# projects

application_id: 10472017
project_number: 5R01ES032189-03
project_title: Exposome and Precision Medicine in NAFLD
administering_ic: NIEHS
award_notice_date: 2022-07-29
opportunity_number: RFA-ES-18-007
application_type: 5
activity_code: R01
ic: ES
serial_number: 032189
program_official: SCHUG, THADDEUS
project_start_date: 2020-08-28
project_end_date: 2025-07-31
study_section: ZES1-JAB-D(VT)
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and it is often associated with obesityand metabolic disruption. NAFLD has a variable clinical course and only some patients develop nonalcoholicsteatohepatitis (NASH) and progressive fibrosis which increase mortality. An environmental contribution toNAFLD has previously been demonstrated by special exposure cohort studies and animal models. Howeverdata gaps prevent the clinical application of this emerging environmental health scientific knowledge to impactthe clinical care of NAFLD patients through a precision medicine approach. This project proposes a new high-impact virtual consortium (the NAFLD-ViCTER) to conduct synergistic multidisciplinary translationalexposomics research in adult NAFLD patients to address these knowledge gaps. It tests the hypothesis thatenvironmental exposures contribute to NAFLD severity natural history and response to therapy via hepatictranscriptional reprogramming resulting in metabolic disruption. The consortium is composed of investigatorswith synergistic expertise and resources from three centers including: Matt Cave (PI University of Louisville)Naga Chalasani (Co-I Indiana University) and Dean Jones (Co-I Emory University). The specific aims are: 1)To determine the environmental exposures associated with adult NAFLD severity in a cross-sectional study. Thisanalytical cross-sectional study with internal comparisons utilizes previously collected archived de-identifiedmaterials from adult patients with NAFLD characterized by vibration-controlled transient elastography andhistology. Untargeted high-resolution exposomics (HRE) will be performed in plasma. Sex differences will beinvestigated. Exposome-wide association studies (EWAS) vs. NAFLD severity biomarkers will be performed. 2)To elucidate the mechanisms by which environmental exposures increase the severity of NAFLD. This analyticalcross-sectional study utilizes materials from Aim 1 along with previously determined genotyping and hepaticmRNA-SEQ data. Untargeted high-resolution metabolomics (HRM) will be performed in plasma. MWAS andtranscriptome wide association studies (TWAS) will be performed vs. (i) NAFLD severity biomarkers and (ii) theexposures associated with NAFLD severity using data-driven integrative and pathway analyses. Gene:environment interactions will be examined. 3) To determine the environmental chemicals associated with NASHhistologic progression and response to therapy in a longitudinal study. Archived de-identified data and plasmaspecimens from a previously-published multi-center placebo-controlled clinical trial of obeticholic acid for adultNASH will be utilized. Plasma HRE/HRM will be performed and the exposures/metabolic signatures associatedwith NASH histologic progression and response to therapy will be determined using the placebo and obeticholicacid treated patients respectively. NAFLD-ViCTER will transform the clinical understanding of the environmentalcontribution to NAFLD. It will pave the way for precision medicine incorporating exposomics in NAFLD.

project_terms:
Acids;Address;Adult;Agonist;Animal Model;Archives;Biological Markers;Clinical;Clinical Research;Cohort Studies;Controlled Clinical Trials;Cross-Sectional Studies;Data;Disease Progression;Doctor of Philosophy;Double-Blind Method;Effectiveness;Environmental Exposure;Environmental Health;Environmental Risk Factor;Etiology;Fibrosis;Funding Mechanisms;Genes;Genotype;Hepatic;Hepatology;Histologic;Histology;Human;Indiana;Institution;Knowledge;Liver diseases;Longitudinal Studies;Mass Spectrum Analysis;Measurement;Metabolic;National Institute of Environmental Health Sciences;Natural History;Obesity;Participant;Pathogenesis;Pathway Analysis;Patients;Pilot Projects;Placebo Control;Placebos;Plasma;Publishing;Research;Research Personnel;Research Subjects;Resolution;Resources;Sampling;Severities;Severity of illness;Sex Differences;Specimen;Steatohepatitis;Strategic Planning;Study models;Testing;Therapeutic;Treatment outcome;Universities;attenuation;authority;clinical application;clinical care;clinical decision-making;cohort;data de-identification;elastography;environmental chemical;gene environment interaction;insight;liver stiffness;mRNA sequencing;metabolome;metabolomics;mortality;multidisciplinary;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;precision medicine;prevent;transcriptional reprogramming;transcriptome;treatment response;vibration;virtual

public_health_relevance:
This project proposes a new high-impact virtual consortium to conduct synergistic multidisciplinary translationalexposome research in nonalcoholic fatty liver disease (NAFLD). It will transform the scientific understanding ofthe environmental contribution to NAFLD thereby paving the way for a new precision medicine approach topatients with this liver disease.


application_id: 10471942
project_number: 5UH3CA233282-05
project_title: (ACCSIS) Accelerating Colorectal Cancer Screening through Implementation Science in Appalachia
administering_ic: NCI
award_notice_date: 2022-08-16
opportunity_number: RFA-CA-17-038
application_type: 5
activity_code: UH3
ic: CA
serial_number: 233282
program_official: GRIMES, GENEVIEVE M
project_start_date: 2018-09-19
project_end_date: 2025-03-31
study_section: Special Emphasis Panel[ZRG1-AARR-N(52)R]
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: PASKETT, ELECTRA D.
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:
Modified Project Summary/Abstract SectionThis multi-site project aims to increase screening and follow-up for colorectal cancer (CRC) in central Appalachia a medically underserved region recognized as one of three distinct hotspots for CRC mortality. Specifically the Appalachian Regional Commission classifies 32 eastern Ohio (OH) counties and the 54 counties in eastern Kentucky (KY) as north central and central Appalachia respectively. CRC incidence and mortality rates in the area are among the highest in the nation and neither state meets the national target of 80% of eligible residents screened for CRC. There have been few randomized intervention trials addressing multiple levels of influence on CRC screening behaviors and outcomes in this region. To address this gap investigators at the University of Kentucky and The Ohio State University will build on a 12-year collaborative history strong relationships with Appalachian communities and health clinics and extensive experience with community-based cancer prevention and control intervention research to develop implement and evaluate a multilevel intervention (MLI)  adapted from evidence-based interventions that include components targeting clinics and providers (in-reach) and the community (outreach)  to increase CRC screening follow-up and referral-to-care among patients age 50-74 in 12 counties in Appalachian KY and OH. The overall goals of this project are to contribute to the evidence-base for a MLI that increases rates of CRC screening follow-up and referral-to-care particularly in rural medically underserved populations and help showcase best practices for how MLIs can be scaled-up to reduce the burden of CRC in the U.S. For the Planning-Exploratory Phase (UG3) in Year 1 our specific aims are to: 1) Pilot test measure and refine a MLI to increase rates of CRC screening follow-up and referral-to-care in Appalachian OH and Appalachian KY; and 2) Provide evidence supporting transition to the Implementation Phase (UH3) [per NCI approval]. For the Implementation Phase (UH4) in Years 2-5 our specific aims are to: 1) Test the revised MLI in a group randomized trial delayed intervention to assess the impact of the MLI on increasing rates of CRC screening follow-up and referral-to-care among Appalachian KY and Appalachian OH populations; and 2) Assess dissemination and sustainability of the intervention. The project will be implemented in collaboration with community and clinical partners in 12 counties 6 in Ohio and 6 in Kentucky. Counties will be randomized to early or delayed intervention after baseline data collection. The main outcome will be CRC screening as defined by US Preventive Services Task Force guidelines and measured by clinic electronic health records and county- level behavioral assessments using random digit dialed telephone surveys similar to CDCs Behavioral Risk Factor Surveillance System. Our work will be accomplished through collaboration with the ACCSIS Coordinating Center other ACCSIS Research Projects ACCSIS Steering Committee and Workgroups NCI and community partners. If effective this MLI will be disseminated to our clinical and community partners throughout Appalachia.

project_terms:
Address;Administrator;Advisory Committees;Age;Appalachian Region;Area;Area Health Education Centers;Behavior assessment;Behavioral Risk Factor Surveillance System;Cancer Control;Caring;Centers for Disease Control and Prevention (U.S.);Characteristics;Clinic;Clinical;Collaborations;Colorectal Cancer;Communication;Communities;Community Health;Community Health Systems;Community Outreach;County;Data Collection;Digit structure;Disease;Electronic Health Record;Evidence based intervention;Fright;Geography;Goals;Guidelines;Health;Health Care Costs;Health Personnel;Incidence;Intervention;Intervention Studies;Intervention Trial;Kentucky;Knowledge;Life;Link;Localized Malignant Neoplasm;Low Income Population;Measures;National Cancer Institute;Neighborhood Health Center;Ohio;Outcome;Patients;Phase;Play;Population;Poverty;Preventive care;Preventive service;Provider;Public Health;Randomized;Recording of previous events;Research;Research Personnel;Research Project Grants;Role;Rural;Rural Appalachia;Rural Community;Savings;Site;Source;Surveys;System;Telephone;Testing;Trust;Underserved Population;United States;Universities;Work;base;behavioral outcome;cancer education;cancer health disparity;cancer prevention;colorectal cancer screening;community clinic;community organizations;community-level factor;effective intervention;evidence base;experience;follow-up;health care availability;health care delivery;implementation science;improved;interest;medically underserved;medically underserved population;mortality;pilot test;randomized trial;safety net;scale up;screening;underserved area;uptake


application_id: 10471895
project_number: 5R00CA225633-05
administering_ic: NCI
award_notice_date: 2022-08-15
opportunity_number: PA-18-398
application_type: 5
activity_code: R00
ic: CA
serial_number: 225633
program_official: AMIN, ANOWARUL
project_start_date: 2020-09-11
project_end_date: 2023-08-31
study_section: NSS
contact_pi_person_id: 14359954
contact_pi: GUO, HOUFU
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
budget_start_date: 2022-09-01
project_title:
Determining structural features of a collagen lysyl hydroxylase that promotes lung cancer metastasis

project_abstract:
Project Summary/Abstract:Candidate: Dr. Guo has received broad training in biochemistry and structural biology. He is a postdoctoralfellow at MD Anderson Cancer Center seeking to understand how collagen lysyl hydroxylase (LH) structuralfeatures regulate lung cancer metastasis. Dr. Guo is a highly productive investigator with 18 peer-reviewedpapers (6 of which as first or co-first author). As recognition of his achievements he received numerousawards during his doctoral and postdoctoral training.Career Development/Training: Dr. Guo's mentors at MD Anderson include Dr. Jonathan Kurie a physician-scientist with expertise in lung cancer biology and mouse modeling of human lung cancer and Dr. John Tainera renowned protein crystallographer studying macromolecular assemblies to inform drug design. AdditionallyDr. Guo will receive training from Dr. Mitsuo Yamauchi (UNC-Chapel Hill) a collagen biochemist who wasamong the first to elucidate how collagens are modified by LHs. These investigators have designed a trainingprogram centered on their key scientific disciplines that will strengthen Dr. Guo's abilities in their respectivefields and provide the skills needed for a smooth transition to independence.Research: Our group has shown that high expression of LH2 drives lung cancer metastasis and induces acollagen cross-link switch in tumor stroma. LH2 is a therapeutic target of interest but selective LH inhibitorsare not available a deficiency due in part to a lack of structural insight into LH2. The objective of my proposalis to elucidate LH2 structural features that promote lung cancer metastasis. In my preliminary results Idescribe new methods to produce human LH2 protein and assay its activity and the structure of the catalyticdomain of a viral LH homologue which revealed a homodimer stabilized by Fe+2-binding. I found that the twoactive sites flank a deep surface cleft on the dimer interface suggesting that dimerization creates a collagen-binding site and that basic residues adjacent to the active site are positioned to form salt bridges withtelopeptidyl acidic residues on collagen. From these findings I hypothesize that LH2 has telopeptidyl-LHactivity owing to unique features that allow it to form Fe2+-stabilized dimeric structures that interact withtelopeptidyl lysines on collagen. I will test this hypothesis by determining how LH dimer assemblies arestabilized by Fe2+-binding and interact with telopeptidyl lysine residues to regulate collagen cross-link formationand lung tumorigenesis.In sum my proposal will address the clinical problem of lung cancer metastasis. The novelty rests inpreliminary results that provide the first structural insights into a collagen LH hypotheses that challenge currentparadigms and technologies that facilitate quantification of LH enzymatic activity and evaluation of candidatemetastasis drivers.

project_terms:
2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine;Acanthamoeba;Achievement;Active Sites;Address;Aldehydes;Alleles;Arginine;Aspartate;Award;Binding;Binding Sites;Biochemical;Biochemistry;Biological Assay;Biology;C-terminal;Cancer Biology;Cancer Center;Cartilage;Catalytic Domain;Charge;Clinical;Collagen;Complex;Crystallization;Crystallography;Development;Dimerization;Discipline;Disease;Drug Design;Enzymes;Epithelial;Epithelial Cells;Evaluation;Family member;Foundations;Future;Gelatinase B;Glutamates;Growth;Homologous Gene;Human;Hydrophobicity;Hydroxylysine;KRAS2 gene;Laboratories;Leucine;Lung;Lung Adenocarcinoma;Lung Neoplasms;Lysine;Malignant neoplasm of lung;Mentors;Metastatic Neoplasm to the Lung;Methods;Mus;Mutation;N-terminal;Neoplasm Metastasis;Paper;Peer Review;Physicians;Positioning Attribute;Postdoctoral Fellow;Proline;Proteins;Reporting;Research;Research Personnel;Rest;Scientist;Sodium Chloride;Structure;Sum;Surface;Technology;Testing;Training;Training Programs;Tumor Tissue;Tumor-infiltrating immune cells;Tyrosine;Viral;antagonist;bone;career development;clinical application;crosslink;design;dimer;human model;inhibitor;insight;interest;lung tumorigenesis;macromolecular assembly;malignant breast neoplasm;mouse model;mutant;novel;post-doctoral training;prognostic value;protein structure;sarcoma;skills;structural biology;therapeutic target;tumor;tumor growth;tumorigenesis

public_health_relevance:
Project NarrativeBuilding on evidence from my mentors laboratory that the collagen modifying enzyme lysyl hydroxylase 2(LH2) induces a collagen cross-link switch in tumor stroma and thereby drives lung adenocarcinomametastasis I have generated a crystal structure of an informative viral homologue of LH2. The structuralfeatures of that enzyme are the basis for my hypothesis that LH2 has a novel dimerization interface and basicresidues adjacent to the active site that confer its unique collagen telopeptidyl LH activity. Testing thishypothesis will inform LH2 biology and may have broad clinical applicability because LH has been implicated inthe metastatic activity of multiple tumor types and the development of fibrotic diseases.


application_id: 10471419
project_number: 5R01NS102920-04
project_title: Transformation of Paraplegic Paralysis to Overground Stepping in Humans
administering_ic: NINDS
award_notice_date: 2022-08-18
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 102920
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2019-09-30
project_end_date: 2024-08-31
study_section: Bioengineering of Neuroscience, Vision and Low Vision Technologies Study Section[BNVT]
contact_pi_person_id: 10737162
contact_pi: GERASIMENKO, YURY
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:
Project SummaryIt is becoming increasingly evident that the spinal circuitries below a paralyzing injury have a functional potentialthat far exceeds what has been thought to be possible. From recent studies in mice and rats with motor completeparalysis we know that the lumbosacral spinal cord can be neuromodulated electrically (eEmc) andpharmacologically (fEmc) to enable motor control including full weight-bearing stepping. The main goal of theproject is the development of noninvasive multiple neuromodulatory strategies to facilitate full weight bearingoverground stepping in paralyzed subjects. Recently we demonstrated that four chronic completely paralyzedindividuals regained the ability to stand independently and the ability to voluntarily flex the hip knee and anklewhen being stimulated epidurally. We propose to accomplish similar outcomes using a novel noninvasivemulti-site spinal cord stimulation strategy in concert with pharmacological modulation with stand and steptraining to neuromodulate the lumbosacral circuitry so that completely paralyzed individuals can regain somelocomotor function as well as voluntary movements. We propose to develop these strategies further bycombining these interventions with an exoskeleton technology so that individuals with complete paralysiscan regain significant levels of community mobility. We will determine the effectiveness of noninvasive spinalstimulation and administration of buspirone (a monoaminergic agonist) treatment for facilitating of locomotoractivity in the gravity-neutral apparatus body weight supported stepping on a treadmill and stepping in the EKSOrobotic device to achieve full weight bearing stepping in paralyzed subjects in rolling walker. It is anticipated thatthe early stages of development of this technology could be available within the clinic to improve motor functionwithin a matter of a few years. These interventions have the potential to improve health and can impact thequality of life and in many cases can likely to lead to reduced health costs and a lower burden not only to theparalyzed individuals but also to their families and caregivers.

project_terms:
Agonist;Ankle;Awareness;Body Weight;Buspirone;Chronic;Clinic;Communities;Cutaneous;Development;Devices;Diagnosis;Electrodes;Family Caregiver;Force of Gravity;Generations;Goals;Health;Health Care Costs;Hip region structure;Human;Individual;Injury;Intervention;Knee;Lead;Lesion;Locomotion;Lower Extremity;Mediating;Motion;Motor;Motor Activity;Movement;Mus;Musculoskeletal Equilibrium;Neurostimulation procedures of spinal cord tissue;Outcome;Painless;Paralysed;Paraplegia;Performance;Pharmacology;Probability;Property;Quality of life;Rattus;Recovery;Recovery of Function;Sensory;Series;Site;Speed;Spinal;Spinal Cord;Spinal Injuries;Spinal cord injury;Spinal cord injury patients;Step training;Technology;Training;Volition;Walkers;Weight-Bearing state;connectome;cost;effectiveness evaluation;exoskeleton;exoskeleton device;experience;experimental study;improved;insight;limb movement;motor control;motor function improvement;motor function recovery;neuroregulation;novel;relative effectiveness;robot assistance;robotic device;technology development;tool;treadmill

public_health_relevance:
Project NarrativeWe have demonstrated that the human lumbosacral spinal cord can be neuromodulated with epiduralstimulation to enable recovery of standing and volitional control of the lower limbs after complete motorparalysis. We now propose to develop several novel noninvasive and complementary neuromodulatorytechnologies using exoskeleton device to recovery of motor functions including overground weightbearingmobility and their volitional control of movement after severe (motor complete and incomplete paralysis).


application_id: 10471252
project_number: 5F30EY031545-03
project_title: Ocular complications of CHARGE Syndrome: The role of Sox11
administering_ic: NEI
award_notice_date: 2022-09-13
opportunity_number: PA-19-192
application_type: 5
activity_code: F30
ic: EY
serial_number: 031545
program_official: AGARWAL, NEERAJ
project_start_date: 2020-09-01
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1-F03A-N(20)L]
contact_pi_person_id: 15716225
contact_pi: KRUEGER, LAURA
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Disruptions in eye development are associated with structural birth defects such as microphthalmiaanophthalmia and coloboma (collectively referred to as MAC) and are a significant cause of pediatricblindness. Ocular abnormalities often occur alongside those of brain and craniofacial defects highlighting thesignificant signaling interactions between the developing structures of the head; indeed MAC is a commonfeature of systemic congenital malformation syndromes. One example is CHARGE syndrome a genetic neuralcristopathy characterized by coloboma heart defects choanal atresia growth retardation genitalabnormalities and ear abnormalities. Mutations in chromodomain helicase binding protein 7 (CHD7) anddefects in neural crest cell development and migration have been implicated in the pathogenesis of CHARGEsyndrome however the mechanisms underlying the ocular birth defects observed in CHARGE patients havenot been identified. Our laboratory studies the development of the vertebrate visual system using zebrafish (Danio rerio).Previous work from our lab has shown that knockdown of Sox11 a member of the SoxC family of transcriptionfactors in zebrafish results in microphthalmia coloboma brain trunk and heart defects all phenotypesobserved in CHARGE syndrome. Furthermore we found that Sox11 is required for the expression of Bonemorphogenic proteins (BMPs) during ocular development. In humans a duplication of Sox11 has beenidentified in a patient clinically diagnosed with CHARGE syndrome and CHD7 has been shown to directlyinteract with Sox11 and Sox4 in neural stem cells. Based on these data my central hypothesis is that the lossof Sox 11 expression leads to disruptions in neural crest cell dynamics as well as alterations in BMP signalingduring development. This hypothesis will be tested in the following aims 1) Determine the role that Sox11 andChd7 play in the specification proliferation survival and migration of cranial neural crest cells and 2)Determine whether Sox11 and Chd7 deficiency alters cranial BMP signaling. This proposal will employinnovative and cutting edge live imaging techniques as well as advanced biochemical and molecular biologyapproaches and will leverage the power of the zebrafish model to tackle an important problem in ocularpediatric genetics. Successful completion of this project will define the role of Sox11 in the pathogenesis of the oculardefects such as those observed in CHARGE syndrome and make progress towards improving theidentification management and treatment of congenital eye malformations. Additionally this predoctoralproposal allows the candidate to develop unique technical critical thinking and effective communication skillscrucial to a physician-scientist specializing in ophthalmic pediatric genetics.!

project_terms:
Anophthalmos;Binding Proteins;Biochemical;Biological Models;Blindness;Brain;CHARGE syndrome;CHD7 gene;Cephalic;Childhood;Choanal Atresia;Chromatin;Chromosomal Duplication;Code;Coloboma;Communication;Communication Research;Confocal Microscopy;Congenital Abnormality;Craniofacial Abnormalities;Critical Thinking;DNA Binding Domain;Data;Defect;Development;Disease;Ear;Eye;Eye Development;Eye diseases;Family;Fetal Development;Fluorescence-Activated Cell Sorting;Future;Genes;Genetic;Genetic Research;Genital;Genitalia;Goals;Growth;Head;Heart Abnormalities;Human;Image;Imaging Techniques;Immunoprecipitation;Inherited;Label;Laboratories;Laboratory Study;Light;Microphthalmos;Microscopy;Modeling;Molecular Biology;Morphogenesis;Mutation;Names;Neural Crest Cell;Pathogenesis;Pathway interactions;Patients;Phenotype;Physicians;Play;Process;Proteins;Regulation;Reporter;Research;Research Ethics;Role;SOX11 gene;SOX4 gene;Scientist;Signal Pathway;Signal Transduction;Signaling Protein;Structural Congenital Anomalies;Structure;Syndrome;Testing;Training;Transcription Coactivator;Transgenic Organisms;Visual impairment;Visual system structure;Work;Zebrafish;base;bone morphogenic protein;clinical diagnosis;clinical phenotype;developmental genetics;eye formation;helicase;improved;innovation;knock-down;malformation;member;migration;mutant;nerve stem cell;novel therapeutics;pre-doctoral;preservation;relating to nervous system;sex;sight restoration;skills;sry Genes;transcription factor;vision development

public_health_relevance:
Microphthalmia anophthalmia and coloboma (collectively referred to as MAC) are congenital ocular disordersthat are a significant cause of visual impairment. The proposed research will define the role of protein codinggene Sox11 in development of the eye and will determine if defects in Sox11 cause inherited eye diseases.Findings from this project will further our understanding of eye formation during fetal development and provideavenues for future treatments of inherited eye diseases.!


application_id: 10470923
project_number: 5U01DA051377-02
project_title: Development of Agents for Synthetic Opioid Overdose
administering_ic: NIDA
award_notice_date: 2022-07-28
opportunity_number: PAR-19-039
application_type: 5
activity_code: U01
ic: DA
serial_number: 051377
program_official: VEMURI, KIRAN R V
project_start_date: 2021-09-01
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZRG1-MDCN-B(50)R]
contact_pi_person_id: 7842243
contact_pi: PRISINZANO, THOMAS EDWARD
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:
Fentanyl is a synthetic opioid that is approximately 100 times stronger than morphine and is used for thetreatment of pain as well as an adjuvant for anesthesia. It is also considered an incapacitating agent a chemicalthat produces a disabling condition that persists for hours to days after exposure has occurred such as in anunexpected chemical attack. As an opioid fentanyl depresses the central nervous system and respiratoryfunctions and can be lethal by respiratory depression. Due to its high potency ingestion of just a few milligramsof fentanyl or other synthetic opioid can be deadly to an opioid nave individual. Furthermore first responders ata chemical attack site who come in contact with free base fentanyl analogues are at significant risk for life-threatening toxicities.Currently there are three opioid antagonists available on the market that have potential to reverse the effects offentanyl namely naloxone naltrexone and nalmefene. The most commonly used is naloxone which is approvedfor administration by a variety of routes including intravenous intramuscular subcutaneous and intranasal.However recent reports suggest that higher doses or repeated dosing of naloxone (due to recurrence ofrespiratory depression) may be required to reverse fentanyl-induced respiratory depression. This highlights thepressing need for a more potent and longer acting opioid antagonist to combat fentanyl-induced respiratorydepression.Previous studies and our own preliminary results indicate that structural modification of naltrexone can increaseits potency and duration of action. Our central hypothesis is that structural modification of naltrexone will lead tonovel opioid receptor antagonists with the potential to treat overdose by fentanyl and related analogues inindividuals at high risk of exposure. The specific aims of this proposal are (1) identify opioid antagonists withenhanced pharmacodynamic and pharmacokinetic properties; (2) determine and optimize the in vivo activity ofopioid antagonists in mice and for their effectiveness in reversing the effects of fentanyl in preclinical models ofantinociception iteratively with Aim 1; and (3) determine and optimize the in vivo activity of opioid antagonists inrats and for their effectiveness in reversing the effects of fentanyl and selected analogues in preclinical modelsof opioid-induced locomotor and respiratory depression iteratively with Aim 1. The design synthesis evaluationof these molecules will have a broad impact on development of new pharmacologic probes that are designed tointeract with high potency and long duration at opioid receptors. This information will facilitate the identificationof safe and effective therapeutics that would rescue individuals after an acute and unexpected exposure tofentanyl and related analogues.

project_terms:
Acute;Adjuvant;Anesthesia procedures;Antidotes;Centers for Disease Control and Prevention (U.S.);Cessation of life;Chemical Warfare;Chemicals;Chemistry;Country;Development;Dose;Effectiveness;Evaluation;Event;Exposure to;FDA approved;Fentanyl;Gases;Generations;Goals;Half-Life;Hospitalization;Hostage;Hour;In Vitro;Individual;Ingestion;Inhalation Anesthetics;Intramuscular;Intravenous;Laboratories;Lead;Life;Metabolic;Military Personnel;Modification;Morphine;Moscow;Mus;Naloxone;Naltrexone;Neuraxis;Neuropharmacology;Opioid;Opioid Antagonist;Opioid Receptor;Pain management;Persons;Pharmaceutical Preparations;Pharmacology;Pre-Clinical Model;Property;Rapid screening;Rattus;Recurrence;Reporting;Research;Research Personnel;Respiratory physiology;Risk;Route;Safety;Series;Serum;Site;Survivors;Testing;Therapeutic;Time;Toxic effect;Ventilatory Depression;Work;aerosolized;analog;antagonist;base;carfentanil;combat;design;experience;experimental study;fentanyl overdose;first responder;follow-up;high risk;improved;in vivo;incapacitating agents;mass casualty;milligram;mouse model;nalmefene;noradrenergic;novel;opioid overdose;overdose death;pharmacokinetics and pharmacodynamics;subcutaneous;synthetic opioid;therapeutically effective;water solubility

public_health_relevance:
Project NarrativeOur central hypothesis is that structural modification of naltrexone will lead to novel opioid receptor antagonistswith the potential to treat overdose by fentanyl and related analogues in individuals at high risk of exposure. Thedesign synthesis evaluation of these molecules will have a broad impact on development of new pharmacologicprobes that are designed to interact with high potency and long duration at opioid receptors. This information willfacilitate the identification of safe and effective therapeutics that would rescue individuals after an acute andunexpected exposure to fentanyl and related analogues.


application_id: 10470910
project_number: 5R01DK130478-02
administering_ic: NIDDK
award_notice_date: 2022-07-05
opportunity_number: RFA-DK-20-021
application_type: 5
activity_code: R01
ic: DK
serial_number: 130478
program_official: ROY, CINDY
project_start_date: 2021-09-01
project_end_date: 2023-06-30
study_section: ZDK1-GRB-G(M3)S
contact_pi_person_id: 9839693
contact_pi: LIANG, YING
other_pis: HUANG, GANG
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-07-01
project_title:
Mechanism of the short- and long-term effects of COVID-19-induced Alarmins on hematopoietic stem and progenitor cells.

project_abstract:
ABSTRACTThe long-term goal of this proposal is to understand the long-term sequalae of acute COVID-19 infection onhematopoietic and immune damages and to identify the key pathways and mechanism by which COVID-19-associated cytokine dysregulation alters HSC function and differentiation. SARS-CoV-2 infection causes localand systemic damages due to dysregulated immune response and cytokine production. Its long-term negativeeffects on body tissue and organ remain largely unknown. Our published work showed that SARS-CoV-2infection dramatically increased neutrophil production and neutrophil-associated S100A8/A9 (Alarmin) release.Persistent high level of S100A8/A9 is a negative prognostic biomarker for the disease severity and mortality.Although the function of S100A8/A9 on mature blood cells have been studied its functional effect onhematopoietic stem cells (HSCs) are unknown. Our preliminary data show that S100A8/A9 causes loss ofquiescence and differentiation of HSC toward myeloid progenitors at the expense of HSCs. Toll-like receptor 4(TLR4) the endogenous receptor of S100A8/A9 is highly expressed in HSCs and S100A8/A9 activates itscanonical downstream MAPK (mitogen-activated protein kinase) pathway. Very interestingly S100A8/A9 causesdownregulation of epigenetic regulator Setd2 leading to the c-Myc upregulation in HSCs. c-Myc is a keydownstream target of both MAPK and Setd2 pathways. MAPK Setd2 and c-Myc are important regulators of HSCproliferation and myeloid differentiation. We hypothesize that SARS-CoV-2-induced S100A8/A9 activates TLR4signaling which converts to c-Myc in HSCs resulting in loss of quiescence and self-renewal myeloiddifferentiation skewing and long-term impairment of hematopoiesis. Since HSC is responsible for the life-longproduction of blood cells including all types of immune cells any functional damages of HSCs would later onhave profoundly negative effects on the immune response. Therefore understanding the cellular and molecularmechanism by which S100A8/A9 regulates HSCs and hematopoiesis would contribute a new evidence base toaccelerate advances in diagnostics therapeutics clinical management of COVID-19 patients in acute infectionand recovery phases.1

project_terms:
2019-nCoV;Acute;Apoptosis;Blood Cells;COVID-19;COVID-19 cytokine storm;COVID-19 pandemic;COVID-19 patient;Cell Differentiation process;Cells;Chronic;Clinical;Clinical Management;Data;Diagnostic;Disease;Disease Progression;Dose;Down-Regulation;Epigenetic Process;Equilibrium;Fluorouracil;Functional disorder;Generations;Goals;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Human;Immune;Immune response;Immunosuppression;Impairment;In Vitro;Infection;Inflammation;Knockout Mice;Knowledge;Life;Lipopolysaccharides;MAP Kinase Gene;Mediating;Mitogen-Activated Protein Kinases;Modeling;Molecular;Mus;Myelogenous;Myeloid Cells;Myelosuppression;Organ;Outcome;Pathway interactions;Patients;Pharmacologic Substance;Phase;Production;Prognostic Marker;Proteins;Publishing;Recombinants;Recovery;Regulation;Role;S100A8 gene;SARS-CoV-2 infection;Severities;Severity of illness;Signal Transduction;Stress;TLR4 gene;Therapeutic;Tissues;Transgenic Mice;Up-Regulation;Variant;Work;acute infection;adverse outcome;antagonist;body system;c-myc Genes;cytokine;evidence base;exhaustion;functional disability;hematopoietic stem cell differentiation;hematopoietic stem cell quiescence;human model;long term consequences of COVID-19;long-term sequelae;loss of function;mortality;mouse model;neutrophil;progenitor;receptor;response;self-renewal;severe COVID-19;stem cell function;stem cell proliferation

public_health_relevance:
PROJECT NARRATIVEWe hypothesize that SARS-CoV-2-induced S100A8/A9 activates TLR4 signaling which alters hematopoieticstem cell (HSC) function and myeloid differentiation. Dissecting the detail mechanisms and pathways responsiblefor adverse and long-term outcomes of SARS-CoV-2 infection will help the diagnostics therapeutics and clinicalmanagement of COVID-19 patients in acute infection and recovery phases.


application_id: 10470124
project_number: 5P30CA177558-10
project_title: Protocol Review and Monitoring System
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5640
contact_pi_person_id: 1926108
contact_pi: ANTHONY, LOWELL B.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The Markey Cancer Center's (MCC) clinical research mission is to conduct the highest quality research intothe causes and treatment of cancer. In accordance with the CCSG guidelines for National Cancer Institute-designated Cancer Centers MCC has established appropriate mechanisms for assuring rigorous scientificscrutiny and oversight of cancer-relevant clinical trials through the Protocol Review and Monitoring System(PRMS). The MCC Protocol Review and Monitoring Committee (PRMC) is responsible for independent peerreview of scientific merit feasibility and prioritization of new protocols and monitoring all trials for scientificprogress and accrual (including termination of studies not meeting MCC scientific goals). Protocols are submitted to the PRMC following review by disease groups called Clinical Care andResearch Teams (CCARTs) for fit with the portfolio and endorsement by investigators and review by theFeasibility Review Committee (FRC) for operational feasibility. The goal of prior review and input by theCCARTs and FRC is to enrich the scientific quality and prioritization of protocols submitted to the PRMC. ThePRMC ensures that all interventional cancer research studies involving human subjects conducted under theauspices of the MCC: 1) serve and support the mission of MCC including prioritization of research trialsrelevant to catchment area needs; 2) have high scientific merit; 3) are statistically sound and appropriatelydesigned; 4) are feasible for timely completion based on the available patient population and in the context ofthe current trial portfolio; 5) are prioritized based on MCC criteria and in light of actively accruing trials; and 6)are inclusive of underserved populations (e.g. women minorities children). After activation protocols aremonitored by the PRMC for ongoing scientific progress and accrual per MCC policy. The PRMC has ultimateauthority to suspend or close protocols for low accrual or significant change in scientific merit and theresponsibility for continuous monitoring of its efficiency and quality in the timely review of trials. During this funding period the PRMS has undergone significant improvement in procedures and policyupdates. Specifically the PRMS enhanced scientific rigor of its review process by increasing senior reviewersstandardizing review criteria and scoring and adopting more stringent accrual monitoring practices The PRMShas a new Chair and Co-chair free from conflicts of interest with the other clinical research bodies and thePRMC members now comprises mainly senior faculty and a greater diversity of scientific disciplines. From2013 to 2016 the PRMC reviewed and/or prioritized 284 new protocols of which 264 (93%) were approvedand 20 (7%) were disapproved; and reviewed 279 active protocols for scientific progress closing 37 protocolsdue to low accrual or a change in scientific merit. As the MCC grows the PRMS will continue rigorous scientificreview of protocols appropriate prioritization adherence to MCC's mission and inclusion of trials with ascientific focus relevant to the catchment area of Kentucky.

project_terms:
Adherence;Adopted;Basic Science;Biometry;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Intervention;Cancer Research Project;Catchment Area;Center for Translational Science Activities;Charge;Clinical Cancer Center;Clinical Oncology;Clinical Protocols;Clinical Research;Clinical Sciences;Clinical Trials;Committee Members;Conduct Clinical Trials;Conflict of Interest;Data;Development;Discipline;Disease;Education;Enrollment;Ensure;Faculty;Funding;Goals;Growth and Development function;Guidelines;Individual;Industry;Institution;Institutional Review Boards;Intervention;Intervention Studies;Kentucky;Laboratory Research;Light;Malignant Neoplasms;Mission;Modification;Monitor;National Cancer Institute;Nature;Outcome;Pathology;Patients;Peer Review;Performance;Pharmacology;Policies;Procedures;Process;Protocols documentation;Radiology Specialty;Research;Research Personnel;Resources;Review Committee;Role;Safety;Scientific Advances and Accomplishments;Standardization;System;Time;Underserved Population;Universities;Update;Woman;Work;authority;base;cancer clinical trial;cancer prevention;cancer research center director;cancer therapy;clinical care;clinical translation;clinically relevant;community engagement;design;human subject;innovation;interest;investigator-initiated trial;member;mid-career faculty;minority children;mortality;patient population;professor;protocol development;research study;senior faculty;sound


application_id: 10470122
project_number: 5P30CA177558-10
project_title: Clinical Protocol and Data Management
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5639
contact_pi_person_id: 6772940
contact_pi: ARNOLD, SUSANNE M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Part I: Clinical Protocol and Data Management (CPDM). CPDM facilitates all clinical cancer research atthe Markey Cancer Center (MCC) and is responsible for an increase to over 1000 interventional accruals peryear and 9357 interventional accruals over the reporting period. The CPDM has 3 major components: theClinical Research Office (CRO) the Quality Assurance (QA) Office and the MCC Data and Safety MonitoringPlan (DSMP). Oversight is provided by the Associate Director for Clinical Translation Susanne Arnold MD(DT) who supervises the CRO Medical Director (Jonathan Feddock MD [DT]) and the Precision MedicineCenter (PMC) Director (Jill Kolesar PharmD MS [DT]) assisted by the Associate Director for Administration(David M. Gosky MA MBA). The CRO consists of 4 operational units: Finance Regulatory Clinical andPrecision Medicine providing investigators with centralized expertise and support for the implementationcoordination and execution of cancer clinical trials. The Cancer Research Informatics Shared Resource Facilitysupports the CRO through centralized clinical trials management and reporting to the National Cancer Institute(NCI). The CRO staff focuses on MCC's mission vision and values to support investigators in the highestquality clinical cancer research with adherence to all federal and state guidelines. Part II: Data and Safety Monitoring. All cancer clinical trials conducted by MCC investigators or the MCCResearch Network include oversight of data and safety monitoring. The MCC DSMP approved by the NCI in2013 and revised annually provides guidance for the conduct of all cancer clinical trials in accordance with theNCI CCSG requirements. The Data and Safety Monitoring Committee (DSMC) assures patient safety andprotocol compliance by MCC investigators and staff and has monitored 1654 trials during the reporting period.The QA Office and the Audit Committee perform monitoring and auditing of trials including 107 trials over thereporting period as well as assisting in 9 successful external audits. Part III: Inclusion of Women and Minorities in Clinical Research. MCC leadership investigators andstaff are committed to the inclusion of women all minorities and our National Institutes of Health-designatedspecial population of Central Appalachia in cancer clinical trials. While many trials have genomic histologic orstage-specific entry criteria every effort is made toward inclusion with a focus on clinical trials with highminority incidence such as breast cancer (African-American) hepatocellular carcinoma (Hispanic/LatinoAfrican-American) and prostate cancer (African-American). Females represent over 60% of accruals totreatment interventions and 1892 women were accrued to interventional protocols in 2016. Part IV: Inclusion of Children in Clinical Research. UK's Pediatric Oncology and Hematology Divisionhas a broad portfolio of trials via the Children's Oncology Group and investigator-initiated trials spanningcommon (leukemia/lymphoma neuroblastoma Wilms tumor osteosarcoma) to rare pediatric cancers.

project_terms:
Adherence;African American;Appalachian Region;Biometry;Cancer Center;Cancer Center Support Grant;Catchment Area;Child;Clinical;Clinical Cancer Center;Clinical Data;Clinical Management;Clinical Medicine;Clinical Protocols;Clinical Research;Clinical Research Associate;Clinical Trials;Conduct Clinical Trials;Data;Data Collection;Data Management Resources;Devices;Disease;Doctor of Pharmacy;Ensure;Ethnic Origin;Female;Funding Agency;Gender;Genomics;Goals;Guidelines;Hispanic;Histologic;Incidence;Institution;Institutional Review Boards;Intervention;Investigation;Investigational Drugs;Kentucky;Latino;Leadership;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of prostate;Minority;Mission;Monitor;NCI Center for Cancer Research;National Cancer Institute;National Clinical Trials Network;Nephroblastoma;Neuroblastoma;Nurses;Participant;Pediatric Hematology;Pediatric Oncology;Pediatric Oncology Group;Peer Review;Performance;Physician Executives;Primary carcinoma of the liver cells;Procedures;Protocol Compliance;Protocols documentation;Race;Reporting;Research;Research Activity;Research Personnel;Research Priority;Resource Allocation;Resource Sharing;Risk;Safety;Services;Special Population;Supervision;System;Toxic effect;Training;Translational Research;United States Food and Drug Administration;United States National Institutes of Health;Universities;Vision;Woman;anticancer research;base;cancer clinical trial;clinical care;clinical translation;data management;design;experience;improved;industry partner;informatics shared resource;investigator-initiated trial;leukemia/lymphoma;malignant breast neoplasm;minority children;operation;osteosarcoma;patient safety;precision medicine;protocol development;quality assurance;response;support tools;working group


application_id: 10470118
project_number: 5P30CA177558-10
project_title: Leadership Planning and Evaluation
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5638
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT B. Mark Evers MD serves as Director for the Markey Cancer Center (MCC). Dr. Evers is assisted bynationally recognized leaders in cancer research clinical care prevention and education including: SusanneM. Arnold MD (Associate Director for Clinical Translation); Kathleen OConnor PhD (Associate Director forCancer Education and Mentoring); Daret St. Clair PhD (Associate Director for Basic Research); ThomasTucker PhD MPH (Associate Director for Cancer Prevention and Control); Heidi Weiss PhD (AssociateDirector for Shared Resources); and David M. Gosky MA MBA (Associate Director for Administration). Thishighly experienced Senior Leadership team has worked together since 2009 to ensure consistency in theshared vision and goals of the MCC; foster synergistic and highly collaborative interactions among the basictranslational and clinical components of the MCC; effectively leverage all available resources at the Universityof Kentucky state and national levels; engage in clinical trials community outreach education and mentoring;and oversee all activities of the MCC. Continual planning and evaluation are key to the development andsustained excellence of the MCC and helps ensure its strong scientific trajectory. Planning and evaluationactivities are accomplished through the External and Internal Advisory Boards the Directors Council andcommittees that provide the Director and Senior Leadership ongoing guidance and support. The MCC ExternalAdvisory Board is the primary external mechanism that provides review and advice on the MCCs progress inbasic translational and community research as well as oversight on MCCs leadership and strategic direction.Internal planning and evaluation mechanisms include: the advice and support of MCCs Senior Leaders whoformally comprise the Directors Council; MCC Research Program Leaders and Shared Resource Facility(SRF) Directors; an Education and Mentoring Committee; and an Internal Advisory Board comprised of deanscenter directors and department chairs at the university. Dr. Evers and the Senior Leadership established thefirst strategic plan for the MCC in 2009 which served as an initial road map to guide the development ofscientific research programs the reorganization of SRFs required to facilitate and achieve the scientific goalsand strategic recruitments of basic and translational scientists who synergized and further strengthened theongoing research efforts. In 2012 to reflect the tremendous progress that occurred since Dr. Everss arrival anupdated plan redefined the strategic goals for the next 5 years based on the strong foundations that were inplace. In 2017 through an extensive review and vetting process Senior Leadership developed a new strategicplan around pillars of excellence in basic research cancer prevention and control clinical translationeducation and mentoring and community engagement and outreach. Strong foundations of institutionalsupport philanthropy SRFs strategic relations administration and planning and evaluation support the 2017-2022 Strategic Plan.

project_terms:
Address;Advisory Committees;Area;Basic Science;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Research Project;Catchment Area;Clinical;Clinical Research;Clinical Trials;Collaborations;Communities;Community Outreach;Consultations;Decision Making;Department chair;Development;Doctor of Philosophy;Education;Ensure;Evaluation;Faculty Recruitment;Feedback;Fostering;Foundations;Funding;Funding Mechanisms;Future;Goals;Grant;Growth;Infrastructure;Kentucky;Lead;Leadership;Maps;Medicine;Mentors;Mission;NCI Center for Cancer Research;National Cancer Institute;Outcome;Phase I/II Clinical Trial;Policies;Population Research;Precision Medicine Initiative;Prevention education;Process;Reporting;Research;Resource Sharing;Resources;Review Committee;Science;Strategic Planning;Training and Education;Translational Research;Translations;Universities;Update;Vision;Work;anticancer research;base;cancer education;cancer prevention;cancer research center director;career development;clinical care;clinical translation;college;community based participatory research;community engagement;early phase clinical trial;experience;inter-institutional;meetings;member;mentoring community;operation;precision medicine;programs;recruit;training opportunity;translational scientist


application_id: 10470117
project_number: 5P30CA177558-10
project_title: Developmental Funds
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5637
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT CCSG developmental funds are vital to furthering the strategic mission and vision of the Markey CancerCenter (MCC) and providing added value to MCC members. The MCC utilizes developmental funds leveragedwith institutional and philanthropic funds to support pilot grants emerging Shared Resource Facilities (SRFs)and strategic new faculty recruitments. Pilot grant funding from the CCSG supports collaborative andinterdisciplinary cancer research focusing on MCC priority areas; funded projects are carried out byinteractions between MCC members in our 4 Research Programs (Cancer Cell Biology and Signaling; CancerPrevention and Control; Drug Discovery Delivery and Translational Therapeutics; and Genomic InstabilityEpigenetics and Metabolism) and supported by our 5 existing SRFs (Biostatistics and Bioinformatics;Biospecimen Procurement and Translational Pathology; Cancer Research Informatics; Flow Cytometry andCell Sorting; and Redox Metabolism) and 2 developing SRFs (Behavioral and Community-Based Researchand Oncogenomics). Pilot funds stimulate high return on investment research that makes a significant impactin the fields of basic clinical population and translational cancer research. In the last funding period 19 pilotprojects were funded (using $475000 from the CCSG leveraged with $425000 from the institution) leading to11 subsequent external grants totaling $6583106 in total project costs a return of $13.86 per CCSG dollarinvested. In particular developmental funds have allowed both basic and clinician scientists to advance theirresearch projects including those involving clinical and health disparity issues pertinent to the MCC catchmentarea and successfully compete for extramural funding. CCSG developmental funds have also supported theadvancement of MCC basic science research from the bench to the bedside by providing funding for projectsthat are currently accruing patients in clinical trials. These developmental funds have enhanced MCC's growthand productivity by facilitating key faculty recruitments during the current funding period: namely in support ofthe addition of new faculty for molecular epidemiology and for precision medicine whose research and talentsclosely align with the MCC mission. In the upcoming funding period CCSG Developmental Funds will be usedto address 2 Specific Aims: 1) foster innovative and collaborative science through the funding of pilot grants inareas prioritized by the MCC Strategic Plan and reflecting the scientific aims of MCC's 4 Research Programs;and 2) support of 2 developing SRFs in alignment with our objective of providing enhanced services to MCCResearch Programs. To achieve these aims the MCC requests $200000 per year in Developmental Funds.Completion of these aims through the use of Developmental Funds will allow MCC to achieve several keyobjectives as outlined in the MCC Strategic Plan including advancement of precision medicine initiativesenhancing transdisciplinary collaborations in areas of metabolic reprogramming and tumor resistance anddevelopment of novel investigator-initiated clinical trials.

project_terms:
Address;Appalachian Region;Area;Award;Basic Science;Behavioral;Behavioral Research;Bioinformatics;Biometry;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Control Research Program;Cancer Research Project;Catchment Area;Cell Separation;Cellular biology;Clinic;Clinical;Clinical Trials;Communities;Community Outreach;Comprehensive Cancer Center;Development;Education;Epidemiologist;Epigenetic Process;Evaluation;Extramural Activities;Faculty;Faculty Recruitment;Feedback;Flow Cytometry;Fostering;Funding;Funding Agency;Genomic Instability;Genomics;Goals;Grant;Growth;Informatics;Institution;Investments;Kentucky;Malignant Neoplasms;Metabolic;Metabolism;Methodology;Mission;Molecular;Molecular Epidemiology;Morbidity - disease rate;NCI Center for Cancer Research;National Cancer Institute;Oxidation-Reduction;Participant;Pathology;Patient Care;Patients;Peer Review;Philanthropic Fund;Pilot Projects;Population;Positioning Attribute;Precision Medicine Initiative;Productivity;Publications;Reporting;Research;Research Personnel;Research Project Grants;Resistance development;Resource Sharing;Resources;Science;Scientist;Secure;Services;Signal Transduction;Strategic Planning;Talents;Technology;Therapeutic Human Experimentation;Universities;Vision;anticancer research;base;bench to bedside;cancer cell;cancer genomics;cancer prevention;community based research;community setting;cost;design;drug discovery;flexibility;health disparity;high risk;innovation;interdisciplinary collaboration;member;mortality;novel;precision medicine;programs;recruit;translational cancer research;translational therapeutics;tumor


application_id: 10470115
project_number: 5P30CA177558-10
project_title: Community Outreach and Engagement
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5636
contact_pi_person_id: 8310976
contact_pi: HULL, PAMELA CARMEN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT  The National Cancer Institute (NCI)-designated University of Kentucky (UK) Markey Cancer Center (MCC) defines its catchment area as the Commonwealth of Kentucky with a special focus on the underserved communities of Appalachian Kentucky. There is no greater need for a Comprehensive NCI Cancer Center than in Kentucky which is recognized for the highest overall cancer incidence and mortality rates in the United States significantly elevated rates of cancer risk factors such as tobacco use and obesity and severe socioeconomic disparities. The MCC has been at the forefront of combatting cancer and its related disparities in Kentucky for over 40 years through innovative cancer research clinical care and community outreach. Led by Dr. Robin Vanderpool (CP) Director of MCC Community Outreach and Engagement MCCs community outreach and engagement infrastructure includes: the MCC Network consisting of the MCC Research Network (MCCRN 6 community sites) and MCC Affiliate Network (MCCAN 18 community hospitals); the developing Behavioral and Community-Based Research Shared Resource Facility (BCBR SRF); the Kentucky Cancer Registry; multiple cancer center and state outreach programs; well-aligned MCC cancer research projects; UKs rurally placed health care professional education and community resources; and other vested local state national and international stakeholders. Utilizing this unique infrastructure and diverse network of partners as well as data- and context-driven approaches to working with communities MCC has an extensive portfolio of innovative and impactful projects focused on effective cancer control practices and health policy recommendations that have reached thousands of Kentucky residents and health care professionals. With continued CCSG funding the MCC is well positioned to use this remarkable and expanding infrastructure to impact cancer within and beyond Kentucky and respond to emerging public health issues. The MCCs overarching goal for community outreach and engagement is to accelerate science-to-practice translation across the cancer care continuum by leveraging and expanding its outreach and engagement infrastructure and network of partners within and beyond the Commonwealth of Kentucky. Specific Aims are: (1) to enhance the MCCs ability to define and characterize its catchment area using cancer surveillance data cancer registry and health insurance data linkages and locally derived population health assessment data; (2) to increase dissemination and implementation of evidence-based clinical practices and cancer control programming within and beyond MCCs catchment area; and (3) to enrich bidirectional relationships and structures for conducting community outreach and engagement within and beyond MCCs catchment area. In achieving these aims MCC is solidly positioned to enhance and expand its existing community outreach and engagement initiatives over the next 5-year CCSG funding period to further reduce Kentuckys significant cancer burden and improve quality of life among all Kentuckians.

project_terms:
Appalachian Region;Basic Science;Behavior;Behavioral Research;Belief;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Research Project;Catchment Area;Centers for Population Health;Clinical Research;Communities;Community Health Education;Community Healthcare;Community Hospitals;Community Outreach;Comprehensive Cancer Center;Continuity of Patient Care;Data;Data Linkages;Dissemination and Implementation;Education;Environmental Exposure;Faculty;Family;Fostering;Funding;Funding Mechanisms;General Population;Goals;Grant;Health;Health Insurance;Health Personnel;Health Policy;Health Professional;High Prevalence;Improve Access;Incidence;Infrastructure;International;Kentucky;Knowledge;Localized Malignant Neoplasm;Malignant Neoplasms;Methods;Mission;Molecular;NCI Center for Cancer Research;National Cancer Institute;Obesity;Patients;Pattern;Positioning Attribute;Professional Education;Public Health;Quality of life;Recording of previous events;Registries;Research;Research Personnel;Resource Sharing;Resources;Risk Factors;Robin bird;SEER Program;Science;Screening for cancer;Services;Site;Solid;Structure;Survival Analysis;Survivors;Tobacco use;Training;Translations;Underserved Population;United States;Universities;anticancer research;base;cancer care;cancer education;cancer health disparity;cancer risk;clinical care;clinical practice;community based participatory research;community based research;community center;community engagement;evidence base;genetic linkage analysis;health assessment;health communication;improved;innovation;low socioeconomic status;member;mortality;neoplasm registry;neoplasm resource;opioid abuse;outreach;outreach program;policy recommendation;population health;precision medicine;rural setting;socioeconomic disparity;surveillance data;tumor;underserved community


application_id: 10470113
project_number: 5P30CA177558-10
project_title: Genomic Instability Epigenetics and Metabolism Research Program
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5635
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The Genomic Instability Epigenetics and Metabolism (GEM) Research Program represents a restructuringand programmatic expansion of the former Redox Injury and Repair (RR) Research Program to reflectburgeoning research strengths of participating members with expertise in highly complementary researchthrusts. GEM research efforts are central to the overall Markey Cancer Center (MCC) mission to decrease theburden of cancer in Kentucky surrounding communities and the nation. GEM investigators determine geneticepigenetic and metabolic mechanisms that promote cancer development fuel tumor progression andcontribute to therapeutic resistance. The overall goal of this program is to gain a comprehensive understandingof the basic mechanisms of these processes to facilitate development of novel and rational approaches forcancer prevention and therapy. To achieve this goal GEM has established 3 inter-related themes: 1) researchinto genomic instability and DNA repair will identify how innate DNA repair pathways interact withenvironmental mutagens to impact carcinogenesis; 2) research on epigenetic mechanisms of malignancy willdelineate how alterations in the epigenome and gene transcription influence carcinogenesis; and 3) researchon cancer metabolic reprogramming will decipher the role of metabolic processes that contribute to cancerdevelopment with a focus on mitochondrial function and redox-mediated dysregulations. The themes areconceptually linked and feature robust faculty collaboration. GEM program members are pioneers and expertsin redox biology DNA repair epigenetic regulation and cancer metabolism. The program consists of 18members from 6 departments in the Colleges of Medicine and Arts and Sciences. The program's cancer-related funding is over $4.9M total annual funding ($3.3M direct costs of which 33% is from the NationalCancer Institute). GEM program members have actively used MCC Shared Resource Facilities since initialCancer Center Support Grant funding in 2013. Members have published 164 manuscripts (2013 to 2017) ofwhich 72 (44%) are inter-programmatic 36 (22%) are intra-programmatic and 99 (60%) are inter-institutional.The program is co-led by 2 researchers with complementary scientific and leadership expertise. Dr. JohnD'Orazio (a physician scientist focusing on DNA repair) and Dr. Peter Zhou (a specialist in epigenetic andmetabolic reprogramming of epithelial-mesenchymal transmission) bring together expertise in geneticinstability and cancer (D'Orazio Theme 1) epigenetic regulation and metabolism (Zhou Themes 2 and 3). Inaddition to their scientific leadership roles each offers significant strengths in clinical translation junior facultymentoring communications among MCC programs and expertise on populations within the MCC catchmentarea.

project_terms:
Adenocarcinoma;Affect;Area;Arts;Attention;Automobile Driving;Autophagocytosis;Basic Science;Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Prevention Intervention;Catchment Area;Chromatin;Collaborations;Communication;Communities;Complex;DNA Repair;DNA Repair Pathway;DNA-(apurinic or apyrimidinic site) lyase;DNA-Directed RNA Polymerase;Development;Diagnostic;Direct Costs;Disease;EZH2 gene;Environment;Enzymes;Epigenetic Process;Epithelial;Extramural Activities;Faculty;Fatty-acid synthase;Funding;Future;Gene Expression;Genetic;Genetic Transcription;Genome Stability;Genomic DNA;Genomic Instability;Goals;Growth;Head and Neck Squamous Cell Carcinoma;Histone H3;Homeostasis;Immunotherapy;Impaired cognition;Impairment;In Situ;Intervention;Investigation;Kentucky;Large Intestine Carcinoma;Lead;Leadership;Link;Lysine;Malignant - descriptor;Malignant Neoplasms;Manuscripts;Mediating;Mediator of activation protein;Medicine;Mesenchymal;Metabolic;Metabolism;Mission;Mitochondria;Molecular;Morbidity - disease rate;Mutagenesis;Mutation;National Cancer Institute;Neoplasm Metastasis;Normal Cell;Nucleosomes;Nucleotide Excision Repair;Oncogenic;Oxidation-Reduction;Paracrine Communication;Phenotype;Physicians;Play;Polycomb;Polymerase;Population;Positioning Attribute;Prevention therapy;Preventive;Process;Publications;Publishing;Research;Research Personnel;Research Project Grants;Resource Sharing;Role;Science;Scientist;Signal Pathway;Slice;Snails;Solid Neoplasm;Specialist;Therapeutic;Tissues;Translating;Translational Research;Triad Acrylic Resin;Universities;aerobic glycolysis;base;cancer cell;cancer initiation;cancer prevention;carcinogenesis;cell transformation;chemotherapy;clinical translation;college;environmental agent;environmental mutagens;epigenetic regulation;epigenetic therapy;epigenome;faculty mentor;injury and repair;inter-institutional;interest;melanocyte;member;metabolome;mitochondrial dysfunction;mortality;non-genetic;novel;programs;recruit;targeted treatment;therapy resistant;transmission process;treatment response;tumor;tumor metabolism;tumor progression


application_id: 10470112
project_number: 5P30CA177558-10
project_title: Drug Discovery Delivery and Translational Therapeutics Research Program
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5634
contact_pi_person_id: 2020455
contact_pi: KOLESAR, JILL MARIE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT  The Drug Discovery Delivery and Translational Therapeutics (DT) Program at the Markey Cancer Center (MCC) is scientifically focused on identifying novel targets and biomarkers and discovering and developing new drugs targeting these biomarkers. The MCC catchment area population has both a high cancer risk related to excessive carcinogen exposure and lack of access to cutting-edge clinical trials due to geographical isolation and poor socioeconomic status. The DT program vision is to understand the unique molecular and phenotypic markers of cancer in Kentucky as well as barriers to accessing care and integrate that knowledge to inform drug discovery development and delivery of early phase clinical trial efforts for a hard-to-reach Appalachian Kentucky population. MCC investigators are international leaders in biomarker discovery (Theme 1) with ongoing translational studies including more than 600 participants evaluating the role of environmental carcinogens and identifying biomarkers of lung cancer. DT pharmaceutical scientists work to discover and develop new anticancer agents targeting identified mutations and phenotypes (Theme 2) partnering with Cancer Cell Biology and Signaling (CS) and Genomic Instability Epigenetics and Metabolism (GEM) program members. For example a novel modulator of 4E-BP1 phosphorylation a validated colon cancer target was identified from the Appalachian natural products repository. DT investigators lead clinical trials focusing on cancers relevant to the catchment area (Theme 3) and have enrolled more than 500 patients to lung colon and ovarian interventional treatment and diagnostic trials. They regularly partner with Cancer Prevention and Control (CP) CS and GEM program members to inform and advance MCC basic science for example translating early identification of the anticancer activity of PAR-4 in CS to clinical trials focused on a PAR-4 secratagogue. DT is a cross-disciplinary program of 47 investigators from 6 colleges and 18 departments who work together to develop novel anticancer therapies and translate these therapies into the clinic. This productive program has total annual external cancer-related funding of $8.5M ($5.9M annual direct costs of which 28% is from the NCI). Members published 366 publications over the current funding period 99 (27%) of which are inter-programmatic 84 (23%) are intra-programmatic and 189 (52%) are inter-institutional. The DT program Co-leaders Drs. Jill Kolesar and Jon Thorson have a long-standing collaboration and bring complementary expertise in biomarker discovery drug development and early clinical trials. Both direct key resources supporting the DT program the MCC Precision Medicine Center and the UK Center for Pharmaceutical Innovation respectively. Each leader brings critical strengths including local national and international collaborations entrepreneurial relationships and active participation in NCI initiatives. Taken together the DT program has a cohesive and collaborative team that translates novel biomarkers into targets for effective anticancer treatments.

project_terms:
Adjuvant;Appalachian Region;Automobile Driving;Basic Science;Binding Proteins;Bioinformatics;Biological Markers;Biometry;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Intervention;Cancer Patient;Carcinogen exposure;Catchment Area;Cellular biology;Characteristics;Clinic;Clinical Cancer Center;Clinical Data;Clinical Pathology;Clinical Protocols;Clinical Trials;Collaborations;Colon;Colon Carcinoma;Community Outreach;Complex;DNA;Development;Devices;Diagnosis;Diagnostic Trial;Direct Costs;Dissemination and Implementation;EIF4EBP1 gene;Early Therapeutic-Clinical Trials Network;Early identification;Engineering;Enrollment;Environmental Carcinogens;Epigenetic Process;Eukaryotic Initiation Factors;Evaluation;Ewings sarcoma;Fatty Acids;Fli-1 protein;Frequencies;Funding;Genomic Instability;Geography;Goals;Grant;Health Services Accessibility;High-Risk Cancer;Hydroxychloroquine;Informatics;Infrastructure;International;Intervention;Investigation;Investigational New Drug Application;Investments;Kentucky;Knowledge;Laboratory Research;Lead;Libraries;Ligands;Ligase;Link;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Metabolism;Mission;Molecular;Molecular Abnormality;Molecular Target;Mutation;Natural Product Drug;Natural Products;Ovarian;PAWR gene;Participant;Pathology;Patients;Pharmacologic Substance;Pharmacy facility;Phenotype;Phosphorylation;Physicians;Population;Precision Medicine Initiative;Preclinical Testing;Protocols documentation;Publications;Publishing;Reporting;Research;Research Personnel;Resources;Role;Science;Scientist;Signal Transduction;Socioeconomic Status;Squamous Cell Lung Carcinoma;Therapeutic Agents;Therapeutic Human Experimentation;Therapeutic Trials;Translating;Translations;Universities;Vision;Work;Writing;anticancer activity;anticancer research;anticancer treatment;biomarker discovery;cancer biomarkers;cancer cell;cancer clinical trial;cancer genomics;cancer prevention;cancer subtypes;cancer therapy;clinical development;clinical implementation;cohesion;college;cross disciplinary program;data management;design;drug candidate;drug development;drug discovery;druggable target;early phase clinical trial;evidence base;exome sequencing;individual patient;inhibitor;innovation;inter-institutional;malignant breast neoplasm;member;metabolomics;molecular marker;mutational status;neoplasm registry;new therapeutic target;novel;novel anticancer drug;novel marker;novel therapeutics;phenotypic biomarker;pre-clinical;precision medicine;programs;recruit;repository;research facility;screening;senior faculty;synergism;targeted agent;targeted biomarker;targeted treatment;translational study;translational therapeutics;treatment response;treatment trial;tumor


application_id: 10470110
project_number: 5P30CA177558-10
project_title: Cancer Prevention and Control Research Program
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5633
contact_pi_person_id: 10885868
contact_pi: STAPLETON, JEROD L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT  Markey Cancer Center's (MCC) Cancer Prevention and Control (CP) Research Program unites highly complementary strengths in the areas of population-based research and community-based cancer control research with the overarching goal of reducing cancer disparities in Kentucky with an emphasis on the state's Appalachian and rural populations. Kentucky has the highest overall cancer incidence and mortality rates among all 50 United States. Alarmingly the cancer incidence and mortality rates in Appalachian Kentucky are far higher than the rates for the non-Appalachian area of the state. These elevated rates are driven by a variety of underlying factors including low socioeconomic status low educational attainment high risk behaviors cultural barriers and environmental exposures. Strengths of the CP program include studies focused on uncovering the role environmental exposures play in Kentucky's high cancer incidence rates testing intervention programs that address unique cultural barriers and smoking cessation policy development initiatives. CP program members are also national leaders in developing population-based methods and measures that facilitate inter-programmatic cancer research. The CP program combines these strengths to address 3 thematic areas: identification of social cultural behavioral genetic and environmental factors that contribute to the elevated cancer incidence and mortality rates (Theme 1); design testing implementation and evaluation of intervention strategies that address identified risk factors (barriers) and reduce the cancer burden (Theme 2); and development of population-based methods and measures that facilitate inter-programmatic cancer research directed at more precisely identifying the distribution of treatment patterns and biomarkers in the population (Theme 3). Most recently the CP program recruited 2 National Cancer Institute-funded cancer molecular epidemiologists to build on its unique research resources. The current 28-member CP team draws from 5 colleges and 12 departments at the University of Kentucky thus promoting active interdisciplinary translational research. CP productivity is reflected by total annual external cancer-related funding of over $9.7M ($6.7M annual direct costs) and 245 total publications in the current funding period 30 (12%) of which are inter-programmatic 83 (34%) intra-programmatic and 162 (66%) inter-institutional. CP research encompasses all segments of the cancer control continuum: prevention early detection treatment and survivorship. CP studies address a number of cancer sites including those that disproportionately contribute to Kentucky's high cancer burden (i.e. lung colon breast and cervical cancers). Thus the CP program is integral to achieving the overall MCC mission to reduce cancer morbidity and mortality in the Commonwealth.

project_terms:
Address;Age;Appalachian Region;Area;Behavioral;Behavioral Genetics;Biological Markers;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Control Research;Cancer Control Research Program;Cancer Patient;Catchment Area;Collaborations;Colon Carcinoma;Colorectal Cancer;Communities;Country;County;Data Linkages;Data Set;Development;Diagnosis;Direct Costs;Early Diagnosis;Education;Effectiveness of Interventions;Environmental Carcinogens;Environmental Exposure;Environmental Risk Factor;Epidemiologist;Evaluation;Evidence based intervention;Exposure to;Funding;Genetic;Goals;Incidence;Informatics;Intervention;Intervention Studies;Kentucky;Laboratories;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Measures;Metals;Methods;Mission;Molecular;Morbidity - disease rate;National Cancer Institute;Natural Language Processing;Obesity;Outcomes Research;Pathology;Pathology Report;Patients;Pattern;Play;Policy Developments;Population;Population Research;Poverty;Prevalence;Prevention;Process;Productivity;Program Research Project Grants;Provider;Publications;Registries;Reporting;Research;Research Personnel;Resources;Risk Factors;Role;Rural;Rural Appalachia;Rural Population;Sampling;Site;Smoking;Social Identification;Testing;Time;Tissue Banks;Tissues;Translational Research;United States;Universities;Vulnerable Populations;Work;anticancer research;base;cancer health disparity;cancer prevention;cancer recurrence;cancer risk;cancer site;carcinogenesis;college;design;disadvantaged population;experience;federal poverty level;high risk;high risk behavior;high school;innovation;insight;inter-institutional;intervention program;low socioeconomic status;malignant breast neoplasm;member;mortality;neoplasm registry;novel;population based;programs;protein expression;recruit;smoking cessation;social;social media;socioeconomics;survivorship;tool;trait;underserved area;virtual


application_id: 10470109
project_number: 5P30CA177558-10
project_title: Cancer Cell Biology and Signaling Research Program
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5632
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The Markey Cancer Center's Cancer Cell Biology and Signaling (CS) Research Program includes a robustarray of thematically driven projects performed by a cohesive and highly collaborative group of investigators.The overarching goal is to better understand cancer signaling networks in order to identify novel targets thatcan be exploited to create new therapeutic combinations. To achieve this objective the CS program is dividedinto 3 thematic areas: 1) Aberrant proliferation and survival networks 2) Determinants of tumor progressionand metastasis and 3) Interaction of tumor cells with their microenvironment. Inter-related subthemes withineach goal reflect the scope of the research projects and individual expertise across the cross-cutting topic ofCell Signaling. These include regulation of oncogene/tumor suppressor and kinase/phosphatase genenetworks (Theme 1); contribution of cell motility/ epithelial-mesenchymal transition and cancer stem cells totherapeutic resistance (Theme 2); and examination of cellular and matrix contributions to cancer developmentand progression (Theme 3). Members of the CS program are experts in defining cancer signaling pathwaysthat underlie the mechanisms of cancer cell survival proliferation invasion and metastasis and decipheringthe relationship between the tumor and the micro- and macro-environments that modulate the dynamics oftumor progression. CS members include leaders in the field of survival/apoptosis signaling in response togrowth factors/cytokines adhesion and anoikis as well as experts in the processes of epithelial-mesenchymaltransition cell motility and invasion. The 26 members of the program represent 3 colleges at the University ofKentucky and 9 different departments reflecting diverse disciplinary perspectives that provided significant newinsights into CS program thematic areas. The CS program has a total annual external cancer-related funding of$7.4M ($5.1M annual direct costs of which $2.4M (48%) is from the National Cancer Institute). Memberspublished 231 publications between 2013 and 2017 of which 90 (39%) are inter-programmatic 55 (24%) areintra-programmatic and 134 (58%) are inter-institutional. Led by CS program Co-leaders Drs. VivekRangnekar (an expert in studying cell survival and apoptosis) and Rina Plattner (an expert in tumor invasionand metastasis) CS research focuses on reducing the most serious cancer burdens in Kentucky by identifyingnovel therapeutic targets in signaling pathways that drive cancer development and progression. Incollaboration with other program leaders and Associate Directors for Basic Research and Clinical Translationresearch of the CS program has led to 2 new clinical trials and eight new patents. Additionally working with theAssociate Director for Cancer Education and Mentoring the Co-leaders of the CS program have instituted arobust mentoring system to ensure the success of junior faculty. By bringing a wide array of expertise andprogrammatic strengths the CS program collectively provides a rich environment to facilitate multidisciplinarycollaboration and builds a productive pipeline for translation of CS science into the clinic.

project_terms:
Achievement;Adhesions;Adipocytes;Animal Model;Anoikis;Apoptosis;Appalachian Region;Area;Bacteria;Basic Science;Cancer Burden;Cancer Center;Cancer Center Support Grant;Catchment Area;Cell Survival;Cellular biology;Chloroquine;Climate;Clinic;Clinical Trials;Collaborations;Cytoskeleton;Development;Diabetes Mellitus;Direct Costs;Drosophila genus;Drug Combinations;Engineering;Ensure;Environment;Epithelial;Extracellular Matrix;FDA approved;Faculty;Funding;Future;Gene Proteins;Goals;Grant;Group Meetings;Growth Factor;Immune checkpoint inhibitor;Immunologist;Incidence;Individual;Institutes;Interdisciplinary Study;Intestinal Hormones;Joints;Kentucky;Legal patent;Link;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Medicine;Mentors;Mesenchymal;Mission;Morbidity - disease rate;NCI Center for Cancer Research;National Cancer Institute;Nature;Neoplasm Metastasis;Neurotensin;Obesity;Oral;PAWR gene;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Postdoctoral Fellow;Process;Program Description;Public Health;Publications;Publishing;Regulation;Research;Research Personnel;Research Project Grants;Role;Science;Signal Pathway;Signal Transduction;Stilbenes;System;Testing;Transitional Cell;Translational Research;Translations;Tumor Cell Invasion;Tumor Suppressor Genes;Tumor Suppressor Proteins;Underserved Population;Universities;Zebrafish;base;breast cancer progression;cancer cell;cancer education;cancer initiation;cancer stem cell;cell motility;clinical translation;cohesion;collaborative environment;college;colon cancer treatment;cytokine;drug discovery;gene network;inhibitor;insight;inter-institutional;leukemic stem cell;melanoma;member;mortality;neoplastic cell;new therapeutic target;novel;novel drug combination;novel therapeutics;programs;recruit;resistance mechanism;response;smoothened signaling pathway;stem cell division;stem cells;success;targeted treatment;therapy resistant;tool;translational therapeutics;tumor;tumor microenvironment;tumor progression


application_id: 10470108
project_number: 5P30CA177558-10
project_title: Redox Metabolism Shared Resource Facility
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5631
contact_pi_person_id: 8329002
contact_pi: BUTTERFIELD, D. ALLAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The Redox Metabolism Shared Resource Facility (RM SRF) is a cancer-center managed SRF thatprovides critical services for University of Kentucky (UK) Markey Cancer Center (MCC) Research Programs.Notably the RM SRF is one of only a small number of facilities directly associated with a National CancerInstitute-designated Cancer Center that provides expertise and analyses in oxidative stress cellularenergetics metabolomics and proteomics in cancer and cancer biology. Over the last 4 years of CCSGfunding the RM SRF has successfully demonstrated its high value-added role for MCC investigators doingbasic science clinical and cancer prevention and control research in the MCC's Kentucky catchment area.There is increasing evidence that oxidative damage with sequelae of altered cellular energetics andmetabolism as well as protein alterations underlie the initiation promotion invasion metastasis and treatmentof cancers. Moreover oxidative stress is implicated in the side effects of normal tissue injury following cancertherapy. As such the 4 basic services provided by the RM SRF are: 1) analysis of markers of oxidative andnitrosative stress; 2) molecular biological manipulation of biological systems to investigate redox signalsincluding measurements of mitochondrial function by Seahorse technology; 3) proteomics identification ofdifferentially expressed differentially oxidized or differentially covalently modified proteins in various cancer-related systems; and 4) profiling and Stable Isotope Resolved Metabolomics of cancer tissue and cells aservice that began in 2015 following a $6M UK investment in nuclear magnetic resonance and massspectrometry equipment. Key improvements since initial CCSG funding include expanding services and scopetoward metabolomics as well as increasing staff. This SRF is directed by Dr. D. Allan Butterfield (GEM) with Dr.Haining Zhu (GEM) as Associate Director. With the exciting addition of metabolomics analyses to the SRF Dr.Richard Higashi (GEM) an expert in the assessment of metabolites and metabolic pathways has been addedas Associate Director of RM SRF for metabolomics. Fifty-four MCC members used RM SRF services sinceMCC funding began a 43% increase from year 1 to year 4 of CCSG funding. Of these 39 were members withpeer-reviewed funding. RM SRF leadership and staff actively participate in the development of newapplications and methodologies for a better understanding of the roles of oxidative stress and metabolism incancer and cancer chemotherapy and provide technical assistance with experimental design and interpretationof results for MCC principal investigators. RM SRF technical staff have knowledge of the latest and mostcurrent sample handling and preparation methods so that reliable precise and artifact-free assay results canbe obtained. The RM SRF facilitates research with the other MCC SRFs to improve the analytical power ofvarious cutting-edge technologies for understanding of the enormous cancer burden in Kentucky.

project_terms:
Affect;Appalachian Region;Area;Australia;Basic Science;Bioenergetics;Biological;Biological Assay;Biology;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control Research;Catchment Area;Cell Respiration;Cells;Centers of Research Excellence;Chemotherapy-Oncologic Procedure;Clinical;Comprehensive Cancer Center;Consultations;Development;Education;Educational workshop;Equipment;Europe;Experimental Designs;Faculty;Free Radicals;Funding;Future;Genomics;Genus Hippocampus;Goals;Immunotherapy;Incidence;Institution;International;Investments;Kentucky;Knowledge;Leadership;Malignant Neoplasms;Mass Spectrum Analysis;Measurement;Mentors;Metabolic;Metabolic Pathway;Metabolism;Methodology;Methods;Mission;Mitochondria;Molecular;Morphologic artifacts;NCI Center for Cancer Research;National Cancer Institute;Neoplasm Metastasis;Normal tissue morphology;Nuclear Magnetic Resonance;Obesity;Oxidation-Reduction;Oxidative Stress;Oxides;Patients;Peer Review;Phase;Population;Post-Translational Protein Processing;Preparation;Principal Investigator;Protein Array;Proteins;Proteomics;Research;Research Personnel;Resource Sharing;Resources;Role;Sampling;Science;Services;Signal Transduction;Strategic Planning;System;Techniques;Technology;Tissues;Training;Training and Education;Translational Research;United States;United States National Institutes of Health;Universities;bench to bedside;biological systems;biomarker discovery;biomarker validation;cancer prevention;cancer therapy;data integration;differential expression;high risk population;improved;innovation;insight;interest;lens;member;metabolomics;metabolomics resource;mortality;nitrosative stress;oxidative damage;precision medicine;programs;recruit;response;service utilization;side effect;stable isotope;tissue injury;tumor metabolism


application_id: 10470107
project_number: 5P30CA177558-10
project_title: Flow Cytometry and Cell Sorting Shared Resource Facility
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5630
contact_pi_person_id: 1878476
contact_pi: COHEN, DONALD A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The Flow Cytometry and Cell Sorting Shared Resource Facility (FCCS SRF) facilitates high impact cancerscience within the Markey Cancer Center (MCC) and is aided by current CCSG funding. The FCCS SRF hasbeen in continuous operation at the University of Kentucky (UK) since 1983 and under the direction of DonaldCohen PhD since 1992. Although an institutional core facility at UK during the current period of CCSGfunding 68% of users were MCC members and 53% of users were peer-reviewed funded MCC members. Tosupport research efforts of MCC members the FCCS SRF provides state-of-art flow cytometric services andcomprehensive immune monitoring services to support cancer research by all 4 Research Programs. A varietyof flow cytometric services including multi-parametric cell phenotyping (up to 12 biomarkers simultaneously)allows users to analyze surface and intracellular biomarkers DNA content cell cycle apoptosis and necrosiscytokine/growth factor synthesis signal transduction and cell activation. Under guidance by MCC leadershipthe FCCS SRF recently expanded services to provide MCC members comprehensive immune monitoring forhuman basic and clinical cancer research. Immune monitoring services include processing fresh blood andtumor tissue for isolation of immune and non-immune cells for functional assay and cryopreservation andbanking of cells for later analysis. Banking services are provided in collaboration with the BiospecimenProcurement and Translational Pathology SRF and the Cancer Research Informatics SRF. Freshly isolatedand banked cell samples can be analyzed for a number of cellular functions including synthesis ofcytokines/growth factors/other soluble factors by ELISA ELISPOT and Luminex multiplexing in addition to flowcytometric approaches. Assays are also offered to quantify antigen-specific T cell proliferation cytotoxicityantibody synthesis and cytokine production in human systems. Cellular product services include generation ofdendritic cells and macrophages from blood and/or tumor tissue and expansion of T cells from blood and/ortumor tissue. In collaboration with the Biostatistics and Bioinformatics SRF FCCS offers high dimensional dataanalysis for multi-parameter flow cytometry and Luminex multi-analyte profiling for identification of complex cellpopulations and rare cell subsets. Over the previous CCSG funding period FCCS services have contributed to118 publications 49 grants funded during the last four years and has initiated consultation and collaborationon 4 clinical trials by MCC members. The comprehensive flow cytometry and immune monitoring servicesoffered by FCCS in combination with FCCS immune assay design services are providing MCC researcherswith the exceptional opportunities to interrogate novel cancer biomarkers and the immune system interactionsin studies involving basic and clinical cancer research at the MCC.

project_terms:
Address;Animals;Antibodies;Apoptosis;Applications Grants;Basic Science;Bioinformatics;Biological Assay;Biological Markers;Biometry;Blood;Cancer Center;Cancer Center Support Grant;Cancer Science;Catchment Area;Cell Cycle;Cell Separation;Cell physiology;Cells;Clinical;Clinical Cancer Center;Clinical Research;Clinical Trials;Cloning;Collaborations;Complex;Computers and Advanced Instrumentation;Consult;Consultations;Core Facility;Cryopreservation;Data;Data Analyses;Dendritic Cells;Development;Doctor of Philosophy;Enzyme-Linked Immunosorbent Assay;Experimental Designs;Faculty;Flow Cytometry;Flow Cytometry Shared Resource;Fresh Tissue;Funding;Generations;Goals;Grant;Growth Factor;Health;Human;Immune;Immune system;Immunologic Monitoring;Immunologics;Immunology procedure;Individual;Informatics;Kentucky;Laboratories;Leadership;Malignant Neoplasms;Mentors;Mentorship;Mission;Monitor;National Cancer Institute;Necrosis;Pathology;Peer Review;Persons;Phenotype;Ploidies;Population;Production;Publications;Research;Research Design;Research Personnel;Research Support;Resource Sharing;Sampling;Services;Signal Transduction;Speed;Surface;System;T-Cell Proliferation;T-Lymphocyte;Techniques;Tissue Expansion;Training;Tumor Tissue;United States National Institutes of Health;Universities;anticancer research;antigen-specific T cells;base;cancer biomarkers;cancer immunotherapy;career;cell bank;cost effective;cytokine;cytotoxicity;design;enzyme linked immunospot assay;improved;innovation;instrument;instrumentation;macrophage;meetings;member;multidimensional data;novel;operation;phenotypic biomarker;pre-clinical;pre-clinical research;programs;tumor immunology


application_id: 10470106
project_number: 5P30CA177558-10
project_title: Cancer Research Informatics Shared Resource Facility
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5629
contact_pi_person_id: 9276771
contact_pi: DURBIN, ERIC B.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The Cancer Research Informatics Shared Resource Facility (CRI SRF) serves as a Markey Cancer Center(MCC)-managed resource that develops and applies informatics methods and technologies to enable theadvancement of science through the curation and open investigator access to high quality data from a widevariety of institutional sources. CRI has expanded MCC's data ecosystem to cover MCC's entire catchmentarea of Kentucky through linkages and integration with high quality population-based data from theSurveillance Epidemiology and End Results (SEER) Kentucky Cancer Registry. Enhanced and expandedthrough CCSG support and implementing changes recommended from the last CCSG review the CRI hasbeen highly innovative in the provision of comprehensive informatics services readily available to cancer centerinvestigators. Services are broadly categorized into: 1) provision of integrated data from the patient-centriccancer research data warehouse; 2) research in clinical decision support for MCC's Molecular Tumor Board; 3)high-performance computing (HPC) and big data storage support for bioinformatics analyses and machinelearning approaches to natural language processing (NLP); 4) data management to ensure complete andaccurate clinical trial and biospecimen data; 5) automated screening of eligible patients for clinical trialrecruitment; 6) identification and annotation of human biospecimens; 7) software and database developmentfor research and data dissemination; 8) informatics support for study planning and grant preparation; and 9)mentorship training and education. CRI services have been utilized by 103 MCC members 55 of whom (53%)are peer-reviewed funded members. CRI infrastructures and data management applications enable efficientinteractions among the Research Programs and other SRFs such as a portal for basic science researchers toaccess bioinformatics analysis results. CRI develops and supports critical informatics technologies indatabases data warehousing NLP deep phenotyping HPC mobile device apps data sharing and datadissemination. CRI closely coordinates the acquisition and provision of institutional informatics resources incollaboration with the University of Kentucky (UK) Institute for Biomedical Informatics the UK Center forClinical and Translational Science UK HealthCare Information Technology and the UK Center forComputational Sciences. CRI has established strategic alliances with informatics centers of excellence andnational agencies to enhance Kentucky data and to collaboratively develop informatics tools and datastandards serving the greater cancer research community. In addition CRI faculty and staff serve as nationalinformatics leaders in cancer data exchange standards and innovative software applications adopted acrossthe United States. CRI is led by Dr. Eric B. Durbin (CP) and is tightly integrated with the Biostatistics andBioinformatics; Biospecimen Procurement and Translational Pathology; and Oncogenomics SRFs through theprovision of essential informatics services that enhance the other MCC SRF service offerings.

project_terms:
Adopted;Appalachian Region;Basic Science;Big Data;Bioinformatics;Biometry;Cancer Center;Cancer Center Support Grant;Cancer Control;Catchment Area;Cellular biology;Clinical;Clinical Cancer Center;Clinical Sciences;Clinical Treatment;Clinical Trials;Collaborations;Communities;Computational Science;Computer software;Data;Data Reporting;Data Set;Data Sources;Data Storage and Retrieval;Databases;Development;Educational workshop;Ensure;Epigenetic Process;Evaluation Research;Faculty;Foundations;Funding;Genomic Instability;Goals;Grant;Healthcare;High Performance Computing;Human;Informatics;Information Technology;Infrastructure;Institutes;Kentucky;Knowledge;Knowledge Discovery;Leadership;Machine Learning;Maintenance;Malignant Neoplasms;Medicine;Mentors;Mentorship;Metabolism;Methods;Mission;Molecular;NCI Center for Cancer Research;National Cancer Institute;Natural Language Processing;Outcome Measure;Pathology;Patient-Focused Outcomes;Patients;Peer Review;Phenotype;Population Research;Preparation;Research;Research Personnel;Resource Informatics;Resources;Role;SEER Program;Science;Scientist;Services;Signal Transduction;Source;Supporting Cell;Technology;Therapeutic Studies;Tissue Microarray;Training and Education;Translational Research;Treatment outcome;United States;Universities;analytical method;anticancer research;biomedical informatics;cancer cell;cancer genomics;cancer prevention;clinical center;clinical decision support;clinical decision-making;cohort;data dissemination;data ecosystem;data exchange;data management;data quality;data sharing;data standards;data warehouse;design;diverse data;drug discovery;evidence base;genomic biomarker;handheld mobile device;improved;informatics shared resource;informatics tool;innovation;interoperability;machine learning method;member;mortality;multidimensional data;national surveillance;neoplasm registry;next generation sequencing;novel;population based;precision medicine;programs;recruit;research and development;research data dissemination;response;screening;surveillance data;translational therapeutics;tumor


application_id: 10470104
project_number: 5P30CA177558-10
project_title: Biostatistics and Bioinformatics Shared Resource Facility
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5628
contact_pi_person_id: 7719959
contact_pi: WEISS, HEIDI L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The Biostatistics and Bioinformatics Shared Resource Facility (BB SRF) is an essential cancer center-managed resource and has played a critical role as members in team science by providing statistical andbioinformatics expertise to enable and enhance the Markey Cancer Centers (MCC) basic clinical andpopulation research. BB SRF services are categorized broadly into: 1) study planning power and sample sizecalculations for grant applications; 2) design and implementation support for clinical trials; 3) statisticalanalyses including interim and final analysis for the entire spectrum of cancer research studies; 4)bioinformatics methods for design and analysis of high-throughput omics data; 5) statistical programming fordata quality control and data processing; and 6) mentoring education and general consultation to MCCinvestigators. BB SRF services are coordinated with other MCC SRFs with hand-offs and integrated workflowsto ensure comprehensive seamless and non-overlapping support. During the current funding cycle the BBSRF has made significant scientific impact by employing technical methodologies directly supporting MCCResearch Program themes. These technical methodologies include development and implementation of state-of-the-art data processing and data analysis pipelines and software for several genomic platforms with specificapplications to Kentuckys Appalachian population; novel differential analysis and classification methodologiesfor metabolomics and exosome data for lung breast and pancreas cancers; adaptive and model-based dosefinding designs and state-of-the art designs for early phase trials with biomarker and genomic evaluations oftargeted therapies; statistical methodologies for population-based cancer prevention studies includingnonparametric estimation and hypothesis testing of risk factor distributions relative survival estimation andstatistical methods for cancer registry and large claims databases to support research in MCCs research inhealth disparities. In addition to support as co-investigators in 52 newly funded grants and over 40 investigator-initiated trials BB SRF faculty engaged in novel methodological work to enhance the science of MCCResearch Programs. During the current CCSG funding cycle the BB SRF supported 128 MCC members (81peer-reviewed funded) from all 4 MCC Research Programs representing 74% coverage from the total MCCmembership. The BB SRF has significantly increased usage and value added metrics expanded its services and hasgrown in personnel from 8 faculty and staff to a current total of 14 to address the growth and emergingresearch directions of the MCC. The highly experienced personnel and diverse skill set of the BB SRF addssignificant value to the execution of scientifically rigorous research at the MCC and demonstrates that the BBSRF is well positioned to support the MCC as a Comprehensive Cancer Center for the Commonwealth ofKentucky in this renewal application.

project_terms:
Address;Adoption;Appalachian Region;Applications Grants;Area;Basic Science;Bioinformatics;Bioinformatics Shared Resource;Biological;Biological Markers;Biometry;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Surveillance Research;Cell Separation;Cellular biology;Classification;Clinical;Clinical Cancer Center;Clinical Research;Clinical Trials;Collaborations;Communities;Community Outreach;Comprehensive Cancer Center;Computer software;Consultations;Data;Data Analyses;Data Science;Databases;Development;Disease;Dose;Early Therapeutic-Clinical Trials Network;Education;Education and Outreach;Ensure;Epigenetic Process;Evaluation;Experimental Designs;Faculty;Flow Cytometry;Funding;Genomic Instability;Genomics;Grant;Growth;Hand;Human Resources;Immunologic Monitoring;Informatics;Journals;Kentucky;Lead;Leadership;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mentors;Mentorship;Metabolism;Methodology;Methods;Mission;Modeling;Molecular;Monitor;Multicenter Trials;NCI Center for Cancer Research;National Cancer Institute;Oxidation-Reduction;Pathology;Peer Review;Play;Population;Population Research;Population Study;Positioning Attribute;Precision medicine trial;Process;Quality Control;Reproducibility;Research;Research Design;Research Personnel;Research Priority;Research Support;Resource Sharing;Resources;Risk Factors;Role;Sample Size;Science;Series;Service provision;Services;Signal Transduction;Site;Statistical Data Interpretation;Statistical Methods;Survival Analysis;Technical Expertise;Testing;Toxic effect;Training;Training Activity;Training Programs;Training and Education;Translational Research;Universities;Work;Writing;anticancer research;base;biomarker-driven;cancer cell;cancer health disparity;cancer immunotherapy;cancer prevention;computerized data processing;cost effective;data analysis pipeline;data management;data quality;design;drug discovery;early phase clinical trial;early phase trial;exosome;experience;genomic platform;health disparity;high throughput analysis;improved;innovation;investigator-initiated trial;lectures;malignant breast neoplasm;meetings;member;metabolomics;multidisciplinary;neoplasm registry;next generation sequencing;novel;population based;precision medicine;precision medicine clinical trials;programs;research study;skills;statistics;success;targeted treatment;translational clinical trial;translational genomics;translational study;translational therapeutics;tumor immunology;working group


application_id: 10470103
project_number: 5P30CA177558-10
project_title: Biospecimen Procurement and Translational Pathology Shared Resource Facility
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5627
contact_pi_person_id: 9876819
contact_pi: BOCKLAGE, THERESE JEANNE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT  The Biospecimen Procurement and Translational Pathology Shared Resource Facility (BPTP SRF) is a Markey Cancer Center (MCC)-managed resource. It facilitates the use of well-annotated human and animal specimens and provides a wide range of translational pathology technical services in support of MCC clinical translational population-based and basic science research. Over the award period the BPTP SRF has increased annual biospecimen dispensation from 1738 in FY12 to 4446 in FY17 (156% increase) increased the total number of MCC users by 23% (48 in FY17 up from 39 in FY12) including 38 peer-reviewed funded MCC users in FY17 (49% of all BPTP users) and expanded its range of services. New services include: targeted and time sensitive collections such as intra-operative rapid fresh tissue collections supporting work in cancer metabolism; the development of novel model systems (e.g. Warburg tissue slices for metabolic analysis patient-derived xenograft organoids); review of all clinical trials including investigator-initiated trials to identify specimen collection needs and develop collection protocols; fresh tissue collections and rapid blood processing for clinical trials resulting in support for 40 clinical trials over the funding period. The addition of a research histology laboratory operated per clinical guidelines allows for an increased capacity for technical services such as histology immunohistochemistry molecular pathology laser capture microscopy and DNA/RNA extraction. BPTP SRF has increased its consent capacity through the cross training of all BPTP SRF staff as well as by using a universal opt-in consent for repository collections. BPTP SRF's name change reflects its increased focus on translational pathology facilitated by the support of faculty in the University of Kentucky (UK) Department of Pathology who assist BPTP SRF staff in the development and interpretation of novel assays on-site evaluation of specimen content and quality for fresh tissue dispense and identification of retrospective study and tissue microarray cohorts from surgical archive specimens dating back to 1995. This partnership strengthened by BPTP's leadershipC. Darrell Jennings MD chair of the Department of Pathology and Laboratory Medicine with Associate Director Qiuying Shi MD Assistant Professor in Pathologyensures MCC investigators have a clear path to the specimen resources and pathologic services essential to their work. The BPTP SRF has streamlined operations by transitioning to the OnCore database and adding a manager to oversee daily operations leveraging existing resources within the MCC including the Clinical Research Office the Surveillance Epidemiology and End Results Kentucky Cancer Registry and Cancer Research Informatics and Biostatistics and Bioinformatics SRFs as well as non-MCC entities such as the Department of Pathology and Laboratory Medicine UK Office of Research Integrity and the Center for Clinical and Translational Science.

project_terms:
Ambulatory Care Facilities;Animals;Appalachian Region;Area;Award;Back;Basic Science;Bioinformatics;Biological Assay;Biological Markers;Biological Models;Biometry;Blood;Cancer Center;Cancer Center Support Grant;Clinical;Clinical Cancer Center;Clinical Data;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Collection;Communities;Comprehensive Cancer Center;Computer software;Consent;Consultations;Custom;DNA;Data;Databases;Department chair;Development;Education;Ensure;Evaluation;Faculty;Familiarity;Formalin;Fostering;Freezing;Fresh Tissue;Funding;Future;Genetic;Genetic Markers;Genomics;Goals;Growth;Guidelines;Histologic;Histology;Histopathology;Hospitals;Human;Immunohistochemistry;In Situ;In Situ Hybridization;Informatics;Institutional Review Boards;Kentucky;Laboratories;Laboratory Research;Lasers;Leadership;Liquid substance;Malignant Neoplasms;Medicine;Metabolic;Microscopy;Mission;Modeling;NCI Center for Cancer Research;Names;Obesity associated cancer;Operative Surgical Procedures;Organoids;Outcome;Paraffin Embedding;Pathologic;Pathologist;Pathology;Patient Care;Patients;Peer Review;Play;Population;Procedures;Protocols documentation;RNA;Research;Research Design;Research Personnel;Research Training;Resistance;Resource Sharing;Resources;Retrospective Studies;Role;SEER Program;Sampling;Science;Scientist;Services;Site;Slice;Specimen;Standardization;Students;Therapeutic Clinical Trial;Therapeutic Human Experimentation;Time;Tissue Banks;Tissue Embedding;Tissue Microarray;Tissues;Training;Training and Education;Translating;Translational Research;Tumor Tissue;United States Office of Research Integrity;Universities;Work;anticancer research;biological specimen archives;biomarker evaluation;cancer health disparity;cancer immunotherapy;clinical center;clinical investigation;cohort;consent capacity;digital imaging;direct patient care;faculty support;histological stains;human tissue;imaging system;innovation;interest;investigator-initiated trial;member;metabolomics;molecular pathology;neoplasm registry;next generation;novel;operation;patient derived xenograft model;patient population;patient privacy;population based;precision medicine clinical trials;preservation;professor;programs;prospective;repository;response;sample collection;tissue biomarkers;tumor;tumor immunology;tumor metabolism


application_id: 10470102
project_number: 5P30CA177558-10
project_title: Career Enhancement
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5626
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTInnovation and progress in cancer research require dedication to the career development of the nextgeneration of cancer researchers. Accordingly the University of Kentuckys Markey Cancer Center (MCC)with a robust annual institutional investment of $450000 and the dedication of its members established acomprehensive Oncology Career Enhancement Program. Over the past funding cycle this program hasprovided enriching experiences for nearly 570 K-12 and undergraduate students; extensive research trainingfor 50 high school students 223 undergraduates and 544 graduate/postdoctoral researchers; and mentorshipto 46 junior faculty. Notably key education activities address the academic challenges of rural AppalachianKentucky and underrepresented minorities through the support from 4 grants that include Continuing Umbrellaof Research Experiences and Geographic Management of Health Disparities Program National CancerInstitute supplements. Academic and professional development of all trainees through intensive mentoredresearch engagement and/or formal research training at the undergraduate graduate and postdoctoral levelscomplement elementary and high school education strategies. Formal curricula in cancer biology have beenestablished at the undergraduate masters and pre-doctoral levels that provide the academic context for thistraining. Furthermore 4 T32 training programs support cancer career development for trainees including 2funded by the National Cancer Institute 1 of which is uniquely devoted to surgeon-scientists. Overall MCCtraining and career development extramural support has risen by 52% since 2012 to 26 grants totaling $2.3M(direct costs) in 2017. Early-career faculty benefit from team-based mentoring through formal mentoringcommittees a Grant Writing Study Hall the Clinical Trials Boot Camp and synergistic mentorship throughvarious institutional efforts. This mentorship has resulted in 95 awarded grants (50 extramural 45 intramural)and the development of 11 clinician scientists who went on to lead 31 clinical trials. A rich set of seminarsymposia meetings and other career enhancement activities facilitate successful career development for allindividuals engaged in cancer research and clinical practice. All current and proposed career enhancementactivities leverage the robust research strengths within the MCCs 4 Research Programs to provide immersivetraining across the pipeline and to ensure that faculty within these programs successfully develop asindependent scientists. The MCCs collective efforts also draw on strong institutional training resources toachieve 2 overarching goals of this program: to guide cohesive growth and coordinate transdisciplinaryeducation and mentoring endeavors across the MCC; and to integrate with other efforts campus wide. ThroughCCSG support this comprehensive program will continue to evolve innovative curricula and strategically linkedinitiatives that prepare trainees and early-career faculty for modern cancer career opportunities. Furthermorethese efforts will drive research innovation that will improve the lives of all Kentuckians.

project_terms:
Address;Appalachian Region;Award;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical;Clinical Trials;Community Outreach;Complement;County;Data;Dedications;Development;Direct Costs;Education;Educational Curriculum;Ensure;Evolution;Extramural Activities;Faculty;Fostering;Funding;Geography;Goals;Grant;Growth;High School Student;Immersion;Incidence;Individual;Investments;K-12 student;Kentucky;Lead;Link;Malignant Neoplasms;Mentors;Mentorship;Mission;Modernization;NCI Center for Cancer Research;National Cancer Institute;National Cancer Program;Oncology;Outcome;Physicians;Population;Research;Research Personnel;Research Training;Resources;Rural Appalachia;Scientist;Series;Surgeon;Time;Training;Training Programs;Training and Education;Translational Research;Underrepresented Minority;Universities;Writing;anticancer research;base;cancer education;career;career development;clinical practice;cohesion;community engagement;early-career faculty;education research;educational atmosphere;elementary school;experience;faculty research;health disparity;health management;high school;higher education;improved;innovation;interest;meetings;member;mortality;next generation;pre-doctoral;programs;symposium;undergraduate student


application_id: 10470101
project_number: 5P30CA177558-10
project_title: Administration
administering_ic: NCI
award_notice_date: 2022-09-03
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5625
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT  Markey Cancer Center (MCC) Administration provides efficient and effective administrative support to MCC's Director Senior Leadership Research Program Leaders Shared Resource Facility (SRF) Directors and MCC members. The role of MCC Administration is to operationalize MCC's most critical research functions by fulfilling the following Specific Aims: 1) to accelerate the remarkable evolution of the MCC by leveraging resources and expanding MCC's infrastructure; 2) to promote the strategic planning and evaluation efforts of the MCC; and 3) to support the comprehensive basic science clinical and cancer prevention activities of the MCC by fostering transdisciplinary and translational science. The MCC is a matrix cancer center with administrative staff providing support to 119 MCC members from 28 departments in 8 University of Kentucky colleges with 28 faculty recruited in the last 4 years. MCC Administration leverages the expertise of its team members while operating in an innovative and efficient manner. New initiatives supported since the last grant cycle include: 1) implementing iLab Solutions (Agilent Technologies) across SRFs; 2) deploying $4.2M for new seed grant opportunities; 3) developing the Markey Women Strong program in collaboration with the Markey Cancer Foundation to provide two $50000 awards annually to female researchers in the MCC; 4) supporting a 38% increase of direct cancer-related research funding from $19.9M to $27.4M (corresponding 36% increase of total cancer-related research funding from $28.4M to $38.7M) between 2012-2017; 5) facilitating 7 successful CCSG supplement applications; 6) initiating development of 2 SRFs (Oncogenomics and Behavior and Community-Based Research); 7) providing full support for a Center of Biological Research Excellence application and funded award; 8) establishing the Department of Toxicology and Cancer Biology and the Center for Environmental and Systems Biochemistry to support research and educational efforts; 9) increasing the number of MCC Network sites from 8 in 2013 to 24 in 2017; 10) creating the MCC Research Network; 11) promoting communication throughout the MCC and catchment area with a new website and additional social media platforms; 12) fostering growth of the Clinical Research Office and creating the Clinical Research Enrollment and Development of Investigational Trials program to recognize faculty for clinical research efforts; 13) overseeing the expansion of space including a dedicated Precision Medicine Center (PMC) a new inpatient floor with 63 additional beds and dedicated administrative space for the MCC Affiliate and Research networks; 14) planning utilization of 2 MCC research floors (50329 sq. ft.) in the new Research Building 2 scheduled to open in 2018; 15) creating the MCC Community Outreach Program and establishing the annual Expressions of Courage event for cancer survivors; and 16) facilitating development and implementation of the 2017-2022 Strategic Plan.

project_terms:
Administrator;Award;Basic Science;Beds;Behavior;Behavioral Research;Biochemistry;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Survivor;Catchment Area;Clinical;Clinical Research;Clinical Trials;Collaborations;Communication;Communities;Community Outreach;Comprehensive Cancer Center;Development;Enrollment;Ensure;Evaluation;Event;Evolution;Faculty;Faculty Recruitment;Female;Floor;Fostering;Foundations;Funding;Funding Agency;Future;Goals;Grant;Growth;Infrastructure;Inpatients;Investigation;Kentucky;Leadership;Malignant Neoplasms;NCI Center for Cancer Research;Nursing Faculty;Reporting;Research;Research Activity;Research Personnel;Research Support;Resource Sharing;Resources;Role;Schedule;Secure;Seeds;Services;Site;Strategic Planning;Students;System;Technology;Toxicology;Training;Translational Research;Universities;Update;Vision;Woman;Work;anticancer research;base;biological research;cancer genomics;cancer prevention;cancer research center director;college;community based research;experience;innovation;meetings;member;outreach;outreach program;precision medicine;programs;recruit;social media;square foot;success;symposium;web site


application_id: 10469895
project_number: 5P20GM121327-05
administering_ic: NIGMS
award_notice_date: 2020-12-21
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: MCGUIRL, MICHELE
project_start_date: 2021-08-13
project_end_date: 2021-12-31
study_section: ZGM1-RCB-6(CI)
subproject_number: 9621
contact_pi_person_id: 11597020
contact_pi: FONG, KA-WING
other_pis: ZHOU, BINHUA P
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Androgen Receptor;Androgens;Binding;Cancer Center;Cancer Etiology;Cells;Cessation of life;Clinical;Complex;Consumption;DNA;Data;Deposition;Development;Disease;Enzymes;Epigenetic Process;Genes;Genetic Transcription;Genomics;Glucuronides;Growth;Histone H3;Kentucky;Lysine;Malignant neoplasm of prostate;Mediating;Metabolic;Metabolic Pathway;Metabolic hormone;Metastatic Prostate Cancer;Methyltransferase;Molecular;Oncogenic;Outcome;Pathway interactions;Prostate Cancer therapy;Receptor Activation;Repressor Proteins;Research;SETDB1 gene;Testing;Universities;advanced prostate cancer;androgen deprivation therapy;base;castration resistant prostate cancer;epigenetic silencing;genetic corepressor;genetic signature;genomic locus;inhibitor/antagonist;knock-down;men;new therapeutic target;novel;overexpression;prostate cancer cell;prostate cancer progression;steroid hormone;sugar;targeted treatment;transcription factor;tumor metabolism

public_health_relevance:
TRIM28 forms a transcriptional co-repressor complex with SETDB1 and was recently found to be aberrantly upregulated in advanced prostate cancer. In this proposed research I aim to demonstrate that the expression of the steroid hormone metabolic enzymes UGT2B15 and UGT2B17 which are involved in androgen elimination are epigenetically silenced by the TRIM28 complex. Targeting the TRIM28-SETDB1 axis should restore the androgen eliminating pathway and ultimately suppress castration-resistant prostate cancer progression.


application_id: 10469603
project_number: 5R21OD031964-02
project_title: Development of long-term preservation and revival protocols for Drosophila
administering_ic: OD
award_notice_date: 2022-07-16
opportunity_number: PAR-19-176
application_type: 5
activity_code: R21
ic: OD
serial_number: 031964
program_official: ZOU, SIGE
project_start_date: 2021-08-15
project_end_date: 2024-07-31
study_section: Development - 2 Study Section[DEV2]
contact_pi_person_id: 16031718
contact_pi: TEETS, NICHOLAS
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 Summary: This project will improve methods for cryopreserving the model organismDrosophila melanogaster thereby reducing the time and resources needed to maintain diversegenetic stocks. Two of the primary challenges for successful cryopreservation in Drosophila arepromoting uptake of cryoprotectants through embryonic membranes and overcoming the toxicityof these cryoprotective compounds. To address these challenges we will use a two-prongedapproach. First we will use dietary additives to increase cryoprotectants in fly embryos. Secondwe will optimize methods for using sonoporation to further augment cryoprotective moleculesand load embryos with LATE EMBRYOGENESIS ABUNDANT PROTEIN(s) (LEAPs) a class ofproteins that protect against osmotic stress and promote freeze tolerance. After optimizingloading of cryoprotectants and LEAPs we will vary freezing and thawing rates to identifyconditions that can successfully recover live flies from ultralow temperatures.Specific aims and research design: Specific Aim 1: Improving the efficacy ofsonoporation to introduce cryoprotectants into embryos. We have devised a modified dietthat increases trehalose and proline in embryos and here will optimize sonoporation methods tofurther augment cryoprotectant levels. Sonoporation uses ultrasonic frequencies in conjunctionwith lipid microbubbles to generate small pores in cells and drive uptake of solutes. We will usefluorescent molecules to optimize sonoporation methods and these optimized methods will thenbe used to load augment cryoprotectants and load LEAPs into embryos. LEAPs have previouslybeen shown to increase stress tolerance of D. melanogaster cell lines.Specific Aim 2: Investigate freezing and thawing strategies to improve cryopreservation.We will test the ability of cryoprotectant-loaded fly embryos to survive various freezing/thawingrates. Three different strategies to freeze (and subsequently thaw) fly embryos will be exploredusing established methods for insect cryopreservation.Significance: This project will significantly improve the efficiency by which cryoprotectivemolecules can be introduced into D. melanogaster embryos. Current cryopreservation methodsare technically challenging and inaccessible to most labs. The methods developed here willprovide routine inexpensive strategies for overcoming the impermeability of embryos to manycryoprotectants. Successful strategies will be tested in multiple commonly used geneticbackgrounds and mutant strains to test the extent to which these preservation strategies areeffective in different genotypes.

project_terms:
Address;Animal Model;Animals;Arthropods;Biomedical Engineering;Cell Line;Cells;Collaborations;Communities;Cost Savings;Cryopreservation;Data;Desiccation;Development;Devices;Diet;Disease;Drosophila genus;Drosophila melanogaster;Embryo;Embryonic Development;Erythrocytes;Freeze Drying;Freezing;Frequencies;Genes;Genetic;Genetic Research;Genetic Transformation;Genotype;Goals;Homo sapiens;Human;Insecta;Interdisciplinary Study;Lipids;Measures;Membrane;Methods;Microbubbles;Microfluidics;Molecular;Molecular Weight;Mutation;Nature;Organism;Postdoctoral Fellow;Preparation;Process;Production;Proline;Proteins;Protocols documentation;Research;Research Design;Resources;Seeds;Stress;Technology;Temperature;Testing;Time;Toxic effect;Trehalose;Ultrasonics;Water;authority;cold temperature;cost;dietary;dietary manipulation;dietary supplements;experience;fly;improved;mutant;novel strategies;nucleic acid delivery;preservation;prevent;solute;sonoporation;stress tolerance;success;training opportunity;undergraduate student;uptake

public_health_relevance:
The fruit fly (Drosophila melanogaster) is an outstanding model organism that possesses similargenes to nearly 75% of those causing disease in humans (Homo sapiens) but labs working withflies have no means to store them for prolonged periods. Thus fly labs invest substantialresources into continuous rearing of fly strains. In this project we will develop strategies forintroducing protective molecules into fly embryos that will facilitate routine storage of flies at lowtemperature.


application_id: 10469507
project_number: 5R44NS108804-04
project_title: Mimicking synuclein toxicity in plant cells to identify novel neuroprotective leads
administering_ic: NINDS
award_notice_date: 2022-08-19
opportunity_number: PA-19-272
application_type: 5
activity_code: R44
ic: NS
serial_number: 108804
program_official: GILCHRIST, FLOY ANNETTE
project_start_date: 2018-09-01
project_end_date: 2025-08-31
study_section: Special Emphasis Panel[ZRG1-ETTN-A(13)B]
contact_pi_person_id: 79296917
contact_pi: HUANG, CHIFU
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:
AbstractA general mechanism for neurodegeneration including Parkinson's disease and Alzheimer's dementia is thebreakdown and subsequent aggregation of misfolded neuronal proteins. In the synucleinopathies for exampleneurotoxicity is associated with the cleavage of mis-folded alpha-synuclein (ASYN) probably mainly byasparagine endopeptidase (AEP) [Zhang et al 2017]. This generates neurotoxic peptides that then aggregatewith ASYN in lysosomes forming the Lewy inclusion bodies associated with neurodegeneration. A very similarmechanism exists in plant cells in which plant AEP breaks down misfolded proteins to produce vacuolaraggregates associated with programmed cell death (PCD) [Hatsugai et al 2015]. However plants do notcontain ASYN so in order to mimic ASYN toxicity plant cells were transformed to express the misfolding-prone A53T variant of human ASYN (phase I). Thymoquinone was then used to trigger plant PCD [Hassanienet al 2013] and the plant cells expressing ASYN-A53T were shown to be significantly more susceptible to thistoxicity than controls. In phase II a mutant population of these transgenic (ASYN) plant cells will be selected forsurvival under this procedure. This is an example of target-directed evolution in which mutants that surviveselection should evolve toward increased biosynthesis of metabolites that inhibit AEP and/or ASYN toxicity.Individual mutant plant cell clones with ASYN-protective activity will be identified by screening extracts ofresistant cultures and micro-analytical methods [Kelley et al 2019] will then be used to identify activemetabolites as leads. Lobelia cardinalis cell cultures were used in phase I because we had previouslytransformed these with the human dopamine transporter gene to mimic MPP+-induced dopaminergicneurotoxicity [Brown et al 2016]. In phase II we will also use the medicinal plant Polygonum multiflorum whichcontains a stilbene that inhibits ASYN toxicity [Zhang et al 2018]. Phase II aims to identify novel leads thatengage the AEP and ASYN targets and to test the most promising of these in cellular and animal models ofsynucleinopathy. Leads will be developed with the University of Kentucky Parkinson's Disease ResearchCenter and a pharmaceutical partner. Identification of leads that engage these targets will also support target-directed evolution in mutant plant cells as a commercial platform for drug discovery.

project_terms:
1-Methyl-4-phenylpyridinium;Agrobacterium;Alzheimer's Disease;Anabolism;Animal Model;Apoptosis;Asparagine;Biotechnology;Cell Culture Techniques;Cell model;Cells;Chemicals;Clone Cells;Complementary DNA;Development;Directed Molecular Evolution;Endopeptidases;Enzymes;Exposure to;Foundations;Genes;Human;In Vitro;Inclusion Bodies;Individual;Kentucky;Lead;Lobelia;Lysosomes;Materials Testing;Mediating;Medicinal Plants;Methods;Modification;Molecular;Mutagenesis;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Neurotoxins;Parkinson Disease;Pathologic;Peptide Hydrolases;Peptides;Pharmacologic Substance;Phase;Plant Roots;Plants;Polygonum;Population;Procedures;Process;Proteins;Research;Resistance;Risk;Stilbenes;Substance Use Disorder;Technology Transfer;Testing;Therapeutic;Toxic effect;Transgenic Organisms;United States National Institutes of Health;Universities;Variant;aged;alpha synuclein;analytical method;asparaginylendopeptidase;base;commercialization;cytotoxic;dopamine transporter;drug discovery;expectation;gain of function mutation;inhibitor;misfolded protein;mutant;neurotoxic;neurotoxicity;novel;novel therapeutics;programs;screening;substance use treatment;synuclein;synucleinopathy

public_health_relevance:
Project narrativeSeveral human neurodegenerative diseases including familial Parkinson's disease share a mechanism inwhich the enzymatic modification and subsequent aggregation of a nerve cell protein called alpha-synucleinkills nerve cells. Plant root cells contain a similar enzyme but they do not contain alpha-synuclein. By creatingplant cells expressing human alpha-synuclein the applicants will be able to seek novel plant metabolites thatinhibit this neurotoxic process and that will lead to novel drugs to treat these devastating neurodegenerativediseases.


application_id: 10468226
project_number: 5R01HL149164-03
project_title: Length-dependent activation in human myocardium
administering_ic: NHLBI
award_notice_date: 2022-08-08
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 149164
program_official: ADHIKARI, BISHOW B
project_start_date: 2020-09-15
project_end_date: 2024-07-31
study_section: Clinical and Integrative Cardiovascular Sciences Study Section[CICS]
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH S
other_pis: TANNER, BERTRAND C.W.
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:
ABSTRACTThis translational project uses human biospecimens procured from organ donors and patients undergoingcardiac transplant to advance understanding of a cellular-level mechanism that underpins the Frank-Starlingrelationship. Specifically the project focuses on length-dependent activation defined as the increased maximumforce and Ca2+ sensitivity of contraction induced by myocardial stretch. The mechanisms that underlie length-dependent activation remain unclear but may involve thick-filament regulation and transitions between the newlydiscovered OFF and ON states of myosin.Co-PI Campbell has spent a decade building a biobank that now contains >10000 myocardial specimens from>360 patients. Pilot experiments performed by Co-PI Tanner with these samples show that length-dependentchanges in Ca2+ sensitivity are eliminated in myocardium from patients who have non-ischemic heart failure butpreserved in myocardium from organ donors and patients who have ischemic heart failure. New computermodeling predicts that these functional effects reflect destabilization of the myosin OFF state in patients whohave non-ischemic heart failure. This hypothesis is supported by additional experiments that used fluorescentpolarization techniques to assess OFF/ON dynamics in the thick filaments of human myocardium. Further pilotstudies tested the effects of peptides targeted to the thick filament. Peptides that stabilize the OFF state reducedthe Ca2+ sensitivity of contraction at long sarcomere length while destabilizing peptides enhanced Ca2+ sensitivityat short length. The length-dependence of these effects was predicted by our computer modeling.The project builds on these data from human biospecimens and integrates the skills and resources of fivecardiovascular researchers a statistician and a physician-scientist who specializes in advanced heart failure.The Aims explore the global hypothesis that length-dependent activation is reduced in patients who have non-ischemic heart failure because their cardiac thick filaments are biased towards the ON state.Aim 1: Test the hypothesis that length-dependent changes in Ca2+ sensitivity are reduced in myocardium from patients who have non-ischemic heart failure.Aim 2: Test the hypothesis that the OFF state of the thick filament is destabilized in myocardium from patients who have non-ischemic heart failure.Aim 3: Target OFF/ON transitions to manipulate the Ca2+ sensitivity of human myocardium.

project_terms:
American;Biochemical;Biological Assay;Biophysics;Calcium;Cardiac;Cardiomyopathies;Cardiovascular system;Computer Models;Data;Data Set;Dependence;Development;Disease;Electrophoresis;Genetic;Genomics;Head;Heart Transplantation;Heart failure;Histologic;Histology;Human;Impairment;Infarction;Kentucky;Length;Levosimendan;Mus;Muscle Cells;Muscle Contraction;Mutation;Myocardial;Myocardial Ischemia;Myocardium;Myosin ATPase;Organ Donor;Patients;Penetrance;Peptides;Pharmacologic Substance;Phenotype;Physicians;Physiologic pulse;Pilot Projects;Preparation;Property;Regulation;Research;Research Personnel;Resources;Sampling;Sarcomeres;Scientist;Specimen;Stretching;Structure;Sturnus vulgaris;Techniques;Testing;Thick Filament;Transplantation;Universities;base;biobank;biophysical techniques;design;experimental study;gel electrophoresis;genomic data;human data;organ transplant recipient;predictive modeling;preservation;skills

public_health_relevance:
NARRATIVEThis project analyzes samples of cardiac muscle procured from organ donors and patients who have heartfailure. Experiments will test how the muscle contraction changes as the samples are stretched and whether thecontraction can be modulated with specially designed molecules. The results of this project will accelerate thedevelopment of better therapies for patients who have different types of heart failure.


application_id: 10468197
project_number: 5R01AG069909-02
project_title: The role of satellite cells in skeletal muscle hypertrophy with aging
administering_ic: NIA
award_notice_date: 2022-04-18
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AG
serial_number: 069909
program_official: BOYCE, AMANDA T
project_start_date: 2021-08-15
project_end_date: 2026-04-30
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: MCCARTHY, JOHN JOSEPH
congressional_district: 06
department: OTHER CLINICAL 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: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Ablation;Adult;Affect;Age;Aging;Cell Communication;Cell Nucleus;Cell fusion;Cells;Characteristics;Chronic;Clinical;Collagen;Communication;Deterioration;Doxycycline;Elderly;Endothelial Cells;Exercise;Extracellular Matrix;Female;Fibroblasts;Fibrosis;Foundations;Gene Expression;Genes;Genetic Transcription;Grant;Growth;Human;Hypertrophy;Immunohistochemistry;Impairment;In Vitro;Label;Mechanics;Messenger RNA;MicroRNAs;Modeling;Molecular;Mononuclear;Morbidity - disease rate;Mus;Muscle;Muscle satellite cell;Muscular Atrophy;Natural regeneration;Output;Phenocopy;Plantaris muscle;Population;Population Dynamics;Process;Production;Quality of life;Reporter;Reporting;Rodent;Role;Skeletal Muscle;Stimulus;Systemic disease;Tamoxifen;Testing;Therapeutic;Therapeutic Uses;Time;Transcript;Wasting Syndrome;age related;aged;base;cell age;extracellular vesicles;human old age (65+);in vivo;intercellular communication;interest;male;mortality;mouse model;muscle aging;muscle form;muscle hypertrophy;novel;patient population;physical inactivity;prevent;progenitor;response;sarcopenia;satellite cell;single-cell RNA sequencing;skeletal muscle growth;skeletal muscle wasting;stem cells;transcriptome;transcriptome sequencing;young adult


application_id: 10468031
project_number: 5R01DA016718-15
project_title: Licit and Illicit Opioids: Comparative Studies in Humans
administering_ic: NIDA
award_notice_date: 2023-07-20
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DA
serial_number: 016718
program_official: WANG, JIA BEI
project_start_date: 2004-07-10
project_end_date: 2026-07-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: MISCELLANEOUS
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 Opioid misuse including prescription opioids heroin and fentanyl is epidemic in the United States andis associated with high morbidity and mortality. The current National Survey on Drug Use and Health estimatesthat at least 2.6 million people met criteria for an opioid use disorder (including prescription opioids and heroin).Opioid-related overdose deaths continue to climb with nearly 30000 deaths reported in 2014. Toxicologicalevidence from post-mortem studies reveals that polypharmacy is a very common finding in opioid-relateddeaths and it is especially common to find co-occurring substances with sedative properties. Despite thewidespread acknowledgment that non-opioid sedatives may enhance the risk of death from an opioidoverdose few controlled data exist on the pharmacodynamic effects of opioids in combination with theseagents and their co-prescription by providers is common. These studies aim to fill this critical knowledge gapby assessing agents with sedative properties that commonly are 1) prescribed with opioids (i.e.benzodiazepines gabapentin) 2) abused in combination with opioids and 3) found in combination at autopsy(benzodiazepines alcohol and gabapentin). Three inpatient human laboratory studies will be conducted thatemploy rigorous controlled experimental procedures to characterize the pharmacological interaction betweenoxycodone when taken in combination with either alprazolam (Experiment 1) alcohol (Experiment 2) orgabapentin (Experiment 3). Individuals with appropriate recreational drug use histories who are otherwisehealthy will be enrolled. An initial dose finding phase will precede each study to ensure subject safety andscientific rigor before proceeding to a robust randomized controlled design. The three studies will employrandomized placebo-controlled within-subject double-blind crossover designs and will be conducted in acontrolled hospital setting where appropriate medical supervision is available. Key safety outcomes includingexpired CO2 and other respiratory function indices pharmacodynamic measures related to abuse potentialand cognitive/psychomotor performance will be thoroughly examined over a range of doses for all drugs alone.Pharmacokinetic data (Exp. 1) will also be collected to assess the potential pharmacokinetic interaction as anunderlying mechanism of action and experimental analgesia/algesia data will be collected in Exp. 3 asgabapentin is commonly co-prescribed for pain relief with opioids. The analytic approach will include traditionalstatistics and modified isobolographic analyses to further elucidate the nature of the pharmacodynamicinteractions. The findings from these studies may directly inform prescribing practices and inform clinicalguidelines for physicians and other providers regulatory decision-making and may provide new information fortargeted interventions to reduce the harms of polysubstance prescribing and misuse.

project_terms:
Absence of pain sensation;Alcohols;Alprazolam;Autopsy;Benzodiazepines;Carbon Dioxide;Cessation of life;Characteristics;Clinical;Cognitive;Comparative Study;Crossover Design;Data;Decision Making;Dose;Double-Blind Method;Drug Controls;Drug Interactions;Drug Kinetics;Drug usage;Enrollment;Ensure;Epidemic;Fentanyl;Guidelines;Harm Reduction;Health;Heroin;Hospitals;Human;Individual;Inpatients;Intervention;Knowledge;Laboratories;Laboratory Study;Measures;Medical;Metabolic Pathway;Morbidity - disease rate;Nature;Opioid;Opioid agonist;Outcome;Overdose;Oxycodone;Pain Disorder;Persons;Pharmaceutical Preparations;Pharmacodynamics;Phase;Physicians;Physiological;Placebo Control;Polypharmacy;Procedures;Property;Provider;Psychomotor Performance;Randomized;Recording of previous events;Reporting;Research;Research Personnel;Respiratory physiology;Risk;Safety;Sedation procedure;Supervision;Surgeon;Surveys;Testing;Time;Toxicology;United States;Work;abuse liability;benzodiazepine abuse;cognitive performance;experience;experimental study;gabapentin;illicit drug use;illicit opioid;indexing;mortality;mortality risk;non-opioid analgesic;off-label use;opioid abuse;opioid misuse;opioid mortality;opioid overdose;opioid use disorder;overdose death;pain model;pain relief;participant safety;pharmacologic;prescription opioid;randomized controlled design;recreational drug use;safety outcomes;sedative;statistics;targeted agent;volunteer

public_health_relevance:
PROJECT NARRATIVEOpioid fatal and non-fatal overdoses have reached epidemic levels in the United States and many are theresult of combined use or misuse of opioids with other sedative-like substances. This research will provideimportant information on the relative safety and abuse-related risks of combining oxycodone with threedifferent classes of sedatives: benzodiazepines alcohol and gabapentinoids. The results of these studies mayinform medical prescribing practices and regulatory drug control.


application_id: 10467277
project_number: 1R01HL163977-01
project_title: Data-driven optimization of therapy for heart failure
administering_ic: NHLBI
award_notice_date: 2022-04-28
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 163977
program_official: SHANBHAG, SUJATA MADHUKAR
project_start_date: 2022-05-01
project_end_date: 2026-04-30
study_section: Modeling and Analysis of Biological Systems Study Section[MABS]
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH S
other_pis: LEE, LIK CHUAN ;WENK, JONATHAN F
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Algorithm Design;Algorithms;Area;Artificial Intelligence;Atrial Fibrillation;Baroreflex;Biophysics;Blood Circulation;Cardiac;Cardiology;Cardiovascular system;Caring;Clinical;Clinical Data;Computer Models;Computer software;Data;Data Analyses;Development;Devices;Dimensions;Doctor of Philosophy;EFRAC;Elements;Engineering;Enrollment;Foundations;Future;Geometry;Goals;Growth;Heart;Heart failure;Intelligence;Interdisciplinary Study;Intervention;Kentucky;Left ventricular structure;Machine Learning;Magnetic Resonance Imaging;Manuscripts;Microfilaments;Modeling;Molecular;Myocardial;Myosin ATPase;Paper;Patient-Focused Outcomes;Patients;Physiological;Physiology;Positioning Attribute;Pulmonary artery structure;Randomized Clinical Trials;Reflex action;Registries;Research;Research Personnel;Rewards;Running;Science;Scientist;Signal Transduction;Stress;Structure;Swarm intelligence;System;Techniques;Testing;Therapeutic;Therapeutic Intervention;Thick;Time;Universities;algorithm development;algorithm training;blood pressure control;blood pump;clinical care;computer program;gradient boosting;improved;innovation;laptop;novel therapeutic intervention;optimal treatments;outcome prediction;pressure;random forest;research vision;response;simulation;standard care;success;therapeutic evaluation;treatment optimization;ventricular assist device;wireless


application_id: 10466923
project_number: 5R01AI140195-05
project_title: Innate immunity and inflammatory response of macrophages to Legionella infection
administering_ic: NIAID
award_notice_date: 2022-08-08
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AI
serial_number: 140195
program_official: ERNST, NANCY L
project_start_date: 2018-09-14
project_end_date: 2024-08-31
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryDepending on the signals in vitro macrophages can undergo transient and reversible differentiationinto two main subsets: pro-inflammatory M1 (classically activated) or anti-inflammatory M2(alternatively activated) phenotype. Upon exposure of macrophages to high levels of glucose in vitroor in diabetic patients in vivo they undergo differentiation and activation into a M1 pro-inflammatorystate which produces pro-inflammatory cytokines mediated by cellular reprogramming of metabolismthrough upregulating aerobic glycolysis. The M1 pro-inflammatory differentiation of macrophages isan import arm of the innate immune response to control bacterial infections. Our preliminary datashow that when macrophages engulf the intracellular bacterial pathogen Legionella pneumophila(Lp) they rapidly respond by differentiation into an activated M1-like pro-inflammatory phenotype.Despite this rapid macrophage pro-inflammatory activation the Legionella-containing vacuole(LCV) bypasses macrophage activation by limiting its fusion to lysosomes. We show that the earlyM1-like pro-inflammatory differentiation of human monocytes-derived macrophages (hMDMs) toLp is an innate immune response to cytosolic hyper-glucose generated through rapid degradation ofglycogen by the injected Legionella amylase (LamA) effector. We discovered that Lp has evolved alysosomal degradation bypass pathway within the pro-inflammatory hMDMs by injecting the MavEeffector which becomes localized in a micro-domain on the cytosolic side of the LCV membrane.The mavE-deficient mutant is targeted by hMDMs to the lysosomes for degradation and the mutantis totally attenuated in vitro and in vivo. We have resolved the novel three dimensional crystal structureof MavE which shows a cytosolic surface-exposed domain with an NPxY eukaryotic motif involvedin binding to phosphotyrosine-binding adaptor proteins. Our central hypothesis is: the M1-like pro-inflammatory activation of hMDMs to Lp infection is an innate immune response to the cytosolichyper-glucose elicited by LamA and the pathogen utilizes MavE to bypass the innate immunemacrophage pathway of lysosomal degradation. To test the hypothesis our specific aims are:Specific Aim I: The mechanisms of M1-like pro-inflammatory differentiation of hMDMs inresponse to the effect of LamA; and Specific Aim II: The mechanisms of evasion of the innatemacrophage function of lysosomal degradation through utilization of a lysosomes bypasspathway mediated by MavE. Upon completion of our proposed studies we will discover themechanism of the innate pro-inflammatory response of macrophages to Lp and the lysosomaldegradation bypass pathway maneuvered by the pathogen to avoid a fatal fate.

project_terms:
3-Dimensional;Adaptor Signaling Protein;Amylases;Animal Model;Anti-Inflammatory Agents;Attenuated;Bacterial Infections;Binding;Bypass;Case Study;Crystallization;Cytosol;Data;Exhibits;Glucose;Glycogen;Glycolysis;Growth;Human;Immune;In Vitro;Infection;Infection Control;Inflammatory;Inflammatory Response;Innate Immune Response;Knowledge;Legionella;Legionella pneumophila;Legionnaires' Disease;Lung;Lysosomes;Macrophage Activation;Mediating;Membrane;Metabolism;Morbidity - disease rate;Mus;Natural Immunity;Pathway interactions;Phenotype;Phosphotyrosine;Proteins;Role;Side;Signal Transduction;Structure;Surface;Testing;Up-Regulation;Vacuole;aerobic glycolysis;arm;community acquired pneumonia;cytokine;diabetic patient;in vivo;innate immune mechanisms;innate immune pathways;macrophage;monocyte;mortality;mutant;novel;pathogen;pathogenic bacteria;response

public_health_relevance:
Project narrativeUpon exposure of macrophages to high levels of glucose in vitro or in vivo they undergodifferentiation and activation into a M1 pro-inflammatory state. Our proposed studies willdecipher the mechanisms of the pro-inflammatory response of human macrophages to higherlevels of intracellular glucose generated upon engulfing Legionella.


application_id: 10465560
project_number: 1F30NS124136-01A1
administering_ic: NINDS
award_notice_date: 2022-04-04
opportunity_number: PA-21-050
application_type: 1
activity_code: F30
ic: NS
serial_number: 124136
suffix: A1
program_official: CORRIVEAU, RODERICK A
project_start_date: 2022-05-08
project_end_date: 2025-07-07
study_section: Special Emphasis Panel[ZRG1 F03A-T (20)]
contact_pi_person_id: 15915830
contact_pi: SHADE, LINCOLN
other_pis: Not Applicable
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adult;Age;Aging;Alzheimer's Disease;Architecture;Autopsy;Bioinformatics;Biological;Biological Assay;Blood Vessels;Brain;Brain Pathology;Cells;Cerebrovascular Disorders;Cerebrovascular system;Cessation of life;Chromosomes;Clinical;Clinical Research;Cognitive;Complex;DNA Methylation;Data;Data Set;Dementia;Development;Diabetes Mellitus;Disease;Epidemiologist;Fellowship;Functional disorder;Gene Expression;Generations;Genetic;Genetic Risk;Genetic study;Genomics;Genotype;Hypertension;Impaired cognition;Individual;Internet;Knowledge;Memory;Mentors;Methods;Methylation;Modality;Molecular;Multiomic Data;Outcome;Participant;Pathologic;Pathology;Pathway interactions;Phenotype;Pilot Projects;Prefrontal Cortex;Preparation;Process;Research;Research Personnel;Resources;Risk;Risk Factors;Sampling;Source;Statistical Methods;Testing;Training Programs;Translating;United States National Institutes of Health;Update;aged;arteriole;brain arteriolosclerosis;career;case control;cell type;clinical risk;cohort;comorbidity;design;endophenotype;experience;functional genomics;genetic association;genetic risk factor;genome wide association study;genome-wide;hippocampal sclerosis;human old age (65+);insight;molecular phenotype;multidisciplinary;multiple omics;neuroimaging;neuropathology;new therapeutic target;recruit;religious order study;risk sharing;risk variant;skills;therapeutic target;trait;translational genomics


application_id: 10465311
project_number: 1F31DK131920-01A1
project_title: High fat diet-induced adrenergic dysfunction and resolution of adipose inflammation
administering_ic: NIDDK
award_notice_date: 2022-02-17
opportunity_number: PA-21-052
application_type: 1
activity_code: F31
ic: DK
serial_number: 131920
suffix: A1
program_official: BODDIE, THOMAS ARTIS
project_start_date: 2022-04-01
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZDK1 GRB-2 (J1)]
contact_pi_person_id: 14522014
contact_pi: PENA CALDERIN, ERNESTO HECTOR
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
project_abstract:
Excess nutrient consumption promotes systemic and tissue-specific inflammatory responses inhibiting insulinreceptor signaling pathways and prevents glucose uptake. Although specific molecular and cellular mechanismsthat lead to the development of insulin resistance remain unclear chronic inflammation is central to obesity-induced T2D. Diet-induced adipose tissue (AT) expansion with infiltration of classically activated macrophagesand production of pro-inflammatory cytokines perpetuates chronic inflammation and insulin resistance.Therapeutic approaches that directly interrupt innate immune responses are problematic however as they couldlead to immunosuppression and thus have limited therapeutic applicability. We have shown that persistentinflammation in diabetes and obesity is due to a deficiency in the processes that normally resolve inflammation.Nonetheless mechanisms by which obesity induces perturbations in pro-resolving pathways and promote thedevelopment of unmitigated chronic inflammation remains undefined. Physical inactivity contributes to increasedadiposity markers of inflammation chronic disease and premature death while physical activity protects againstthe development of obesity and chronic inflammation independent of reductions in weight. Cellular mechanismsby which physical activity protects against chronic inflammation however remain largely unknown. Recent workhas shown that resolution of inflammation is mediated in part by enzymatic (15-12- 5-lipoxygenase andcyclooxygenases) conversion of polyunsaturated fatty acids into specialized proresolving lipid mediators (SPMs;e.g. resolvins lipoxins maresins and protectins) that act to quell inflammatory signaling. Importantly our laband others have also shown that obese-diabetic mice treated with SPMs display elevated alternatively activatedmacrophages with reduced AT inflammation improved insulin sensitivity and enhanced wound healing capacity.Additionally our lab has shown that high fat diet-induced insulin resistance develops due to elevated pro-inflammatory lipid mediator leukotriene B4 (LTB4) production and that BLT-1 (LTB4 receptor) deficient mice areprotected against diet-induced insulin resistance a paradigm that also persists in atherosclerotic lesions. Thesefindings suggest that imbalanced production of pro-inflammatory and proresolving lipid mediators contribute toobesity-induced insulin resistance. Our preliminary data show that exercise increases AT SPM biosynthesis andis inhibited by short duration high fat diet (HFD) feeding. We also find that HFD inhibits exercise-inducedalternatively activated adipose tissue macrophages (ATM) levels. Interestingly adrenal gland expression ofbiosynthetic enzymes and catecholamine levelswhich our lab has previously shown to stimulate SPMbiosynthesis in macrophagesare reduced following HFD feeding. Thus we hypothesize that HFD-inducedadrenergic dysfunction inhibits the proresolving response to exercise in AT. In pursuit of the scientific questionsherein I will hone my basic laboratory skills learn advanced techniques develop professional skills and networkall of which will propel me towards achieving my goal of becoming an independent investigator in academia.

project_terms:
Academia;Adipocytes;Adipose tissue;Adrenal Glands;Adrenergic Agents;Adrenergic Receptor;Anabolism;Animals;Arachidonate 5-Lipoxygenase;Arterial Fatty Streak;CD59 Antigen;Catecholamines;Cells;Cessation of life;Chronic;Chronic Disease;Consumption;Data;Dental crowns;Development;Diabetes Mellitus;Diabetic mouse;Diet;Enzymes;Exercise;Functional disorder;Glucose;Goals;High Fat Diet;Immune;Immunohistochemistry;Immunosuppression;Individual;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Innate Immune Response;Insulin Receptor;Insulin Resistance;Interruption;Knowledge;LTB4R gene;Laboratories;Lead;Learning;Leukotriene B4;Lipoxins;Macrophage Activation;Measures;Mediating;Metabolism;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Obesity;Pathway interactions;Phenotype;Physical activity;Polyunsaturated Fatty Acids;Process;Production;Prostaglandin-Endoperoxide Synthase;RNA Interference;Research Personnel;Resistance development;Resolution;Signal Pathway;Signal Transduction;Sorting - Cell Movement;Structure;Techniques;Testing;Therapeutic;Tissue Expansion;Tissues;Weight;Work;cardiorespiratory fitness;cytokine;diet and exercise;feeding;glucose uptake;improved;inflammatory marker;insight;insulin sensitivity;lipid mediator;lipidomics;macrophage;magnetic beads;obesity development;physical inactivity;premature;prevent;receptor expression;response;sedentary;skills;systemic inflammatory response;wound healing

public_health_relevance:
PROJECT NARRATIVEChronic inflammation is a central feature in the development of obesity-induced insulin resistance and type 2diabetes. Although physical activity protects against adiposity and chronic inflammation the cellular mechanismsremain undefined. We will assess how exercise and diet contribute to the development of adipose tissueinflammation and diet-induced insulin resistance.


application_id: 10465282
project_number: 5R21AG070659-02
administering_ic: NIA
award_notice_date: 2022-06-10
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AG
serial_number: 070659
program_official: BENNANI-BAITI, MICHAEL
project_start_date: 2021-09-01
project_end_date: 2025-05-31
study_section: Biostatistical Methods and Research Design Study Section[BMRD]
contact_pi_person_id: 14549909
contact_pi: ZHENG, QI
other_pis: Not Applicable
congressional_district: 03
department: BIOSTATISTICS & OTHER MATH SCI
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
budget_start_date: 2022-06-01
project_title:
Global significance test based on quantile regression with applications to genomic studies of Alzheimers disease

project_abstract:
Project Summary/AbstractAlzheimer's disease (AD) is one of the leading causes of death for the elderly with no current cure. Genomicsstudies such as mapping expression quantitative trait loci (eQTL) and differential gene expressions play acritical role in understanding the biological mechanisms of AD and developing potential therapeutic treatments.In genomics studies there has been growing awareness that the covariates (e.g. quantitative gene expression)may have changing effects on the distribution of responses (e.g. disease phenotypes) reecting a heterogeneouscovariates-response association. Those heterogeneous associations shed insight on scientic discoveries andentail signicant implications but are often neglected by most existing analysis procedures conned to a narrowaspect of the response distribution (e.g. standard linear regression focusing on the mean or quantile regressionat a single quantile level). Thus the development of valid and efcient hypothesis tests to detect heterogeneousassociations is of great value to genomics studies of complex diseases such as AD. This proposal aims to develop several quantile regression-based global signicance tests which utilize allinformation across a well-chosen region of quantile levels and provide researchers with evaluations of the overallimpacts of covariates on the response. Inspired by our preliminary data analysis on the two studies of aging anddementia namely Religious Orders Study (ROS) and Memory and Aging Project (MAP) we will rst proposea global signicance test to thoroughly evaluate covariates' impact across all quantile levels of the responsevariable (Aim 1). Then motivated by high-dimensional genomics data of AD in ROS/MAP we will further developtwo global signicance tests for high-dimensional responses and covariates data respectively (Aim 2). Moreoverwe will apply the proposed tests in Aims 1-2 to the genomics data generated by ROS/MAP to identify eQTL anddifferentially expressed genes that can be used to prioritize risk genes of AD for identifying developing potentialtreatments (Aim 3). We will also provide a user-friendly R package to implement the proposed tests. The innovation of our proposal is three-fold. (i) By evaluating the impacts of covariates on responses acrossthe entire quantile domain the proposed global signicance tests have a superior power to identify heterogeneouscovariates-response associations compared to alternative methods. (ii) As the proposed tests neither impose anystringent model assumption nor require additional splines smoothing or re-sampling or shrinkage estimation theycan be broadly implemented in large-scale genomics data. (iii) Our proposed test in Aim 2 will serve as a usefultool for detecting heterogeneous associations between covariates and multiple responses. The successful completion of this project will facilitate detecting heterogeneous associations and thesubsequent scientic discoveries in AD genomics studies for developing treatments. Moreover our tests canbe applied to a broad scope of biomedical elds resulting in a fruitful avenue for promoting public health.

project_terms:
Affect;Age-Years;Aging;Alzheimer's Disease;Awareness;Biological;Biomedical Research;Brain Diseases;Cause of Death;Cohort Studies;Complex;Confounding Factors (Epidemiology);Data;Data Analyses;Dementia;Development;Dimensions;Disease;Disease regression;Elderly;Etiology;Evaluation;Foundations;Gene Expression;Gene Expression Profiling;Genes;Genetic Predisposition to Disease;Genomics;Goals;Heritability;Joints;Light;Linear Regressions;Memory;Methods;Modeling;Neurodegenerative Disorders;Pattern;Persons;Phenotype;Play;Probability;Procedures;Public Health;Quantitative Trait Loci;Research Personnel;Role;Sampling;Single Nucleotide Polymorphism;Standardization;Testing;Therapeutic;Tissue-Specific Gene Expression;United States;base;biological research;differential expression;disease phenotype;flexibility;follow-up;genome-wide;genomic data;genomic tools;high dimensionality;improved;innovation;insight;multidimensional data;neglect;novel;religious order study;research and development;response;risk variant;statistics;theories;tool;user-friendly

public_health_relevance:
NarrativeThe novel global signicance test methods developed out of this proposal will provide useful statistical toolsfor testing heterogeneous covariates-response associations in broad biomedical researches. Our methods forhandling data with high-dimensional responses and covariates will make our global tests especially useful forgenomic studies of complex diseases that deal with thousands of genes and millions of SNPs. The ndings out ofour application genomic studies about Alzheimer's disease will not only validate our test methods but also curatea list of risk genes that are potentially important for developing therapeutic treatment.


application_id: 10465270
project_number: 5R35ES028373-06
project_title: Environmental Liver Disease
administering_ic: NIEHS
award_notice_date: 2022-08-25
opportunity_number: RFA-ES-16-008
application_type: 5
activity_code: R35
ic: ES
serial_number: 028373
program_official: SCHUG, THADDEUS
project_start_date: 2017-09-15
project_end_date: 2025-08-31
study_section: ZES1-LWJ-K(R)
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Liver disease is a major global health problem. Fatty liver disease or excess accumulation of lipids inhepatocytes affects more than 25% of the worldwide adult population but children and adolescents may alsobe affected. Chronic liver disease may progress to cirrhosis and liver cancer resulting in liver-related death ortransplantation. Liver disease also impacts the development of diabetes and cardiovascular disease. Liverdiseases may be caused or influenced by exposures to environmental chemicals but this is an understudiedarea. To address these problems this project establishes a major integrative and collaborative researchprogram the Environmental Liver Disease Revolutionizing Innovative Visionary Environmental Health ResearchProgram (ELD-RIVER). ELD-RIVER will have a transformative impact in the field. The project investigates two broad scientificthemes: (i) the impact of endocrine and metabolism disrupting chemicals (EDCs/MDCs) in fatty liver diseaseand (ii) other liver diseases (such as liver cancer) associated with chemical exposures. The ELD-RIVER takes abroad integrative scientific approach by investigating relevant chemicals; nutrient:chemical interactions; bothanimal models and human subjects; and both sexes through state-of-the-art methods including multi-omics.EDC/MDC exposures may also impact liver disease through their effects on obesity and diabetes. Thus obesityand diabetes endpoints will also be evaluated. While the specific projects are expected to evolve over time the initial work focusses on exposures topolychlorinated biphenyls and vinyl chloride. Both of these chemicals currently rank in the top five in the Agencyfor Toxic Substances and Disease Registry (ATSDR) Substance Priority List. ELD-RIVER strictly adheres to theprinciples of scientific rigor and reproducibility and data transparency and availability. ELD-RIVER leveragesexisting collaborations between multiple organizations including academia government agencies industry andscientific/medical societies. The vision is for ELD-RIVER to become the global hub for environmental liverdisease research. To accomplish its translational mission the program integrates the work of basic scientistsepidemiologists and physicians. The project will also develop diagnostic biomarkers new treatments practiceguidelines and it has the potential to impact policy change. Along the way unique institutional education/trainingresources will be utilized so that ELD-RIVER will help produce the next generation of environmental healthscientists. The work proposed is relevant to Strategic Plan of the National Institute of Environmental HealthSciences (Themes 1 2 and 5 and Goals 1 4 7 and 8).

project_terms:
Academia;Address;Adolescent;Adult;Affect;Animal Model;Area;Cardiovascular Diseases;Cessation of life;Chemical Exposure;Chemicals;Child;Cirrhosis;Collaborations;Data;Development;Diabetes Mellitus;Endocrine;Environment;Environmental Health;Epidemiologist;Exposure to;Goals;Government Agencies;Health;Hepatocyte;Industry;Lipids;Liver;Liver diseases;Malignant neoplasm of liver;Medical Societies;Metabolism;Methods;National Institute of Environmental Health Sciences;Nutrient;Obesity;Physicians;Poison;Policies;Polychlorinated Biphenyls;Population;Practice Guidelines;Reproducibility;Research;Resources;Scientist;Strategic Planning;Time;Training and Education;Transplantation;Vinyl Chloride;Vision;Work;chronic liver disease;diagnostic biomarker;disease registry;environmental chemical;fatty liver disease;global health;human subject;innovation;next generation;programs;sex;translational goal

public_health_relevance:
Liver disease is an important health problem which may be caused or influenced by exposures to chemicals inthe environment. To study this problem this project establishes an integrative and collaborative researchprogram the Environmental Liver Disease Revolutionizing Innovative Visionary Environmental Health ResearchProgram (ELD-RIVER).


application_id: 10464893
project_number: 5R13DC016831-06
project_title: International Society for Neurogastronomy Symposium
administering_ic: NIDCD
award_notice_date: 2022-08-08
opportunity_number: PA-18-648
application_type: 5
activity_code: R13
ic: DC
serial_number: 016831
program_official: SULLIVAN, SUSAN L
project_start_date: 2017-09-26
project_end_date: 2024-03-19
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe objective of this conference grant request is to provide support for certain aspects ofthe annual meeting of the International Society of Neurogastronomy (ISN) for the next fiveyears. ISN is a relatively new society whose composition of scientists cliniciansnutritionists agricultural experts food service professionals and chefs naturallypredisposes it to focus on translational issues fundamental to how the chemical sensesimpact human health. The first two specific objectives are to provide a venue andopportunity that brings these groups together and facilitates the synergies that arise whendistinctly different fields interact productively. The third specific objective is to attract andstimulate the young scientists that are the future of the field of neurogastronomy. Thefourth specific objective is to do outreach that serves health and culinary professionals byinforming them about the impact that smell and taste has upon diet nutrition and thegrowing health problems of obesity-related diseases. The fifth specific objective is toensure that this new field embraces a culture of diversity weaving this principle into itsearly development by recruiting persons of diverse backgrounds to the conference.

project_terms:
Agriculture;Area;Chemicals;Clinical;Development;Diet;Diet Habits;Diet and Nutrition;Disabled Persons;Eating;Ensure;Environment;Equation;Equilibrium;Event;Faculty;Food;Food Services;Formulated Food;Fostering;Funding;Future;Goals;Grant;Health;Health Promotion;Human;International;Knowledge;Life;Mission;Neurosciences;Nutritional;Nutritionist;Obesity associated disease;Perception;Persons;Policies;Quality of life;Recruitment Activity;Science;Scientist;Smell Perception;Societies;Stimulus;Structure;Taste Perception;Training;Underrepresented Populations;Veterans;Work;design;drinking;food consumption;improved;interest;meetings;member;multisensory;outreach;preference;recruit;social;sound;symposium;synergism

public_health_relevance:
PROJECT NARRATIVEA major part of the mission of the International Society of Neurogastronomy (ISN) is topromote the study of flavor and its use to enhance the quality of human life channeling ourgrowing knowledge of neurogastronomy and chemosensory science into translationalaction needed to overcome the ways in which flavor preferences are often hijacked tocause unhealthy eating habits. ISN promotes cooperation between scientists and foodprofessionals towards altering the balance of this equation in our culture. ISNs annualmeeting provides an important mechanism for facilitating the interactions betweenchemosensory scientists neuroscientists clinicians nutritional scientists agriculturalscientists and food professionals needed to develop strategies for using flavor properly -strategies that are both practical and scientifically sound.


application_id: 10464584
project_number: 1F31DE031948-01
administering_ic: NIDCR
award_notice_date: 2022-02-22
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: DE
serial_number: 031948
program_official: SARE, RACHEL
project_start_date: 2022-08-15
project_end_date: 2024-08-14
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 15957875
contact_pi: COOPER, KELLEY N
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-08-15
project_title:
Mechanisms and Immune consequences of atypical efferocytosis of neutrophils during Porphyromonas gingivalis infection.

project_abstract:
PROJECT SUMMARY/ABSTRACTNeutrophils recruited to the sites of bacterial infection or inflammation eventually undergo apoptosis and arecleared in situ by phagocytic cells such as macrophages. Efferocytosis or the phagocytic uptake of apoptoticcells (AC) is a highly selective process that relies upon the recognition of apoptosis associated ligands suchas phosphatidylserine (PS) by efferocytic receptors on the engulfing cells. These interactions initiatedownstream signaling that shuts down inflammatory pathways and orchestrates the hydrolytic breakdown ofACs within phagosomes/efferosomes for their eventual clearance. Several pathogens can manipulateefferocytosis in order to subvert immune clearance. We found that the periodontal pathogen Porphyromonasgingivalis uses a novel mechanism to dysregulate efferocytosis by causing the uptake of live neutrophils in aPS independent manner possibly bypassing engagement and/or activation of PS binding efferocytic receptors.Our preliminary data show that this atypical efferocytosis of live cells resulted in sustained production of pro-inflammatory cytokines and a profound failure of macrophages to activate pro-resolution pathways. Wehypothesize that P. gingivalis mediated atypical efferocytosis perpetuates inflammation in periodontal diseaseand breakdown of immune tolerance. In Aim 1 of this proposal we will delineate specific signaling pathwaysthat mechanistically link ingestion of live neutrophils to the generation of proinflammatory cytokines. In Aim 2of this proposal we will determine whether ingestion of live neutrophils results in degradation delays due toincomplete maturation of the efferosomes resulting in diminished hydrolytic capacity. Defects in clearance ofACs within efferosomes is increasingly linked to chronic inflammation and autoinflammatory sequalae in alarge number of diseases. Overall the data generated from this grant will not only shed mechanistic insightsatypical efferocytosis caused by a P. gingivalis but will also be useful in designing new therapeutic approachesto abate chronic inflammation associated with periodontitis. Furthermore this application includes acomprehensive training plan that will enable me to strengthen my ability to define scientific questions andanswer them using the strong technical skillset and conceptual understanding. I will continue to expand myexpertise in areas of host-pathogen interactions innate immune responses and cellular signaling pathwaysand the knowledge and skill sets gained from the proposed training will be invaluable moving forward as Ipursue a career as an independent investigator.

project_terms:
Abate;Anti-Inflammatory Agents;Apoptosis;Apoptotic;Area;Autoimmune Diseases;Bacterial Infections;Binding;Bypass;CREB1 gene;Cell physiology;Cells;Chronic;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Data;Defect;Degradation Pathway;Digestion;Disease;Excision;Failure;Generations;Goals;Grant;Homeostasis;Immune;Immune Tolerance;In Situ;In Vitro;Infection;Inflammation;Inflammatory;Ingestion;Innate Immune Response;Kinetics;Knowledge;Left;Ligands;Link;Mediating;NF-kappa B;Necrosis;Neutrophil Infiltration;Oral;PTPN6 gene;Pathway interactions;Peptide Hydrolases;Periodontal Diseases;Periodontitis;Periodontium;Phagocytes;Phagosomes;Phenotype;Phosphatidylserines;Physiological;Porphyromonas gingivalis;Predisposition;Process;Production;Receptor Activation;Research Personnel;Resolution;Secondary Prevention;Signal Pathway;Signal Transduction;Site;Surface;Training;Trypsin;autoinflammatory;career;chronic infection;cytokine;design;gingipain;immune clearance;in vivo;insight;macrophage;neutrophil;new therapeutic target;novel;novel therapeutic intervention;oral pathogen;pathogen;pathogenic bacteria;periodontopathogen;receptor;receptor binding;response;skills;uptake

public_health_relevance:
NARRATIVEPeriodontal diseases are highly prevalent oral inflammatory diseases that cause the destruction of tooth-supporting structures and enhance susceptibility to several chronic inflammatory and autoimmune disorders. Inthe proposed studies we will determine how the oral pathogen Porphyromonas gingivalis dysregulatesclearance of dying cells leading to persistent inflammation. Understanding these mechanisms will provideopportunities for designing novel therapeutic targets in the treatment of periodontal diseases.


application_id: 10463617
project_number: 5R01AA028435-03
administering_ic: NIAAA
award_notice_date: 2022-08-04
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AA
serial_number: 028435
program_official: MURRAY, GARY
project_start_date: 2020-08-01
project_end_date: 2025-07-31
study_section: Special Emphasis Panel[ZRG1-IFCN-C(02)M]
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
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
budget_start_date: 2022-08-01
project_title:
Role of exosomes in the coordinated migration of neural crest cells and placodes and ethanol-induced teratogenesis

project_abstract:
Fetal Alcohol Spectrum Disorders (FASD) is the leading known cause of mental retardation. Growing evidencesuggests a major contribution of the disruption of neural crest cell (NCC) and placode (PC) migration to ethanol-induced craniofacial and cranial nerve defects. However there is a fundamental gap in understanding howethanol disrupts the coordinated migration of NCCs and PCs in embryos. Exosomes have recently emerged asan important mode of intercellular communication. Exosomes carry and transfer a variety of active moleculesincluding microRNAs to and act on local and distant recipient cells and affect their functions. We have recentlydemonstrated that exosomes derived from human NCCs mediated ethanol-induced repression of SDF1/CXCR4signaling and subsequently disrupted the coordinated migration of NCCs and PCs and that disruption of NCCand PC migration contributes to ethanol-induced craniofacial and cranial nerve defects in zebrafish embryos.The overall objective of this proposal is to elucidate the mechanisms by which exosomes mediate ethanol-induced repression of SDF1/CXCR4 signaling disruption of the coordinated migration of NCCs and PCs andcraniofacial and cranial nerve defects and to establish plant-derived exosome-like nanoparticles as a feasiblestrategy for the prevention of FASD. The central hypothesis of this project is that ethanol disrupts the coordinatedmigration of NCCs and PCs through NCC-derived exosome-mediated repression of SDF1/CXCR4 signalingsubsequently leading to craniofacial and cranial nerve defects and that modulation of SDF1/CXCR4 signalingby grape exosome-like nanoparticles (GELNs) or GELNs loaded with miRNA modulators can prevent ethanol-induced teratogenesis. To test our hypothesis the following specific aims will be addressed: Aim 1: Tocharacterize the role of exosomes in ethanol-induced disruption of the coordinated migration of NCCs and PCsin vitro and in zebrafish embryos. Aim 2: To elucidate the mechanisms by which NCC-derived exosomes mediateethanol-induced repression of SDF1/CXCR4 signaling and disruption of the coordinated migration of NCCs andPCs. Aim 3: To test the hypothesis that exosomes derived from NCCs mediate ethanol-induced craniofacial andcranial nerve defects and that modulation of SDF1/CXCR4 signaling by GELNs or GELNs loaded with miRNAmodulators represents a novel therapeutic strategy for preventing FASD. The proposed work is innovativebecause this is the first study attempting to prevent FASD through the newly recognized role of exosomes inintercellular communication and the actions of SDF1/CXCR4 signaling in modulating the coordinated migrationof NCCs and PCs. It also represents the first attempt to prevent FASD using edible plant-derived exosome-likenanoparticles. The proposed research is expected to characterize a novel exosome-mediated intercellularinteraction between NCCs and PCs during ethanol-induced teratogenesis. Such results will be significantbecause the insights gained from this study will help in elucidating the mechanisms underlying FASD and yieldexosome-based strategies for the prevention of FASD.

project_terms:
Address;Affect;Alcohols;CRISPR/Cas technology;CXCL12 gene;CXCR4 gene;Cells;Cephalic;Congenital Abnormality;Cranial Nerves;Craniofacial Abnormalities;Data;Defect;Distant;Edible Plants;Embryo;Ethanol;Fetal Alcohol Spectrum Disorder;Grapes;Human;In Vitro;Knowledge;Laboratories;Life;Mediating;Mental Retardation;MicroRNAs;Mission;Modeling;Molecular;National Institute on Alcohol Abuse and Alcoholism;Neural Crest Cell;Pathogenesis;Plants;Prevention;Prevention strategy;Public Health;Regulation;Repression;Research;Role;Signal Transduction;Site;Skeleton;Testing;Therapeutic;Therapeutic Intervention;Work;Zebrafish;alcohol effect;alcohol exposure;base;craniofacial;exosome;fetal;in vivo;innovation;insight;intercellular communication;migration;nanoparticle;novel;novel strategies;novel therapeutic intervention;prevent;preventive intervention;public health relevance;sensory system;teratogenesis;transcriptome sequencing;translational potential

public_health_relevance:
PUBLIC HEALTH RELEVANCE The proposed research is relevant to public health because the insights gainedby the accomplishments of the proposed studies will help in elucidating the molecular mechanisms underlyingethanol-induced birth defects and characterizing a novel exosome-mediated intercellular interaction betweenneural crest cells and placodes during ethanol-induced teratogenesis. These studies are expected to establishthe administration of edible plant-derived exosome-like nanoparticles as a novel strategy for the prevention ofhuman FASD. Thus the proposed research is relevant to the NIAAA's mission that pertains to using theknowledge gained in uncovering target sites for alcohol's action on the embryonic and fetal stages of life to begindeveloping potential therapeutic or preventative interventions.


application_id: 10463101
project_number: 1F31AA030172-01
project_title: Early environmental risk for the development of urgency and subsequent problem drinking
administering_ic: NIAAA
award_notice_date: 2022-02-09
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: AA
serial_number: 030172
program_official: RUFFIN, BEVERLY
project_start_date: 2022-04-24
project_end_date: 2024-04-23
study_section: Special Emphasis Panel[ZAA1 GG (32)]
contact_pi_person_id: 77814237
contact_pi: ATKINSON, EMILY A.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The proposed study aims to investigate longitudinally childhood maladaptive emotion socialization as a riskfactor for the development of urgency (the tendency to act rashly when experiencing strong emotions) andsubsequent problem drinking in adolescents. Identifying potentially modifiable antecedents of urgency isimportant because a large body of literature has implicated urgency in the risk process for adolescentproblematic drinking (as well as other impulsigenic behaviors such as bulimic behavior risky sex andgambling) (Berg et al. 2016; Coskunpinar et al. 2013; Fischer et al. 2008; Stautz & Cooper 2013).Adolescent drinking is associated with numerous public health harms including physical safety risks increasedrisk for psychiatric disorder increases in maladaptive personality traits and increased risk for premature death(Birkley et al. 2015; De Bellis et al. 2000; Hingson & Zha 2006; Kaminer 2016; Marshall 2014; Guller &Smith 2015). The relationship between urgency and problem drinking reciprocal such that increases in eachfactor precipitate increases in the other (Riley et al 2016). Though the relationship between urgency andproblem drinking has been studied extensively little is known about the etiology of urgency itself. Cyders andSmith (2008) proposed a developmental model of urgency in which childhood temperament and environmentalfactors increase risk for urgency but only temperament has been examined in the literature (Waddell et al.2021). Hersh and Hussong (2009) identified a significant relationship between negative parental emotionsocialization and increased substance use in adolescence and in our own work we found cross-sectionalassociations consistent with the hypothesis that urgency mediates the predictive influence of maladaptiveemotion socialization on adolescent drinking (Atkinson et al. under review). To date no studies haveexamined longitudinally the relationship between childhood maladaptive emotion socialization urgency andsubsequent problem drinking. The research component of this proposal involves a two-wave longitudinaldesign to (a) test whether maladaptive emotion socialization predicts increases in urgency (b) examine thepossibility that maladaptive emotion socialization predicts problem drinking mediated by urgency and (c)examine whether these relationships are invariant by race and gender in a sample of 9th grade students.Identifying environmental risk factors for the development of urgency will provide clear targets for earlyintervention and prevention efforts: interrupting the development of urgency is likely to reduce risk for problemdrinking and related behaviors. The training component of this proposal includes (1) the execution andmanagement of a longitudinal study in a public school setting including data collection liaising with schoolofficials and follow-up; (2) development of complex statistical analytic skills; (3) further advanced training inresearch ethics; (4) preparation of research reports for publication; (5) presenting original research atinternational scientific meetings; and (6) mentoring post-baccalaureate and undergraduate research assistants.

project_terms:
Addictive Behavior;Address;Adolescence;Adolescent;Adolescent and Young Adult;Alcohol abuse;Alcohol consumption;Asian;Award;Behavior;Binge Eating;Bulimia;Caregivers;Cessation of life;Child;Childhood;Clinical;Complex;Data Collection;Development;Dimensions;Disadvantaged;Distress;Early Intervention;Economically Deprived Population;Emotional;Emotions;Environmental Risk Factor;Ethnic Origin;Etiology;Exanthema;Expressed Emotion;Functional disorder;Future;Gambling;Gender;Goals;Hispanic;Informal Social Control;International;Interruption;K-Series Research Career Programs;Lead;Learning;Life;Link;Literature;Longitudinal Studies;Measures;Mediating;Mental Depression;Mental disorders;Mentors;Meta-Analysis;Modeling;Outcome;Parents;Participant;Personality Traits;Play;Precipitating Factors;Preparation;Prevention;Process;Prospective Studies;Public Health;Publications;Race;Regulation;Reporting;Research;Research Assistant;Research Design;Research Ethics;Risk;Risk Behaviors;Risk Factors;Role;Safety;Sampling;Schools;Scientist;Smoking;Socialization;Socioeconomic Status;Students;Temperament;Testing;Time;Training;Variant;Work;adolescent alcohol abuse;alcohol use disorder;base;design;drinking;experience;follow-up;high risk sexual behavior;high school;longitudinal design;meetings;multi-racial;ninth grade;premature;prevent;programs;sex;skills;substance use;therapy development;underage drinking;undergraduate research

public_health_relevance:
Urgency consistently predicts problem drinking and many other risky or addictive behaviors; however littleis known about the factors that contribute to the development of urgency. Identifying environmental riskfactors for urgency could inform the development of early intervention and prevention efforts aimed atreducing urgency and subsequent problem drinking. The proposed project is part of a developmentallysensitive program of research designed to examine the effects of environmental factors such asmaladaptive emotion socialization on later problem drinking via emotion-based risk factors.


application_id: 10462626
project_number: 5R01AR078316-02
administering_ic: NIAMS
award_notice_date: 2022-07-16
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AR
serial_number: 078316
program_official: WASHABAUGH, CHARLES H
project_start_date: 2021-08-05
project_end_date: 2027-05-31
study_section: Musculoskeletal Rehabilitation Sciences Study Section[MRS]
contact_pi_person_id: 10137938
contact_pi: NOEHREN, BRIAN
other_pis: FRY, CHRISTOPHER
congressional_district: 06
department: OTHER CLINICAL 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: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-06-01
project_title:
Sex-based Muscular Adaptations Capillary dysfunction and functional decline impact Knee-related psychosocial outcomes after acute knee injury (SMACK)

project_abstract:
AbstractFollowing an Anterior Cruciate Ligament (ACL) reconstruction females have worse outcomes; howeverskeletal muscle biology and function have preferentially been studied in males. These observations suggestthat there are sex-based differences in the biological mechanisms contributing to recovery of muscle function.Intriguing pilot data in this proposal show preferential impairment in the recovery of quadriceps muscle andfunction and diminished psychosocial recovery in females as compared to males following ACL reconstruction.This proposal seeks to test the novel hypothesis that following an ACL injury females experience exaggeratedmuscle cellular and molecular deficits hindering their recovery of strength resulting in pronounced deficienciesin gait mechanics and disproportionally worse psychosocial recovery compared to males. By identifying thecellular and molecular foundation of sex-based differences subsequent clinical trials can test sex specificapproaches to improve outcomes for women after ACL injury. We will in Aim 1 define the molecular cellularand morphological sex-based differences in quadriceps muscle after ACL injury and reconstruction. In Aim 2determine the effect of sex on knee function after an ACL reconstruction. Lastly in Aim 3 will determine thetiming and magnitude of psychosocial recovery differences between females and males following an ACLreconstruction. Results from this work will exert an immediate impact on clinical practice guidelines as well asidentify critical therapeutic targets needed to propel subsequent evidence-based clinical trials designed toimprove rehabilitative outcomes for females.

project_terms:
Acute;Atrophic;Biofeedback;Biological;Biology;Biopsy;Biopsy Specimen;Blood capillaries;Caring;Cellular Morphology;Clinical;Clinical Practice Guideline;Clinical Trials;Clinical Trials Design;Combined Modality Therapy;Complement;Data;Development;Exhibits;Female;Fiber;Foundations;Functional disorder;Future;Gait;Gene set enrichment analysis;Growth;Hypertrophy;Immunohistochemistry;Impairment;Injury;Intervention;Joints;Knee;Knee Injuries;Knee joint;Knowledge;Limb structure;Mechanics;Molecular;Molecular and Cellular Biology;Morphology;Muscle;Muscle Fibers;Muscle function;Operative Surgical Procedures;Orthopedic Surgery;Outcome;Pathway Analysis;Pathway interactions;Patient Outcomes Assessments;Pharmacology;Phenotype;Physical Function;Physical therapy;Positioning Attribute;Postoperative Care;Procedures;Protocols documentation;Recovery;Recovery of Function;Regenerative capacity;Rehabilitation Outcome;Rehabilitation therapy;Reporting;Self Efficacy;Skeletal Muscle;Testing;Time;Woman;Work;anterior cruciate ligament injury;anterior cruciate ligament reconstruction;base;clinical development;density;endurance exercise;evidence base;exercise training;experience;follow-up;functional decline;improved;improved outcome;knee mechanics;limb injury;male;multidisciplinary;muscle strength;new therapeutic target;novel;novel therapeutic intervention;psychosocial;quadriceps muscle;reconstruction;regenerative rehabilitation;resilience;response;response to injury;satellite cell;sex;statistics;surgery outcome;therapeutic target;transcriptome sequencing;vastus lateralis

public_health_relevance:
Project NarrativeAnterior Cruciate Ligament reconstructions are a common procedure resulting in significant impairments in thequadriceps muscle and females have worse outcomes than males. The identification of biological targetsunderlying poorer recovery in females after injury is lacking limiting the development of evidence-basedtherapies. We propose to define the muscle molecular and cellular sex-based differences underlying poorfunctional recovery the recovery of muscle function and gait mechanics as well as determine the timing andmagnitude of the psychosocial recovery differences between females and males to define sex as a biologicalvariable across scales to mitigate these differences in recovery through novel interventions.


application_id: 10462509
project_number: 5U18FD006408-05
administering_ic: FDA
award_notice_date: 2022-07-06
opportunity_number: RFA-FD-18-001
application_type: 5
activity_code: U18
ic: FD
serial_number: 006408
program_official: DAGRES, AARON
project_start_date: 2018-09-01
project_end_date: 2024-06-30
study_section: ZFD1-SRC(99)
contact_pi_person_id: 15008074
contact_pi: GILLIS, REBECCA
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-07-01
project_title:
Kentucky's Flexible Funding Model - Infrastructure Development and Maintenance for State Manufactured Food Regulatory Program.

project_abstract:
KENTUCKY CABINET FOR HEALTH AND FAMILY SERVICES DEPARTMENT FOR PUBLIC HEALTHRFA-FD-18-001FLEXIBLE FUNDING MODEL  INFRASTRUCTURE DEVELOPMENT AND MAINTENANCE FOR STATE FOOD REGULATORY PROGRAMS (U 18)SUMMARYThe goal of the Kentucky Food Safety Branch is to continue to be an active participant in the nationallyintegrated food protection system. Chief in accomplishing this goal as well as the goal of continuingprogram improvement is participation in the MFRPS. The five year Cooperative Funding Agreement hasallowed our state food protection program to address many of the identified gaps and obstacles andhas allowed our agency to implement a fully-functional MFRPS program in Kentucky. This in turn hasallowed our state to achieve and sustain significant to full conformance with the MFRPS.In summary the intended outcome of the Cooperative Agreement Funding Application is to furtheradvance efforts for a nationally integrated food safety system by utilizing available federal (FDA) fundingassistance thus allowing Kentucky's State Manufactured Food Regulatory Program to continuallyimprove and maintain full conformance with the Manufactured Food Regulatory Program Standards(MFRPS). The MFRPS program funding will be utilized to ensure that Kentucky's manufactured foodregulatory programs develop and maintain best practices for a high-quality regulatory program. Fullparticipation in the MFRPS program will assist our federal (FDA) partners in establishing a uniform basisfor measuring and improving the performance of manufactured food regulatory programs in the UnitedStates.

public_health_relevance:
MFRPS OutcomeThe intended outcome of the Flexible Funding Model  Infrastructure Development and Maintenancefor the Manufactured Food Regulatory Programs Standards (MFRPS) is to further advance efforts for anationally integrated food safety system that by utilizing available federal (FDA) assistance to allowKentucky to further develop and maintain best practices for a highquality regulatory program.Conformance and maintenance with the program standards will provide a uniform basis for measuringand improving the performance of Kentucky's manufactured food regulatory program assist Kentuckyin better direct regulatory activities at reducing foodborne illness hazards in plants that manufactureprocess pack or hold foods.


application_id: 10461977
project_number: 5R21DC019602-02
project_title: Hearing Healthcare Assessment in Rural Communities (HHARC)
administering_ic: NIDCD
award_notice_date: 2022-07-12
opportunity_number: RFA-DC-19-001
application_type: 5
activity_code: R21
ic: DC
serial_number: 019602
program_official: KING, KELLY ANNE
project_start_date: 2021-08-04
project_end_date: 2023-07-31
study_section: ZDC1-SRB-R(39)
contact_pi_person_id: 11512687
contact_pi: BUSH, MATTHEW LEE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Administrator;Adult;Affect;Appalachian Region;Area;Chronic;Communication impairment;Communities;Country;County;Depressed mood;Development;Diagnosis;Diagnostic;Disease;Education;Elderly;Employment;Enabling Factors;Enrollment;Environmental Risk Factor;Epidemiology;Evaluation;Face;Geographic state;Goals;Health;Health Personnel;Health Services Accessibility;Healthcare;Healthcare Systems;Hearing;Hearing Tests;Intervention;Kentucky;Lead;Life;Measurable;Medical;Methods;Morbidity - disease rate;Occupational;Outcome;Patients;Phase;Population;Positioning Attribute;Precede-Proceed Model;Predisposing Factor;Prevalence;Prevention;Primary Health Care;Protocols documentation;Provider;Public Health;Reinforcing Factor;Research;Resources;Rural;Rural Appalachia;Rural Community;Rural Health Centers;Time;United States;Vulnerable Populations;Well in self;barrier to care;base;care delivery;experience;health care availability;health care delivery;health care service;health care service utilization;hearing impairment;hearing loss treatment;improved;innovation;medical specialties;medically underserved;mortality;novel;pilot test;practice-based research network;preference;prevent;primary care services;programs;rural area;rural patients;rural underserved;screening;social;therapy development;treatment comparison;underserved community;urban setting;virtual;young adult


application_id: 10461939
project_number: 5R41NS122722-02
project_title: High-density optical tomography of cerebral blood flow and metabolism in small animals
administering_ic: NINDS
award_notice_date: 2022-06-17
opportunity_number: PA-18-870
application_type: 5
activity_code: R41
ic: NS
serial_number: 122722
program_official: AUBRECHT, TARYN GRACE
project_start_date: 2021-08-15
project_end_date: 2025-07-31
study_section: Special Emphasis Panel[ZRG1-ETTN-C(10)B]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078515036
primary_uei: HSZNRZ4JS954
duns_number: 078515036
uei: HSZNRZ4JS954
fips: US
organization_id: 10032228
organization_name: BIOPTICSTECHNOLOGY, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405131245
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTMany clinical situations including stroke expose the brain to insufficient cerebral blood flow (CBF) that cannotmaintain normal cerebral metabolic rate of oxygen consumption (CMRO2) requirements thereby leading tocerebral ischemic/hypoxic stresses and neurological disorders. Effective interventions are dependent on thefindings of CBF/CMRO2 improvement and eventually neural recovery. Rodents (mice and rats) make up 95% ofresearch animals. However one major limitation with neuroscience research in rodent models is lack ofaffordable noninvasive imaging technologies for continuous and longitudinal monitoring of CBF and CMRO2variations. Large imaging modalities (e.g. CT PET and MRI) require expensive instrumentation and are difficultto use for longitudinal monitoring. Portable inexpensive optical/ultrasonic technologies greatly expand choicesfor continuous cerebral monitoring although most systems lack the combination of high tempo-spatial resolutionwide field-of-view and proper penetration depth into deep brains. Moreover none of currently availabletechniques enable simultaneous imaging of CBF cerebral tissue oxygen saturation (StO2) and CMRO2. Toovercome these limitations researchers at University of Kentucky (UK) have developed an innovativeCCD/CMOS based speckle contrast diffuse correlation tomography (scDCT: US Patent #9861319) techniqueto accommodate noninvasive noncontact fast high-density 3D imaging of CBF distributions in mice rats pigletsand human neonates. While effective scDCT has not been optimized for dissemination and commercializationin terms of imaging performance (signal-to-noise ratio temporal-spatial resolution accuracy easy-to-use) andinstrument cost and portability. In collaboration with UK Bioptics Technology LLC (BOT) proposes to developoptimize validate and commercialize an affordable portable easy-to-use multi-wavelength scDCT (MW-scDCT) technique for repeated longitudinal imaging of CBF StO2 and CMRO2 distributions in rodents. Newmethodologies and algorithms will be developed to achieve a nearly real-time high-density 3D imaging ofcerebral function. The MW-scDCT will be rigorously tested and optimized using head-simulating phantoms withknown optical and hemodynamic properties (Aim 1). In vivo calibration and evaluation of absolute measurementswith MW-scDCT will be conducted against standard perfusion MRI and histological examination in rats with orwithout stroke (Aim 2). Finally optimized MW-scDCT devices will be disseminated to several neuroscienceresearchers inside and outside UK to collect feedback regarding instrument applicability and user experience.With preliminary feedback from these selected end-users we expect to identify refinements and improvementsneeded for the MW-scDCT in a continued Phase-II study to produce an optimal product-level device forcommercialization. The ultimate use will be expanded to larger animal models and human subjects. Howeverthis Phase-I project will begin with rodents as using small animals is easier more economical and efficient forcommercializing the device thereby paving the way for future commercialization of clinical-level devices.

project_terms:
3-Dimensional;Acute;Aging;Algorithmic Software;Algorithms;Animal Experimentation;Animal Model;Animals;Biological Markers;Biomedical Research;Brain;Brain Neoplasms;Brain imaging;Calibration;Cerebrovascular Circulation;Cerebrovascular Disorders;Cerebrum;Chronic;Clinical;Collaborations;Computer software;Development;Devices;Diffuse;Dyes;Evaluation;Feedback;Fluorescence;Functional Imaging;Funding;Future;Head;Histologic;Homeostasis;Human;Hypoxia;Image;Imaging Device;Imaging technology;Industrialization;Infant;Intervention;Investigation;Kentucky;Laboratories;Legal patent;Magnetic Resonance Imaging;Measurement;Measures;Medical;Metabolic;Metabolism;Methodology;Monitor;Mus;Neonatal;Neonatal Brain Injury;Neurologic;Neurons;Neurosciences;Neurosciences Research;Noise;Optical Tomography;Optics;Outcome;Oxygen;Oxygen Consumption;Pathologic;Pathology;Penetration;Performance;Perfusion;Phase;Positron-Emission Tomography;Property;Rattus;Recovery;Research Personnel;Resolution;Rodent;Rodent Model;Signal Transduction;Small Business Innovation Research Grant;Small Business Technology Transfer Research;Stress;Stroke;System;Techniques;Technology;Testing;Therapeutic Intervention;Three-Dimensional Imaging;Time;Tissues;Ultrasonics;United States National Institutes of Health;Universities;Variant;Work;base;brain health;clinical application;commercialization;cost;density;design;effective intervention;experience;hemodynamics;human imaging;human subject;imager;imaging modality;in vivo;innovation;instrument;instrumentation;light weight;metabolic rate;multimodality;neonatal brain development;neonate;nervous system disorder;non-invasive imaging;phase 1 study;phase 2 study;portability;pre-clinical;relating to nervous system;response;serial imaging;stress disorder;stroke model;therapeutically effective;tissue oxygenation;tissue phantom;tomography;tool;user-friendly

public_health_relevance:
PROJECT NARRATIVEContinuous and longitudinal monitoring of brain blood flow oxygenation and metabolism provides an opportunityto rapidly manage cerebrovascular diseases and neurological disorders. In collaboration with University ofKentucky Bioptics Technology LLC proposes to develop validate and commercialize an innovative affordableportable/mobile and ergonomic optical device for noninvasive noncontact fast high-density imaging of brainblood flow oxygenation and metabolism distributions in small animals (rodents). Completion of this STTRproject will provide a unique noninvasive brain monitoring tool for basic neuroscience research in numerousacademic and industrial laboratories.


application_id: 10461853
project_number: 5R01AI150767-03
project_title: Structure and function of Burkholderia contact-dependent growth inhibition (CDI) systems
administering_ic: NIAID
award_notice_date: 2022-08-19
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AI
serial_number: 150767
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2020-09-17
project_end_date: 2025-08-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 10751521
contact_pi: GARCIA, ERIN C
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:
ABSTRACTSocial interactions between bacteria impact infectious disease transmission and progression. The molecularmechanisms underlying bacteria-bacteria competition and communication also represent a largely unexploredset of therapeutic targets that could be manipulated to treat or prevent infections. Contact-dependent growthinhibition (CDI) is a phenomenon in which Gram-negative bacteria deliver the toxic C-terminus of a largepolymorphic surface protein (BcpA) to the cytoplasm of neighboring bacteria upon direct cell-cell contactinhibiting the growth of the targeted recipient cell unless it produces an appropriate immunity protein (BcpI).While CDI systems have been investigated almost exclusively for their ability to mediate inter-bacterialcompetition our previous work indicated that CDI systems also facilitate inter-bacterial communication byinducing specific gene expression and phenotypic changes in immune recipient bacteria (those producing theappropriate immunity protein BcpI). Thus CDI systems enable bacterial self/nonself discrimination throughseveral overlapping mechanisms all of which could be exploited therapeutically. However fundamental gapsin knowledge of CDI system molecular function prevent a clear understanding of how these proteins impactbacterial sociality and limit the development of CDI system-based antimicrobials decontaminants or vaccines.Thus our long term goal is to identify the molecular mechanisms underlying CDI system function towardmanipulating these proteins for the treatment or prevention of infectious disease. Our preliminary data showthat Burkholderia species provide a tractable model system for interrogating CDI system biology. This proposalseeks to understand how BcpA is delivered from one bacterium to another and how this process shapesbacterial behavior. Toward these goals the proposal tests the hypothesis that Burkholderia BcpA exchange iscontrolled by BcpA-specific domains recipient cell receptors and the physiological state of the recipient cellwhich together impact microbial community development. The proposed model will be tested by (1) identifyingthe recipient factors that impact BcpA import and (2) defining BcpA domains responsible for maintainingappropriate delivery to recipients and testing the role of BcpA delivery in Burkholderia communities. Togetherthis research will provide critical insight into a specific mechanism of bacterial cell-cell communication leadingto advancement in the prevention or treatment of bacterial infections.

project_terms:
Address;Anti-Bacterial Agents;Bacteria;Bacterial Adhesion;Bacterial Antibiotic Resistance;Bacterial Infections;Bacterial Proteins;Behavior;Binding;Biogenesis;Biological;Biological Models;Burkholderia;Burkholderia pseudomallei;Cell Communication;Cell surface;Cell-Cell Adhesion;Cells;Communicable Diseases;Communication;Communities;Community Developments;Complex;Cytoplasm;Data;Decontaminant;Development;Discrimination;Disease Progression;Ecology;Escherichia coli;Family;Foundations;Future;Gene Expression;Goals;Gram-Negative Bacteria;Growth;Immune;Immunity;Infection;Infection prevention;Investigation;Knowledge;Lipopolysaccharides;Mediating;Membrane;Membrane Proteins;Microbial Biofilms;Modeling;Modification;Molecular;Pathogenicity;Periodicity;Phenotype;Physiological;Play;Predisposition;Prevention;Process;Proteins;Receptor Cell;Research;Role;Shapes;Signal Transduction;Social Interaction;Structure;Surface;System;Systems Biology;Testing;Therapeutic;Toxic effect;Toxin;Vaccines;Work;antimicrobial;base;disease transmission;genetic approach;insight;microbial community;mouse model;new therapeutic target;novel therapeutic intervention;nuclease;prevent;protein function;receptor;social;therapeutic target

public_health_relevance:
PROJECT NARRATIVEMany bacteria including pathogenic Burkholderia species utilize specific surface proteins todeliver an anti-bacterial protein toxin to neighboring bacteria upon direct cell-cell contact. Ourproposed studies aim to determine the molecular requirements on both the `killer' and `target'cells for this inter-bacterial communication. By studying anti-bacterial proteins produced bythese bacteria this research will lay the foundation for the development of new antimicrobialtherapies against Burkholderia and other antibiotic resistant bacteria.


application_id: 10461752
project_number: 5R01CA258421-02
project_title: Gold-derived therapeutic compounds for disease application
administering_ic: NCI
award_notice_date: 2022-08-16
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 258421
program_official: FU, YALI
project_start_date: 2021-08-04
project_end_date: 2026-07-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 11956743
contact_pi: AWUAH, SAMUEL GORMAN
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_terms:
4T1;Adopted;Animals;Antineoplastic Agents;Apoptosis;Autophagocytosis;Biogenesis;Bioinformatics;Biological;Biology;Biometry;Breast Cancer Cell;Cancer Biology;Cancer Model;Cessation of life;Chemicals;Complex;Data;Development;Disease;Drug Kinetics;Drug Targeting;Electron Transport;Environment;Exhibits;FRAP1 gene;Fostering;Goals;Gold;Gold Compounds;Growth;Impairment;In Vitro;Inbred BALB C Mice;Knowledge;Lead;Libraries;Ligands;Locales;Malignant Neoplasms;Maximum Tolerated Dose;Medical;Metabolic;Metastatic Neoplasm to the Liver;Mitochondria;Modeling;Modification;Morphology;Neoplasm Metastasis;Normal Cell;Normal tissue morphology;Outcome;Oxidative Phosphorylation;Pathway interactions;Patients;Pharmacodynamics;Process;Prognostic Marker;Property;Proteins;Proteomics;Regimen;Research;Respiration;Respiratory Chain;Specificity;Structure;Structure-Activity Relationship;Synthesis Chemistry;Testing;Therapeutic;Therapeutic Agents;Therapeutic Index;Toxic effect;Work;analog;anti-cancer;anticancer activity;antitumor agent;antitumor effect;base;cancer cell;cell growth;clinical efficacy;clinical subtypes;comparative;drug development;drug discovery;effective therapy;improved;in vitro Assay;in vivo;innovation;insight;malignant breast neoplasm;mitochondrial dysfunction;mouse model;nanomolar;new therapeutic target;novel;novel strategies;novel therapeutic intervention;patient derived xenograft model;prevent;programs;rational design;response;scaffold;small molecule;targeted agent;targeted treatment;therapeutic target;tool;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor xenograft;uptake


application_id: 10461734
project_number: 5R01CA247365-04
project_title: Chemical Biology of the Control of Neddylation by DCN1
administering_ic: NCI
award_notice_date: 2022-06-29
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: CA
serial_number: 247365
program_official: FU, YALI
project_start_date: 2019-07-01
project_end_date: 2024-06-30
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 6620313
contact_pi: GUY, RODNEY KIPLIN
other_pis: SCHULMAN, BRENDA A;SINGH, BHUVANESH
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractThe long-term goal is to generate and use complimentary chemical and biological probes to study the cullinRING ubiquitin ligases (CRLs) and understand their activation controlled by the interaction of by the Defectivein Cullin Neddylation 1 (DCN1) and UBE2M proteins. Because the CRLs ultimately control ubiquitination of manydiverse proteins thus regulating their stability intracellular localization and function having spatiotemporalcontrol over DCN-mediated CRL activity has the potential to unravel the mechanism regulating key cellularsignaling networks and driving disease progression. The health relatedness of this project lies in two facts: 1)DCN1 is an oncoprotein amplified in squamous cell carcinomas that drives a highly malignant phenotype and2) CRL driven ubiquitination is a validated target in multiple diseases particularly cancer and immunedysfunction. Therefore inhibitors of the DCN1-UB2M interaction that are potent selective and bioavailable havethe potential to be developed as antitumor drugs and possibly for other diseases. Ubiquitination is regulated bya highly complex dynamic and redundant network. Inhibitors of DCN1-UB2M will allow direct interrogation ofthe function of sub-portions of the network and are likely to unveil fundamental principles of the regulationubiquitination. The generation of complementary cellular and mouse genetic models will enable independentverification of hypotheses. Finally the DCN1-UBE2M interaction requires N-terminal acetylation of UBE2M acommon posttranslational modification controlling protein interactions. Therefore a strategy for targeting N-terminal acetylation dependent protein interactions could be widely applicable. The research design andmethods for achieving these goals involves the integrated and recursive use of structure-driven hypothesis-based medicinal chemistry; in vitro biochemical measures of affinity and inhibitory potency; in vivo measures ofcompound efficacy and pharmacodynamic responses; and in vitro and in vivo measures of compoundbioavailability distribution metabolism excretion and toxicity. The overall goal is to develop new complimentarychemical and biological tools to understand the regulation of the ubiquitin-like protein NEDD8 and uncover thespecific role of DCN-mediated neddylation in Cullin-RING ligase substrate receptor exchange growth factorsignaling and driving tumor progression. Our aims are: Aim 1: Improve the potency and oral exposure of ourcurrent DCN1/2 inhibitors and generate new chemical probes with sufficient potency and selectivity to enableourselves and others to study the consequences of inhibiting this E2-E3 interaction in cells and animals. Aim 2.Investigate how the composition of cellular CUL1 and CUL3 ligases dynamically responds to environmentalperturbations and the importance of DCN1/2 in this process. Aim 3: Use genetic and pharmacologicalapproaches to study the effects of inhibiting DCN1 activity in animal tumor models.

project_terms:
3q26;Acetylation;Affinity;Amines;Amino Acids;Animals;Automobile Driving;Binding;Biochemical;Biological;Biological Availability;Biological Process;Biology;Bromodomain;C-terminal;CUL1 gene;CUL3 gene;CUL5 gene;Cell Nucleus;Cells;Charge;Chemicals;Clinical;Complex;Contact Inhibition;Cullin Proteins;Cytosol;Data;Development;Disease;Disease Progression;Drug Targeting;Enzymes;Excretory function;Family member;Foundations;Generations;Genetic;Genetic Models;Goals;Growth Factor;Health;Homeostasis;Human;Hydrophobicity;Immune System Diseases;In Vitro;Ligase;Ligation;Lysine;Malignant Neoplasms;Mammals;Measures;Mediating;Metabolism;Methionine;Modeling;Molecular;Mus;N-terminal;Names;Nature;Oncogenes;Oncoproteins;Oral;Pathway interactions;Pattern;Pharmaceutical Chemistry;Pharmacodynamics;Pharmacology;Phenotype;Post-Translational Protein Processing;Process;Proteasome Inhibitor;Protein Isoforms;Proteins;RBX1 gene;Regulation;Reporting;Research Design;Research Methodology;Role;Sequence Homology;Side;Signal Transduction;Squamous cell carcinoma;Structure;Substrate Specificity;System;Testis Brain;Tissues;Toxic effect;Ubiquitin;Ubiquitin Like Proteins;Ubiquitin family;Ubiquitination;antitumor drug;base;cancer therapy;clinically significant;combinatorial;drug discovery;improved;in vivo;inhibitor;knock-down;malignant phenotype;mouse genetics;novel therapeutics;pre-clinical;receptor;response;small molecule;spatiotemporal;success;three dimensional cell culture;tool;tumor;tumor progression;ubiquitin ligase;ubiquitin-protein ligase

public_health_relevance:
Project NarrativeDysregulation of the Cullin-RING ubiquitin Ligases (CRLs) which regulate the stability and interactionsof many proteins inside the cell is associated with a growing number of diseases including cancer. Thegoal of this proposal is to develop new complimentary chemical and biological tools to understand theregulation of the CRLs by the ubiquitin-like protein NEDD8. The proposed studies will provide useful toolsfor understanding key biological processes and may also lay the foundation for the development of noveltherapeutics for the treatment of cancer and other diseases.


application_id: 10461109
project_number: 5R01DA048892-03
project_title: DAT- Integrated Outpatient Treatment of Opioid Use Disorder and Injection-Related Infections
administering_ic: NIDA
award_notice_date: 2022-07-28
opportunity_number: PA-19-055
application_type: 5
activity_code: R01
ic: DA
serial_number: 048892
program_official: DUFFY, SARAH Q
project_start_date: 2020-09-30
project_end_date: 2024-08-31
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 14788426
contact_pi: FANUCCHI, LAURA
other_pis: LOFWALL, MICHELLE RENEE
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:
ABSTRACTDAT18-06: Hospitalizations for complications of opioid use disorder (OUD) like infectious endocarditis (IE) andother severe injection-related infections (SIRI) have increased dramatically along with the opioid epidemic.Persons with OUD hospitalized with SIRI often remain inpatient to complete prolonged intravenous (IV)antibiotic courses due to several assumptions such as 1) if outpatient patients will inject illicit drugs into the IVcatheter and will fail to complete prescribed antibiotic regimens and 2) if inpatient patients will not inject drugsbecause of the increased supervision and will complete the antibiotic regimen. No evidence supports theseassumptions and unfortunately the inpatient stay is not only very costly to the healthcare system butinfrequently includes comprehensive OUD treatment. In contrast outpatient parenteral antibiotic therapy(OPAT) via a peripherally-inserted central catheter (PICC) is the standard of care for continuing IV medicationsfor patients without injection drug use (IDU) once medically stable and is commonly used in treatmentinfections requiring prolonged IV antibiotics. OPAT is cost-effective associated with improved patientsatisfaction and with decreased risks of hospital-acquired infections. Development of innovative outpatientclinical models is urgently needed to improve the management and transition plan of persons with OUD andSIRI given the costs and risks associated with prolonged hospitalizations. We conducted a successful pilotproof-of-concept randomized study to establish the safety and feasibility of discharging inpatients with OUDand SIRI to complete IV antibiotics in an innovative integrated outpatient model combining BUP treatmentwith OPAT. This 12-week outpatient randomized parallel-group study builds on our preliminary work todemonstrate efficacy of the integrated outpatient care model (B-OPAT: BUP treatment with OPAT). Patientswith OUD and SIRI will be randomized (1:1) to either B-OPAT (n=45) or treatment-as-usual (TAU) (n=45) andcompared on the primary outcome of the proportion of urine samples negative for illicit opioids and on criticalsecondary outcomes including completion of recommended IV antibiotic therapy self-reported number of daysof illicit opioid abstinence and retention in outpatient treatment. The study will also incorporate acomprehensive economic evaluation of the integrated outpatient care model as well as a qualitativeinvestigation to inform future implementation and dissemination. These results will demonstrate the efficacyand cost effectiveness of an integrated outpatient care model to provide outpatient treatment of OUD and SIRIafter hospitalization.

project_terms:
Abstinence;Address;Adoption;Alcohol consumption;Ambulatory Care;Antibiotic Therapy;Antibiotics;Buprenorphine;Catheters;Client satisfaction;Clinical;Counseling;Criminal Justice;Development;Dissemination and Implementation;Dose;Drug usage;Effectiveness of Interventions;Endocarditis;Enrollment;Evidence based treatment;Health Care Costs;Health Care Sector;Health Services;Healthcare Systems;Home;Hospitalization;Hospitals;Illicit Drugs;Infection;Injections;Inpatients;Intervention;Interview;Intravenous;Investigation;Length of Stay;Medical;Medical Care Team;Methadone;Modeling;National Institute of Drug Abuse;Nosocomial Infections;Observational Study;Outcome;Outpatients;Participant;Patient Self-Report;Patient-Focused Outcomes;Patients;Peripheral;Persons;Pharmaceutical Preparations;Phase;Pilot Projects;Population;Productivity;Provider;Quality-Adjusted Life Years;Randomized;Randomized Clinical Trials;Reach Effectiveness Adoption Implementation and Maintenance;Regimen;Research;Resources;Risk;Running;Sampling;Schedule;Self Administration;Supervision;Testing;Time;Tobacco Use Disorder;Urine;Work;addiction;buprenorphine treatment;clinical practice;cost;cost effective;cost effectiveness;economic evaluation;effectiveness outcome;future implementation;health care model;health care service organization;health care settings;health economics;illicit drug use;illicit opioid;improved;injection drug use;innovation;opioid epidemic;opioid use;opioid use disorder;primary outcome;response;safety and feasibility;secondary outcome;standard of care;treatment as usual

public_health_relevance:
PROJECT NARRATIVEHospitalizations for severe injection-related infections have increased along with the opioid epidemic andsome of these infections require prolonged courses of intravenous (IV) antibiotic therapy. There are currentlyno outpatient care models that incorporate evidence-based treatment of opioid use disorder withbuprenorphine with management of IV antibiotics. Demonstration of a successful integrated outpatient modelincorporating buprenorphine treatment and outpatient parenteral antibiotic therapy may change current clinicalpractice improve patient outcomes and be cost-effective.


application_id: 10461098
project_number: 5F30HD103319-03
administering_ic: NICHD
award_notice_date: 2022-08-03
opportunity_number: PA-19-192
application_type: 5
activity_code: F30
ic: HD
serial_number: 103319
program_official: CHINN, JUANITA JEANNE
project_start_date: 2020-08-02
project_end_date: 2024-08-01
study_section: Special Emphasis Panel[ZRG1-F18-Z(20)]
contact_pi_person_id: 16164179
contact_pi: HANSEN, ANNA
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: 2022-08-02
project_title:
Social and biological determinants of pregnancy-related mortality and morbidity among rural underserved women

project_abstract:
ABSTRACT Over the past two decades the number of women dying from pregnancy-related causes in the UnitedStates has nearly doubled and cases of severe maternal morbidity have nearly tripled.2 3 Researchconcerning the factors influencing pregnancy-related mortality (PRM) and severe maternal morbidity (SMM)has previously neglected women in Central Appalachia despite the risk profile of this health disparatepopulation. This study utilizes a rigorous mixed methods approach guided by the conceptual framework foraction on the social determinants of health adopted by the World Health Organization to identify structural andintermediary determinants influencing Central Appalachian women's risk for SMM and PRM.1 4 This study is highly innovative in that it is the first study nationally outside the National Center for HealthStatistics (NCHS) to utilize a new database from the NCHS which links morbidity and mortality data.Furthermore it is the first known study to focus on SMM and PRM in women living in Central Appalachia andmay yield critical intervention insights for this underserved health disparate population. The following aims will:(1) Identify predictors of PRM and SMM in Central Appalachia. This aim will perform hierarchical logisticregressions on nation-wide data from the NCHS to determine risk and protective factors influencing women'srisk of SMM and PRM at delivery and one year postpartum.(2) Elucidate healthcare providers' and patients' perspectives on underlying mechanisms of PRM and SMM inCentral Appalachia. In-depth semi-structured interviews will be conducted with: (1) 10 patients who haveexperienced SMM and (2) 10 healthcare providers and 10 EMTs in Central Appalachia who have providedcare for patients experiencing SMM and PRM. The PI will leverage resources and expertise from the University of Kentucky's Center for Health EquityResearch Research Data Center and a highly supportive interdisciplinary mentorship team who are expertsin rural health disparities implementation science and maternal-fetal medicine. Mentorship by team memberswill provide the PI with ample training concerning the implementation of mixed methods studies projectmanagement responsible conduct of research and the dissemination of findings. This training will provide thePI with the skillset necessary to carry out the specific aims and lay the foundation for the PI to become anindependent physician-scientist with an extramurally supported research portfolio in the field of maternalhealth. Results from this study will produce essential knowledge concerning predictors of SMM and PRM in anat-risk population and identify factors influencing poor maternal outcomes which may be targeted by futureinterventions. Findings may also inform development of future empirical investigations into in other ruralpopulations.

project_terms:
Address;Adopted;Alaska Native;American;Appalachian Region;Biological;Caring;Cessation of life;Chronic Disease;County;Data;Data Set;Databases;Death Records;Detection;Development;Diabetes Mellitus;Diagnosis;Discipline of obstetrics;Disease;Distress;Emergency Medical Technicians;Epidemiology;Etiology;Evaluation;Evidence based intervention;Extramural Activities;Female of child bearing age;Foundations;Future;Health;Health Personnel;Healthcare;High Prevalence;Home;Hospitalization;Hypertension;Intervention;Interview;Investigation;Kentucky;Knowledge;Link;Location;Logistic Regressions;Maternal Health;Maternal-fetal medicine;Medical;Mentors;Mentorship;Methods;Mississippi;Morbidity - disease rate;Mothers;Native Americans;Organ;Outcome;Participant;Patient Care;Patients;Pattern;Persons;Physicians;Policies;Population;Populations at Risk;Postnatal Care;Postpartum Period;Postpartum Women;Poverty;Pregnancy;Pregnancy Complications;Pregnancy Outcome;Pregnant Women;Prevalence;Prevention;Provider;Regression Analysis;Research;Research Support;Residencies;Resources;Risk;Risk Factors;Rural;Rural Appalachia;Rural Population;Scientist;Structure;Sum;Training;United States;United States National Center for Health Statistics;United States National Institutes of Health;Universities;Validity of Results;Woman;World Health Organization;black women;burden of illness;cultural competence;data centers;evidence base;experience;health care availability;health disparity populations;health equity;health inequalities;implementation science;innovation;insight;maternal outcome;member;mortality;mortality risk;neglect;obstetric care;predictive modeling;prepregnancy;protective factors;research data dissemination;residence;responsible research conduct;rural area;rural health disparities;rural setting;rural underserved;secondary analysis;severe maternal morbidity;social;social determinants;social health determinants;sociodemographic factors

public_health_relevance:
This study elucidates social and medical determinants underlying death and severe morbidity attributable topregnancy in an underserved health disparate population namely rural Appalachian women. Findings mayinform the development of evidence-based culturally competent interventions among this population. Resultsmay inform development of future empirical investigations in other underserved rural populations (e.g. ruralwomen in the Mississippi Delta region and rural Native American women)..


application_id: 10460928
project_number: 5R21DA053324-02
administering_ic: NIDA
award_notice_date: 2022-07-28
opportunity_number: PAR-19-064
application_type: 5
activity_code: R21
ic: DA
serial_number: 053324
program_official: LYNCH, SEAN EDWARD WINTERS
project_start_date: 2021-09-01
project_end_date: 2024-08-31
study_section: ZDA1-SXM-M(09)S
contact_pi_person_id: 8423409
contact_pi: BORDERS, TYRONE FINLEY
other_pis: ZALLER, NICKOLAS D
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: 2022-09-01
project_title:
Clinician and Patient Experiences with COVID-19 Induced Rapid Transitions to Telehealth for Opioid Use Disorder Treatment

project_abstract:
AbstractThe COVID-19 pandemic has caused rapid changes in health care delivery from in-person to telehealthservices including the treatment of persons with opioid use disorder (OUD). Telehealth services (e.g.telephone calls and video-to-home or VTH) have been effectively used in psychiatry but we have verylittle information about primary care clinicians or patients experiences using telehealth for visitsassociated with medication for opioid use disorder (MOUD) (e.g. buprenorphine). Understanding theseissues among rural OUD patients during the COVID-19 pandemic is imperative because they are at highrisk of drug use relapse isolation and loneliness and mental health declines. We propose to conduct a mixed-methods study of rural primary care clinicians and patients receivingMOUD. We will conduct qualitative interviews among a sample of 30 rural primary care clinicians toevaluate their practices abilities and experiences using telehealth (telephone and VTH) to diagnose andtreat patients with OUD perceived or experienced facilitators and barriers to implementing telehealth andobservations about OUD patients treatment adherence. Simultaneously we will conduct quantitativesurveys among a sample of 250 patients who are receiving MOUD. The quantitative surveys will evaluateOUD patients perspectives of the acceptability of telehealth services experiences using telehealthservices treatment continuity and drug use outcomes. Specific Aims are to: 1. Describe (usingqualitative methods) rural primary care clinicians abilities and actual experiences transitioning totelehealth for patients receiving MOUD their evaluations of how patients drug use and mental healthchanged when transitioning to telehealth and characteristics of patients who did/did not adjust well totelehealth; 2. Identify (using quantitative methods) rural MOUD patients predictors of treatmentcontinuity satisfaction with telehealth services and preferences for in-person vs. telehealth services; and3. Identify (using quantitative methods) rural MOUD patients predictors of drug use relapse actualoverdose and overdose risk. This study is very time-sensitive during a time of rapid changes in the essential delivery of telehealthservices caused by the COVID-19 crisis that may have long-lasting implications for persons receivingtreatment for OUD.

project_terms:
Adopted;African American population;Age;Arkansas;Buprenorphine;COVID-19;COVID-19 pandemic;Characteristics;Diagnosis;Drug Prescriptions;Drug abuse;Drug usage;Ecology;Evaluation;Exploratory/Developmental Grant;Funding;Grant;Healthcare;Home;Interview;Kentucky;Loneliness;Medical;Mental Health;Methods;National Institute of Drug Abuse;Nurse Practitioners;Outcome;Patients;Persons;Pharmaceutical Preparations;Physician Assistants;Physicians;Population;Primary Care Physician;Primary Health Care;Psychiatry;Qualitative Methods;Relapse;Research;Rural;Sampling;Services;Substance Use Disorder;Surveys;System;Telephone;Time;Travel;Visit;clinical practice;demographics;experience;health care delivery;high risk;opioid use;opioid use disorder;overdose risk;practice setting;preference;recruit;relapse risk;response;rural area;satisfaction;telehealth;treatment adherence;treatment services

public_health_relevance:
NarrativeThe COVID-19 pandemic has caused rapid changes in health care delivery. This study will provide timesensitive information about primary care clinicians and patients experiences switching from in-person totelehealth services for the treatment of opioid use disorder that could be applied to better meet patientsneeds and reduce opioid use in the U.S.


application_id: 10459886
project_number: 3R35ES032876-01S1
project_title: Chromosome Instability Drives Metal-Induced Lung Cancer
administering_ic: NIEHS
award_notice_date: 2022-02-09
opportunity_number: PA-21-071
application_type: 3
activity_code: R35
ic: ES
serial_number: 032876
suffix: S1
program_official: CARLIN, DANIELLE J
project_start_date: 2022-02-09
project_end_date: 2024-06-30
contact_pi_person_id: 6094413
contact_pi: WISE, JOHN PIERCE
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY OF THE FUNDED PARENT GRANTLung cancer is the leading cause of cancer death with little improvement in survivability over many decades.Understanding and support for lung cancer have suffered from the stigma that the disease is merely aconsequence of tobacco use when in fact other agents are a major factor in the disease. Many people with lungcancer have never used tobacco and only a minority of tobacco users actually get lung cancer. However whilelung cancer kills more people than colon breast and prostate cancer combined it receives less federal fundingthan each of these cancers alone. Chromosome instability (CIN) is a hallmark of lung cancer. All establishedlung carcinogens cause CIN yet the mechanisms for how they do have received little attention. Metal exposureis a worldwide health concern. Metals cause lung cancer and carcinogenic metals are a component in tobacco.Metals are poor mutagens but potently induce CIN yet how metals cause lung cancer and CIN is poorlyunderstood. We focus our R35 program on understanding the mechanisms for how metal carcinogens induceCIN in lung cancer. We use hexavalent chromium [Cr(VI)] a human lung carcinogen of major public healthconcern as our primary metal of interest although we will compare Cr(VI) outcomes with other metal lungcarcinogens. We will study how Cr(VI) induces structural and numerical CIN considering human lung fibroblastepithelial and induced pluripotent stem cell models. We will progress our studies from individual cell types tomore complex three-dimensional mixed cell culture studies. We enhance and deepen our understanding ofthese mechanisms with a One Environmental Health approach which leverages the ability of wildlife to resistCr(VI)-induced CIN and provide novel insights into its carcinogenic mechanism. Moreover we maximize theimpact of these findings by translating our outcomes into animals and into a powerful and unique collection ofhuman subjects and populations ranging from workers with primarily Cr(VI) exposure to workers with a mixedmetal exposure including Cr. This combined approach of humans animals and cell lines with One EnvironmentalHealth tools will give us unprecedented insight into how metals induce structural and numerical CIN. In particularwe will define: 1) key mechanisms for metal-induced CIN; 2) how these mechanisms persist and are heritable atthe cellular level to cause neoplastic disease; and 3) how they translate to animals and humans. Thus ourproposed R35 program will revolutionize our understanding of Cr(VI) CIN metal carcinogenesis and lungcancer while also providing important insights for other cancers that involve CIN. Outcomes will include majorscientific breakthroughs in understanding: 1) how metals cause normal human lung cells to become neoplastic;2) how to detect this neoplastic transformation when it occurs; 3) how to more effectively target lung cells thathave transformed and 4) how to prevent neoplastic change from occurring leading to improved risk assessmenttreatments and health outcomes for people exposed to metals.

project_terms:
3-Dimensional;Address;Affect;Animals;Anti-Inflammatory Agents;Antiinflammatory Effect;Antioxidants;Attention;Automobile Driving;Beets;Betaine;Biological Markers;Breast Cancer Cell;Cancer Etiology;Carcinogens;Cell Line;Cells;Cessation of life;Chromosomal Instability;Collection;Colon Carcinoma;Complex;Data;Disease;Endothelial Cells;Environment;Environmental Health;Epithelial;Event;Exposure to;Fibroblasts;Food;Funding;Hazardous Substances;Health;Health Benefit;Heritability;Human;Individual;Inflammasome;Inflammation;Inflammatory;Inflammatory Response;Investments;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Metal Carcinogenesis;Metal exposure;Metals;Minority;Mus;Mutagens;National Institute of Environmental Health Sciences;Natural Products;Neoplastic Cell Transformation;Outcome;Particulate;Pathway interactions;Persons;Population;Property;Public Health;Rattus;Regulatory Pathway;Reporting;Risk Assessment;Risk Management;Role;Signal Transduction;Structure of parenchyma of lung;Tobacco;Tobacco use;Translating;Umbilical vein;United States;Work;Workplace;anti-cancer;cancer cell;carcinogenesis;carcinogenicity;cell type;chromium hexavalent ion;environment related cancer;genotoxicity;human subject;improved;in vivo;induced pluripotent stem cell;insight;interest;malignant breast neoplasm;mixed cell culture;neoplastic;novel;novel strategies;parent grant;potential biomarker;prevent;programs;repaired;response;social stigma;stem cell model;targeted biomarker;therapeutic target;tobacco user;tool;tumor progression

public_health_relevance:
PROJECT NARRATIVE OF THE FUNDED PARENT GRANTLung cancer is the number one cause of cancer death in the United States and metals are a major cause of thedisease. Our study focuses on how hexavalent chromium a metal with widespread exposure known to causelung cancer causes chromosome instability a hallmark event in lung cancer. Our findings will transform ourunderstanding of how metals cause chromosome instability and lung cancer which may spur new potentialtreatment targets new approaches to reduce and prevent metal-induced lung cancer and new insights to betterdetermine and manage safer exposure levels for this major public health concern.


application_id: 10459779
project_number: 1R56AG074613-01
administering_ic: NIA
award_notice_date: 2021-08-31
opportunity_number: PA-20-185
application_type: 1
activity_code: R56
ic: AG
serial_number: 074613
program_official: HSIAO, JOHN
project_start_date: 2021-09-01
project_end_date: 2022-08-31
study_section: Special Emphasis Panel[ZRG1-BDCN-W(02)]
contact_pi_person_id: 9562586
contact_pi: STOWE, ANN MARIE
other_pis: GERMAN, DWIGHT C.;ZHANG, RONG ;ZHU, DAVID C
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-09-01
project_title:
Biomarkers to track effective interventions that delay dementia onset in participants of the "Risk Reduction for Alzheimer's Disease (rrAD)" trial

project_abstract:
Project SummaryIt is often hard to distinguish between Alzheimers disease (AD) and AD-related dementias (ADRD) includingVascular contributions to Cognitive Impairment and Dementia (VCID) due to a similar clinical presentation ofmemory loss and the presence of cardiovascular (CV) risk factors (e.g. hypertension dyslipidemia). While CVrisk factors have available drug therapies increased physical activity also significantly lowers these co-morbidities. Unfortunately evidence linking CV and exercise interventions to the prevention of cognitive declineis inconclusive nor are biomarkers available to determine the efficacy of pre-dementia lifestyle interventions.This ancillary R01 will use plasma-based biomarkers and neuroimaging from subjects enrolled in our NIH-funded trial Risk Reduction for Alzheimers Disease (rrAD; NCT02913664). This phase II randomizedcontrolled trial will determine the independent and combined effects of Intensive pharmacological Reduction ofVascular Risk factors (IRVR; i.e. blood pressure lipids) and aerobic exercise (Ex) on cognitive function.Participants were randomized into 2-year interventions (IRVR Ex IRVR+Ex and a control arm of standardcare (SC)) with plasma and neuroimaging collected at baseline and yearly. Of the 513 rrAD subjects (63%females; 34% aged 71-85; 13% African-American; 4% Hispanic/Latino) 41% of enrolled subjects have finishedtheir 2-year follow-up. The rrAD trial is anticipated to be completed by the end of October 2021 with an overallattrition rate <15%. Banked longitudinal rrAD plasma samples will be used to test the hypothesis that 1)benchmark AD 2) benchmark VCID and/or 3) novel circulating brain-derived biomarkers can be modulated bypositive lifestyle interventions. Aim 1 will test if the benchmark AD biomarkers A42/A40 ratio will increasewhile pTau181 will decrease with IRVR+Ex. Higher ratios and lower tau will be associate with our secondaryoutcome measure of preserved hippocampal volume measured by 3D T1-weighted MRI as compared to SC.Aim 2 will test if primary benchmark endothelial VCID biomarkers will reveal effects of vascular and exerciseinterventions on cerebrovascular health. We will test if lower pathologic angiogenic proteins (i.e. VEGF-DPlGF bFGF) measured longitudinally decrease with intervention. Lower expression will coincide withsecondary outcome measures of increased regional cerebral blood flow (i.e. arterial spin labeling MRI) andfewer white matter hyperintensities (i.e. T2 FLAIR MRI). Aim 3 will test if vascular and exercise interventionsalter the neurotrophic cargo of circulating neuronal-enriched extracellular vesicles (EVs). We will test IRVR+Exlowers pro- (i.e. uncleaved) brain-derived neurotrophic factor (BDNF) and increases mature BDNF in neuronal-enriched EVs. Higher BDNF will coincide with the secondary outcome measure of stronger resting-statefunctional MRI connectivity associated with the default mode network. We hypothesize that AD VCID and EVbiomarkers not only identify individuals with high risk for AD/ADRDs but can also track efficacy of independentand combined lifestyle interventions that improve cerebrovascular health and delay dementia onset.

project_terms:
3-Dimensional;Address;Adult;Aerobic Exercise;African American;Age;Aging;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease related dementia;Alzheimer's disease risk;Alzheimers disease biomarker;Amyloid beta-Protein;Angiogenic Proteins;Benchmarking;Biological Assay;Biological Markers;Biological Specimen Banks;Blood;Blood - brain barrier anatomy;Blood Pressure;Blood Vessels;Blood specimen;Brain;Brain Ischemia;Brain-Derived Neurotrophic Factor;Cardiovascular system;Cell Communication;Cell surface;Cells;Cerebral small vessel disease;Cerebrovascular Circulation;Clinical;Clinical Trials;Cognitive;Data;Dementia;Dyslipidemias;Endothelium;Enrollment;Exercise;FGF2 gene;Family history of;Female;Functional Magnetic Resonance Imaging;Funding;High Prevalence;Hippocampus (Brain);Hispanics;Hypertension;Impaired cognition;Individual;Intervention;Latino;Life Style;Link;Lipid Binding;Lipids;Magnetic Resonance Imaging;Measurable;Measures;Memory;Memory Loss;National Institute of Neurological Disorders and Stroke;Neurocognitive;Neurons;Outcome Measure;PGF gene;Participant;Pathologic;Patients;Pharmacology;Pharmacotherapy;Phase;Physical activity;Plasma;Prevention;Randomized;Randomized Controlled Trials;Rest;Risk Reduction;Sampling;Signal Transduction;Site;Spin Labels;Structure;Testing;United States National Institutes of Health;Validation;Vascular Cognitive Impairment;Vascular Endothelial Growth Factor D;White Matter Hyperintensity;abeta deposition;aged;arm;base;blood lipid;brain health;cardiovascular disorder risk;cardiovascular risk factor;cerebrovascular health;cognitive function;cohort;comorbidity;effective intervention;exercise intervention;extracellular vesicles;follow-up;high risk;high risk population;improved;lifestyle intervention;nervous system disorder;neural network;neuroimaging;novel;particle;preservation;primary outcome;secondary outcome;specific biomarkers;standard care;tau Proteins;theranostics;vascular cognitive impairment and dementia;vascular risk factor

public_health_relevance:
Project NarrativeAlzheimers disease is a devastating neurologic disorder that will impact millions in the U.S. within thenext decades. This ancillary R01 will use blood specimens and neuroimaging from our NIH-funded trialRisk Reduction for Alzheimers Disease (rrAD) to identify biomarkers that track effective lifestyleinterventions to delay dementia in individuals with cardiovascular disease risks and at a high-risk forAD. We will utilize current benchmark biomarkers for 1) AD and 2) vascular contributions to cognitiveimpairment (VCID) along with 3) novel circulating brain-derived extracellular vesicles (EV) to identifymechanisms for the independent and combined neuroprotective effects of exercise and intensivecardiovascular risk reduction over the 2 years of trial enrollment.


application_id: 10459639
project_number: 5KL2TR001996-06
project_title: Institutional Career Development Core
administering_ic: NCATS
award_notice_date: 2022-07-19
opportunity_number: PAR-18-940
application_type: 5
activity_code: KL2
ic: TR
serial_number: 001996
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
arra_indicator: N
project_abstract:
PROJECT SUMMARY  KL2 INSTITUTIONAL CAREER DEVELOPMENT The University of Kentucky Center for Clinical and Translational Science (CCTS) proposes to sustain andenhance the current KL2 program currently in its ninth year of National Institutes of Health (NIH) support. Byproviding two to three years of release time (75% effort) and research funding support for mentored careerdevelopment the program is designed to accelerate the academic growth for the next generation of leaders inclinical and translational research (CTR). The program has four programmatic objectives: 1) to provide acurriculum that meets core training needs of CTR scholars 2) to support a mentored program of researchtraining that expedites development of research careers 3) to support personalized training programs thatexpedite CTR career development and 4) to provide continuous assessment and quality improvement of bothindividual scholar career development and overall KL2 program. The program has garnered strong institutionalsupport; across the nine years the initial two NIH-supported training slots have been expanded to seven slots(four NIH-supported three institutionally supported). The program supports career development of scholarswith research interests that cross the lifespan (prenatal through elderly) and the full spectrum of clinical andtranslational science including translational clinical community/policy studies and clinical and translationalresearch (CTR) methods/processes (e.g. biomedical informatics) focusing on a broad array of health topics.Scholars and mentors represent a wide range of disciplines and colleges including Medicine NursingDentistry Pharmacy Health Sciences Public Health Education Engineering and Arts and Sciences. Allprogram graduates (n=18) remain actively engaged in CTR have made important contributions to sciencethrough published research and have successfully competed for extramural funding with 14 as principalinvestigators. We are requesting renewed NIH support of four KL2 scholar training slots. The training of aminimum of three additional institutionally sponsored early-career scholars will continue to be fully integratedwith these NIH-supported scholars to sustain a cohort of at least seven scholars. The foundation of theproposed program will continue to be practical research experiences within multidisciplinary teams guided byexperienced mentors with a Faculty Oversight Committee monitoring the successful career development ofthese future CTR leaders. Educational technology promotes vigorous yet efficient competency trainingprograms. Further our enhanced team science training programs will focus specifically on developingleadership skills. Institutionally sponsored pipeline programs targeting undergraduates medical studentsresidents fellows and clinical instructors several focused on underrepresented minorities will support theavailability of a strong and diverse pool of candidates for the KL2 program. In sum the KL2 program isaccelerating the career development of future leaders of the biomedical research workforce who are wellprepared to address todays complex research challenges and spearhead future advances in human health.

project_terms:
Address;Arts;Biomedical Research;Clinical;Clinical Research;Clinical Sciences;Communities;Competence;Complex;Dentistry;Discipline;Discipline of Nursing;Educational Curriculum;Educational Technology;Elderly;Engineering;Extramural Activities;Faculty;Foundations;Funding;Future;Growth;Health;Health Sciences;Human;Individual;Kentucky;Leadership;Longevity;Medical Students;Medicine;Mentors;Monitor;Pharmacy facility;Policies;Principal Investigator;Process;Public Health Education;Publishing;Research;Research Methodology;Research Training;Science;Sum;Time;Training;Training Programs;Training Support;Translational Research;Underrepresented Minority;United States National Institutes of Health;Universities;biomedical informatics;career;career development;clinical center;cohort;college;design;experience;instructor;interest;multidisciplinary;next generation;prenatal;programs;research and development;skills;undergraduate student


application_id: 10459638
project_number: 5UL1TR001998-06
project_title: Kentucky Center for Clinical and Translational Science
administering_ic: NCATS
award_notice_date: 2022-08-10
opportunity_number: PAR-18-940
application_type: 5
activity_code: UL1
ic: TR
serial_number: 001998
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
arra_indicator: N
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;National Center for Advancing Translational Sciences;Neurosciences;Obesity;Participant;Patients;Persons;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: 10459637
project_number: 5TL1TR001997-06
project_title: NRSA Training Core
administering_ic: NCATS
award_notice_date: 2022-07-25
opportunity_number: PAR-18-940
application_type: 5
activity_code: TL1
ic: TR
serial_number: 001997
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: 1888410
contact_pi: RUSH, CRAIG R
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:
Contact PD/PI: Kern Philip A. NRSA-Training-001 (003)PROJECT SUMMARY  TL1 TRAINING PROGRAM The University of Kentucky (UK) Center for Clinical and Translational Science (CCTS) proposes to sustainand enhance the current pre-doctoral and post-doctoral TL1 program currently in its ninth year of NationalInstitutes of Health (NIH) support. By providing a multidisciplinary training program that integrates traineesacross diverse fields and offers rigorous and solid translational research education the TL1 program haseffectively prepared clinicians- and scientists-in-training for careers as leaders in clinical and translationalscience. The UK TL1 program features substantial collaborations across a robust cohort of productiveinvestigators a talented pool of qualified applicants solid infrastructure and strong institutional support. Theprogram takes advantage of the physical juxtaposition of UKs six health care colleges (Medicine NursingPharmacy Public Health Health Sciences Dentistry) and key disciplines on the main campus (e.g.Engineering Social Work Biology Psychology Education) to train scholars across wide-ranging fieldsnecessary for successful clinical and translational research (CTR). The program supports career developmentof scholars with research interests that cross the lifespan (prenatal through elderly) and the full spectrum ofclinical and translational science including translational clinical community/policy studies and CTRmethods/processes (e.g. biomedical informatics) focusing on a broad array of health topics. The TL1 traineesare making important contributions to science through published work and all of the program graduates areactively engaged in CTR. This program and other CCTS-sponsored efforts are engaging underserved studentsin projects focused on health disparities of Kentucky and the Central Appalachian area. We are requestingrenewed NIH support for eight TL1 scholars. The foundation of the proposed program will continue to bepractical research experiences within multidisciplinary teams guided by experienced mentors along witheducational and training offerings such as certificate Masters and PhD degrees to ensure successful careerdevelopment of these future CTR leaders. Scholar competency assessments based on the Clinical ResearchAppraisal Inventory serve to guide new program offerings with the theory that trainees who have highconfidence in their skills are more likely to pursue a career in CTR. UK CCTS-developed pipeline programstargeting professional and graduate students including new initiatives to support health equities researchersand trainees from under-represented groups will ensure the availability of a strong pool of candidates for theTL1 program. In sum the TL1 program is designed to accelerate career development of future leaders in thetranslational science workforce who will be prepared to address todays complex research challenges andspearhead advances in human health.Project Summary/Abstract Page 1236Contact PD/PI: Kern Philip A. NRSA-Training-001 (003)BIBLIOGRAPHY AND REFERENCES CITED1. Fowler BJ Gelfand BD Kim Y Kerur N Tarallo V Hirano Y Amarnath S Fowler DH Radwan M Young MT Pittman K Kubes P Agarwal HK Parang K Hinton DR Bastos-Carvalho A Li S Yasuma T Mizutani T Yasuma R Wright C and Ambati J. Nucleoside reverse transcriptase inhibitors possess intrinsic anti- inflammatory activity. Science 346:1000-3 2014. PMCID:PMC4274127.2. Ambati J Fowler B and Ambati K inventors; Compositions and Methods for Treating Retinal Degradation patent 20180044327. 2018 Feb 15 2018.3. Sherwood AR Johnson MB Delgado-Escueta AV and Gentry MS. A bioassay for Lafora disease and laforin glucan phosphatase activity. Clin Biochem 46:1869-76 2013. PMCID:PMC3864130.4. Albuquerque R Vora P and Bell N inventors; Provision Patent: System and Method for Assessment of Choroidal Blood Flow Noninvasively Using Color Amplification patent 13177N/2191US5. The CTSA Program at NIH: Opportunities for Advancing Clinical and Translational Research. Available at http://www.nationalacademies.org/hmd/Activities/Research/CTSAreview.aspx. Accessed 20196. Brown CA Jiang Y Smith CD and Gold BT. Age and Alzheimer's pathology disrupt default mode network functioning via alterations in white matter microstructure but not hyperintensities. Cortex 104:58-74 2018.PMCID:PMC6008234.7. Gupta VA Sousa M Kraitman N Annabathula R Vsevolozhskaya O Leung SW and Sorrell VL. Coronary artery calcification predicts cardiovascular complications after sepsis. J Crit Care 44:261-6 2018.8. Areephanthu CJ Bole R Stratton T Kelly TH Starnes CP and Sawaya BP. Impact of Professional Student Mentored Research Fellowship on Medical Education and Academic Medicine Career Path. Clin Transl Sci 8:479-83 2015. PMCID:PMC4626384.9. Bandura A. Self-efficacy: toward a unifying theory of behavioral change. Psychol Rev 84:191-215 1977.10. Mullikin EA Bakken LL and Betz NE. Assessing Research Self-Efficacy in Physician-Scientists: The Clinical Research APPraisal Inventory. Journal of Career Assessment 15:367-87 2007.11. Robinson GF Switzer GE Cohen ED Primack BA Kapoor WN Seltzer DL Bakken LL and Rubio DM. A shortened version of the Clinical Research Appraisal Inventory: CRAI-12. Acad Med 88:1340-5 2013.PMCID:PMC3758379.12. Pusek S Knudson B and Tsevat J. Personalized training pathways for translational science trainees: building on a framework of knowledge skills and abilities across the translational science spectrum. J Clin Transl Sci 2020 (in press).References Cited Page 1237

project_terms:
Address;Age;Alzheimer's disease pathology;Anti-Inflammatory Agents;Appalachian Region;Area;Behavioral;Biological Assay;Biology;Blood flow;Cardiovascular system;Career Choice;Caring;Certification;Clinical;Clinical Research;Clinical Sciences;Collaborations;Color;Communities;Competence;Complex;Dentistry;Discipline;Discipline of Nursing;Doctor of Philosophy;Education;Elderly;Engineering;Ensure;Equipment and supply inventories;Fellowship;Foundations;Future;Glucans;Gold;Health;Health Sciences;Healthcare;Human;Humpback Dolphins;Infrastructure;Journals;Kentucky;Knowledge;Lafora Disease;Legal patent;Longevity;Medical Education;Medicine;Mentors;Methods;National Research Service Awards;Nucleosides;Pathway interactions;Pharmacy facility;Phosphoric Monoester Hydrolases;Physicians;Policies;Postdoctoral Fellow;Process;Psychology;Public Health;Publishing;Research;Research Activity;Research Methodology;Research Personnel;Retina;Reverse Transcriptase Inhibitors;Science;Scientist;Self Efficacy;Sepsis;Social Work;Solid;Sum;System;TNFSF15 gene;Talents;Training;Training Programs;Translational Research;Underrepresented Populations;United States National Institutes of Health;Universities;Work;base;biomedical informatics;career;career development;clinical center;cohort;college;coronary artery calcification;design;education research;experience;graduate student;health disparity;interest;multidisciplinary;pre-doctoral;prenatal;programs;skills;student mentoring;theories;underserved students;white matter


application_id: 10459548
project_number: 5R21ES033323-02
project_title: Cardiovascular Benefits of Inhaled Biogenic Volatile Organic Compounds
administering_ic: NIEHS
award_notice_date: 2022-07-29
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: ES
serial_number: 033323
program_official: SCHUG, THADDEUS
project_start_date: 2021-08-01
project_end_date: 2024-07-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
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:
Program Director/Principal Investigator (Last First Middle): Conklin Daniel J. Ph.D.ABSTRACTExtensive epidemiological evidence suggests that exposure to vegetation and residential proximity togreenspaces lowers the risk of all-cause mortality cardiovascular disease anxiety depression and aggression.Although it has been suggested that urban greenspaces exert their beneficial effects by removing air pollutantsand promoting physical activity plants emit biogenic volatile organic chemicals (BVOCs) which by elicitingbeneficial cardiovascular and neurological effects could mediate the salutary effects of vegetation. Vegetation isa major underappreciated domain of the natural environment that has received limited interest. Exposure togreenspace within the natural environment has been linked to improvements in cardiovascular health. Wepropose that plant-derived BVOCs including pinenes limonene and citronellol stimulate distinct signalingpathways in part by activating the transient receptor potential ankyrin-1 (TRPA1) channel on cardiovasculartargets. In endothelial cells for example activation of TRPA1 releases nitric oxide that lowers blood pressureimproves cardiovascular function and tamps down inflammation and thrombosis leading to an overall decreasein cardiovascular disease risk. Completion of this project will rigorously establish beneficial cardiovascular effectsof inhaled BVOCs that are prevalent in human environments. Moreover our studies will provide a first test ofhypothesis that beneficial effects of inhaled BVOCs are mediated in part by TRPA1. These preclinical studiesmay also lead to the development of biomarkers of exposure to greenness which likely will be useful in clinicalevaluation of the potential therapeutic use of greenness (e.g. planting trees) to decrease CVD risk in humanpopulations.PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

project_terms:
ANK1 gene;Acute;Adult;Affect;Aggressive behavior;Air Pollutants;Anti-Inflammatory Agents;Antiinflammatory Effect;Anxiety;Attention;Blood Pressure;Blood Vessels;Cardiac;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Cell physiology;Cells;Chemical Exposure;Chrysanthemum;Cypress;Data;Doctor of Philosophy;Endothelial Cells;Endothelium;Environment;Environmental Risk Factor;Epidemiology;Eucalyptol;Exposure to;Female;Frequencies;Future;Green space;Health;Heart Rate;Human;Inflammation;Inflammatory;Inhalation;Intravenous;Juniper;Knowledge;Lead;Life Style;Link;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Mental Depression;Metabolism;Molecular;Monoterpenes;Mus;National Institute of Environmental Health Sciences;Neurologic Effect;Nitric Oxide;Oral;Pathway interactions;Pharmacology;Physical activity;Physiological;Plants;Population;Principal Investigator;Production;Radio;Rattus;Risk;Role;Screening procedure;Shapes;Signal Pathway;Signal Transduction;Sleep;Stress;TRPA channel;Telemetry;Testing;Therapeutic Uses;Thrombosis;Time;Trees;United States;Vasodilation;Work;aerosolized;anti-cancer;biomarker development;blood pressure reduction;cardioprotection;cardiovascular disorder risk;cardiovascular effects;cardiovascular health;dosimetry;heart rate variability;hemodynamics;hypertensive;improved;in vitro Assay;indoor air;interest;lifestyle factors;limonene;linalool;male;mortality;normotensive;preclinical study;prevent;programs;receptor;research clinical testing;urinary;volatile organic compound

public_health_relevance:
Program Director/Principal Investigator (Last First Middle): Conklin Daniel J. Ph.D.NarrativeWe propose that plant-derived biogenic volatile organic chemicals (BVOCs) including pinenes limonene andcitronellol stimulate distinct signaling pathways in part by activating the transient receptor potential ankyrin-1(TRPA1) channel on cardiovascular targets. In endothelial cells for example activation of TRPA1 releases nitricoxide that lowers blood pressure improves cardiovascular function and tamps down inflammation andthrombosis leading to an overall decrease in cardiovascular disease risk. Completion of this project will verifybeneficial cardiovascular effects of inhaled BVOCs and also lead to the development of biomarkers of exposureto greenness.PHS 398/2590 (Rev. 06/09) Page Continuation Format Page


application_id: 10459472
project_number: 5P30AG072946-02
project_title: Core G: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2022-07-08
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9600
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: Research Education ComponentThe Research Education Component (REC) of the UK-ADRC offers a variety of research educational activitiesand comprehensive mentored research skills development programs that will enhance the development of thefuture workforce to meet the nations biomedical behavioral and clinical needs in Alzheimers disease andrelated dementias (ADRD) research. The REC will leverage resources within and outside the UK-ADRC tocreate an outstanding multidisciplinary and collaborative environment for training the next generation ofresearchers in scientific areas that parallel the theme of our ADRC (Transitions from Normal to Late-Life Multi-Etiology Dementias) and with an emphasis on increasing representation of researchers from diversebackgrounds. We will continue to build on a long history of collaborative and dedicated faculty a strongfoundation in multidisciplinary team science and an outstanding track record of success in mentoring andeducation of researchers across the training spectrum. We will also establish a new REC Scholar programaimed at junior investigators (Assistant Professors senior research associates or clinical fellows). Thisprogram will support junior investigators from diverse multidisciplinary fields to pursue mentored basictranslational or clinical research in ADRD and follow a customized training plan to help the scholars movetoward their career development goals. This training will be done in a supportive and collaborative academicenvironment with substantial training resources and an experienced and dedicated training faculty. Scholarswill have the opportunity to learn state-of-the-art research skills in disciplines that have been identified ascritically needed areas for the ADRC workforce of the future. Examples of training areas where the UK-ADRChas strong expertise include analysis of longitudinal clinical outcomes clinical trial design MRI imaging andnovel fluid biomarkers quantitative neuropathology and AD mimics data analysis/ study design in mixeddementias and health literacy and inequities. REC goals will involve interactions with all the UK-ADRC Coresand will be achieved through the following specific aims.Aim 1. Provide education programs and research skills development opportunities for investigators at UK.Aim 2. Identify select support and retain REC scholars from diverse backgrounds and disciplines to engagein ADRD research.Aim 3. Develop an individualized mentoring plan and educational program for each REC scholar to enableadvancement to independent research and funding in ADRD research.Aim 4. Evaluate progress of the REC scholars address barriers towards the goal of independence in ADRDresearch and refine delivery of the programs educational structure and processes.Following completion of the Program participants will have the knowledge expertise and confidence tosuccessfully pursue a long-term career in dementia research.

project_terms:
Achievement;Address;Advisory Committees;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimer's disease related dementia;Area;Basic Science;Behavioral;Biological Markers;Clinical;Clinical Research;Clinical Trials Design;Communities;Competence;Custom;Data Analyses;Dementia;Development;Discipline;Early Diagnosis;Education;Educational Activities;Elderly;Environment;Etiology;Exposure to;Faculty;Foundations;Funding;Future;Goals;Image;Individual;Interdisciplinary Study;Kentucky;Knowledge;Leadership;Learning;Liquid substance;Magnetic Resonance Imaging;Mentors;Monitor;NCI Scholars Program;Outcome;Participant;Postdoctoral Fellow;Prevention Research;Process;Program Development;Recording of previous events;Research;Research Design;Research Personnel;Research Project Grants;Resources;Science;Scientist;Standardization;Structure;System;Teacher Professional Development;Training;Training Programs;Translational Research;Universities;career;career development;collaborative environment;education research;experience;health inequalities;health literacy;high school;improved;innovation;instrument;investigator training;longitudinal analysis;mixed dementia;multidisciplinary;neuropathology;next generation;novel;prevent;professor;programs;recruit;skill acquisition;skills;success;therapy development;training opportunity;treatment research;undergraduate student


application_id: 10459471
project_number: 5P30AG072946-02
project_title: Core F: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2022-07-08
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9599
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adopted;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimers disease biomarker;Biological Markers;Blood;Brain Pathology;Cerebral small vessel disease;Clinic;Clinical;Cognitive;Collection;Complex;Consensus;Data;Dementia;Disease;Elderly;Etiology;Gait;Goals;Image;Impaired cognition;Individual;Inflammation;International;Kentucky;Lead;Lewy Body Dementia;Lewy body pathology;Liquid substance;Longitudinal cohort;MRI Scans;Magnetic Resonance Imaging;Measures;Modality;Participant;Pathologic;Pathology;Physical activity;Plasma;Positron-Emission Tomography;Research;Research Project Grants;Role;Sleep;Sleep disturbances;Standardization;System;Universities;aging population;base;biomarker development;biomarker performance;blood-based biomarker;cohort;digital;insight;interest;meetings;multimodality;neuroinflammation;normal aging;novel;novel marker;precision medicine;wearable device


application_id: 10459470
project_number: 5P30AG072946-02
project_title: Core E: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2022-07-08
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9598
contact_pi_person_id: 9662252
contact_pi: SCHMITT, FREDERICK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;African American;African American population;Aging;Agreement;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimer's disease related dementia;Americas;Autopsy;Awareness;Biological Markers;Brain;Brothers;Caring;Catchment Area;Censuses;Centers for Disease Control and Prevention (U.S.);Cessation of life;Church;Clinic;Clinical;Clinical Research;Clinical Trials;Cognitive;Collaborations;Communities;Consent;Data;Databases;Dementia;Development;Disease;Education;Elderly;Elements;Enrollment;Etiology;Event;Extramural Activities;Fostering;Foundations;Genetic;Goals;Grant;Health Promotion;Healthcare;International;Kentucky;Lead;Link;Longitudinal cohort;Measures;Minority;Minority Groups;Mission;Neck;Outcome;Participant;Pathology;Play;Protocols documentation;Reporting;Research;Research Activity;Research Support;Resources;Risk;Risk Assessment;Role;System;Testing;Therapeutic Trials;Time;Underrepresented Populations;Universities;Update;Work;base;checkup examination;clinical examination;cohort;community engagement;dementia risk;demographics;education research;effectiveness evaluation;efficacy evaluation;ethnic minority population;health disparity;health literacy;improved;innovation;meetings;mixed dementia;neuropathology;outreach;outreach program;programs;racial and ethnic;racial minority;recruit;research study;response;success;volunteer;willingness


application_id: 10459469
project_number: 5P30AG072946-02
project_title: Core D: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2022-07-08
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9597
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Autopsy;Biological;Biological Markers;Biological Specimen Banks;Biometry;Brain;Brain Diseases;Brain imaging;Brain region;Caring;Catalogs;Cerebrospinal Fluid;Cerebrovascular Disorders;Cerebrum;Clinical;Clinical Trials;Cognitive;Collaborations;Complement;Consensus;Correlation Studies;Correlative Study;DNA;Data;Databases;Dementia;Dementia with Lewy Bodies;Deposition;Diagnosis;Diagnostic;Disease;Down Syndrome;Elderly;Ensure;Etiology;Evaluation;Freezing;Frontotemporal Lobar Degenerations;Genetic study;Genomics;Goals;Impaired cognition;Individual;Infrastructure;Institutes;Investigation;Kentucky;Laboratory Research;Lesion;Medical Genetics;Memory;Methodology;Methods;Mission;Nerve Degeneration;Neurofibrillary Tangles;Oxidative Stress;Pathologic;Pathology;Patients;Plasma;Preventive measure;Process;Protocols documentation;Publishing;Research;Research Personnel;Research Support;Resources;Running;Sampling;Senile Plaques;Serum;Services;Specimen;Staging;Standardization;Syndrome;System;Tauopathies;Therapeutic;Thinness;Time;Tissue Banks;Tissue Sample;Tissues;Universities;Work;age related;age related neurodegeneration;aging brain;alpha synuclein;blood product;brain tissue;cerebrovascular pathology;clinical biomarkers;cohort;data management;digital;digital pathology;early satiety;experience;genome wide association study;hippocampal sclerosis;innovation;limbic-predominant age-related TDP-43 encephalopathy;meetings;mixed dementia;neuroinflammation;neuropathology;novel;pre-clinical;protein TDP-43;religious order study;statistics;symposium;synucleinopathy;tau Proteins;tool


application_id: 10459468
project_number: 5P30AG072946-02
project_title: Core C: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2022-07-08
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9596
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Advisory Committees;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Applications Grants;Attention;Bioinformatics;Biological Markers;Biometry;COVID-19 pandemic;Clinical;Clinical Data;Clinical Trials;Clinical Trials Data Monitoring Committees;Cognitive;Collaborations;Communities;Consult;Data;Data Analyses;Data Collection;Dementia;Development;Elderly;Elements;Enrollment;Environment;Epidemiology;Etiology;Evaluation;Event;Experimental Designs;Extramural Activities;Faculty;Funding;Generations;Genetic;Gerontology;Information Systems;Interruption;Kentucky;Leadership;Life;Literature;Manuscripts;Methodology;Mission;Neuroepidemiology;Observational Study;Online Systems;Participant;Pathology;Pilot Projects;Procedures;Psychology;Public Health;Publications;Reporting;Research;Research Design;Research Methodology;Research Personnel;Resources;Risk Factors;Role;Sampling;Seasons;Services;Statistical Data Interpretation;Study Section;System;Tablets;Time;Training;Universities;Ursidae Family;Vision;base;central database;clinical biomarkers;cohort;dashboard;data dictionary;data management;data warehouse;direct application;doctoral student;education research;electronic data capture system;improved;innovation;interest;meetings;member;mixed dementia;neuropathology;novel;outreach;programs;recruit;statistics;student training;success;user-friendly;web app;web site


application_id: 10459467
project_number: 5P30AG072946-02
project_title: Core B: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2022-07-08
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9595
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimer's disease related dementia;Area;Automobile Driving;Autopsy;Biological Markers;Brain;Clinic;Clinical;Clinical Trials;Cognitive;Collaborations;Communities;Correlative Study;Dementia;Development;Diagnosis;Disease;Education;Elderly;Enrollment;Ensure;Environment;Etiology;Family;Fostering;Foundations;Funding;Genetic;Goals;Heterogeneity;Image;Individual;Industry;Infrastructure;Intervention;Kentucky;Link;Liquid substance;Longitudinal cohort;Measures;Minority;Minority Groups;Mission;Participant;Pathologic;Pharmaceutical Preparations;Phase;Phenotype;Play;Prevention;Productivity;Publications;Recommendation;Research;Research Personnel;Research Project Grants;Research Support;Role;Syndrome;System;Trademark;United States National Institutes of Health;Universities;Work;base;clinical biomarkers;clinical phenotype;cohort;design;driving force;high risk;innovation;minority engagement;multidisciplinary;normal aging;novel;novel therapeutic intervention;parity;pre-clinical;preclinical study;research clinical testing;success;therapeutic development;translational therapeutics


application_id: 10459466
project_number: 5P30AG072946-02
project_title: Core A: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2022-07-08
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9594
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Administrator;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimer's disease related dementia;Autopsy;Biological;Brain;Brain Pathology;Capital;Caregivers;Cessation of life;Clinical;Cognitive;Cognitive aging;Collaborations;Communication;Communities;Dementia;Development;Doctor of Philosophy;Elderly;Ensure;Environment;Etiology;Fostering;Foundations;Goals;Heterogeneity;Human Resources;Human Volunteers;Impaired cognition;Individual;Infrastructure;Kentucky;Knowledge;Leadership;Modality;Monitor;Neurosciences;Occupational activity of managing finances;Pathogenicity;Pathology;Patients;Prevention;Research;Research Activity;Research Personnel;Resources;Risk;Risk Factors;Science;Strategic Planning;Structure;System;Tissues;Training and Education;Translational Research;United States;Universities;accurate diagnostics;beneficiary;cognitive development;cohort;comorbidity;diagnostic strategy;disease heterogeneity;effective therapy;innovation;meetings;multidisciplinary;novel therapeutics;pre-clinical;prevent;programs;success;training opportunity;treatment strategy;volunteer


application_id: 10459464
project_number: 5P30AG072946-02
project_title: University of Kentucky Alzheimer's Disease Research Center
administering_ic: NIA
award_notice_date: 2022-07-08
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
program_official: ELLIOTT, CERISE
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G(M1)
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
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:
Address;African American;Aging;Alzheimer's Disease;Alzheimer's disease related dementia;Area;Autopsy;Awareness;Basic Science;Biological;Biological Markers;Biometry;Brain;Caring;Cessation of life;Clinical;Clinical Research;Clinical Trials;Cognitive;Cognitive aging;Collaborations;Collection;Communities;Community Outreach;Dementia;Development;Disease;Education;Education and Outreach;Elderly;Ensure;Environment;Etiology;Family;Goals;Health Personnel;Heterogeneity;Impaired cognition;Impairment;Individual;Infrastructure;Kentucky;Knowledge;Longitudinal cohort;Mission;NCI Scholars Program;Neurodegenerative Disorders;Outcome;Pathogenicity;Pathology;Recommendation;Research;Research Personnel;Research Project Grants;Resources;Risk;Training;Translating;Translational Research;United States;United States National Institutes of Health;Universities;aging brain;beneficiary;central database;clinical practice;cognitive development;cohesion;cohort;collaborative environment;community partnership;comorbidity;data management;driving force;education research;experience;innovation;neuropathology;next generation;normal aging;novel therapeutics;outreach;pre-clinical;programs;recruit;research study;statistics;success;volunteer


application_id: 10459399
project_number: 5R01EY021769-10
project_title: Vertebrate photoreceptor development and regeneration
administering_ic: NEI
award_notice_date: 2022-08-08
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: EY
serial_number: 021769
program_official: NEUHOLD, LISA
project_start_date: 2012-08-01
project_end_date: 2024-07-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 10184513
contact_pi: MORRIS, ANN C
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYInherited retinal dystrophies such as retinitis pigmentosa (RP) are a leading cause of blindness forwhich there is currently no cure. One potential treatment for retinal degenerative diseases is cell-based transplantation therapy whereby precursor cells are transplanted into the diseased eye toreplace the lost photoreceptors. While this is an exciting possibility several challenges to theimplementation of transplantation therapies must be overcome including the inefficient integration ofphotoreceptor precursors into the recipient retina and the difficulty of obtaining sufficient numbers ofphotoreceptor precursors for clinical application. To improve protocols for the in vitro culture of suchcells we must have a better understanding of the transcriptional networks that promote specificationof photoreceptor precursors. One of the long-term goals of our laboratory is to contribute to theseefforts by studying photoreceptor development and regeneration in the zebrafish. The zebrafish isespecially useful for studying photoreceptor biology because its retina contains numerous conesubtypes in addition to rods. Furthermore unlike mammals the zebrafish retina is able to regenerateneurons in response to experimental damage. The experiments described in this proposal will definethe role of three transcription factors -- Sox Sox11 and Her9 -- during retinal neurogenesis throughthe application of gene targeting and molecular genetic approaches. Our specific aims are as follows:Specific Aim I: Determine the role of Sox4 and Sox11 in photoreceptor differentiation. Using newlygenerated loss-of-function mutants in this aim we will 1) determine whether there is a dosage effectof Sox4/11 activity on rod photoreceptor number; 2) use state-of-the-art time-lapse imaging todetermine when and where Sox4 expression is required to achieve proper rod photoreceptordevelopment; 3) determine precisely how Sox4/11 regulate Hh and Bmp signaling; and 4) identify themolecular targets of Sox4/11. Specific Aim II: Determine the cause and extent of photoreceptordefects in the zebrafish her9 mutant. In this aim we will 1) determine the mechanism forphotoreceptor defects in her9 mutants; 2) determine whether loss of Her9 impairs vision; 3) identifythe upstream signaling pathway(s) that regulate her9 expression in the retina; and 4) determinewhether Her9-mediated VEGF expression in the avascular zebrafish retina regulates retinalprogenitor cell proliferation and differentiation. Completion of our proposal will bridge important gapsin our understanding of the molecular mechanisms of vertebrate photoreceptor differentiation andreveal underlying principles relevant to the development of approaches for the treatment of humanretinal degenerative disease.

project_terms:
Adoption;Animal Model;Biochemical;Biology;Blindness;Cell Differentiation process;Cell Transplantation;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Cone;Data;Defect;Development;Developmental Biology;Disease;Embryo;Event;Evolution;Eye diseases;Family;Gene Targeting;Genetic;Genetic Diseases;Genetic Transcription;Goals;Health;Homologous Gene;Human;Image;In Vitro;Inherited;Injury;Laboratories;Mammals;Mediating;Microphthalmos;Modeling;Molecular;Molecular Genetics;Molecular Target;Morphogenesis;Morphology;Mutation;Natural regeneration;Nerve Regeneration;Neurons;Optics;Pathway interactions;Photoreceptors;Protocols documentation;Retina;Retinal Cone;Retinal Degeneration;Retinal Dystrophy;Retinitis Pigmentosa;Rod;Role;SOX11 gene;SOX4 gene;Signal Pathway;Signal Transduction;Suggestion;System;Therapeutic;Time;Transcription Repressor;Transgenic Organisms;Transplantation;Vascular Endothelial Growth Factors;Vertebrate Photoreceptors;Visual;Visual impairment;Visual system structure;Work;Zebrafish;base;cellular imaging;clinical application;dosage;experimental study;gene regulatory network;gene therapy;genetic approach;genome editing;imaging modality;improved;in vivo;loss of function;member;mouse genome;mutant;neurogenesis;notch protein;novel;optic cup;photoreceptor degeneration;precursor cell;response;retinal neuron;retinal progenitor cell;retinal rods;stem cell differentiation;stem cell proliferation;therapy development;transcription factor;transplantation therapy

public_health_relevance:
PROJECT NARRATIVE/RELEVANCE TO HUMAN HEALTHThe development of therapies to treat visual impairment resulting from photoreceptordegeneration will directly benefit from studies of animal models such as the zebrafish whichdevelops ex utero remains optically transparent throughout development and which displaysthe capacity for injury-induced neural regeneration. The goal of our proposal is to define the roleof the transcription factors Sox4 Sox11 and Her9 in the development of photoreceptor cellsand to identify the pathways that regulate their expression and what they in turn regulate. Thisinformation will facilitate efforts to understand photoreceptor developmental biology and to guidephotoreceptor differentiation from stem cells in vitro and in vivo for therapeutic purposes.


application_id: 10459072
project_number: 4U44AA026126-03
administering_ic: NIAAA
award_notice_date: 2021-08-31
opportunity_number: PAR-15-154
application_type: 4
activity_code: U44
ic: AA
serial_number: 026126
program_official: PATTERSON, JENICA DAWN
project_start_date: 2017-08-25
project_end_date: 2024-08-31
study_section: ZAA1-DD(44)
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-09-01
project_abstract:
Abstract Alcohol dependence affects at least 4% of the US population with a financial cost in excess of $100Bn. Prevention of relapse in patients attempting to reduce alcohol consumption is a major therapeutic target but current treatments are ineffective and there is an urgent need for new medications. Major factors in causing relapse include the protracted symptoms of withdrawal from alcohol which are relieved by returning to drinking. Alcohol withdrawal is also implicated in the neurodegeneration that is associated with dependence. There is abundant evidence that the glutamate/NMDA receptor (NMDAR) is a molecular target in alcohol withdrawal and that inhibitory modulators of the NMDAR are potentially valuable as anti-relapse pharmacotherapy. Target validation identified polyamine enhancement of NMDAR function via the NR2B subunit as a specific target in alcohol withdrawal and molecular screening identified several lead compounds. JR220 was the most active novel compound from an aryliminoguanidine series and its cellular effects on neuronal cultures were consistent with NMDAR inhibition via this site. JR220 was then tested in a variety of rodent screens relevant to alcohol dependence withdrawal and neurotoxicity including several screens in other laboratories. The drug was highly active in all of these screens with a potency 5-200x that of acamprosate which is FDA-approved for the prevention of relapse. JR220 caused mild sedation at higher doses but there was no overt toxicity even on repeated administration. Pharmacokinetic studies in the rat showed dose dependent elevations of concentrations in plasma after intraperitoneal subcutaneous and oral administration (oral bioavailability >70%). Concentrations obtained in brain were ~10x higher than plasma suggesting an active uptake system at the blood/brain barrier. On repeated once daily dosing for 7 days JR220 did not accumulate in plasma or brain and no overt toxicity was observed. The only concern is that the plasma half-life following oral administration may be too short for once-a-day dosing in relapse prevention. This can be addressed by formulation as an oral extended release formulation or by a transdermal patch (which would also have other advantages for treatment of alcohol use disorders). Intellectual property in JR220 as a treatment for aspects of alcohol withdrawal and the transdermal patch formulation of JR220 are covered by provisional applications to the USPTO. The preliminary data indicates that JR220 is an excellent candidate as an anti-relapse medication and the current proposal is to develop the drug further for this use. The aim is now to complete the studies required prior to submission of the drug to the FDA for consideration as an investigational new drug (IND). Thus in the proposed studies we will complete investigation of metabolism and metabolite identification in vitro and Absorption Distribution Metabolism and Excretion in vivo. The studies will also include a screen for off target actions and studies on safety and toxicology in two species. These studies will include escalating acute dose studies and sub-chronic studies (to reflect the maintenance of patients on anti-relapse medication). JR220 will be produced under GMP conditions and production scaled up to meet requirements for future human trials. If an IND designation is obtained the objective will then be to partner with a major pharmaceutical company in testing the drug in a human safety trial and then in clinical trials in alcohol dependent volunteers. The objective is to develop JR220 for relapse prevention and neuroprotection to provide a pharmacotherapy that is more effective for these therapeutic targets than others currently available.

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

public_health_relevance:
Project NarrativeDependence on alcohol is a very serious problem in the US with a huge medical and financial burden. Currenttreatments are unsatisfactory and new medications are required. The applicants have synthesized a novel drugthat has shown great promise in preclinical development and this proposal is to obtain the data necessarybefore investigation of the drug in the human.


application_id: 10458764
project_number: 5R01AG073122-02
project_title: Immunoproteasome inhibitors for the treatment of Alzheimers disease
administering_ic: NIA
award_notice_date: 2022-05-06
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AG
serial_number: 073122
program_official: GROTHAUS, PAUL G
project_start_date: 2021-08-01
project_end_date: 2023-04-30
study_section: Drug Discovery for the Nervous System Study Section[DDNS]
contact_pi_person_id: 8152159
contact_pi: KIM, KYUNG BO
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:
Project SummaryWith the failure of nearly all clinical trials for AD drugs in the pipeline to date identification of a new class of drugcandidates has become imperative to bring about effective AD therapies. A major obstacle is the lack ofpromising new drug targets unrelated to the events leading to the accumulation of the amyloid-beta (A) and tau-protein. We recently reported that linear peptide epoxyketones targeting the immunoproteasome (iP) aninducible variant of the 20S constitutive proteasome (cP) may represent a new class of AD drugs that canameliorate cognitive deficits independently of A or tau accumulation. While displaying promising efficacyhowever the prospect of these linear peptide epoxyketones for clinical use in AD appears limited at this timedue to potential issues of having a poor brain accessibility in vivo metabolic instability and short circulation time(largely attributable to the ABCB1-mediated drug efflux at the BBB and enzymatic hydrolysis by peptidases andepoxide hydrolases). Yet the family of peptide epoxyketones (short peptides with C-terminal -epoxyketonewarhead) remain attractive drug candidates considering their pharmacological advantages conferred by theirproven target specificity for the proteasomes and long-term safety in the clinic.Our current findings reveal that some of the peptide epoxyketone family members containing a macrocycle havethe ability to resist the ABCB1-mediated efflux and metabolic stability superior to their linear counterparts andthe potential to be a meaningful new treatment for patients with AD. Our objective in this application is to identifyand characterize one of these macrocyclic compounds best suited for brain iP inhibition in vivo and proceed tothe next phase of drug development. To do this in aim 1 we will prepare the current sets of promising macrocyclicpeptide epoxyketones with different structural features that displayed comparable target inhibition and biologicalactivity in vitro and in cellulo on a gram scale. In aim 2 we will characterize in vivo properties of each macrocyclicpeptide epoxyketone to identify a lead drug candidate. In aim 3 we will verify in vivo efficacy and the proposedmechanism of action of the lead drug candidate [iP inhibition  (NLRP3 inflammasome)  suppression ofmicroglial IL-1 release  blockade of astrocytes transformation (to A1 subtype)  neuronal survival] using twomouse models of AD (APP/PS1 and PS19 tau transgenic mice). By completing the proposed study we will haveidentified a lead candidate with the best attributes for IND enabling studies and novel mode of action. Theseresults are expected to have an important positive impact by examining the validity of the previously untappediP-targeting approach for AD therapy and potentially offering a new direction for AD drug discovery.

project_terms:
ABCB1 gene;APP-PS1;Affect;Alkenes;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Astrocytes;Biological;Blood Circulation;Brain;C-terminal;Clinic;Clinical;Clinical Trials;Cognitive deficits;Data;Development;Dose;Drug Efflux;Drug Targeting;Drug or chemical Tissue Distribution;Ensure;Epoxide hydrolase;Epoxy Compounds;Event;Excretory function;Failure;Family;Family member;Human;Hydrolysis;In Vitro;Inflammasome;Interleukin-1 alpha;Lead;Macrocyclic Compounds;Mediating;Metabolic;Metabolism;Mus;Organ;Pathway interactions;Patients;Peptide Hydrolases;Peptides;Permeability;Pharmaceutical Preparations;Pharmacology;Phase;Property;Reaction;Reporting;Safety;Specificity;Therapeutic;Time;Toxic effect;Transgenic Mice;Variant;abeta accumulation;analog;base;brain tissue;chemical stability;clinical candidate;clinical development;comparative;drug candidate;drug development;drug discovery;drug disposition;expectation;in vitro activity;in vivo;inhibitor;lead candidate;mouse model;multicatalytic endopeptidase complex;neuronal survival;new therapeutic target;novel;novel drug class;pharmacokinetics and pharmacodynamics;preclinical study;reduce symptoms;success;tau Proteins;tau aggregation

public_health_relevance:
Project Narrative:Given the prospect to develop effective AD therapies via current therapeutic strategies seems limited at thispoint in this application we propose to develop a new class of AD drugs that target previously unrecognizedpathways in AD drug development. We expect to identify a lead AD drug to stop or slow down the progressionof AD in a manner independent of A or tau aggregation that needs to be further investigated in clinical trials.Successful completion of our study will have an important positive impact because currently available drugs onlyoffer temporary relief from the symptoms of AD.


application_id: 10458701
project_number: 5R35GM142679-02
project_title: Chromatin Regulation of Tissue Regeneration and Stem Cell Function
administering_ic: NIGMS
award_notice_date: 2022-06-21
opportunity_number: PAR-20-117
application_type: 5
activity_code: R35
ic: GM
serial_number: 142679
program_official: PHILLIPS, ANDRE W
project_start_date: 2021-09-01
project_end_date: 2026-06-30
study_section: Special Emphasis Panel[ZRG1-CB-J(55)R]
contact_pi_person_id: 10461818
contact_pi: DUNCAN, ELIZABETH MARIE
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adult;Animal Model;Animals;Biochemical;Biological Process;Cells;Chromatin;Cilia;Complex;Cues;Custom;Data;Development;Developmental Process;Embryonic Development;Enzymes;Epithelial;Essential Genes;Event;Gene Expression;Gene Expression Regulation;Gene Targeting;Genes;Genetic;Genetic Transcription;Genome;Genomic approach;Genomics;Heterogeneity;Injury;Laboratory Study;Link;MLL gene;Mediator of activation protein;Methods;Molecular;Natural regeneration;Organism;Pattern;Planarians;Platyhelminths;Pluripotent Stem Cells;Population Heterogeneity;Process;Proteins;RNA Interference;Regenerative capacity;Regulation;Research;Role;Signal Transduction;Structure;Techniques;Testing;Tissue Differentiation;Tissues;Translating;Work;cell type;comparative;comparative genomics;in vivo;innovation;interest;novel;regenerative;response;single cell analysis;stem cell function;stem cells;tissue regeneration;trait;transcription factor


application_id: 10458636
project_number: 5R01DK119619-05
project_title: Exercise-induced skeletal muscle exosomes promote adipocyte lipolysis
administering_ic: NIDDK
award_notice_date: 2022-07-26
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: DK
serial_number: 119619
program_official: CASTLE, ARTHUR
project_start_date: 2018-09-19
project_end_date: 2024-07-31
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
other_pis: PETERSON, CHARLOTTE A.
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SummaryExosomes are small extracellular vesicles that have emerged over the past few years as novel mediators ofintercellular communication. We recently reported that exosomes released from activated skeletal muscle stemcells regulate extracellular matrix remodeling during muscle hypertrophy through the transport of skeletalmuscle-specific miR-206 to fibroblasts. The discovery of this novel role for muscle stem cells inspired us tofurther explore if exosomes are released from muscle cells in response to resistance exercise and if so theirimpact on target tissues. Based on preliminary data we hypothesize that enhanced adrenergic signaling inadipose tissue in response to resistance exercise is mediated in part by exosomal muscle-specific miR-1activation of 3-adrenergic receptor (3-AR) expression. In particular we have developed a working model inwhich exercise causes skeletal muscle cells to release exosomes containing muscle-specific miR-1 thattransport miR-1 to adipocytes. As a result CAATT/enhancer binding protein alpha (C/EBP) activates 3-ARgene expression through miR-1-mediated repression of AP-2 thereby enhancing catecholamine sensitivity ofadipocytes and promoting the release of fatty acids and glycerol into the circulation as the result of increasedlipolysis. The purpose of the proposed studies is to test our working model by pursuing the following aims inboth mice and humans: Aim 1: Determine if exercise-induced exosomal miR-1 enhances adipocyte adrenergicsignaling through activation of 3-AR expression; Aim 2: Determine if human skeletal muscle fiber-derivedexosomes directly promote adipocyte lipolysis through enhanced -adrenergic signaling; Aim 3: Determine ifan acute bout of resistance exercise in humans promotes miR-1-mediated adipocyte lipolysis. Our preliminarydata provide the first evidence demonstrating that resistance exercise-induced exosomes mediate thebeneficial effect of exercise on adipose tissue metabolism. A better understanding of the role of exosomes inthe systemic adaptations that occur in response to resistance exercise are expected to provide thefundamental knowledge necessary to use exosomes as a platform for the delivery of exercise mimetics to treatobesity.

project_terms:
AR gene;Acute;Address;Adipocytes;Adipose tissue;Adrenergic Agents;Adrenergic Receptor;Aerobic Exercise;Biological Assay;Biological Models;Biopsy;Blood Circulation;Blood specimen;Catecholamines;Colon Carcinoma;Coronary heart disease;Data;Development;Disease;Electric Stimulation;Exercise;Extracellular Matrix;Fatty Acids;Fatty acid glycerol esters;Female;Fibroblasts;Gene Expression;Genes;Glycerol;Heart failure;High Fat Diet;Human;Isoproterenol;Knowledge;Lipolysis;Mediating;Mediator of activation protein;Metabolism;Modeling;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle satellite cell;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Participant;Pathway interactions;Public Health;Reporter Genes;Reporting;Repression;Role;Serum;Signal Transduction;Skeletal Muscle;Source;Stimulus;Testing;Thinness;Tissues;Untranslated Regions;base;enhancer binding protein;exosome;experimental study;extracellular vesicles;fat burning;gain of function;gene repression;in vitro Model;intercellular communication;male;malignant breast neoplasm;mimetics;muscle hypertrophy;novel;novel therapeutic intervention;obesity development;prevent;resistance exercise;response;subcutaneous;transcription factor;vastus lateralis;young adult

public_health_relevance:
NARRATIVEObesity is known to exacerbate numerous diseases that represent urgent public health problems includingheart failure coronary heart disease type 2 diabetes breast and colon cancer. The purpose of the proposedstudy is to investigate the mechanism through which resistance exercise causes skeletal muscle tocommunicate with adipose tissue to promote the burning of fat. The findings from this study are expected toprovide the fundamental knowledge necessary to develop a novel therapeutic strategy to treat obesity usingexosomal miR-1 delivery to adipose tissue.


application_id: 10458581
project_number: 5R01DE024509-09
project_title: Filifactor alocis interactions with neutrophils
administering_ic: NIDCR
award_notice_date: 2022-08-22
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DE
serial_number: 024509
program_official: MCNEALY, TAMARA L
project_start_date: 2014-07-01
project_end_date: 2024-08-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 8652094
contact_pi: URIARTE, SILVIA M
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:
AbstractPeriodontitis is one of the six most common chronic inflammatory diseases affecting ~ 50% of the adults in theUSA. The etiology of periodontitis is strongly associated with changes in both the microbial composition anddensity of an indigenous symbiotic community to a more diverse dysbiotic microbial community. High-throughputsequencing techniques applied to characterize the composition of the periodontal microbiota obtained fromdisease sites revealed the presence of high number of newly appreciated oral pathogens. Among these is theGram-positive anaerobic rod Filifactor alocis present in high numbers in the oral biofilm of periodontal diseasesites compared to healthy sites. The challenge now is to determine the potential pathogenicity virulencemechanisms and possible immune subversion arsenal of F. alocis. The response that the host mounts to thebacterial challenge plays a major role in disease progression. Neutrophils are the primary leukocyte recruited tothe subgingival crevice and their interaction with the microbial community is a key determinant of oral healthstatus. Understanding how the host responds to the different microbial challenges will increase our knowledgeof the disease process. The current proposal will test the hypothesis that F. alocis undermines neutrophil effectorfunctions to promote its survival. We will test our hypothesis by the following specific aims: Aim 1: To define F.alocis regulation of neutrophil vesicular trafficking to evade killing and promote bacteria colonization and boneloss. The goal of this aim will be to test the hypothesis that F. alocis manipulates neutrophil signaling pathwaysto uncouple the bactericidal activity from the inflammatory response to successfully evade killing. Aim 2: Tocharacterize F. alocis ability to modulate apoptosis in human neutrophils. The goal of this aim will be to test thehypothesis that F. alocis modulates neutrophils apoptotic program as a virulence strategy to preserve anintracellular niche within the neutrophil phagosome. The current project is a collaborative effort from aninvestigator who is an expert in the field of neutrophil biology and inflammation and its interactions with emergingoral pathogens (Dr. Uriarte) and an expert in the field of oral pathogens and host cell responses using in vivomodels of periodontitis (Dr. Lamont). The proposed collaborative efforts offer an innovative and strong frameworkto characterize the pathogenic potential of F. alocis. In addition the data generated from this application will filla significant gap in our knowledge and lay the foundation for development of new therapeutic approaches tocombat periodontitis.

project_terms:
Address;Adult;Affect;Alveolar Bone Loss;Anaerobic Bacteria;Apoptosis;Apoptotic;Bacteria;Biology;Bone Marrow;Cells;Chemotaxis;Communities;Complex;Cytoplasmic Granules;Data;Development;Disease;Disease Progression;Etiology;Exocytosis;Experimental Models;Focal Infection;Foundations;Fusobacterium nucleatum;Gene Expression;Generations;Gingiva;Goals;Health Status;High-Throughput Nucleotide Sequencing;Human;Immune;Immune response;In Vitro;Indigenous;Infection;Inflammation;Inflammatory;Inflammatory Response;Intention;Knowledge;Laboratories;Leukocytes;Longevity;Mediating;Molecular;Mus;NF-kappa B;Oral;Oral health;Organism;Pathogenesis;Pathogenicity;Pathology;Periodontal Diseases;Periodontal Pocket;Periodontitis;Phagocytes;Phagosomes;Play;Porphyromonas gingivalis;Process;Proteins;Publishing;Reactive Oxygen Species;Regulation;Research;Research Personnel;Rod;Role;Secure;Signal Pathway;Signal Transduction;Site;Stimulus;TLR2 gene;Techniques;Testing;Tissues;United States;Virulence;Work;antimicrobial;bactericide;bone loss;chronic inflammatory disease;combat;cytokine;defined contribution;density;dysbiosis;extracellular;host-microbe interactions;in vivo;in vivo Model;innovation;microbial;microbial community;microbial composition;microbicide;microbiota;neutrophil;novel therapeutic intervention;oral bacteria;oral biofilm;oral pathogen;pathogenic bacteria;periodontopathogen;preservation;prevent;programs;recruit;response;trafficking;transcriptome;transcriptome sequencing

public_health_relevance:
Project NarrativePeriodontitis is a chronic inflammatory disease induced by oral pathogenic bacteria that affects ~50% of theadults in the United States. Oral health status is maintained by the presence of white blood cells which areinvolved in killing the oral bacteria that cause periodontitis. In the current study we propose to define how anewly appreciated bacterium manages to avoid being killed by the white blood cells; with the intention of filling asignificant gap in the understanding of which factors contribute to periodontal disease.


application_id: 10458567
project_number: 5P30GM127211-05
project_title: Pilot Projects Program
administering_ic: NIGMS
award_notice_date: 2022-08-04
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127211
project_start_date: 2018-08-01
project_end_date: 2025-07-31
study_section: ZGM1-RCB-3
subproject_number: 5343
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The primary objective of the Phase III Pilot Project Program of the COCVD is to build upon and expandmomentum by providing short-term funding for meritorious pilot studies that focus on obesity as a risk factor forhuman diseases. Working in parallel with identified areas of biomedical research strength at our institution theprogram will emphasize support for pilot projects that examine the relationship between obesity andcardiovascular diseases type 2 diabetes cancer and neurodegenerative diseases. The Program will supportstudies for junior/new investigators to study obesity as a risk factor for human diseases establishedinvestigators who include obesity as a risk factor within their area of disease specialization andmultidisciplinary teams of investigators for submission of programmatic grant applications. Decisions onsupport will follow NIH-format review by members of the COCVD during Phase I and II of the programsupplemented by members with specific expertise (e.g. cancer). Initial scientific merit reviews will besubmitted to the Internal Scientific Advisory Committee for initial ranking determinations followed by theExternal Advisory Committee for their review and input. Pilot Project grants are designed for 1 year ($50000)with a second year contingent upon progress. The successes of the program to date in operation and functionwill carry into Phase III of the COCVD.

project_terms:
Advisory Committees;Appalachian Region;Applications Grants;Area;Biomedical Research;Cardiovascular Diseases;Categories;Centers of Research Excellence;Clinical Sciences;Clinical and Translational Science Awards;Consultations;Core Facility;Data;Development;Diabetes Mellitus;Disease;Extramural Activities;Floor;Funding;Funding Opportunities;Generations;Goals;Grant;Head;Health;Infrastructure;Institution;Kentucky;Link;Malignant Neoplasms;Mentors;Modernization;Names;Nerve Degeneration;Neurodegenerative Disorders;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Peer Review;Phase;Pilot Projects;Process;Program Research Project Grants;Publications;Research;Research Personnel;Research Support;Resources;Risk Factors;Secure;Services;Standardization;Substance abuse problem;Talents;Translational Research;United States National Institutes of Health;Universities;base;biomedical facility;cancer type;clinical center;design;driving force;experience;health disparity;human disease;member;multidisciplinary;operation;programs;recruit;success;translational study


application_id: 10458566
project_number: 5P30GM127211-05
project_title: Core D - Energy Balance and Body Composition Core
administering_ic: NIGMS
award_notice_date: 2022-08-04
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127211
project_start_date: 2018-08-01
project_end_date: 2025-07-31
study_section: ZGM1-RCB-3
subproject_number: 5342
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Energy Balance and Body Composition Core (Core D) serves investigators across the institution toquantify energy balance and body composition in mice. Accurate quantification of these parameters isessential for studies focused on obesity with wide-spread capabilities for metabolism-related studies. Thecore houses 24 LabMaster TSE chambers that quantify food and water intake physical activity and indirectcalorimetry in mice a common model for studies focused on the effect of diet or genetics on the developmentof obesity. The Core also houses an EchoMRI to quantify lean and fat mass and total body water inconscious mice. Both systems allow for non-invasive longitudinal assessment of energy balance and bodycomposition. Competent core staff maintain and oversee the use of the LabMaster TSE system and trainpersonnel in use of the EchoMRI. Core Directors assist in study design and data handling and analysis.Over 50 Principal Investigators use the LabMaster TSE system annually for studies on >700 mice/year whilethe EchoMRI is used by more than 25 laboratories annually. These systems are not duplicated at theinstitution or within the Commonwealth and are vital to our ability to reduce the epidemic of obesity inKentucky. In Phase III of the program we will broaden our focus to include obesity as a risk factor forcardiovascular diseases diabetes cancer and neurodegenerative diseases. This will increase use of thesystem to support an anticipated larger user base with targeted growth within these areas across theinstitution. We will also purchase a new system from institutional support that will markedly expandcapabilities of this core in quantifying energy metabolism in mice. Also during Phase III of the program thecore for this system including all equipment will be relocated to a modern animal care facility within a newresearch building that is dedicated to the study of these health disparities. We anticipate that this core willtransition to self-sustaining capacity over the course of Phase III support of the COCVD.

project_terms:
Acclimatization;Adipose tissue;Animals;Area;Blood Pressure;Body Composition;Body Water;Body Weight;Cardiovascular Diseases;Cells;Chronic;Collaborations;Communities;Conscious;Consultations;Coupled;Data Analyses;Diabetes Mellitus;Diet;Eating;Energy Metabolism;Equipment;Exercise;Experimental Models;Fatty acid glycerol esters;Fees;Food Energy;Fostering;Funding;Genetic;Genome;Growth;Health care facility;Human Resources;Indirect Calorimetry;Individual;Institution;Intervention;Kentucky;Laboratories;Longitudinal Studies;Magnetic Resonance Imaging;Malignant Neoplasms;Measurement;Metabolism;Methods;Modernization;Mus;Neurodegenerative Disorders;Obese Mice;Obesity;Obesity Epidemic;Obesity associated disease;Phase;Physical activity;Pilot Projects;Principal Investigator;Proteins;Recommendation;Regulation;Research;Research Design;Research Personnel;Resources;Running;Services;Standardization;Structure;Study models;System;Therapeutic;Thinness;Time;Tissues;Training;United States National Institutes of Health;Water consumption;Weight;animal care;base;cardiovascular risk factor;data handling;diet-induced obesity;dietary;energy balance;experience;feeding;health disparity;improved;insight;mid-career faculty;obesity development;operation;outreach program;programs;time use


application_id: 10458565
project_number: 5P30GM127211-05
project_title: Core C - Pathology
administering_ic: NIGMS
award_notice_date: 2022-08-04
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127211
project_start_date: 2018-08-01
project_end_date: 2025-07-31
study_section: ZGM1-RCB-3
subproject_number: 5341
contact_pi_person_id: 1879534
contact_pi: KATZ, WENDY S
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Phase III Pathology Core has evolved from a need for specialized expertise in assessing the morphologyof adipose tissue as a link between obesity and cardiovascular diseases. The Core has developed extensiveexpertise in tissue processing paraffin embedding sectioning and basic stains for adipose tissue as well asmany other tissues from a range of species. The Phase III Pathology Core will continue to provide centralizedservices for basic histology procedures and imaging simplifying and standardizing the collection of pathologydata. Within Phase III this core will build upon experience and expand equipment capabilities with an updatedembedding center provision of immunostaining services and through partnering with the Center for Clinicaland Translational Sciences (CCTS) Biospecimens Core Biobank. This Biobank collects several tissuesincluding adipose tissue from several locations from humans to speed the pace of translational studies.During Phase II of the COCVD this core performed 376 projects (to date) for 42 investigators processing>6000 samples embedding >4700 samples and sectioning >3600 sections to generate almost 30000 slides.In year 8 of the current program this core has provided services to more than 150 projects and routinelyservices more than 50 projects/year. With expanded services by partnering with the CCTS to serve as apathology conduit for investigators wishing to analyze human tissue morphology and with an expansion of thefocus of the COCVD to include obesity as a risk factor for type 2 diabetes cancer and neurodegenerativediseases we anticipate that increased demand for the services of this core will transition the core to self-sustaining capacity.

project_terms:
Adipose tissue;Aging;Basic Science;Cardiovascular Diseases;Cell Count;Cell Size;Cellularity;Characteristics;Clinical Sciences;Collaborations;Collection;Communities;Computer software;Data;Diabetes Mellitus;Disease;Equipment;Fees;Fostering;Funding;Goals;Histologic;Histology;Human;Human Characteristics;Image;Image Analysis;Individual;Inflammation;Institution;Laboratory Research;Light Microscope;Link;Location;Malignant Neoplasms;Manuals;Microscope;Microtome - medical device;Morphology;Neurodegenerative Disorders;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Paraffin;Paraffin Embedding;Pathologic;Pathology;Patients;Peripheral;Phase;Procedures;Protocols documentation;Reagent;Research;Research Personnel;Risk Factors;Sampling;Services;Sirius Red F3B;Slide;Specimen;Speed;Stains;Standardization;Structure;Techniques;Tissue Sample;Tissue Stains;Tissues;Training;Translational Research;Trichrome stain method;United States National Institutes of Health;Update;biobank;cardiovascular risk factor;clinical center;design;experience;finesse;health assessment;high resolution imaging;histological specimens;human tissue;interest;mid-career faculty;operation;outreach program;programs;quantitative imaging;tissue processing;translational study


application_id: 10458564
project_number: 5P30GM127211-05
project_title: Core B - Analytical Core
administering_ic: NIGMS
award_notice_date: 2022-08-04
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127211
project_start_date: 2018-08-01
project_end_date: 2025-07-31
study_section: ZGM1-RCB-3
subproject_number: 5340
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Phase III Analytical Core will support research into mechanisms linking obesity lipid metabolism andhuman disease risk through continued use of facility core instrumentation and resources to develop andsupport a suite of analytical services tailored for studies of the relationship between diet obesity and diseasemechanisms using preclinical models and clinical approaches. In addition expansion of services in lipidomicsand stable isotope tracer studies will augment capabilities for small animal metabolic phenotyping. This corehas developed extensive instrumentation that enables quantitation of a broad range of small moleculesuntargeted profiling of lipids in complex mixtures targeted quantification of biomarkers linking obesity todisease and methods for studies of glucose and fatty acid metabolism. Each of these analytical capabilitiesare of direct relevance to studies focused on diet nutrition and obesity in disease development. This core hascontributed data for more than 110 peer reviewed publications since 2008 in high impact journals providedservices for more than 60 investigators and contributed to new grant awards in environmental sciences. Thecore is well equipped and with expanded services is anticipated to develop self-sustaining capacity in PhaseIII of the COCVD.

project_terms:
Adipose tissue;Analytical Chemistry;Animals;Area;Award;Biological Assay;Biological Markers;Blood;Cardiovascular Diseases;Centers of Research Excellence;Clinical;Collaborations;Complex Mixtures;Core Facility;Coupled;Data;Development;Diet;Diet and Nutrition;Dietary Carbohydrates;Dietary Fats;Disease;Ensure;Environmental Science;Fees;Funding;Glucose;Goals;Grant;High Pressure Liquid Chromatography;Human;Incidence;Individual;Institution;Journals;Kentucky;Laboratories;Link;Lipids;Malignant Neoplasms;Mass Fragmentography;Mass Spectrum Analysis;Measures;Medicine;Methods;National Institute of Environmental Health Sciences;Neurodegenerative Disorders;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Obesity associated disease;Peer Review;Phase;Phospholipids;Pre-Clinical Model;Publications;Reporting;Research;Research Personnel;Research Support;Resolution;Resources;Risk Factors;Rural;Services;Structure;Testing;Time;Tissues;Tracer;Training and Education;Triglycerides;United States National Institutes of Health;Urine;analytical method;base;biomarker development;cardiovascular risk factor;cohort;college;computational platform;disorder risk;energy balance;fatty acid metabolism;human disease;human subject;instrumentation;interest;lipid metabolism;lipidomics;metabolic abnormality assessment;metabolic phenotype;obesity development;operation;programs;small molecule;stable isotope;western diet


application_id: 10458563
project_number: 5P30GM127211-05
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2022-08-04
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127211
project_start_date: 2018-08-01
project_end_date: 2025-07-31
study_section: ZGM1-RCB-3
subproject_number: 5339
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Administrative Core of the Phase III Center of Biomedical Research Excellence (COBRE) on Obesity andCardiovascular Diseases (COCVD) will provide administrative oversight for the center. This core is Directed byDr. Lisa Cassis Program Director and Dr. Andrew Morris Program Coordinator who will collectively provideleadership oversight and coordination of the various activities associated with the COCVD to transition theCenter to self-sustaining capacity. This will include oversight of Core facilities and their administration fiscalaccounting programs for cores and pilot projects administrative oversight of the Pilot Project Programimplementation of strategies to assess core performance and increase core use assure adherence toregulatory guidelines and improve the research infrastructure.

project_terms:
Accounting;Achievement;Adherence;Advisory Committees;Animal Welfare;Area;Cardiovascular Diseases;Caring;Centers of Research Excellence;Core Facility;Diabetes Mellitus;Ensure;Evolution;Extramural Activities;Funding;Guidelines;Kentucky;Leadership;Malignant Neoplasms;Monitor;Neurodegenerative Disorders;Obesity;Organization administrative structures;Output;Performance;Phase;Pilot Projects;Policies;Procedures;Reporting;Research;Research Infrastructure;Research Personnel;Research Support;Risk Factors;Services;Structure;Universities;comorbidity;human disease;human subject protection;improved;meetings;programs;research facility;success


application_id: 10458562
project_number: 5P30GM127211-05
project_title: Center of Research on Obesity and Cardiovascular Disease
administering_ic: NIGMS
award_notice_date: 2022-08-04
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127211
program_official: FRINCU, CRINA
project_start_date: 2018-08-01
project_end_date: 2025-07-31
study_section: ZGM1-RCB-3(C3)
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
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:
Phase III of the Center for Biomedical Research Excellence (COBRE) on Obesity and CardiovascularDiseases (COCVD) will further develop and expand upon obesity as an underlying risk factor for thedevelopment of cardiovascular diseases type 2 diabetes cancer and neurodegenerative diseases. Each ofthese diseases are rampant in Kentucky and obesity has been identified as a contributing risk factor for eachcondition. For Phase III of the COCVD we will transition the research core facilities developed during Phase Iand II of this program to independence. We will also support pilot project studies that include obesity as a riskfactor for disease development. We have experienced considerable success having supported 23 juniorinvestigators and 21 pilot project investigators who generated $52 million in extramural funding and publishedmore than 500 scholarly publications. Collectively our team has published more than 280 scholarly articlesthat directly cite COCVD support. We developed an analytical core that provides services in lipidomics andother small molecules a pathology core that provides specialized services to quantify adipose and other tissuemorphology and an energy balance and body composition core that is not duplicated in capacity across theinstitution or the Commonwealth. During Phase III of the COCVD we will transition each core to self-sustaining capacity and upgrade core equipment and use by continuing to provide high quality specializedservices and by expanding core capabilities through provision of additional services that relate obesity to otherdiseases (e.g. cancer). Transition to independence of COCVD cores will be facilitated by use of a vouchersystem to promote core use. We will also continue our strong tradition of pilot project funding which will beexpanded to include studies that focus on obesity as an underlying risk factor for not only cardiovasculardiseases but also type 2 diabetes cancer and neurodegenerative diseases. These areas have beendesignated as areas of strength across the institution (as each disease is a health disparity experienced byKentuckians) and are designated for growth within a new research facility that will focus on Kentucky's healthdisparities. The Administrative Core will oversee all administrative functions of the COCVD and in conjunctionwith the Program Coordinator and the Scientific Internal Advisory Committee will serve as the operational limbof the Center. An External Advisory Committee composed of experts in related fields will provide ongoingassessment and evaluation of the Center. Institutional commitment continues to be outstanding and issupplemented by strong evidence of programmatic growth of direct relevance to this Phase III COCVD.

project_terms:
Adipose tissue;Advisory Committees;Aging;Alzheimer's Disease;Area;Award;Basic Science;Body Composition;Cardiovascular Diseases;Cardiovascular system;Center for Translational Science Activities;Centers of Research Excellence;Chronic Disease;Clinical Research;Clinical Sciences;Core Facility;Death Rate;Development;Diabetes Mellitus;Disease;Equipment;Etiology;Evaluation;Extramural Activities;Fostering;Funding;Gills;Goals;Growth;High Prevalence;Hypertension;Infrastructure;Institutes;Institution;Kentucky;Limb structure;Link;Lipids;Malignant Neoplasms;Mass Spectrum Analysis;Mentors;Morphology;Mus;Neurodegenerative Disorders;Neurosciences;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathology;Phase;Physicians;Pilot Projects;Prevalence;Publications;Publishing;Request for Applications;Research;Research Infrastructure;Research Personnel;Research Support;Risk;Risk Factors;Scientist;Services;Strategic Planning;System;Technology;Tissues;Translating;Translational Research;United States National Institutes of Health;Universities;cancer research center director;cardiovascular risk factor;clinical care;clinical center;comorbidity;dietary;energy balance;experience;health disparity;human disease;improved;lipidomics;obesity development;programs;research facility;small molecule;success;targeted treatment;therapy development;voucher

public_health_relevance:
The Center of Biomedical Research Excellence (COBRE) on Obesity and Cardiovascular Diseases (COCVD)focuses on identification of mechanisms and development of therapies that target obesity as a risk factor forcardiovascular diseases diabetes cancer and neurodegenerative diseases (e.g. Alzheimer's disease).Obesity increases the risk of developing each of these diseases. This Center promotes core facilities andsupports pilot projects that help us understand why obesity increases disease development.


application_id: 10457811
project_number: 5R01DA052203-02
project_title: Influence of 5-HT1b Activation on the Abuse Related Effects of Cocaine
administering_ic: NIDA
award_notice_date: 2022-07-19
opportunity_number: PA-19-055
application_type: 5
activity_code: R01
ic: DA
serial_number: 052203
program_official: FOSTER, KATRINA L
project_start_date: 2021-08-01
project_end_date: 2025-07-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTCocaine use disorder continues to be a significant public health concern. Despite strides in our understandingof the neurobiological underpinnings of cocaine addiction in preclinical models a limited amount of researchhas translated those findings into clinical populations. Such translation is crucial to identify neurobiologicalcircuits that contribute to the problems posed by cocaine use disorder and to guide treatment based on thoseclinical neuroscience findings. Cocaine potently inhibits the reuptake of serotonin (5-HT). Increased synaptic 5-HT resulting from this reuptake inhibition activates multiple 5-HT receptor subtypes. Some of these receptorsubtypes have been implicated in the abuse-related effects of cocaine including its primary reinforcing effects(i.e. cocaine taking behavior). 5-HT1b receptors play a particularly important role in cocaine effects likelybecause they are highly expressed in the mesocorticolimbic system. Preclinical data show that zolmitriptan acommercially available selective 5-HT1b agonist migraine medication approved for human use selectivelyattenuates the reinforcing and other abuse-related effects of cocaine. The overarching goal of this project is toadvance these promising preclinical findings into clinical populations thereby demonstrating that the 5-HT1bsystem plays a key role in the effects of cocaine in humans. To this end 20 non-treatment seeking humansubjects meeting diagnostic criteria for cocaine use disorder will sample doses of intravenous cocaine (0 10and 30 mg/70 kg) in experimental sessions after 3 days of maintenance on oral zolmitriptan (0 2.5 5 and 10mg). A placebo-controlled double-blind within-subjects design will be used such that all subjects experienceall dose conditions in random order. The study will require an approximately 1-month admission to our inpatientunit. After sampling a cocaine dose subjects will make nine choices between that dose and an alternativereinforcer (US$6.00) on a concurrent progressive-ratio choice task that was developed and validated in ourlaboratory. A battery of subjective drug-effect measures and tasks that assess distinct domains of impulsivitywill be completed during the same experimental sessions in which cocaine choice is assessed. The researchproposed here will directly translate findings from preclinical research and provide the initial clinical evidencethat 5-HT1b activation achieved through administration of zolmitriptan reduces the reinforcing and otherabuse-related effects of cocaine as well as cocaine-associated impulsivity. This study will also provide basicscience information about the serotonergic mechanisms underlying the pharmacodynamic effects of cocaine inhumans. As such the outcomes will advance our understanding of the clinical neurobiology of cocaineaddiction.

project_terms:
Abstinence;Admission activity;Agonist;American;Area;Attenuated;Autoreceptors;Basic Science;Behavior;Characteristics;Clinical;Cocaine;Cocaine Dependence;Cocaine Users;Cocaine use disorder;Cues;Data;Decision Making;Disinhibition;Dose;Double-Blind Method;Enrollment;Goals;Human;Impulsivity;Inpatients;Intravenous;Laboratories;Literature;Maintenance;Measures;Mediating;Migraine;Motivation;Nerve Endings;Neurobiology;Neurosciences;Neurosciences Research;Oral;Outcome;Pharmaceutical Preparations;Pharmacodynamics;Placebo Control;Play;Population;Pre-Clinical Model;Psychological reinforcement;Public Health;Reinforcement Schedule;Research;Research Personnel;Role;Sampling;Schedule;Self Administration;Serotonergic System;Serotonin;Serotonin Receptor 5-HT1B;Short-Term Memory;Sucrose;Synapses;System;Time;Translating;Translations;Underserved Population;base;cocaine overdose;cocaine self-administration;cocaine use;craving;design;diagnostic criteria;discounting;experience;experimental study;human subject;inattention;meetings;neurotransmitter release;non-drug;pre-clinical;pre-clinical research;preclinical study;receptor;reinforcer;reuptake;serotonin receptor;zolmitriptan

public_health_relevance:
PROJECT NARRATIVEThe serotonin 5-HT1b system plays key role in the effects of cocaine as indicated by numerous preclinicalstudies. No clinical neuroscience research has advanced these preclinical findings limiting our ability todetermine whether the 5-HT1b system also contributes to cocaine use in humans. The proposed research willfill that gap by determining how administration of a 5-HT1b agonist zolmitriptan impacts the abuse-relatedeffects of cocaine in humans.


application_id: 10457385
project_number: 5R01AA023190-08
project_title: Mechanisms of Probiotics in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2022-08-19
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AA
serial_number: 023190
program_official: WANG, JOE
project_start_date: 2015-09-15
project_end_date: 2022-12-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
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:
Probiotics have been used to prevent/treat a variety of digestive diseases including alcoholic liver disease (ALD).Live probiotics need to colonize the gut to exert their function. Unfortunately underlying disease states providean unfavorable environment for probiotic bacterial gut colonization which diminishes probiotics function. In lastfew years we showed that LGG culture supernatant (LGGs without live bacteria) was effective in the preventionof ALD in experimental models of acute and chronic alcohol exposure in mice. However how LGG supernatantexerts its therapeutic effects is not fully understood. Exosomes are nanoparticles (NPs) derived from cellendocytosis which act as transmitters between cells. Recent studies show that bacteria both Gram-negativeand Gram-positive produce NPs. The NPs derived from bad bacteria have been demonstrated to bepathogenic. However good bacteria- probiotics-derived NPs have not been studied. Our preliminary studyshowed that administration of LGG-derived exosome-like NPs (LDNPs) effectively reversed ALD in binge-on-chronic alcohol exposure mouse model suggesting that probiotic LGGs may exert its function through LDNPsin ALD. LDNPs administration markedly increased intestinal AhR activity IL-22 regenerating islet-derived 3(Reg3) beta and gamma expression which play a key role in maintaining gut microbiota homeostasis andpreventing bacterial intestinal transcytosis. In addition LDNPs administration significantly increased intestinalepithelial cell (IEC) tight junctions and decreased circulating LPS concentration associated with upregulation ofintestinal Nrf2 signaling which is known for protecting intestinal barrier junctions against oxidative stress-induceddamage by alcohol. Metabolomic analysis revealed that LDNPs contain high levels of microbial metabolites oftryptophan which are AhR ligands indicating LDNPs may activate intestinal AhR signaling. Furthermore wedemonstrated that ginger exosome-like nanoparticles (GDNPs) are preferentially taken up by LGG suggestingthat GDNP may serve as a prebiotic to enhance the effects of LGG. These preliminary studies provide thegroundwork for our central hypothesis that by activating intestinal AhR-Nrf2 signaling LDNPs increase intestinalexpression of Il-22 Reg3 and tight junctions and modulate gut microbiota homeostasis and enhance intestinalbarrier function leading to the suppression of ALD. We will test our hypothesis in following three specific aims:(1) Determine the role of bacteria-derived NPs in ALD; (2) Define the mechanisms of the beneficial effect ofLDNPs in ALD; (3) Determine whether ginger-derived exosome-like nanoparticles (GDNPs) treatment enhancesLDNP production and AhR agonist enrichment that lead to improved effects of LDNPs against ALD. Completionof this study is expected to significantly impact the development of LGG-based probiotic therapeutics in thetreatment of alcohol-associated liver diseases.

project_terms:
Acute;Agonist;Alcohol-Induced Disorders;Alcoholic Liver Diseases;Aryl Hydrocarbon Receptor;Bacteria;Bacterial Translocation;Bilophila wadsworthia;Cells;Chronic;Development;Digestive System Disorders;Disease;Endocytosis;Environment;Epithelial;Epithelial Cells;Experimental Models;Ginger;Goals;Growth;Homeostasis;Intestines;Lactobacillus casei rhamnosus;Lead;Liver diseases;Mediating;Mus;Natural regeneration;Oxidative Stress;Pathogenicity;Pathway interactions;Play;Prevention;Prevention strategy;Probiotics;Production;Receptor Signaling;Role;Signal Transduction;Testing;Therapeutic Effect;Tight Junctions;Tryptophan;Up-Regulation;alcohol abuse therapy;alcohol exposure;aryl hydrocarbon receptor ligand;base;dysbiosis;exosome;gut colonization;gut inflammation;gut microbiota;improved;interleukin-22;intestinal barrier;intestinal epithelium;islet;metabolomics;microbial;mouse model;nanoparticle;novel therapeutic intervention;pathogenic bacteria;prebiotics;prevent;probiotic therapy;protective effect;transcytosis

public_health_relevance:
The goals of this project are to investigate the mechanisms of probiotic Lactobacillus rhamnosus GG actionon alcoholic liver disease. This study will have a major impact on the development of a probiotics-based newtherapeutic strategy for the prevention and treatment of alcoholic liver disease.PHS 398/2590 (Rev. 05/01) Page 1 Continuation Format Page


application_id: 10456003
project_number: 5R01DA047952-04
administering_ic: NIDA
award_notice_date: 2022-07-26
opportunity_number: PA-18-345
application_type: 5
activity_code: R01
ic: DA
serial_number: 047952
program_official: FLOURNOY FLOYD, MINNJUAN WYNCEPHEL
project_start_date: 2018-09-30
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZRG1-AARR-K(92)S]
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER R
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
budget_start_date: 2022-08-01
project_title:
Increasing Access to Hepatitis C Treatment in Opioid Endemic Rural Areas: the  Kentucky Viral Hepatitis Treatment (KeY Treat) Study

project_abstract:
ABSTRACTThe overarching goal of the Kentucky Viral Hepatitis Treatment Project (KeY Treat) is to increase access totreatment for the hepatitis C virus (HCV) in a rural Appalachian community in the midst of the opioid/HCVsyndemic. This study seeks to examine whether removing barriers associated with accessing direct-actingantivirals (DAAs) for the treatment of HCV (high out-of-pocket costs insurance restrictions requiring aspecialist abstinence and significant liver damage) will significantly reduce the burden of HCV in PerryCounty Kentucky. The proposed study is made possible by a significant drug donation from Gilead Sciencesfor sofosbuvir/velpatasvir a 12-week once per day pan-genotypic DAA. KeY Treat proposes a multi-prongedapproach to treating HCV using a mid-level provider model. In addition to DAA treatment participants will beoffered access to subsidized medication-assisted treatment syringe services and case management. We willleverage existing resources in the target community (public health jail hospital) as well as ongoing projectsdedicated to increasing access to HCV care in affected communities (ECHO FOCUS) to answer whetherremoving the major barriers to HCV treatment affect access and what barriers remain. All RNA-positiveresidents of Perry County Kentucky will be eligible/recruited for study participation (N900) and the followingspecific aims will be addressed: 1) determination of HCV treatment uptake among rural residents with chronicHCV; 2) examination of the predictors of treatment completion among those enrolled in KeY Treat; 3)examination of the characteristics of participants achieving sustained virologic response (SVR or cure); 4)establishment of long-term re-infection rates among those achieving SVR; 5) examination of 5-year reductionsin incidence and prevalence of HCV in the intervention community compared with a control county in ruralKentucky; and 6) evaluate the impact and cost-effectiveness of KeY Treat using mathematical modeling. Theproposed research has tremendous potential to impact public health in the rural United States. The majority ofcounties identified in CDCs recent HCV/HIV hotspot analysis were rural and there is a real need to improveaccess to DAAs in order to prevent further HCV transmission reduce the burden of advanced liver diseaseand hepatocellular carcinoma in generations to come. Data from KeY Treat will inform policies aroundMedicaid/insurance restrictions for DAAs and will deliver a much needed blueprint for the provision of HCVtreatment in resource-deprived rural areas.

project_terms:
Abstinence;Address;Affect;Aftercare;Age;Antiviral Agents;Appalachian Region;Blood;Caring;Case Management;Centers for Disease Control and Prevention (U.S.);Characteristics;Chronic;Chronic Hepatitis C;Clinical Research;Communities;Community Health;Complement;County;Data;Drug user;Enrollment;Generations;Genotype;Goals;Guidelines;HIV;Health;Health Services Accessibility;Hepatitis C;Hepatitis C Prevalence;Hepatitis C Therapy;Hepatitis C Transmission;Hepatitis C virus;Hepatology;Hospitals;Housing;Improve Access;Incidence;Individual;Infection;Insurance;Intervention;Jail;Kentucky;Letters;Liver diseases;Measures;Medicaid;Modeling;Needle-Exchange Programs;Nurse Practitioners;Opioid;Outcome;Participant;Pharmaceutical Preparations;Pike fish;Policies;Prevalence;Primary carcinoma of the liver cells;Provider;Public Health;RNA;Research;Research Personnel;Resources;Rural;Rural Appalachia;Sampling;Science;Secure;Services;Specialist;Syringes;Tablets;Text;United States;Universities;Viral hepatitis;community intervention;cost;cost effective;cost effectiveness;follow-up;infection rate;liver injury;marginalized population;mathematical model;medication compliance;medication-assisted treatment;opioid abuse;opioid use disorder;portability;prevent;recruit;research study;response;rural area;rural dwellers;rural setting;side effect;syndemic;telehealth;treatment services;uptake;viral RNA

public_health_relevance:
PROJECT NARRATIVEThe hepatitis C virus (HCV) is endemic in rural Appalachia primarily due to abuse of opioids. Direct-actingantivirals (DAAs) are exceedingly effective at curing hepatitis C but access and uptake of DAA treatment islacking in rural areas largely due to high cost and Medicaid restrictions. The Kentucky Viral Hepatitis CTreatment (KeY Treat) project will provide treatment with a DAA to any RNA-positive resident of Perry CountyKentucky to determine whether removing these major barriers will improve access to care and data from KeYTreat will inform policies around Medicaid/insurance restrictions for DAAs and will deliver a much neededblueprint for the provision of HCV treatment in resource-deprived rural areas.


application_id: 10456001
project_number: 5R01EB026893-05
project_title: Controllable In Vivo Genome Editing for Immune-Checkpoint Blockade in Solid Tumors
administering_ic: NIBIB
award_notice_date: 2022-06-03
opportunity_number: PAR-16-044
application_type: 5
activity_code: R01
ic: EB
serial_number: 026893
program_official: CHEN, JERMONT
project_start_date: 2018-08-21
project_end_date: 2024-05-31
study_section: Special Emphasis Panel[ZRG1-SBIB-Q(58)R]
contact_pi_person_id: 14341515
contact_pi: TONG, SHENG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryThe blockade of immune-checkpoint pathways has emerged as a promising therapeutic strategy for a varietyof cancers. However the diverse tumor responses to immunotherapy seen in preclinical and clinical studiesprompt the development of combination immunotherapies that can be tailored to the complex immune milieuof individual patients. On the other hand the severe adverse effects associated with the combination therapieswith multiple antagonist antibodies address the necessity for alternative safe and effective therapeuticapproaches. In light of this we aim to develop a hybrid nanoparticle-viral vector system for CRISPR/Cas9-based in vivo therapeutic genome editing which will be used for multiplexed disruption of immune suppressivepathways in the tumor microenvironment. CRISPR/Cas9 systems are very efficient in generating DNA double-strand breaks thus disrupting genes through the non-homologous end-joining (NHEJ) pathway. Howeverinducing uncontrolled CRISPR/Cas9 activities in vivo may lead to systemic genotoxicity. We will develop anovel in vivo gene delivery system that integrates a baculoviral vector (BV) with magnetic nanoparticles(MNPs). Our studies have shown that by taking advantage of the interplay between the MNP-mediated BVmargination and endocytosis and the innate immunity against insect viruses this delivery system can providespatial and temporal control of CRISPR/Cas9 activity. We will use the MNP-BV system to deliver optimizedCRISPR/Cas9 for gene disruption of immune suppressive signals PD-L1 and TGF- in the tumor tissue. Wewill evaluate CRISPR/Cas9 induced anti-tumor immune responses using two well-established mouse modelsan immunogenic model (MC38) where monotherapy with PD-1 blockade is sufficient and non-immunogenicmodels pancreatic ductal adenocarcinoma (PDAC) which portrays most non-immunogenic human solidtumors that require combination strategies. In aim 1 studies we will design and optimize CRISPR/Cas9gRNAs for targeting PD-L1 and TGF- package Cas9 and gRNAs into a BV vector and construct the MNP-BV system. In aim 2 studies we will evaluate MNP-BV-induced multiplexed gene disruption in cell cultureand determine the on-target and off-target indel rates. In aim 3 studies we will test the controlled in vivodelivery of CRISPR/Cas9 determine the immunological and therapeutic effects of local gene disruption vs.systemic blockade with antagonist antibody in mouse tumor models. The success of the proposed studies willprovide a multiplexed intratumoral immunoengineering platform and pave the way for the clinical translationof a highly efficient in vivo genome editing strategy for personalized cancer immunotherapy.

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

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


application_id: 10455251
project_number: 3OT2OD024898-01S5
administering_ic: OD
award_notice_date: 2021-08-30
opportunity_number: RFA-RM-15-018
application_type: 3
activity_code: OT2
ic: OD
serial_number: 024898
suffix: S5
program_official: QASHU, FELICIA M
project_start_date: 2017-09-20
project_end_date: 2024-08-31
study_section: Anatomical and Functional Mapping of the Innervation of Marjor Internal Organs[AFMI(53)]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
other_pis: HARKEMA, SUSAN J
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:
Functional Mapping with Lumbosacral Epidural Stimulation for Restoration of Bladder Function After Spinal Cord Injury

project_abstract:
PROJECT SUMMARY/ABSTRACT The overall objective of this functional bladder mapping study is to identify the spinal cord epiduralstimulation (scES) configurations (anode/cathode selection amplitude frequency and pulse width) at thelumbosacral level that can promote neural control of bladder storage (capacity) and voiding efficiency afterspinal cord injury (SCI). This comprehensive functional mapping study in both humans and animals in parallelinvolves a novel clinical application of a marketed Medtronic device for bladder dysfunction after SCI. Themapping (human and animal) and training (human) experiments address several specific objectives of theSPARC Program initiative per RFA-RM-15-018 including neural circuit maps regarding functional connectivity(Aim 1) neural plasticity related to stimulation (bladder training experiments  Aim 2) variability (animal-to-animal and patient-to-patient) and research on what organ functions results from different types of stimulation(storage vs voiding and identifying any additional effects on bowel and/or sexual function). The long-term reduction in the cost to the health care system care givers and society would bedramatic. SCI results in impairments of locomotor sensory and autonomic functions severely affecting overallhealth and quality of life. Proper bladder management post-SCI is necessary to decrease the risk of upperurinary tract disease a major source of morbidity. Life-long urologic care is required for SCI individuals yetmost efforts treat symptoms but do not improve intrinsic function. Current therapies for bladder managementafter SCI include catheterization pharmacologic and surgical interventions functional electrical stimulation(peripheral) and urethral stents but all have deleterious effects. We have exciting data from multipleindividuals with severe injuries (AIS A and B) indicating improved bladder function after undergoing a widelyimplemented activity-based rehabilitation locomotor training (LT) which includes stepping using body weightsupport on a treadmill with manual facilitation. In addition we have intriguing preliminary data from severalcompletely paralyzed individuals receiving scES in combination with task specific training that recoveredstanding and voluntary movement and showed improvements in both bladder capacity and voiding efficiency.Our most recent pilot data also indicate an immediate benefit of scES alone on bladder function. Thus wepropose to determine the functional gains that can be achieved in the storage and voiding phases of lowerurinary tract function as a result of activation of spinal circuits with scES in humans with SCI and in a clinically-relevant rodent SCI model. We will test the general hypothesis that bladder capacity and voiding efficiencyincreases with scES post-SCI and to an even greater extent with scES bladder training over time. This proposal involves the collaboration of clinicians and scientists with extensive experience in animaland human SCI models. Our unique approach will utilize the expertise of a multi-disciplinary team (expertise inbladder function neuromodulation rehabilitation engineering and statistics) to 1) determine the optimalstimulation parameters for storage and voiding in SCI research participants already implanted with the scESMedtronic device (16-electrode array from L1-S1); 2) quantify the long-term effects of daily bladder trainingusing optimal stimulation parameters (all the same research participants); 3) measurement of secondarybenefits (bladder medication usage susceptibility to urinary tract infections indirect cardiovascular bowel andsexual function benefits) of long-term bladder training; and 4) address with a small animal model the impact oflocation lesion severity chronicity and gender. Our innovative approach and novel application of thisMedtronic Specify 5-6-5 device will allow us to determine specific types of scES needed for bladder functionwhich will lay the groundwork for expedient translation of this promising technique to larger numbers ofindividuals with SCI in the next phase of the SPARC initiative with additional refinement in parallel using alarge animal SCI model (pig) that is currently under development within the Kentucky Spinal Cord ResearchCenter.

public_health_relevance:
PROJECT NARRATIVESpinal cord injury (SCI) results in devastating effects on overall health and quality of life. TheChristopher and Dana Reeve Foundation have recently estimated that 1275000 people areliving with paralysis from SCI in the United States alone. This country could save an estimated$400 billion on direct and indirect lifetime costs if we can find ways to treat and prevent SCI.Bladder dysfunction affects daily life reduces quality of life and results in numerous life-longhealth complications. Improvements in bladder function have been recently discovered in SCIsubjects while they are undergoing an efficacious rehabilitation intervention activity-basedlocomotor training (LT). In addition multiple individuals with motor complete SCI who havereceived epidural stimulation in combination with LT also have significant improvements inbladder function. This proposal is an early feasibility study in a small number of subjects for anovel clinical application (bladder dysfunction after SCI) of a marketed Medtronic device (initialclinical safety and device functionality study). A parallel animal study will also be done. Theoverall objective of this study is to demonstrate that lumbosacral epidural stimulation may be aviable therapeutic strategy for improving storage (continence) and urination (voiding) after SCI.The knowledge gained from our innovative application of an existing stimulation device maylead to the translation and immediate application to a larger cohort of SCI individuals andprovide immense improvements in quality of life.


application_id: 10455119
project_number: 3P42ES007380-23S2
project_title: KC Donnelly Externship Admin Supplement for Ariel Robinson P42ES007380 UKSRC
administering_ic: NIEHS
award_notice_date: 2021-07-22
opportunity_number: PA-20-272
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S2
program_official: HENRY, HEATHER F
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D(SF)
contact_pi_person_id: 8776790
contact_pi: PENNELL, KELLY G
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY 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: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARYThe University of Kentucky Superfund Research Center (UK-SRC) provides a focused cross-disciplinaryresearch and training environment to address critical human health challenges associated with halogenatedorganic substance exposures. Four center projects and five cores make up the proposed UK-SRC to furtherdevelop research on lifestyle changes (e.g. nutrition and exercise) in addition to two environmental scienceprojects that will focus on the remediation and engineering solutions to this set of problems. Due to theirrelative chemical stability and ubiquity in the environment chlorinated organic contaminants such aspolychlorinated biphenyls (PCBs) and trichloroethylene (TCE) pose significant health risks and enduringremediation challenges including sites such as the Paducah Gaseous Diffusion Plant the largest Superfundsite in Kentucky. The UK-SRCs overall focus for this next cycle is the human health impacts of persistenthalogenated organics (e.g. PCBs TCE and tetrachloroethene (PCE) and in this new cycle of fundingadditional questions about per- and polyfluoralkyl substances (PFAS) will be incorporated. Projects coveringbiomedical research hypothesize that healthy nutrition and exercise components provide a platform to developprimary prevention strategies for diseases associated with environmental toxic insults while also providing thebasis for new risk assessment paradigms. Further novel iron-based nano-structured sensing capture andremediation systems based on biomimetic binding domains and functionalized membrane platforms offerpotential for sustainable advances in technical capability for site remediation. The UK-SRC proposes thefollowing goals: 1) to expedite data-driven discovery as facilitated by the Data Management and Analysis Corethat will provide insight about biomarkers of exposures to generate new information about the relationshipbetween pollutant exposure nutrient intake physical activity and disease risk; 2) to better understand thebiochemical molecular and cellular mechanisms underlying the toxicity of halogenated organic compounds(i.e. PCBs and PFAS) with a specific focus on chronic inflammatory diseases and windows of susceptibility; 3)to foster informed decisions that expedite clean-up of halogenated organic compounds through advancedmaterial-based technologies smart filters and fate and transport science to reduce exposure risks; 4) topromote and interdisciplinary approaches to environmental health science training that accelerate the impact ofcomplex solution-oriented stakeholder-engaged research aimed at reducing exposures and improving humanhealth; and 5) to engage bi-directionally and provide environmental health programmatic activities tovulnerable socially-isolated under-resourced communities in Kentucky especially Eastern Kentucky (i.e.Central Appalachia) where chronic inflammatory diseases exceed national averages and exposure risks toenvironmental pollutants are prevalent. Activities will involve community engaged research and an innovativemeans of integrating projects through the WHY-ENVIRONMENT initiative.

project_terms:
Address;Aging;Appalachian Region;Awareness;Binding;Biochemical;Biological;Biological Markers;Biological Models;Biological Monitoring;Biomedical Engineering;Biomedical Research;Biomimetics;Chemicals;Communication Research;Communities;Complex;Consumption;Data;Data Analyses;Diet and Nutrition;Diffusion;Disease;Disease Outcome;Ecology;Economically Deprived Population;Engineering;Environment;Environmental Engineering technology;Environmental Health;Environmental Pollutants;Environmental Pollution;Evaluation;Exercise;Exposure to;Fiber;Fostering;Funding;Future;Goals;Hazardous Substances;Health;Human;Industry;Intake;Interdisciplinary Study;Intervention;Iron;Kentucky;Life;Life Style;Link;Membrane;Metabolic;Metals;Methods;Molecular;Nanostructures;National Institute of Environmental Health Sciences;Nutrient;Outcome;Oxides;Pathway interactions;Physical activity;Physiological;Plants;Policies;Policy Maker;Polychlorinated Biphenyls;Predisposition;Pregnancy;Prevention;Prevention strategy;Primary Prevention;Problem Sets;Recommendation;Research;Research Project Grants;Research Training;Resources;Risk;Risk Assessment;Risk Management;Science;Scientist;Services;Site;Superfund;System;Techniques;Technology;Tetrachloroethylene;Toxic effect;Toxicant exposure;Training;Translational Research;Trichloroethylene;Universities;Vulnerable Populations;base;chemical stability;chronic inflammatory disease;community engaged research;community engagement;community intervention;community involvement;data management;detection method;dietary;disadvantaged population;disorder prevention;disorder risk;environmental chemical;environmental chemistry;experience;exposure pathway;externship;graphene;healthy lifestyle;human old age (65+);improved;innovation;insight;interdisciplinary approach;lifestyle intervention;lipidomics;metabolomics;next generation;novel;nutrition;organic contaminant;pollutant;polyphenol;prevent;programs;remediation;social;superfund site;tool

public_health_relevance:
PROJECT NARRATIVEOutcomes and results from the proposed activities and research of the UK-SRC will provide importanttechnology tools and insights for primary stakeholders for improving Superfund site risk assessment andmanagement specifically related to the class of compounds known as halogenated organics. In addition theproposed research has implications for novel dietary and exercise recommendations and policyrecommendations for the economically disadvantaged populations of Kentucky.


application_id: 10455105
project_number: 5R01AA028503-03
project_title: Sex Differences in Risk for Alcohol Use Disorder: Neural and Hormonal Influences
administering_ic: NIAAA
award_notice_date: 2022-08-04
opportunity_number: PA-19-091
application_type: 5
activity_code: R01
ic: AA
serial_number: 028503
program_official: MATOCHIK, JOHN A
project_start_date: 2020-09-01
project_end_date: 2025-07-31
study_section: Special Emphasis Panel[ZRG1-BDCN-C(90)S]
contact_pi_person_id: 9711222
contact_pi: WEAFER, JESSICA J
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThe sex gap in alcohol consumption is closing rapidly due to alarming increases in alcohol consumptionamong young women. As such there is an urgent need to determine the factors underlying sex differences inrisk for AUD. Current addiction models propose three neurofunctional domains that drive problematic alcoholuse and therefore serve as candidate sex-specific risk factors: executive function negative emotionality andincentive salience. Data from our lab and others suggest that poor inhibitory control a key component ofexecutive function is a stronger risk factor for women than for men. Moreover we have preliminary evidencethat female drinkers show less engagement of neural circuitry underlying inhibitory control and that this sexdifference is influenced by circulating levels of estradiol. However the degree to which hormonally-moderatedsex differences in executive function extend to the negative emotionality and incentive salience domains andhow these sex differences influence current and future drinking is unknown. Here we will determine: 1) theneurobiological factors contributing to sex-specific risk for AUD in each of these three addiction domains and 2)the degree to which sex differences in each domain influence current and prospective drinking. Femaledrinkers will undergo fMRI to assess neural correlates of inhibitory control (i.e. executive function) negativeemotionality and alcohol cue reactivity (i.e. incentive salience) at three phases of their menstrual cycle: earlyfollicular phase (low estradiol low progesterone) late follicular phase (high estradiol low progesterone) andmid-luteal phase (moderate estradiol high progesterone). Male drinkers will undergo three fMRI scans atmatched intervals. Immediately following each scan participants will complete a session of free-accessintravenous alcohol self-administration. We will then follow participants for 18 months to longitudinally assesschanges in drinking patterns. We hypothesize that hormonally-moderated neural function underlying inhibitorycontrol and negative emotionality will be stronger predictors of current and future alcohol consumption inwomen compared to men whereas neural alcohol cue reactivity will be a stronger predictor for men. Theproject capitalizes on the unique skill sets of the PI (an Early Career Investigator) and a strong collaborativeinvestigative team. The innovative design will provide essential information regarding neural factors influencingdevelopment and maintenance of AUD and critically how this risk is influenced by sex and fluctuations in sexhormones. Ultimately this proposal is a crucial step in a line of research that will lead to the development ofsex-specific prevention and treatment efforts for AUD.

project_terms:
Alcohol abuse;Alcohol consumption;Alcohols;Amygdaloid structure;Anterior;Area;Base of the Brain;Brain;Corpus striatum structure;Data;Development;Emotional;Estradiol;Female;Functional Magnetic Resonance Imaging;Future;Goals;Gonadal Steroid Hormones;Heavy Drinking;Hormonal;Inferior frontal gyrus;Insula of Reil;Intervention;Intravenous;Laboratories;Link;Luteal Phase;Maintenance;Measures;Medial;Menstrual cycle;Modeling;Motor;Negative Finding;Neurobiology;Neurophysiology - biologic function;Participant;Patient Self-Report;Pattern;Pharmacotherapy;Phase;Prefrontal Cortex;Prevention;Progesterone;Research;Research Personnel;Risk;Risk Factors;Scanning;Self Administration;Sex Differences;Signal Transduction;Smoker;Transcranial magnetic stimulation;Woman;addiction;alcohol abuse therapy;alcohol cue;alcohol intervention;alcohol risk;alcohol use disorder;base;career;cingulate cortex;cue reactivity;design;disorder risk;drinking;executive function;follow-up;functional MRI scan;hazardous drinking;incentive salience;innovation;male;men;negative affect;neural circuit;neural correlate;novel;proliferative phase Menstrual cycle;prospective;relating to nervous system;sex;skills;stimulant user;young woman

public_health_relevance:
PROJECT NARRATIVEThe findings from this project will determine sex differences and the influence of sex hormones on neuralfunction underlying risk for Alcohol Use Disorder (AUD) as well as how sex differences in neural functioninfluence current and future alcohol consumption. The results will identify novel brain-based targets for sex-specific prevention and treatment efforts for AUD and will provide information on the optimal timing ofintervention for women based on fluctuating sex hormones. As such the project is a critical step towards thedevelopment of biologically-based sex-specific interventions for AUD.


