;General Population;Goals;Grant;Grant Review;Health;Human;Individual;Life Cycle Stages;Malignant Neoplasms;Mentors;Monitor;National Institute of Environmental Health Sciences;Pilot Projects;Publications;Recommendation;Reporting;Research;Research Peer Review;Research Personnel;Research Project Grants;Research Support;Technology;Toxic Environmental Substances;Toxicology;Translational Research;Universities;Ursidae Family;Work;base;career;career development;citizen science;community engaged research;community engagement;design;improved;lifestyle factors;meetings;member;novel;programs;stem;success;symposium


application_id: 10386906
project_number: 5P30ES030283-03
project_title: Omics and Exposures Facility Core
administering_ic: NIEHS
award_notice_date: 2022-04-01
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
project_start_date: 2020-07-15
project_end_date: 2025-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 6993
contact_pi_person_id: 8638276
contact_pi: MERCHANT, MICHAEL L
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Center for Integrated Environmental Health Sciences (CIEHS) goals are to understand how lifestyle factors interact with exposure to environmental toxicants in human health and disease and toenhance the capacity for environmental health research at the University of Louisville (UofL). UofLshared resource facility cores offer cutting edge scientific services enabling access to high-endequipment advanced techniques and specialized expertise that would typically be inaccessible for aninvestigator. It is essential for the modern environmental health scientist to understand the numerousavailable shared resource facility cores; in terms of accessibility effective experimental design dataacquisitionand -analyses. The Integrated Toxicomics and Environmental Measurement Facility Core(ITEMFC) will create a central resource for CIEHS members allowing them to understand access andeffectively use environmental omics resources. The ITEMFC will coordinate activities between CIEHSmembers and the existing UofL shared resource facility cores. The ITEMFC will be comprised of sixdiscrete technology-centric components: genomics/ transcriptomics proteomics metabolomicsmetallomics metagenomics and controlled inhalation exposure studies. The ITEMFC will focus itsefforts on advising investigators on study design facilitating shared resource facility cores use andeducating Center members and trainees on these technologies. Additionally the ITEMFC will facilitatethe transfer of omics data to the Biostatistics and Informatics Facility Core (BIFC). It will accomplishthese goals through the following specific aims: Aim 1. Increase access and facilitate use of UofLshared resource facility cores. ITEMFC will serve our members by (a) explaining the various cores andhow they operate (b) establishing direct interactions with the right shared resource director to selectthe appropriate technology. We will aid in experimental design and closely collaborate with all FacilityCores to streamline sample handling and data analysis. The ITEMFC will also supplement the cost ofmember studies. Aim 2. Cultivate awareness interest and understanding of the ITEMFC sharedresource facility cores. The ITEMFC will support CIEHS members by (a) drawing attention to theshared resource facility cores (b) suggesting how the ITEMFC may enhance their approach inanswering their research questions and (c) support educating the next generation of environmentalscientists in the various technologies. Aim 3. Facilitate submission of CIEHS members grantapplications proposing to use ITEMFC Resources. The ITEMFC will support CIEHS members in theirgrant applications that include omics-based aims. The integrated services and expertise of the ITEMFCare essential to achieve CIEHS goals and to make progress with regard to understanding the diversepathological consequences of exposure to environmental toxicants together with lifestyle factors.

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


application_id: 10386905
project_number: 5P30ES030283-03
project_title: Biostatistics and Informatics Facility Core
administering_ic: NIEHS
award_notice_date: 2022-04-01
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
project_start_date: 2020-07-15
project_end_date: 2025-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 6992
contact_pi_person_id: 14867184
contact_pi: PARK, JUW WON
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The long-term objective of the Center for Integrated Environmental Health Sciences (CIEHS) is to build aframework that integrates studies on the interactions between combined exposure to pollutants and life stylefactors) in order to understand their role in human health and disease risk at various life stages and asmodified by gender. The Biostatistics and Informatics Facility Core (BIFC) plays a vital role in supportingCIEHS research by providing state-of-the-art statistical and bioinformatics support and training to all CIEHSmembers. The BIFC is an essential resource for designing systematic acquisition and deposition of preclinicaland clinical data as well as for providing intellectual input required for rigorous data analysis. Building theframework to integrate translational basic science research on pollution and lifestyle cofactors influencingchronic disease risk requires sophisticated statistical support. The BIFC addresses this need by using state-of-art techniques related to statistics and informatics as it serves CIEHS members during all phases of theirstudies. The BIFC provides seamless infrastructure and support to CIEHS member research includingpreclinical-basic science patient-oriented clinical research (e.g. the diagnosis prevention and therapy ofenvironmentally-related disorders) public health/population-based research and community-engaged /community-led research. The aims of the BIFC are: 1. Provide state-of-the-art statistical support in designanalysis and dissemination of findings of a range of basic science translational clinical population health andenvironmental epidemiology studies; 2. Provide support for the integration of multi-omics data from both animaland human studies; 3. Facilitate integration of exposure data with lifestyle factors to identify effect modifiersand mediators of the health effects of environmental exposures; 4. Educate center investigators staff andtrainees in new methods related to statistics/omics approaches applicable to their research activities. Areas ofspecial interest include repeated measures models measurement error spatio-temporal methodscomputational biology statistical genetics clinical informatics and Bayesian methods. Several CIEHSmembers currently use the statistical support services of the BIFC Director and staff demonstrating both needand productive interactions. An IDeA grant to the Kentucky Biomedical Research Infrastructure Network andINBRE provides partial support for some BIFC bioinformatics personnel and access to a variety ofbioinformatics and statistical tools. By leveraging and building upon existing resources at UofL the BIFC isable to facilitate access and use of these resources by CIEHS members and expand statistical andbioinformatics support in a more cost efficient manner.

project_terms:
Address;Animals;Area;Basic Science;Bayesian Method;Big Data;Bioinformatics;Biomedical Research;Biometry;Cancer Center;Centers of Research Excellence;Chronic Disease;Clinical;Clinical Data;Clinical Informatics;Clinical Research;Communities;Computational Biology;Consultations;Core Facility;Data;Data Analyses;Deposition;Diagnosis;Disease;Environmental Epidemiology;Environmental Exposure;Environmental Health;Exposure to;Funding;Gender;Genetic;Goals;Grant;Health;Human;Human Resources;Informatics;Infrastructure;Kentucky;Life;Life Style;Measurement;Measures;Mediator of activation protein;Methods;Milieu Therapy;Modeling;Multiomic Data;National Institute of Environmental Health Sciences;Network Infrastructure;Phase;Play;Pollution;Population Research;Population Study;Prevention therapy;Public Health;Research;Research Activity;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Role;Science;Services;Strategic Planning;Superfund;Techniques;Toxic Environmental Substances;Training;Universities;alcohol research;bioinformatics tool;cofactor;community based participatory research;cost efficient;data infrastructure;design;disorder risk;epidemiology study;health science research;interest;lifestyle factors;member;patient oriented;pollutant;population health;pre-clinical;spatiotemporal;statistics;tool


application_id: 10386904
project_number: 5P30ES030283-03
project_title: Integrated Health Science Facility Core
administering_ic: NIEHS
award_notice_date: 2022-04-01
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
project_start_date: 2020-07-15
project_end_date: 2025-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 6991
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The overarching objective of the Integrated Health Sciences Facility Core (IHSFC) of the Center for IntegratedEnvironmental Health Sciences (CIEHS) is to translate basic research on pollution and lifestyle factorsinfluencing human health and chronic diseases. The multi-disciplinary IHSFC provides infrastructure facilitatingtranslational human subjects EHS research for the CIEHS university and community. The ultimate goal is toimprove public health and clinical practice. The IHSFC supports patient-oriented clinical research; group andpopulation-based research; and community engaged/led research. The IHSFC is comprised of two interactingsubunits: the Research Administration and Planning Subunit (RAPS) and the Research ImplementationSubunit (RIS). The IHSFC interacts with other CIEHS cores and the Research Interest Groups (RIGs) to (i)provide access to state-of-the-art instrumentation and technologies; (ii) increase multidisciplinary collaboration;and (iii) enhance partnerships with community-based organizations. The IHSFCs first specific aim is toadminister the IHSFC and plan translational human subjects EHS research. This aim is performed by RAPS.RAPS provides IHSFC access to CIEHS members trainees and the community. RAPS solicits applications forhuman subjects research; and then reviews prioritizes and financially subsidizes supported applications.RAPS defines IHSFC research in the context of the NIEHS Translational Research Framework. Community-proposed research ideas are assigned to an appropriate CIEHS member for development and execution.RAPS provides translational research training/education; and tracks and reports performance metrics to theAdministrative Core for evaluation. RAPS provides scientific study design and community engagementconsultation through linkages to the RIGs and other CIEHS cores. These consultations ensure that all IHSFC-supported studies: (i) are rigorously designed and powered; (ii) are consistent with CIEHSs theme andresearch interests; and (iii) consider the involvement of community organizations impacting this research. TheIHSFCs second specific aim is to implement IHSFC research. This aim is performed by the RIS. RIS provideshuman subjects research services and access to state-of-the-art bio-analytic instrumentation and technologiesthrough linkage to the Integrated Toxicomics & Environmental Measurement Facility Core (ITEMFC). In turnITEMFC measures exposure and omics-based disease biomarkers. RIS leverages UofLs adult Clinical TrialsUnit (CTU) the Kosair Charities Pediatric Clinical Research Units (KCPCRU) and existingcohorts/biorepositories to obtain human subjects data and biological samples. Next RIS provides linkage toother CIEHS cores for biomarker measurement data analysis and knowledge dissemination. Based on thecombination of physician-scientists engaged in EHS research and clinical research units found nowhere elsethe IHSFC has the unique capacity to conduct impactful translational EHS research including biomarkerstudies and interventional clinical trials.

project_terms:
Adult;Affect;Basic Science;Biological;Biological Markers;Biometry;Charge;Charities;Childhood;Chronic Disease;Clinical;Clinical Research;Clinical Trials;Clinical Trials Unit;Communities;Consent;Consultations;Core Facility;Data;Data Analyses;Development;Disease;Doctor of Medicine;Early Diagnosis;Ensure;Environmental Health;Evaluation;Fee-for-Service Plans;Goals;Health;Health Sciences;Health Services Accessibility;Human;Human Resources;Human Subject Research;Informatics;Infrastructure;Institutes;Interdisciplinary Study;Interest Group;Intervention;Knowledge;Life;Measurement;Measures;Metagenomics;Metals;Milieu Therapy;National Institute of Environmental Health Sciences;Nature;Performance;Pharmaceutical Preparations;Physicians;Pilot Projects;Pollution;Population Research;Prevention therapy;Program Evaluation;Proteomics;Public Health Practice;Randomized;Reporting;Research;Research Design;Research Personnel;Research Support;Retrieval;Sampling;Scientist;Services;Technology;Therapeutic Intervention;Time;Training and Education;Translating;Translational Research;Universities;base;biobank;clinical practice;cohort;community engagement;community involvement;community organizations;cost effective;design;experience;follow-up;human data;human subject;improved;innovation;instrument;instrumentation;interest;lifestyle factors;member;metabolomics;multidisciplinary;patient oriented;programs;recruit;response;sample collection;sex;transcriptomics;volatile organic compound


application_id: 10386903
project_number: 5P30ES030283-03
project_title: COMMUNITY ENGAGEMENT
administering_ic: NIEHS
award_notice_date: 2022-04-01
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
project_start_date: 2020-07-15
project_end_date: 2025-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 6990
contact_pi_person_id: 12053538
contact_pi: HUNTINGTON-MOSKOS, LUZ G
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Center for Integrative Environmental Health Sciences (CIEHS) will promote the translation of research onpollution and lifestyle factors to understand their role in human health and diseases. The CIEHS CommunityEngagement Core (CEC) vision is to develop and sustain community-academic partnerships that enhance thehealth of south-central and western Kentucky residents by empirically addressing pollution and lifestyle factorsinfluencing chronic diseases. The aims of the CEC are to: (1) facilitate and support multi-directionalinteractions among residents community agencies and the CIEHS to assess community needs and priorities;(2) facilitate and support multi-directional interactions to increase community awareness and understanding ofCIEHS research and resources; 3) cultivate environmental literacy among identified audiences; and (4) buildcapacity for community-led and community-engaged environmental health research. The approach to engagethe identified audiences has three tiers: (1) engage community residents via housing agencies to assessenvironmental health needs and community priorities; (2) involve healthcare providers to impact the healthcaresystem as it relates to environmental health needs; (3) share environmental health knowledge with communityyouth as a catalyst to promote environmental health literacy within families. In Aim 1 the CEC will work directlywith residents and community partners across south-central and western Kentucky to assess their uniquecommunity needs and priorities. Based upon the needs identified the CEC will translate and disseminateenvironmental health information to our targeted audience including CIEHS research findings (Aim 2). We willcommunicate with communities using multiple traditional (e.g. newspapers factsheets) and non-traditionalformats (e.g. social media platforms). With Aim 3 the CEC will leverage its community engagement efforts toincrease environmental health literacy in a three-tiered staggered approach in the four University of LouisvilleArea Health Education Center (AHEC) regions of south-central and western Kentucky. Outreach andengagement efforts will involve community members healthcare providers and community youth. Establishedresources from the EPA and NIEHS will be accessed including the Partnerships for Environmental PublicHealth. In Aim 4 the CEC will collaborate with the Pilot Projects Program the Stakeholders Advisory Boardand other community organizations to develop and implement through the Integrated Health Sciences FacilityCore (IHSFC ) community-led environmental health research. Aim 4 will also include working closely with theIHSFC to facilitate investigator-initiated community-engaged environmental health studies. The four targetedUofL AHEC areas include smaller urban areas multiple townships and rural areas. Residents in these ruralareas are exposed to diverse environmental exposures from industry (e.g. rural distilleries; urban/smalltown/rural manufacturing) 12 superfund sites and urban and rural agriculture. The CEC is an integral corewithin the CIEHS structure with direct impact on CIEHS research direction and decision-making.

project_terms:
Address;Agriculture;Area Health Education Centers;Awareness;Chronic Disease;Communication;Communities;Core Facility;Decision Making;Diabetes Mellitus;Disease;Ensure;Environmental Exposure;Environmental Hazards;Environmental Health;Exposure to;Family;Gender;Goals;Health;Health Personnel;Health Resources;Health Sciences;Healthcare Systems;Housing;Human;Huntington Disease;Hypertension;Industry;Kentucky;Knowledge;Leadership;Life;Malignant Neoplasms;National Institute of Environmental Health Sciences;Newspapers;Obesity;Pilot Projects;Pollution;Public Health;Research;Research Personnel;Resources;Role;Rural;Structure;Toxic Environmental Substances;Translating;Translational Research;Translations;Universities;Vision;Work;Youth;base;burden of illness;catalyst;community engaged research;community engagement;community involvement;community organizations;experience;faculty research;health knowledge;health literacy;health science research;healthcare community;household environmental exposure;lifestyle factors;literacy;member;outreach;programs;rural area;social media;superfund site;urban area


application_id: 10386902
project_number: 5P30ES030283-03
project_title: ADMINISTRATIVE CORE
administering_ic: NIEHS
award_notice_date: 2022-04-01
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
project_start_date: 2020-07-15
project_end_date: 2025-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 6989
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Louisvilles (UofL) Center for Integrative Environmental Health Science (CIEHS) is building aframework to study the integration of the interactions of pollutants and lifestyle factors in order to betterunderstand the impact on human health and disease risk across life stages and how these interactions aremodified by genetics and gender with the overall goal of improving the health of the Louisville RegionalCommunity. We will achieve this goal by fostering unique translational research on pollution and lifestyle as co-determinants that influence disease risk and facilitating transformative interdisciplinary research on preventionand/or mitigation of disease resulting from exposure to these cofactors at various life stages while consideringgenetics and gender as significant modifiers of outcomes. The CIEHS is designed to leverage existingresources to enhance trans-disciplinary environmental health research at UofL. The Administrative Core is anessential component of CIEHS that will provide scientific leadership and vision coordinate all CIEHSprogrammatic activities maintain open communication among the Cores monitor program progress andmember productivity and provide good stewardship of resources to maximize member productivity. In additionthe Administrative Core facilitates an active Community Engagement program that educates healthcareproviders serving an underprivileged patient population and the community members focusing on youthgroups. The Administrative Core also mentors junior and mid-level faculty through a Career DevelopmentProgram. The Administrative Core coordinates activity between the Community Engagement Core theIntegrated Health Sciences Facility Core the Biostatistics and Informatics Facility Core the IntegratedToxicomics and Environmental Measurement Facility Core and the Research Interest Groups to ensure multi-directional communication between CIEHS scientists and community groups to keep CIEHS research focusedon community needs. The Specific Aims are: 1. Provide leadership in coordinating and integrating Centercomponents and activities; 2. Cultivate and recruit junior and mid-level investigators to enhance careers andresearch programs in environmental health sciences; 3. Assess productivity effectiveness andappropriateness of CIEHS activities and cores; 4. Determine CIEHS membership assess scientificopportunities and areas for collaboration among CIEHS members; 5. Organize CIEHS activities such asretreats invitation of consultants meetings and focus groups; 6. Provide recordkeeping of meeting minutesand measures of success including use of CIEHS facilities publications pilot project awards and new grantapplications resulting from preliminary data enabled by the CIEHS; 7. Organize Internal and External AdvisoryCommittees; 8.Interact with other Environmental Health Science Core Centers (EHSCC) the NIEHS andother appropriate individuals groups organizations.

project_terms:
Advisory Committees;Applications Grants;Area;Award;Biometry;Collaborations;Communication;Communities;Core Facility;Data;Disease;Effectiveness;Electronic Mail;Ensure;Environmental Health;Evaluation;Exposure to;Faculty;Focus Groups;Fostering;Gender;Genetic;Goals;Grant;Health;Health Personnel;Health Sciences;Human;Individual;Informatics;Institutes;Interdisciplinary Study;Interest Group;Lead;Leadership;Life;Life Style;Measurement;Measures;Mediating;Mentors;Mentorship;Methods;Monitor;National Institute of Environmental Health Sciences;Outcome;Output;Pilot Projects;Pollution;Prevention;Process;Productivity;Program Development;Publications;Recruitment Activity;Reporting;Research;Research Personnel;Resources;Schedule;Scientist;Societies;Telephone;Toxic Environmental Substances;Toxicology;Translational Research;Translations;Universities;Vision;Youth;career;career development;cofactor;community engagement;design;disorder risk;health science research;improved;interest;lifestyle factors;meetings;member;patient population;pollutant interaction;programs;recruit;repository;success;symposium


application_id: 10386901
project_number: 5P30ES030283-03
project_title: University of Louisville Center for Integrative Environmental Health Sciences
administering_ic: NIEHS
award_notice_date: 2022-04-01
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
program_official: THOMPSON, CLAUDIA L
project_start_date: 2020-07-15
project_end_date: 2025-03-31
study_section: Environmental Health Sciences Review Committee[EHS(P)]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adult;Agriculture;Alcohol consumption;Alcohols;Area;Basic Science;Biological Models;Biometry;Cardiovascular system;Chemicals;Childhood;Chronic;Chronic Disease;Clinical;Clinical Trials;Clinical Trials Unit;Collaborations;Communication;Communities;Complex;Core Facility;County;Development;Diabetes Mellitus;Diet;Disease;Disease Outcome;Ecosystem;Environment;Environmental Health;Environmental Risk Factor;Etiology;Exposure to;Funding;Gender;Genetic;Genetic Predisposition to Disease;Genotype;Geographic Locations;Goals;Grant;Health;Health Personnel;Health Sciences;Human;Individual;Industrialization;Informatics;Interdisciplinary Study;Interest Group;Investigation;Kentucky;Knowledge;Laboratories;Leadership;Life;Malignant Neoplasms;Measurement;Mental disorders;Mentors;Mentorship;Metals;Modification;Obesity;Pathogenesis;Persons;Pilot Projects;Play;Pollution;Polychlorinated Biphenyls;Positioning Attribute;Predisposition;Program Development;Research;Research Personnel;Research Training;Resources;Role;Rural;Strategic vision;Toxic Environmental Substances;Toxicant exposure;Toxicology;Translating;Translations;United States;Universities;Vinyl Chloride;Youth;addiction;built environment;career development;citizen science;community based participatory research;community based research;community engagement;design;health science research;improved;lifestyle factors;man;member;metropolitan;multidisciplinary;next generation;pollutant;preventive intervention;programs;recruit;response;rural environment;rural healthcare;skills;socioeconomics;stressor;tobacco exposure;tobacco products;urban setting


application_id: 10386881
project_number: 5R01LM013240-03
project_title: Advanced End-to-End Relation Extraction with Deep Neural Networks
administering_ic: NLM
award_notice_date: 2022-04-29
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: LM
serial_number: 013240
program_official: WANG, YANLI
project_start_date: 2020-07-01
project_end_date: 2024-03-31
study_section: Biomedical Computing and Health Informatics Study Section[BCHI]
contact_pi_person_id: 11081240
contact_pi: KAVULURU, VENKATA NAGA RAMAKANTH
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTRelations linking various biomedical entities constitute a crucial resource that enables biomedical data scienceapplications and knowledge discovery. Relational information spans the translational science spectrum goingfrom biology (e.g. proteinprotein interactions) to translational bioinformatics (e.g. genedisease associations)and eventually to clinical care (e.g. drugdrug interactions). Scientists report newly discovered relations in nat-ural language through peer-reviewed literature and physicians may communicate them in clinical notes. Morerecently patients are also reporting side-effects and adverse events on social media. With exponential growth intextual data advances in biomedical natural language processing (BioNLP) methods are gaining prominence forbiomedical relation extraction (BRE) from text. Most current efforts in BRE follow a pipeline approach containingnamed entity recognition (NER) entity normalization (EN) and relation classication (RC) as subtasks. Theytypically suffer from error snowballing  errors in a component of the pipeline leading to more downstream errors resulting in lower performance of the overall BRE system. This situation has lead to evaluation of differentBRE substaks conducted in isolation. In this proposal we make a strong case for strictly end-to-end evaluationswhere relations are to be produced from raw text. We propose novel deep neural network architectures thatmodel BRE in an end-to-end fashion and directly identify relations and corresponding entity spans in a singlepass. We also extend our architectures to n-ary and cross-sentence settings where more than two entities mayneed to be linked even as the relation is expressed across multiple sentences. We also propose to create twonew gold standard BRE datasets one for drugdisease treatment relations and another rst of a kind datasetfor combination drug therapies. Our main hypothesis is that our end-to-end extraction models will yield supe-rior performance when compared with traditional pipelines. We test this through (1). intrinsic evaluations basedon standard performance measures with several gold standard datasets and (2). extrinsic application orientedassessments of relations extracted with use-cases in information retrieval question answering and knowledgebase completion. All software and data developed as part of this project will be made available for public use andwe hope this will foster rigorous end-to-end benchmarking of BRE systems.

project_terms:
Adverse event;Architecture;Area;Benchmarking;Bioinformatics;Biology;Biomedical Research;Black race;Classification;Clinical;Code;Collaborations;Combination Drug Therapy;Communities;Complex;Computer software;Data;Data Set;Dependence;Disease;Distant;Drug Interactions;Encapsulated;Etiology;Evaluation;Fostering;Funding;Future;Generations;Genes;Gold;Growth;Hand;Heart;Information Retrieval;Information Sciences;Intramural Research;Joints;Knowledge Discovery;Label;Language;Lead;Link;Literature;Manuals;Maps;Measures;Methodology;Methods;Modeling;Molecular;Names;Natural Language Processing;Patients;Peer Review;Performance;Periodicity;Pharmaceutical Preparations;Physicians;Process;Reporting;Research;Research Personnel;Resources;Review Literature;Scientist;Semantics;Software Tools;Source;Standardization;Structure;Supervision;System;Terminology;Testing;Text;Training;Translational Research;Trees;United States National Library of Medicine;base;biomedical data science;clinical care;deep neural network;improved;insight;interest;knowledge base;machine learning method;natural language;neural network;neural network architecture;new therapeutic target;novel;off-label use;protein protein interaction;relating to nervous system;side effect;social media;supervised learning;syntax;transfer learning

public_health_relevance:
NARRATIVERelations connecting biomedical entities are at the heart of biomedical research given they encapsulate mech-anisms of disease etiology progression and treatment. As most such relations are rst disclosed in textualnarratives (scientic literature or clinical notes) methods to extract and represent them in a structured format areessential to facilitate applications such as hypotheses generation question answering and information retrieval.The high level objective of this project is to develop and evaluate novel end-to-end supervised machine learningmethods for biomedical relation extraction using latest advances in deep neural networks.


application_id: 10386820
project_number: 5K01MH119942-03
project_title: Examining HIV-related Stigma and HIV Testing Among Formerly Incarcerated African American Youth
administering_ic: NIMH
award_notice_date: 2022-04-22
opportunity_number: PA-19-126
application_type: 5
activity_code: K01
ic: MH
serial_number: 119942
program_official: GREENWOOD, GREGORY LOUIS
project_start_date: 2020-05-01
project_end_date: 2024-04-30
study_section: Population and Public Health Approaches to HIV/AIDS Study Section[PPAH]
contact_pi_person_id: 12373928
contact_pi: KERR, JELANI
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractPersistent HIV health disparities impacts African Americans and are a public health priority. Despite decliningHIV rates nationally African American communities continue to experience disproportionate HIV burden andincreasingly account for the largest share of HIV-related morbidity and mortality in the United States. Theseconcerning disparities necessitate research to inform robust responses that target priority subgroups within thispopulation. High rates of incarceration in many African American communities contribute to high HIV riskenvironments where the risks persist after release from the criminal justice system. Formerly incarceratedAfrican American youth (FIAAY ages 18-24 years) in particular are at heightened risk in terms of sexualbehavior illicit drug use and challenged rates of HIV testing behavior after release. A prominent barrier to HIVtesting and timely diagnosis in this and other vulnerable populations is HIV-related stigma. Thus moreresearch needs to not only examine stigma-related factors that reduce HIV testing behavior but also create abasis for interventions that can reduce stigma and increase HIV testing and HIV preventive behaviors in prioritypopulations such as FIAAY. Towards these goals my proposed study focusing on FIAAY in LouisvilleKentucky will allow me to: 1) develop a risk profile of HIV-negative or HIV status unknown FIAAY at greaterlikelihood of having stigmatizing beliefs related to HIV infection and longitudinally examine the likelihood of HIVtesting based on this profile and 2) delineate mediating and moderating mechanisms by which stigma reducesHIV testing in this population. These actions will help generate knowledge for the development of a multilevelintervention targeting individual and structural factors to reduce HIV-related stigma and increase HIV testingand prevention among this population of vulnerable youth. This Career Development Award will provide thenecessary knowledge and skills to conduct this and future research with criminal justice-involved populations.This entails enhancing my skills in advanced statistical methods such as survival analysis and structuralequation modeling. In addition it will foster content expertise in decision science and the criminal justicesystem which will help inform intervention development. Study methods will include longitudinal survey datacollection (baseline 12-months 24-months) from 274 FIAAY in Louisville KY. This research will inform thedevelopment of stigma-related HIV-risk profiles for FIAAY who are less likely to test and delineate mediatorsand moderators of the stigma-HIV testing relationship. If a relationship between stigma and testing is notdetected other psychosocial factors will be examined to determine mediators and moderators of HIV testing.This study has important downstream benefits for HIV prevention and treatment in this highly vulnerablepopulation.

project_terms:
AIDS prevention;Address;Affect;African American;African American population;Age;Behavior;Behavior Therapy;Behavioral;Belief;Caring;Characteristics;Communities;Criminal Justice;Data;Data Collection;Demographic Factors;Development;Diagnosis;Drug usage;Early Diagnosis;Environment;Equation;Exhibits;Fostering;Fright;Gender;Gender Identity;General Population;Goals;HIV;HIV Infections;HIV Seronegativity;HIV diagnosis;HIV risk;Health;Health behavior;Homophobia;Human immunodeficiency virus test;Imprisonment;Individual;Intervention;K-Series Research Career Programs;Kentucky;Knowledge;Longitudinal Surveys;Mediating;Mediator of activation protein;Methods;Modeling;Morbidity - disease rate;Neighborhoods;Participant;Pathway interactions;Persons;Population;Poverty;Predisposition;Prevention;Prevention strategy;Preventive;Psychosocial Factor;Public Health;Recording of previous events;Research;Research Personnel;Research Project Grants;Risk;Risk Behaviors;Science;Sex Behavior;Sex Orientation;Statistical Methods;Stereotyping;Stigmatization;Subgroup;Survival Analysis;System;Testing;Time;Translational Research;Unemployment;United States;Vulnerable Populations;Work;Youth;aged;base;behavior test;care systems;career development;condoms;experience;health disparity;illicit drug use;improved;male;mortality;pre-exposure prophylaxis;prediction algorithm;prevent;prevention service;psychologic;public health priorities;racial and ethnic disparities;racial disparity;response;sexual risk behavior;skills;social stigma;substance use;testing uptake;therapy development;treatment disparity;uptake

public_health_relevance:
Project NarrativeAfrican American youth with a history of incarceration are at heightened HIV risk thus early detection amongthis group is critical for linkage to prevention and care services improving survival prospects and reducingracial disparities in HIV. Despite the benefits of testing HIV-related stigma remains a significant barrier totimely HIV diagnosis however little research examines the mechanisms by which HIV-related stigma inhibitstesting behavior. This study will delineate the relationships between stigma stigma-related factors and HIVtesting and the information will be used to help generate knowledge for intervention development to improveHIV testing and stigma-reduction for formerly incarcerated African American youth.


application_id: 10386802
project_number: 5UG1DA050069-04
project_title: Kentucky Women's Justice Community Opioid Innovation Network (WJCOIN)
administering_ic: NIDA
award_notice_date: 2022-05-02
opportunity_number: RFA-DA-19-025
application_type: 5
activity_code: UG1
ic: DA
serial_number: 050069
program_official: MULFORD, CARRIE FRIED
project_start_date: 2019-07-15
project_end_date: 2024-04-30
study_section: ZDA1-HXO-H(05)R
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 opioid crisis continues to ravage US communities with overdose deaths at an all-time high. Women aredisproportionately affected by the opioid crisis due to increased pain sensitivity physician prescribing practicesand self-medication as well as a faster trajectory from opioid exposure to the development of opioid use disorder(OUD). The opioid overdose death rate among women has risen 492% since 1999 a higher rate than men(404%). However research on approaches to increase initiation of life-saving medications for opioid use disorder(MOUD) among women is limited. The University of Kentucky proposes to establish the Womens ClinicalResearch Center as part of the NIDA Justice Community Opioid Innovation Network (W-JCOIN). The overallgoal of the W-JCOIN is to increase initiation and maintenance of MOUD among high-risk justice-involved womenin the transition from jail to the community to reduce opioid relapse and overdose. As part of this NIH collaborativenetwork the W-JCOIN will lead a type 1 hybrid effectiveness and implementation trial to examine an innovativeMOUD pre-treatment model using telehealth (alone and in combination with peer navigators) for justice-involvedwomen in transition from jail to the community in 6 experimental and 3 comparison (Services as Usual-SAU)sites. The following aims guide the study: (1) Compare the effectiveness of MOUD Pre-Treatment Telehealth(alone versus in combination with Peer Navigators) to increase MOUD initiation and maintenance among high-risk justice-involved women in the community after release relative to services as usual (SAU). (2) Estimate theincremental cost and cost effectiveness of MOUD Pre-Treatment Telehealth (alone and in combination with PeerNavigators) relative to SAU for high-risk justice involved women with OUD in achieving desired changes inclinical public health and public safety outcomes over one-year post-release. (3) Examine temporal changes inkey implementation constructs hypothesized by the EPIS framework to influence successful innovationimplementation. This application is supported by an experienced team of NIH funded investigators with a trackrecord of engaging in NIH justice research cooperative. The research team is well-positioned to be active membersof the JCOIN network to rapidly conduct studies on quality care for OUD with special focus on underserved andunderstudied justice-involved women. The KY W-JCOIN has the potential for significant impact on the OUDtreatment field by contributing empirical evidence on the effectiveness and implementation of innovativetechnologies to increase initiation and maintenance of life-saving medications during a critical high-risk time ofcommunity re-entry among vulnerable justice-involved women in both urban and non-urban communities. Thelong-term goal of this research is to increase the capacity for the justice system to respond to the opioid crisisthrough increased access to treatment to reduce opioid relapse and overdose.

project_terms:
Affect;Benefits and Risks;Caring;Climate;Clinical;Clinical Research;Communities;Cost Analysis;Criminal Justice;Death Rate;Development;Drug abuse;Drug usage;Effectiveness;Exposure to;Funding;Goals;Health Services Accessibility;High Risk Woman;Hybrids;Imprisonment;Intervention;Jail;Justice;Kentucky;Lead;Leadership;Life;Link;Maintenance;Methods;Modeling;National Institute of Drug Abuse;Opioid;Outcome;Overdose;Perception;Persons;Pharmaceutical Preparations;Physicians;Positioning Attribute;Public Health;Quality of Care;Randomized;Recording of previous events;Recovery;Relapse;Reporting;Research;Research Personnel;Rewards;Safety;Savings;Self Medication;Services;Site;System;Time;Treatment Cost;United States National Institutes of Health;Universities;Woman;arm;base;community reentry;compare effectiveness;comparison group;cost;cost effectiveness;cost-effectiveness ratio;effectiveness implementation trial;experience;follow-up;high risk;improved;incremental cost-effectiveness;innovation;innovative technologies;intervention cost;member;men;opioid epidemic;opioid exposure;opioid injection;opioid mortality;opioid use disorder;organizational readiness;overdose death;pain sensitivity;peer;programs;recidivism;safety outcomes;services as usual;telehealth;treatment as usual

public_health_relevance:
PROJECT NARRATIVEThe University of Kentucky proposes to establish the Womens Clinical Research Center as part of the NIDAJustice Community Opioid Innovation Network (W-JCOIN) with the overall goal of increasing initiation andmaintenance of MOUD among high-risk justice-involved women in the transition from jail to the community toreduce opioid relapse and overdose. The KY W-JCOIN has the potential for significant impact on the OUDtreatment field by contributing empirical evidence on the effectiveness and implementation of innovativetechnologies to increase initiation and maintenance of life-saving medications during a critical high-risk time ofcommunity re-entry among vulnerable justice-involved women in both urban and non-urban communities. Thisresearch will impact the field by increasing the capacity of the justice system to respond to the opioid crisisthrough increased access to MOUD treatment to reduce opioid relapse and overdose.


application_id: 10386349
project_number: 3U18FD006459-03S1
project_title: Kentucky Department of Agriculture Produce Safety Rule Compliance Plan
administering_ic: FDA
award_notice_date: 2021-04-09
opportunity_number: PAR-16-137
application_type: 3
activity_code: U18
ic: FD
serial_number: 006459
suffix: S1
program_official: KEPPLEY, LAURIE
project_start_date: 2018-07-01
project_end_date: 2021-06-30
study_section: ZFD1-SRC(99)
contact_pi_person_id: 15953406
contact_pi: MORRIS, DAVID
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 094630642
primary_uei: Q8K6DER1H1X4
duns_number: 094630642
uei: Q8K6DER1H1X4
fips: US
organization_id: 4536701
organization_name: KENTUCKY STATE DEPARTMENT OF AGRICULTURE
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406018311
organization_country: UNITED STATES
project_abstract:
1Project SummaryThe Kentucky Department of Agriculture (KDA) proposes to explore andestablish a produce safety program in the Commonwealth of Kentucky throughthe support of this U.S Food and Drug Administration (FDA) funding opportunity.The KDA will seek the authority to conduct on-farm inspections inCommonwealth of Kentucky on behalf of FDA and ensure that produce growersof the Commonwealth are made aware of trained as needed and inspected asrequired by the Food Safety Modernization Act (FSMA) Final Rule on ProduceSafety: Standards for the Growing Harvesting Packing and Holding of Producefor Human Consumption (Produce Safety Rule) effective January 2018. ThisKentucky produce safety program is intended to encourage the safe productionof fresh fruits and vegetables to promote the understanding of the ProduceSafety Rule and to ensure compliance with the requirements of the ProduceSafety Rule by covered Kentucky entities. This cooperative agreement is toestablish and maintain a statewide program for farmer education technicalassistance development of an inventory of covered farms and farm inspectionsafter seeking authority under Kentucky law.With the funding made available through this grant KDA and its partnerorganizations will conduct education outreach identification of covered farmsand technical support while KDA will solely conduct activities associated with on-farm inspections after KDA staff complete FDA-required training.Through this program KDA will conduct a state self-assessment and policychanges to ensure a clear state regulatory foundation under Kentucky state law(Kentucky Revised Statutes or KRS) that is well-understood by regulators theregulated and the produce community as a whole. KDA will pursue regulatoryauthority for KDA to act as the lead agency with FDA credentials for theimplementation of the Produce Safety Rule. The education and outreachconducted by the three partner agencies associated with this project will enablethe regulated community to better prepare for this federal regulation. Thesupport of both Competition A and Competition B will be necessary to fullydevelop Kentuckys plan for FSMA Produce Safety Rule implementation.

public_health_relevance:
1Project NarrativeThe Kentucky Department of Agriculture (KDA) applies for Food and DrugAdministration funding and will seek the authority to conduct on-farm inspectionsin Commonwealth of Kentucky on behalf of FDA. KDA and our partners willensure that produce growers of the Commonwealth are made aware of trainedas needed and inspected as required by the Food Safety Modernization Act(FSMA) Final Rule on Produce Safety: Standards for the Growing HarvestingPacking and Holding of Produce for Human Consumption (Produce Safety Rule)effective January 2018.


application_id: 10386020
project_number: 1F31MH127892-01A1
administering_ic: NIMH
award_notice_date: 2021-12-17
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: MH
serial_number: 127892
suffix: A1
program_official: CORNELL, ASHLEY ROSE
project_start_date: 2022-01-01
project_end_date: 2024-12-31
study_section: Special Emphasis Panel[ZRG1 F16-L (20)]
contact_pi_person_id: 15681647
contact_pi: CHRISTIAN, CAROLINE
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
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 ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Behavioral and Momentary Assessment of Fear-based Mechanisms underlying Remission in Weight-restored Anorexia Nervosa

project_abstract:
Project Summary/Abstract Anorexia nervosa (AN) is a psychiatric illness characterized by low weight extreme food restrictionintense fear of weight gain and disturbance in body self-evaluation. AN is markedly persistent and there areno empirically supported treatments for adults with this deadly illness. Indeed over half of individuals withAN do not reach full remission during treatment and approximately one third of individuals experienceat least one relapse after discharge. There is great need for identifying remission-promoting targets to adaptand create optimized interventions for this population. The period of partial remission in AN (i.e. weight-restored individuals who continue to endorse significant cognitive-affective AN pathology) represents a criticaltime for identifying mechanisms underlying remission. Specifically unaddressed cognitive-affective ANsymptoms (e.g. extreme fear of weight gain) at this stage represent the greatest barrier to achieving lasting fullremission and thus mechanisms underlying the persistence vs. reduction of these symptoms are critical tostudy at this stage. AN is highly comorbid with anxiety disorders and shares several maintenance factorsincluding high levels of fear anxiety and harm avoidance. Despite considerable overlap with anxietydisorders fear and avoidance have not been tested as mechanisms inhibiting remission in weight-restored AN. The proposed study will test how fear-based learning (e.g. fear extinction fear renewal fearapproach fear avoidance) relates to AN pathology in the naturalistic environment in a sample of 45 individualsmeeting criteria for AN in partial remission. This study will use both behavioral assessment (i.e. Approach-Avoidance Task Behavioral Approach Task associative fear-learning paradigm) and momentary assessment(i.e. smartphone-based intensive longitudinal data collection) of fear avoidance and approach behaviors toconceptualize how these mechanisms of interest operate in the real world. First we will test whetherbehavioral approach avoidance fear extinction and fear renewal are correlated with real-time approachavoidance fear and AN symptoms (Aim 1). Second vector autoregressive models using the intensive time-series data will elucidate prospective associations across fear-based processes and AN symptoms betweensubjects (Aim 2) and within individuals (Aim 3) to identify group-level and intraindividual targets for care duringthis critical stage in recovery. In the between-subjects models we will test behavioral fear extinction andrenewal as moderators (Aim 2). The opportunities resources and expert consultation afforded by this awardwould support my training goals to collect and analyze behavioral data learn new analytic approaches withintensive longitudinal data and gain experience working with clinical AN participants. Overall this proposedstudy will implement advanced statistics and multimethod research design conducted fully remotelyat an important stage of AN. These results will inform precision relapse prevention interventions andstep-down care improving outcomes for this impairing persistent and costly disorder.

project_terms:
Address;Adult;Affective;Anorexia Nervosa;Anxiety;Anxiety Disorders;Award;Behavior;Behavior assessment;Behavioral;Behavioral Paradigm;Caring;Cellular Phone;Cessation of life;Clinical;Cognitive;Cognitive Therapy;Computers;Consultations;Dangerousness;Data;Data Collection;Development;Disease;Disease remission;Eating Disorders;Empirical Research;Environment;Exposure to;Extinction (Psychology);Food;Fright;Future;Goals;Gold;Impairment;Individual;Intake;Intervention;Investigation;Lead;Learning;Literature;Maintenance;Mental disorders;Modeling;Nutritional;Partial Remission;Participant;Pathology;Persons;Play;Population;Population Intervention;Prevalence;Procedures;Process;Recovery;Relapse;Research;Research Design;Resources;Role;Sampling;Self-Examination;Series;Stimulus;Symptoms;Testing;Time;Training;Treatment outcome;United States;Weight;Weight Gain;approach avoidance behavior;approach behavior;avoidance behavior;base;behavior test;career;cognitive enhancement;comorbidity;conditioned fear;cost;critical period;disorder later incidence prevention;experience;food restriction;healthy weight;improved outcome;interest;meetings;mortality;personalized approach;personalized intervention;prevent;preventive intervention;prospective;reduce symptoms;relapse risk;response;standard care;statistics;theories;treatment optimization;trend;vector;weight restoration

public_health_relevance:
Project Narrative Anorexia nervosa is a costly impairing and persistent psychiatric disorder associated with poortreatment outcomes and high rates of relapse. A large body of evidence suggests anorexia nervosa often co-occurs with anxiety disorders and is characterized by fear and avoidance yet research on these maintainingprocesses in anorexia nervosa are critically lacking. The current study will test the associations across fearextinction renewal approach avoidance and eating disorder symptoms during the critical period of partialremission in anorexia nervosa to identify precision relapse prevention targets that can optimize treatments forthis serious psychiatric disorder.


application_id: 10384509
project_number: 1R43HL162240-01
project_title: Method for Rapid Non-Invasive Assessment of Coronary Stenosis
administering_ic: NHLBI
award_notice_date: 2022-02-10
opportunity_number: PA-20-260
application_type: 1
activity_code: R43
ic: HL
serial_number: 162240
program_official: LUO, JAMES
project_start_date: 2022-02-10
project_end_date: 2023-08-09
study_section: Special Emphasis Panel[ZRG1 CVRS-D (10)]
contact_pi_person_id: 78116905
contact_pi: NICKOLS, JOSH
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 117603648
primary_uei: FFKEQLFJ7JG3
duns_number: 117603648
uei: FFKEQLFJ7JG3
fips: US
organization_id: 10060977
organization_name: VCARDIO INC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402062632
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
vCardio IncMethod for Rapid Non-Invasive Assessment of Coronary StenosisProject SummaryWe have developed a non-invasive technique for quantifying the severity of stenosis (blockage)in coronary arteries. One million invasive coronary angiography (ICA) procedures are performedevery year in patients who present with chest pain or are known to have stable coronary arterydisease (CAD). The goal of the procedure is to determine if there is any significant stenosis thatlimits blood flow to the heart muscle in the coronary arteries. Almost half of ICAs culminate instent placement in coronary arteries in order to relieve the blockage of blood flow. The cardiologistperforming the procedure in the catheterization lab determines the significance of the stenosis byone of two methods: either by visually estimating the degree of stenosis (eyeballing the stenosis)which is the routine practice and is done in the majority of patients or by invasively measuringfractional flow reserve (pressure-wire FFR) which is the Gold Standard test. However pressure-wire FFR is only performed in 10-20% of patients because it is invasive expensive and time-consuming and requires more radiation and contrast exposure.The proposed technology provides an accurate highly sensitive and specific non-invasivemethod to assess the significance of coronary stenosis through coronary angiography withoutpressure-wire FFR measurement. When performed in real-time under 2 minutes this allows thecardiologist to make an informed decision regarding stent placement. Such a method woulddeliver the benefits of pressure-wire FFR measurement in terms of cost savings and improvementin patient symptoms while avoiding disadvantages such as extra cost for the procedure and timeburden. It performs favorably compared to competing technology in terms of accuracy but issuperior to competition with regards to the time required to run the software. This allows us toprovide a truly real-time solution for quantification of coronary stenosis.Our approach uses reduced order modeling methods to model coronary blood flow acrossstenotic coronary lesions and assess the degree of stenosis severity by incorporating residencetime of blood flow through the stenotic segments. The major advantage of this approach over thecompeting solutions is its potential to deliver a real-time virtual solution within seconds. Onceimplemented the solution would merge seamlessly with the current catheterization lab equipmentand provide a real-time objective tool for assessment of coronary lesions by the treatingcardiologists.The objective is to scale the study from an initial successful 54 patient study up to 500 patients(400 patients in derivation cohort and 100 patients in validation cohort) by conducting aretrospective study in patients with known CAD who have undergone coronary angiography andpressure-wire FFR measurement for clinical indications.

project_terms:
3-Dimensional;Arteries;Assessment tool;Blood;Blood flow;Cardiac Catheterization Procedures;Catheterization;Characteristics;Chest Pain;Clinical;Computer Models;Computer software;Consumption;Coronary;Coronary Angiography;Coronary Arteriosclerosis;Coronary Stenosis;Coronary artery;Cost Savings;Derivation procedure;Development;Dimensions;Disadvantaged;Eye;Goals;Gold;Guidelines;Intervention;Ischemia;Lesion;Liquid substance;Machine Learning;Measurement;Measures;Medical;Methods;Modeling;Myocardium;Patients;Pharmaceutical Preparations;Phase;Physics;Procedures;Radiation;Radiation exposure;Retrospective Studies;Running;Sensitivity and Specificity;Severities;Stenosis;Stents;Suggestion;Symptoms;Techniques;Technology;Testing;Time;Validation;base;cohort;computing resources;coronary lesion;interest;laboratory equipment;machine learning algorithm;machine learning model;novel;patient population;pressure;procedure cost;prototype;rapid technique;reconstruction;residence;routine practice;software development;virtual

public_health_relevance:
vCardio incMethod for Rapid Non-Invasive Assessment of Coronary StenosisProject NarrativeThe proposed technology is a software application that provides an accurate non-invasive method to assess the significance of blocked coronary arteries and is meant toreplace the current invasive medical procedure.This application allows the treating cardiologist to make an informed decision regardingstent placement for patients who have blocked coronary arteries and present with chestpain that is not adequately responsive to medications. Such a non-invasive methodwould deliver the benefits of the invasive procedure in terms of improvement in patientsymptoms while avoiding disadvantages such as increased radiation exposure andhigher contrast use for patients and higher cost for the procedure.The software application is cheaper easier and faster than existing invasiveprocedures. It is also can be faster easier or more accurate than existing non-invasiveprocedures.April 2021


application_id: 10383143
project_number: 5R01NS108529-05
project_title: The integrated stress response and oligodendrocyte survival after spinal cord injury
administering_ic: NINDS
award_notice_date: 2022-03-31
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 108529
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2018-06-15
project_end_date: 2023-03-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 7612305
contact_pi: HETMAN, MICHAL
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract. We identified the ER stress response (ERSR) as a potential target for therapeutic interventionsagainst white matter loss and locomotor impairment after spinal cord injury (SCI). Specifically the signalingpathway that involves the ERSR kinase PERK the PERK target elongation initiation factor 2 (eIF2) andPERK-activated transcription factor CHOP may be manipulated in a time-dependent manner to promote SCIrecovery. PERK signaling has a partial overlap with the integrated stress response (ISR) that via severalstress-activated kinases leads to increased levels of phospho-eIF2 (peIF2) transient inhibition of proteinsynthesis and activation of the transcription factor ATF4. ATF4 regulates CHOP as well as genes involved inROS metabolism translational regulation and amino acid synthesis. In this way the ISR attempts to restorehomeostasis. Excessive and prolonged activation of the ISR results in anabolism-associated oxidative stressmitochondrial damage cell death and inflammation. Pro-ISR stimuli such as hypoxia lack of nutrientsoxidative stress and ER stress are present after SCI. However the role of the principal ISR components eIF2 kinases other than PERK and their common downstream target ATF4  has not been addressed in thecontext of white matter loss after contusive SCI. Our overarching hypothesis is that the ISR plays a critical rolein pathogenesis of contusive SCI by promoting OL/OPC death and white matter loss. Aim 1 will examine therole of the 4 upstream ISR kinases (PERK PKR GCN2 HRI which are activated by different stressors) thatphosphorylate eIF2 which in turn inhibits global translation and enhances stress-induced gene expression.We will use a combination of previously optimized gain and loss of function in vitro OPC/OL and in vivo SCIassays that utilize pharmacological inhibitors as well as Hri-/- Pkr-/- and Gcn2-/-mice. Preliminary data from ERstressed OPCs or SCI tissue show activation of these kinases as well as compensatory activation of the ISRpathway when PERK is inhibited. Aim 2 will examine the role of the central ISR effector ATF4 in SCI-associated white matter loss. Our preliminary data show activation of ATF4 after SCI or in ER-stressed OPCs.We will determine whether ATF4 is a mediator of OL/OPC death white matter damage and functional declineafter contusive SCI. In summary current experimental design is based on data from our previouscharacterization of the ERSR after SCI. Here we propose to delineate novel mechanisms of ISR-mediated celldeath after SCI as well as define which of ISR mediators may best be suited for therapeutic translation toacutely treat SCI patients. Such treatments are likely to be applicable to other types of CNS trauma such asTBI and stroke.

project_terms:
Acute;Address;Affinity Chromatography;Amino Acids;Anabolism;Attenuated;Biological Assay;Brain Injuries;Cell Death;Cessation of life;Chronic;Data;Disease;Double-Stranded RNA;Enzymes;Experimental Designs;Functional disorder;Gene Expression;Genes;Glucose;Grant;Homeostasis;Hypoxia;Hypoxia Inducible Factor;Impairment;In Vitro;Inflammation;Intracranial Hemorrhages;Iron;Mediating;Mediator of activation protein;Metabolism;Mitochondria;Mus;Nutrient;Oligodendroglia;Outcome;Oxidative Stress;PERK kinase;Pathogenesis;Pathway interactions;Peptide Initiation Factors;Pharmacological Treatment;Pharmacology;Phosphotransferases;Play;Procollagen-Proline Dioxygenase;Proteasome Inhibition;Protein Synthesis Inhibition;Recovery of Function;Response to stimulus physiology;Ribosomes;Role;Signal Pathway;Signal Transduction;Spinal Cord Contusions;Spinal cord injury;Spinal cord injury patients;Starvation;Stress;Stroke;Testing;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Time;Tissue Sample;Tissues;Transcriptional Activation;Translating;Translational Regulation;Translations;Traumatic CNS injury;Up-Regulation;Work;base;biological adaptation to stress;central nervous system injury;cytotoxic;deprivation;endoplasmic reticulum stress;functional decline;functional outcomes;genetic approach;improved;in vivo;inhibitor;injury recovery;loss of function;new therapeutic target;novel;novel therapeutics;response;stressor;targeted treatment;transcription factor;transcription factor CHOP;transcriptome sequencing;white matter;white matter damage

public_health_relevance:
Project Narrative This grant examines the role of the integrated stress response in functional recovery afterSCI. It follows logically from previous work and looks both to find novel therapeutic agents to abrogate thecytotoxic actions of the integrated stress response. It is hoped that these data will provide new therapeutictargets for pharmacological treatment of the devastating acute and chronic dysfunction that occurs after SCI.


application_id: 10383110
project_number: 1R41OD031942-01A1
project_title: Engineered Exosomes for Targeted Delivery of the CRISPR/Cas9 Genome-editor
administering_ic: OD
award_notice_date: 2022-05-24
opportunity_number: PAR-20-109
application_type: 1
activity_code: R41
ic: OD
serial_number: 031942
suffix: A1
program_official: VONKOLLMAR, DESIREE
project_start_date: 2022-06-01
project_end_date: 2024-05-01
study_section: Special Emphasis Panel[ZRG1 BST-R (10)]
contact_pi_person_id: 8240457
contact_pi: GUPTA, RAMESH C
other_pis: SPENCER, WENDY A
congressional_district: 04
department: Unavailable
primary_duns: 831172668
primary_uei: HSCNW2K7VN97
duns_number: 831172668
uei: HSCNW2K7VN97
fips: US
organization_id: 10023330
organization_name: 3P BIOTECHNOLOGIES, INC.
organization_city: PROSPECT
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400598574
organization_country: UNITED STATES
project_abstract:
Technical Abstract Genetic mutations have been identified as a causative factor in numerous diseases. The genome editingsystem CRISPR/Cas9 is a recent development in gene therapy. Both viral and non-viral vectors have been usedin attempts to direct delivery of Cas9 to specific locations with advantages and limitations similar to those knownfor other nucleic acid-based therapeutics. These challenges have limited the current clinical progress of thisgenome-editing tool. The goal of this project is to develop an effective targeted delivery system for Cas9-mediatedgenome editing. The investigators take advantage of a novel technology for delivery of plasmid DNA (pDNA)based on bovine milk/colostrum exosomes developed in the PI's laboratory. In this project we will apply ourknowledge and extensive experience in exosomes for efficient targeted delivery of the Cas9-mediated genome-editing tool. To establish feasibility we have used pDNA to deliver the coding sequences for Cas9-mediatedknockout of NFB as a model gene. This single plasmid pKO-NFB contains the mammalian-optimized Cas9coding sequence the single-guide RNA (sgRNA) specific to NFB as well as sequences to derive a guide RNA(gRNA) scaffold to assist in the binding of Cas9 to the target DNA. We hypothesize that pKO-NFB ionicallyentrapped in a novel exosome matrix formulated by complexing exosomes and polycationic polyethyleneimine(PEI) will serve as an effective genome-editing tool of NFB. Furthermore use of engineered exosomesprepared by loading milk lactoferrin (LF) onto exosomes will target bronchial epithelium overexpressing LFreceptors. Thus LF-EPM-pKO-NFB administered intranasally (i.n.) will target lung with minimal off-target effectsfor delivery of this genome-editing tool. Our hypothesis is supported by compelling preliminary data: high loadingof nucleic acid onto EPM and protection from degradation functionalization of exosomes by surface-bound LFloading inhibition of NFB expression in H2030 lung cancer cells by LF-EPM delivered pKO-NFBoverexpression of the LF receptor intelectin (also called omentin) in the mouse lung and predominant delivery ofLF-functionalized exosomes to the mouse lung by intranasal delivery. Investigators experienced in exosomesdrug delivery and biological sciences will pursue the following specific aims: Aim 1. Optimize targeted deliveryof CRISPR/Cas9 genome-editing tool using engineered exosomes in vitro. Aim 2. Determine potentialtoxicity and biodistribution and efficacy of engineered exosomes for targeted delivery of CRISPR/Cas9genome-editing tool. If we are successful in achieving these milestones we will move to Phase II. Results fromthis project will provide feasibility data for advancing this genome-editing tool delivery `platform' in a diseasemodel. Cost-effective isolation of exosomes from a biocompatible source combined with ultracentrifugation-independent methods currently being developed in PI's laboratory makes the exosomes production a commercialviability as this novel delivery technology advances.

project_terms:
A549;Adaptive Immune System;Address;Animal Model;Binding;Biodistribution;Biological Sciences;Cattle;Cell Culture Techniques;Cells;Chronic Obstructive Pulmonary Disease;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Colostrum;Complex;DNA;DNA Repair;DNA Sequence Alteration;Data;Detection;Development;Disease;Disease model;Drug Delivery Systems;Drug or chemical Tissue Distribution;Epithelial Cells;Fluorescence;Formulation;Genes;Genome;Genome Components;Goals;Guide RNA;Image;Immune response;In Vitro;Industry Standard;Inflammation;Inflammatory;Inflammatory Response;Inherited;Intravenous;Knock-in;Knock-out;Knowledge;Label;Laboratories;Lactoferrin;Lipofectamine;Lipopolysaccharides;Location;Lung;Mediating;Methods;Milk;Modeling;Mus;Mutation;Non-Viral Vector;Nonhomologous DNA End Joining;Nucleic Acids;Organ;Phase;Plasmids;Polyethyleneimine;Preparation;Production;Proteins;Research Personnel;Route;Source;Structure of parenchyma of lung;Surface;Symptoms;System;TP53 gene;Technology;Testing;Time;Tissues;Toxic effect;Transfection;Ultracentrifugation;Viral;Western Blotting;Wild Type Mouse;alveolar epithelium;base;biomaterial compatibility;bronchial epithelium;chemokine;cost effective;cytokine;delivery vehicle;engineered exosomes;exosome;experience;gene therapy;genome editing;in vivo;inflammatory lung disease;knock-down;lactoferrin receptors;lung cancer cell;microbial;nano;nanoformulation;new technology;novel;nuclease;nucleic acid-based therapeutics;overexpression;plasmid DNA;prevent;protein expression;public health relevance;scaffold;success;systemic toxicity;targeted delivery;tool

public_health_relevance:
Narrative (Public Health Relevance Statement) In this project we will develop novel nano formulations of the genome-editing machinery (CRISPR Cas9)using bovine colostrum exosomes complexed with a polycationic matrix. Exosomes will be attached to milk-derived lactoferrin to target bronchial epithelial cells minimizing off-target effects. This novel and efficientdelivery technology will be developed using plasmid DNA containing all necessary components of this genomeediting tool targeting NFB a hallmark of inflammation and disease development in the lung and other organsusing established cell culture and animal models.


