# projects

application_id: 10208026
project_number: 1R01NS116068-01A1
project_title: Macrophage Depletion Therapy for Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2021-03-02
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: NS
serial_number: 116068
suffix: A1
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2021-03-15
project_end_date: 2025-11-30
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8201969
contact_pi: GENSEL, JOHN C
other_pis: ALILAIN, WARREN JOSEPH
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Acute;Affect;American;Americas;Animal Model;Animals;Anti-Inflammatory Agents;Applications Grants;Autonomic Dysreflexia;Basic Science;Biodistribution;Biological Assay;Bone Marrow;Breathing;Cell Death;Cells;Cervical;Cervical spinal cord injury;Cervical spinal cord structure;Chronic;Clinical;Clinical Trials;Congresses;Contusions;Data;Dichloromethylene Diphosphonate;Distal;Dose;Encapsulated;FDA approved;Flow Cytometry;Forelimb;Frustration;Funding;Goals;Grant;Hand functions;Hindlimb;Hour;Human;Immune;Immune Targeting;Immunologic Deficiency Syndromes;Impairment;Individual;Inflammation;Inflammatory;Inflammatory Response;Injury;Laboratories;Lead;Lesion;Leukocytes;Liposomes;Liver;Locomotion;Locomotor Recovery;Mediating;Minocycline;Modeling;Modification;Motor;Multiple Trauma;Myelopoiesis;Neuroglia;Organ;Outcome;Outcome Measure;Output;Pain;Pathology;Pharmaceutical Preparations;Pharmacotherapy;Phenotype;Population;Production;Publishing;Quality of life;Rattus;Recovery;Recovery of Function;Regulation;Reporting;Research;Research Personnel;Respiration;Rodent;Rodent Model;Sensory;Site;Spinal Cord;Spinal Cord Contusions;Spinal Cord Plasticity;Spinal Injuries;Spinal cord injury;Spleen;Steroids;Testing;Therapeutic;Thoracic spinal cord structure;Time;Tissues;Toxic effect;Translating;Translations;Treatment Efficacy;United States;United States National Institutes of Health;Visceral pain;Voice;arm;axonal sprouting;base;care outcomes;central pattern generator;clinically relevant;functional disability;functional outcomes;improved;improved outcome;indexing;innovation;macrophage;meetings;monocyte;novel therapeutic intervention;pain sensation;pre-clinical;preclinical evaluation;recruit;repaired;respiratory;response;side effect;synaptogenesis;tissue repair;translational impact


application_id: 10207891
project_number: 1R01GM138837-01A1
project_title: Ex vivo single molecule tools to analyze membrane receptor dynamics
administering_ic: NIGMS
award_notice_date: 2021-05-25
opportunity_number: PAR-19-253
application_type: 1
activity_code: R01
ic: GM
serial_number: 138837
suffix: A1
program_official: YEH, ALVIN TIEN-WEI
project_start_date: 2021-06-03
project_end_date: 2025-05-31
study_section: Enabling Bioanalytical and Imaging Technologies Study Section[EBIT]
contact_pi_person_id: 8957529
contact_pi: RICHARDS, CHRISTOPHER I
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Animal Communication;Animal Disease Models;Animal Model;Animals;Biological;Biological Models;Brain;Brain region;Cardiac;Cell Culture Techniques;Cells;Chemicals;Classification;Communication;Complex;Consumption;Data;Data Analyses;Data Set;Development;Dimerization;Disease;Encapsulated;Environment;Exposure to;Future;Goals;Heart;High Performance Computing;Image;In Vitro;Knock-in;Knock-in Mouse;Lead;Machine Learning;Manuals;Measurement;Mediating;Membrane;Membrane Proteins;Methodology;Methods;Monitor;Mus;Organ;Pharmaceutical Preparations;Pharmacotherapy;Physiological;Physiological Processes;Play;Population;Preparation;Process;Process Measure;Property;Protein Dynamics;Proteins;Regulation;Research;Research Methodology;Research Personnel;Role;RyR2;Ryanodine Receptor Calcium Release Channel;Sampling;Signal Transduction;Structure;System;Techniques;Technology;Testing;Therapeutic;Time;Tissues;Training;Vesicle;alpha-SNAP;animal tissue;base;cell type;cluster computing;convolutional neural network;design;in vivo;insight;large datasets;molecular imaging;nanoscale;nanovesicle;novel;open source;postsynaptic neurons;presynaptic;prototype;receptor;response;sex;single molecule;stoichiometry;technique development;therapeutic target;tissue preparation;tool;trafficking


application_id: 10207512
project_number: 5F31DK126400-02
project_title: Role of macrophages in cisplatin-induced kidney injury and progression to chronic kidney disease
administering_ic: NIDDK
award_notice_date: 2021-03-29
opportunity_number: PA-19-195
application_type: 5
activity_code: F31
ic: DK
serial_number: 126400
program_official: MARIC-BILKAN, CHRISTINE
project_start_date: 2020-05-01
project_end_date: 2021-12-17
study_section: ZDK1-GRB-G(M1)
contact_pi_person_id: 16257979
contact_pi: SEARS, SOPHIA MARIE
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 SummaryCisplatin is a commonly used chemotherapeutic agent with dose-limiting nephrotoxicity. 30% of patients whoreceive cisplatin develop acute kidney injury (AKI) or a rapid decrease in kidney function. Development of AKIincreases the risk of chronic kidney disease (CKD) and mortality. Even patients that do not develop AKI byclinical standards are still at risk for long term declines in renal function and CKD development. There arecurrently no therapies approved to prevent or treat cisplatin-induced kidney injury (CDDP-KI). In the pastresearch on CDDP-KI utilized a single high dose model of injury. This model is lethal to mice within 3-4 daysand does not allow for study of long-term renal outcomes. We have developed a more clinically relevantrepeated low dose cisplatin (RLDC) model of CDDP-KI. In this model mice receive 4 weekly low doses ofcisplatin and can survive more than 6 months after treatment [1]. This RLDC model has been shown to inducerenal fibrosis and progressive declines in renal function indicative of CKD development [1 2]. Other models ofkidney fibrosis have demonstrated that macrophages can play a pro-fibrogenic role by differentiating intomyofibroblasts the main effector of fibrotic development. Our preliminary studies show that the RLDC modelcauses accumulation of macrophages and myofibroblasts that persists up to 6 months after treatment. This isaccompanied by a sustained increase in transforming growth factor beta (TGF) which is a mediator ofmacrophage to myofibroblast transition. Lastly we have identified a population of F4/80+ SMA+ CD206+ cellsthat appear after the fourth dose of cisplatin indicative of this transition state. This research proposal willexamine the relationship between macrophage response and susceptibility to CDDP-KI using our RLDC modelof cisplatin-induced injury. We hypothesize that the repeated low dose cisplatin model promotes fibrosisand CKD development through stimulating chronic macrophage activity and macrophage tomyofibroblast transition in the kidney. This hypothesis will be tested with the following aims. Aim 1:Characterize immune response and macrophage to myofibroblast transition during repeated low dose cisplatin.In this aim we will use flow cytometry to analyze the immune cell response to cisplatin induced injury in thekidney. We will also isolate renal macrophages following cisplatin treatment and perform RNAseq to evaluatedevelopment of myofibroblast characteristics. Lastly we will utilize bone marrow chimera models to determineif bone marrow derived immune cells are infiltrating the kidney following cisplatin treatment. Aim 2: Determinethe role of macrophages in repeated low dose cisplatin induced fibrosis and chronic kidney disease. In thisaim we will determine how global depletion of macrophages and inhibition of chemokine (C-C motif) receptor 2(CCR2) monocyte trafficking affects renal function and development of fibrosis in our RLDC model. Completionof these aims will identify novel targets to prevent the AKI to CKD transition associated with CDDP-KI.

project_terms:
Acute Renal Failure with Renal Papillary Necrosis;Affect;Aftercare;Apoptosis;Blood Vessels;Bone Marrow;Cancer Patient;Cell Death;Cells;Characteristics;Chimera organism;Chronic;Chronic Kidney Failure;Cisplatin;Clinical;DNA;Data;Development;Dichloromethylene Diphosphonate;Disease Progression;Dose;Dose-Limiting;Effectiveness;Endothelium;Extracellular Matrix;Fibrosis;Flow Cytometry;Functional disorder;Immune;Immune response;Impairment;Infiltration;Inflammation;Injury;Injury to Kidney;Kidney;Knockout Mice;Life;Liposomes;Longitudinal Studies;Mediator of activation protein;Modeling;Mus;Myofibroblast;Outcome;Patients;Pharmaceutical Preparations;Phase II Clinical Trials;Play;Population;Predisposition;Production;Renal function;Reperfusion Injury;Research;Research Proposals;Risk;Role;Signal Transduction;Testing;Therapeutic;Transforming Growth Factor beta;Treatment-related toxicity;Tubular formation;Tumor-infiltrating immune cells;Ureteral obstruction;Work;cancer cell;cancer therapy;cell injury;chemokine receptor;chemotherapeutic agent;clinically relevant;crosslink;cytokine;glomerulosclerosis;interstitial;kidney allograft;kidney fibrosis;macrophage;monocyte;mortality;mouse model;nephrotoxicity;novel;prevent;prospective test;recruit;response;side effect;success;trafficking;transcriptome sequencing

public_health_relevance:
Project NarrativeAcute kidney injury (AKI) and chronic kidney disease (CKD) are life threatening side effects commonlyassociated with drug therapeutics. We are using a clinically relevant model of cisplatin-induced kidney injury toexamine the role of macrophages in this pathophysiology. Successful completion of this project will lead toclinical therapies to prevent drug-induced kidney injury.


application_id: 10207437
project_number: 5R01AI139671-03
administering_ic: NIAID
award_notice_date: 2021-07-02
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AI
serial_number: 139671
program_official: CHUANG, ELEANORE JENNIFER
project_start_date: 2019-07-05
project_end_date: 2024-06-30
study_section: Biomaterials and Biointerfaces Study Section[BMBI]
contact_pi_person_id: 10329001
contact_pi: STEINBACH-RANKINS, JILL
other_pis: Not Applicable
congressional_district: 03
department: ENGINEERING (ALL TYPES)
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: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-07-01
project_title:
Understanding the Host-Microbiome-Therapeutic Triad: Implications for Designing Alternative Intravaginal Delivery Platforms to Treat Bacterial Vaginosis

project_abstract:
PROJECT SUMMARYBacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome characterized by low levels of lactobacilli whichtypically dominate the vagina in healthy women and overgrowth of diverse anaerobic bacteria most notablyGardnerella vaginalis (G.v.). BV affects ~30% of U.S. women and is associated with increased risk of adversepregnancy outcomes postsurgical infections and sexually transmitted infections (STIs). Current treatmentoptions primarily comprised of orally- or topically-applied antibiotics are initially efficacious; however frequentrelapse is prevalent contributing to recurrent BV infections and adverse side effects. Potential new therapiesincluding prebiotics metabolic products (e.g. lactic acid) and probiotics (lactobacilli) are being studied for theirabilities to re-balance the vaginal microbiome toward normal Lactobacilli and counterbalance G.v. Howeverthese and other methods of BV treatment often require repeated vaginal administrations which can limit theirconvenience and appropriate use. New delivery vehicles that can store and release lactic acid and probioticlactobacilli are needed. However significant gaps remain in our understanding of host microbe and deliveryvehicle interactions contributing to the difficulty in attaining a long-term effective method of protection andtreatment against BV. In this project we seek to develop new therapies to alter BV pathogenesis while advancing theunderstanding of delivery vehicle interactions with the host and vaginal microbes. To achieve these goals wewill optimize the design of a novel delivery platform composed of sequentially-layered or dual-spun polymericelectrospun fibers (EFs) that deliver probiotics test their efficacy in vitro and assess the safety and effectivenessof these fibers in a murine model of BV. These studies will provide the foundation for improved therapeuticoutcomes while providing new insight into the effects of lactic acid-based probiotic fibers on vaginal microbeshost inflammatory response and BV disease markers and progression. While we will initially apply this deliveryapproach to target BV pathogenesis we envision the research outcomes will have a significant impact on thedevelopment of future multipurpose platforms to prevent and treat broader more complex interactions betweenbacterial and viral pathogens in the female reproductive tract.

project_terms:
Adherence;Affect;Anaerobic Bacteria;Antibiotics;Architecture;Atopobium vaginae;Back;Bacteria;Bacterial Counts;Bacterial Vaginosis;Chronic;Coculture Techniques;Complex;Cream;Data;Development;Disease Marker;Disease Progression;Dosage Forms;Effectiveness;Encapsulated;Enzymes;Epithelial;Equilibrium;Female;Fiber;Formulation;Foundations;Future;Gardnerella vaginalis;Gel;Generations;Glycolates;Goals;Health;Homeostasis;In Vitro;Infection;Inflammatory Response;Intravaginal Administration;Lactic acid;Lactobacillus;Malignant Neoplasms;Metabolic;Methods;Microbe;Microbial Biofilms;Modeling;Mucous body substance;Oral;Outcome;Outcomes Research;Pathogenesis;Patients;Physiological;Polymers;Pre-Clinical Model;Probiotics;Recurrence;Regimen;Relapse;Risk;Safety;Sexually Transmitted Diseases;System;Tablets;Testing;Therapeutic;Time;Tissue Model;Topical application;Treatment Efficacy;Triad Acrylic Resin;Uterus;Vagina;Vaginal delivery procedure;Viral;Woman;adverse pregnancy outcome;antimicrobial;base;chemokine;cytokine;design;dysbiosis;host microbiome;improved;insight;member;microbiome therapeutics;mouse model;nanoparticle;novel;novel therapeutics;oral biofilm;pathogen;pathogenic bacteria;pathogenic virus;prebiotics;prevent;reproductive tract;residence;response;safety study;scaffold;side effect;success;therapy outcome;treatment strategy;vaginal infection;vaginal microbiome;vaginal microbiota

public_health_relevance:
PROJECT NARRATIVEBacterial vaginosis is a highly recurrent imbalance of the vaginal microbiota that affects 1/3 of U.S. womenand is associated with numerous adverse health outcomes; however antibiotic-sparing treatments such as thedelivery of probiotic bacteria often require daily administration for effectiveness. We will optimize the design ofa novel delivery platform composed of sequentially-layered or dual-spun polymeric electrospun fibers that willdeliver probiotic lactobacilli and lactic acid then test their efficacy in both in vitro and mouse models of BV.This study will provide a foundation for improved therapeutic outcomes while providing new insight into theeffects of probiotic lactic acid-based fibers on BV disease markers and host inflammatory responses.


application_id: 10207380
project_number: 5F31AI147417-03
administering_ic: NIAID
award_notice_date: 2021-08-05
opportunity_number: PA-18-671
application_type: 5
activity_code: F31
ic: AI
serial_number: 147417
program_official: VINCENT, LEAH REBECCA
project_start_date: 2019-08-09
project_end_date: 2021-08-10
study_section: Special Emphasis Panel[ZRG1-F13-Z(20)L]
contact_pi_person_id: 15691582
contact_pi: KEB, GABRIELLE
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
budget_start_date: 2021-08-09
project_title:
Chlamydia trachomatis Secreted Effector Proteins: Infection Properties and Identification of Host Targets

project_abstract:
Project Summary Chlamydia trachomatis is the causative agent of most commonly reported sexually transmitted diseasein the United States. Disease is most severe in women and can cause detrimental effects to reproductive healthsuch as infertility. Establishment of an intracellular niche within non-immune cells such as mucosal epitheliumis sufficient to drive immunopathology and disease sequela. C. trachomatis lacking both TmeA and TmeB typeIII secretion system effectors generate fewer infectious progeny in tissue culture and have significantlydecreased infectivity in mice. Previous attempts to identify their individual functions utilized fluorescence-reported allelic exchange mutagenesis (FRAEM) but resulted in unclear phenotypes due to cassette-inducedpolar effects. Recently I have developed floxed-cassette allelic exchange mutagenesis (FLAEM) to reversecassette-induced polar effects and generate the first ever markerless C. trachomatis deletion mutant. Ihypothesize that TmeA and TmeB are functionally related and important for establishing the inclusion becausethey are co-transcribed share a common chaperone and are secreted into the host cell at the same time. Theproposed work will utilize the novel marker-less C. trachomatis deletion mutant to determine whenduring chlamydial development TmeA and TmeB are important and identify their eukaryotic host celltargets. The outcomes of this research will directly contribute to our understanding of basic C. trachomatisbiology and how they use secreted effectors to establish an intracellular which will identify potential drug targetsto prevent the spread of infection to millions world-wide.

project_terms:
Alleles;Attenuated;Bacteria;Biological Assay;Biology;Biotin;Cells;Chlamydia Infections;Chlamydia trachomatis;Co-Immunoprecipitations;Cytolysis;Defect;Development;Disease;Drug Targeting;Epithelial;Fluorescence;Genes;Genetic Transcription;Genome;Growth;Hela Cells;Immune response;Immunoprecipitation;In Vitro;Indirect Immunofluorescence;Individual;Infection;Infertility;Invaded;Label;Link;LoxP-flanked allele;Maintenance;Mass Spectrum Analysis;Membrane;Modeling;Molecular;Molecular Chaperones;Mucous Membrane;Mus;Mutagenesis;Outcomes Research;Pathogenesis;Pathology;Pathway interactions;Phenotype;Plasma;Production;Property;Proteins;Reporting;Reproductive Health;Research;Sexually Transmitted Diseases;Stains;Surface;Techniques;Technology;Time;Transcript;Type III Secretion System Pathway;United States;Vacuole;Western Blotting;Woman;Work;immunopathology;in vitro Model;in vivo;interest;mouse model;mutant;new technology;novel marker;prevent;receptor;tissue culture

public_health_relevance:
Project NarrativeChlamydia trachomatis a leading cause of sexually transmitted disease relies on a specialized secretionmechanism to deploy anti-host proteins that are essential to pathogenesis. This proposal contains work thatwill characterize selected proteins to determine their specific contributions to chlamydial disease.


application_id: 10206402
project_number: 1R01AG068055-01A1
project_title: Identifying Associations between Brain Iron Neurocognitive Networks and Protective Factors
administering_ic: NIA
award_notice_date: 2021-04-20
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AG
serial_number: 068055
suffix: A1
program_official: WAGSTER, MOLLY V
project_start_date: 2021-05-01
project_end_date: 2026-02-28
study_section: Special Emphasis Panel[ZRG1 BDCN-L (02)]
contact_pi_person_id: 7993908
contact_pi: GOLD, BRIAN TIMOTHY
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Affect;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease risk;Alzheimers disease biomarker;American;Amyloid beta-Protein;Antioxidants;Attenuated;Base of the Brain;Biological Markers;Blood - brain barrier anatomy;Brain;Cerebrospinal Fluid;Cerebrum;Clinical;Cognition;Cognitive;Cognitive aging;Diet;Diffusion Magnetic Resonance Imaging;Disease Progression;Early Diagnosis;Early Intervention;Early identification;Elderly;Episodic memory;Financial compensation;Functional Magnetic Resonance Imaging;Goals;Health;Image;Impaired cognition;Individual;Intake;Iron;Linear Regressions;Liquid substance;MRI Scans;Magnetic Resonance Imaging;Maintenance;Measures;Mediating;Memory;Memory Loss;Modeling;Neurocognitive;Neurocognitive Deficit;Neuropsychology;Participant;Pathologic;Pathology;Pattern;Performance;Plasma;Positron-Emission Tomography;Predisposition;Regression Analysis;Sampling;Scanning;Short-Term Memory;Signal Transduction;Structure;System;Testing;Time;age related;base;behavior measurement;cognitive function;cognitive process;cognitive reserve;good diet;improved;in vivo;indexing;inflammatory marker;lifestyle factors;neuroimaging;neuroimaging marker;novel;novel marker;pre-clinical;protective factors;relating to nervous system;support network;tau Proteins;tau-1;white matter


application_id: 10206197
project_number: 5R25GM133328-03
project_title: UofL Bridges to Baccalaureate(ULBB)
administering_ic: NIGMS
award_notice_date: 2021-07-19
opportunity_number: PAR-17-210
application_type: 5
activity_code: R25
ic: GM
serial_number: 133328
program_official: STEPANEK, LAURIE ELIZABETH
project_start_date: 2019-07-15
project_end_date: 2024-06-30
study_section: Training and Workforce Development Study Section - C[TWD-C]
contact_pi_person_id: 1858952
contact_pi: KAKAR, SHAM S.
other_pis: DAVIS, RANDALL
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTFor the last three decades biomedical research has been expanding rapidly and has made a great impact inproducing high quality skilled professionals in the U.S. However minorities and the underprivileged continueto be underrepresented (UR) in this work force. While the Trends in International Mathematics and ScienceStudy (TIMSS) and other reports show that US students are greatly improving their academic preparednesscompared to students from most other nations our country's minorities and underprivileged students remainrelatively poorly prepared to enter high technology careers such as biomedical and behavioral sciences. As aresult minorities who constitute about 29% of the total population represent only about 7% of Ph.D.degrees in biomedical and behavioral sciences and hold only about 4% of the R01 biomedical andbehavioral research grants. Many UR students are deprived of the opportunity to experience earlyengagement in science and math. Therefore because they lack the skills and exposure to move directly into4-year baccalaureate programs they enter into 2-year programs at the community and technical colleges.The UofL Bridges to Baccalaureate (ULBB) program will involve the University of Louisville (UofL) andJefferson Community and Technical College (JCTC) joining forces to develop a sustainable program that willintroduce underrepresented and disadvantaged community college students to the career opportunitiesavailable in biomedical and behavioral research and prepare them for successful transition from a 2-yearprogram at JCTC to a 4-year STEM related baccalaureate program at UofL. The ULBB program will focuson: 1) strengthening the partnership between JCTC and UofL to increase the recruitment ofunderrepresented minority and economically disadvantaged high school students into a pathway tobiomedical research careers increasing the graduation rate in Associate in Science (AS) from 12% in 3years to 50% in 2 years 2) providing a pipeline of support and mentoring personnel and programs includingacademic enrichments career development training and research experience during each 10-week summerprogram (two summers) at UofL under the mentorship of internationally renowned faculty that will enhancetransfer rate from a current 30% to 70% of ULBB-supported students and 3) continued mentoring andcounseling of students transferred from JCTC to UofL in a small group setting promoting their involvement inexisting undergraduate education programs to improve the present graduation rate of 33% to 70% of ourtransferred ULBB students leading to increased recruitment to biomedical research graduate education andcareers. The ULBB program is innovative and will not only impact the underrepresented and underprivilegedstudents themselves but also the broader curricular advising and research programs of both partnerinstitutions and the pool of diverse well-qualified scientists entering biomedical research careers.

project_terms:
Achievement;African American;Area;Bachelor's Degree;Behavioral Research;Behavioral Sciences;Biomedical Research;Budgets;Counseling;Country;Developing Countries;Disabled Persons;Disadvantaged;Doctor of Philosophy;Dropout;Economically Deprived Population;Educational workshop;Enrollment;Exposure to;Face;Faculty;Funding;Goals;Graduate Degree;Graduate Education;Graduation Rates;High School Student;Hispanics;Human Resources;Individual;Institution;International;Internships;Knowledge;Mathematics;Mentors;Mentorship;Minority;Pathway interactions;Population;Preparation;Program Sustainability;Readiness;Reporting;Research;Research Personnel;Research Project Grants;STEM field;STEM program;STEM student;Schools;Science;Science Technology Engineering and Mathematics;Science Technology Engineering and Mathematics Education;Scientist;Secondary Schools;Students;System;Talents;Technology;Training;Underrepresented Minority;Underrepresented Students;Universities;Work;academic preparation;bridge to the baccalaureate;career;career development;college;community college;disadvantaged student;early experience;education research;experience;higher education;improved;innovation;mathematical sciences;prevent;programs;recruit;retention rate;skills;stem;student mentoring;summer program;technical college;transfer student;trend;undergraduate education;undergraduate student;underserved students;university student

public_health_relevance:
NARRATIVEThe UofL Bridges to Baccalaureate (ULBB) program will involve the University of Louisville (UofL) and JeffersonCommunity and Technical College (JCTC) joining forces to develop a program that facilitates the transition ofoutstanding students from underrepresented background and enrolled in a two-year program at JCTC toenter into 4-year STEM related baccalaureate programs at UofL. The ULBB program will focus onunderrepresented individuals in the STEM fields especially on African-American Hispanic and economicallydisadvantaged students and will provide paid research internships for the students to participate with fundedresearchers at UofL. The ULBB program will also focus on providing academic preparation combined withextensive pre- and post-transfer mentoring that will facilitate student transfer to 4-year STEM programs andsuccessful completion of the baccalaureate degree with the ultimate goal of increasing recruitment to biomedicalresearch careers.


application_id: 10205784
project_number: 2T35ES014559-16
project_title: Summer Environmental Health Sciences Training Program
administering_ic: NIEHS
award_notice_date: 2021-08-13
opportunity_number: PA-20-162
application_type: 2
activity_code: T35
ic: ES
serial_number: 014559
program_official: SHREFFLER, CAROL A
project_start_date: 2021-08-13
project_end_date: 2027-02-28
study_section: Special Emphasis Panel[ZES1 VSM-S (T)]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: CAVE, MATTHEW C;CONKLIN, DANIEL JOSEPH
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract:This proposal is a competing renewal application for a T35 short term medical student summer trainingprogram in environmental health science research that has been funded by NIEHS for 15 years. The SpecificAims are: 1) To provide hands-on training in basic and clinical environmental health-based research to medicalstudents in a structured mentored environment; 2) To provide an interactive educational experience thatintroduces medical students to the fundamental skills necessary for basic translational and clinicalEnvironmental Health Sciences-based research. The Distinction in Research Track (DIR) a feature added inthe previous award period enhances training for our students to function as environmental health sciencesspecialists in an academic health center setting. This NIEHS T35 training program encourages students toparticipate in the DIR for a continued longitudinal research experience in the 2nd  4th years of medical trainingallowing them to develop research-oriented skills to complete a clinical or translational research project in thethird/fourth years. Publication of peer-reviewed articles as some trainees have achieved as well as thestrength of residency training and first permanent position as physician-scientists are tracked as outcomes.The program will support training of 8 second year medical students in environmental health sciences researchtopics related to chemical exposure induced chronic diseases including diabetes non-alcoholic fatty liverdisease obesity cancer and hormonal regulation of metabolism. UofL medical students in the top half of thefirst year class choose from research projects submitted by 23 mentors in the Schools of Medicine and PublicHealth (ranking them 1-5 for interest). Trainees to be appointed to the T35 training grant are selected after in-person meetings between trainees and mentors to assure `fit'. A successful effort has been made to recruitstudents from underrepresented minorities and disadvantaged backgrounds. During the 11-week summertraining students work with mentors on their research project in clinical or laboratory settings and completetraining in the Responsible Conduct of Research (topics include: reproducibility fabrication and falsification ofdata plagiarism managing scientific data publication practices mentorship responsible authorshipstewardship conflict of interest). Trainees working with human subjects complete human subject and IRBtraining prior to beginning their research. Trainees who use vertebrate animals in mentors' labs complete andpass IACUC training courses. All trainees will attend a weekly Environmental Health Sciences Conferencedesigned to introduce clinical and translational research in environmental health sciences to T35 trainees. Theconference culminates with each Trainee presenting his/her research project to peers and mentors. Traineesalso present the results of their research as posters with peers at a School of Medicine week-long researchcelebration that includes nationally recognized physician-scientists as keynote speakers. Poster contestWinners are eligible to attend the National Student Research Forum the following Spring.

project_terms:
Authorship;Award;Chemical Exposure;Chronic Disease;Clinical;Clinical Research;Conflict of Interest;Data;Diabetes Mellitus;Environment;Environmental Health;Funding;Grant;Health;IACUC;Institutional Review Boards;Laboratories;Malignant Neoplasms;Medical;Medical Students;Mentors;Mentorship;Metabolism;National Institute of Environmental Health Sciences;Obesity;Outcome;Peer Review;Persons;Physicians;Plagiarism;Positioning Attribute;Public Health;Publications;Reproducibility;Research;Research Project Grants;Residencies;Scientist;Specialist;Structure;Student recruitment;Students;Training;Training Programs;Training Support;Translational Research;Vertebrates;Work;base;design;disadvantaged background;experience;health science research;hormone regulation;human subject;interest;medical schools;meetings;non-alcoholic fatty liver disease;peer;peer coaching;posters;programs;responsible research conduct;skills;summer student;symposium;underrepresented minority student


application_id: 10204901
project_number: 5P30CA177558-09
project_title: Clinical Protocol and Data Management
administering_ic: NCI
award_notice_date: 2021-08-16
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;Hispanics;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: 10204899
project_number: 5P30CA177558-09
project_title: Developmental Funds
administering_ic: NCI
award_notice_date: 2021-08-16
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;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;tumor


application_id: 10204897
project_number: 5P30CA177558-09
project_title: Community Outreach and Engagement
administering_ic: NCI
award_notice_date: 2021-08-16
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;Recommendation;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;population health;precision medicine;rural setting;socioeconomic disparity;surveillance data;tumor;underserved community


application_id: 10204892
project_number: 5P30CA177558-09
project_title: Drug Discovery Delivery and Translational Therapeutics Research Program
administering_ic: NCI
award_notice_date: 2021-08-16
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;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/antagonist;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;treatment response;treatment trial;tumor


application_id: 10204890
project_number: 5P30CA177558-09
project_title: Cancer Cell Biology and Signaling Research Program
administering_ic: NCI
award_notice_date: 2021-08-16
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;Genes;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;Therapeutic;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;inhibitor/antagonist;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;tumor;tumor microenvironment;tumor progression


application_id: 10204888
project_number: 5P30CA177558-09
project_title: Flow Cytometry and Cell Sorting Shared Resource Facility
administering_ic: NCI
award_notice_date: 2021-08-16
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;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: 10204887
project_number: 5P30CA177558-09
project_title: Cancer Research Informatics Shared Resource Facility
administering_ic: NCI
award_notice_date: 2021-08-16
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;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;tumor


application_id: 10204885
project_number: 5P30CA177558-09
project_title: Biostatistics and Bioinformatics Shared Resource Facility
administering_ic: NCI
award_notice_date: 2021-08-16
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;Therapeutic;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 study;tumor immunology;working group


application_id: 10204884
project_number: 5P30CA177558-09
project_title: Biospecimen Procurement and Translational Pathology Shared Resource Facility
administering_ic: NCI
award_notice_date: 2021-08-16
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;Structure;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: 10204879
project_number: 5P30CA177558-09
project_title: University of Kentucky Markey Cancer Center - Cancer Center Support Grant
administering_ic: NCI
award_notice_date: 2021-08-16
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
program_official: ROBERSON, SONYA
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Achievement;Address;Appalachian Region;Area;Award;Basic Science;Behavioral Research;Bioinformatics;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Cancer Research Project;Catchment Area;Cell Separation;Cellular biology;Centers of Research Excellence;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Communities;Community Healthcare;Community Networks;Community Outreach;Community Physician;Comprehensive Cancer Center;County;Coupled;Data Sources;Development;Disease;Distress;Early Diagnosis;Ecology;Education;Education and Outreach;Environmental Risk Factor;Epigenetic Process;Faculty Recruitment;Fellowship;Flow Cytometry;Foundations;Funding;Genetic;Genomic Instability;Genomics;Health Professional;Healthcare;Immunotherapy;Incidence;Individual;Informatics;Infrastructure;Institution;Intervention;Intervention Studies;Intervention Trial;Investments;Kentucky;Malignant Neoplasms;Mediator of activation protein;Mentors;Metabolic;Metabolism;Methods;Minority Graduate Student;Minority Groups;Mission;Molecular;Mutation;NCI Center for Cancer Research;National Cancer Institute;Natural Products;Obesity;Obesity associated cancer;Oncology;Outcome;Oxidation-Reduction;Pathology;Patients;Phenotype;Population;Population Research;Population Sciences;Positioning Attribute;Prevention;Prevention therapy;Preventive;Program Development;Publications;Publishing;Quality of life;Radon;Registries;Research;Research Personnel;Resistance;Resource Sharing;Resources;Risk Factors;Role;SEER Program;Science;Scientist;Screening for cancer;Services;Signal Transduction;Site;Strategic Planning;Target Populations;Therapeutic;Training;Transcend;Translating;Translational Research;Translations;Underserved Population;Universities;anticancer research;authority;base;bench to bedside;biomedical informatics;cancer care;cancer genomics;cancer health disparity;cancer prevention;cancer research center director;cancer site;cancer survival;cancer therapy;career development;clinical development;clinical translation;cohort;college;community based research;community engagement;cost;drug discovery;early phase clinical trial;genetic epidemiology;health assessment;health disparity;high school;higher education;improved;innovation;instrumentation;inter-institutional;medically underserved;meetings;member;metabolomics;mortality;multidisciplinary;next generation;novel anticancer drug;outreach;personalized diagnostics;personalized intervention;population health;precision medicine;precision medicine clinical trials;programs;prospective;recruit;repository;response;screening;standard of care;synergism;targeted treatment;treatment response;tumor;tumor metabolism;undergraduate student;underserved community


application_id: 10204300
project_number: 1R21NS121966-01
project_title: Investigating Lung Injury After Cervical Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2021-02-28
opportunity_number: PA-18-358
application_type: 1
activity_code: R21
ic: NS
serial_number: 121966
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2021-04-01
project_end_date: 2024-03-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8838438
contact_pi: ALILAIN, WARREN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary and Abstract In early 2019 the NIH sponsored meeting NIH 2020: Launching a Decade for Disruption in SpinalCord Injury (SCI) Research brought together those living with SCI clinicians and basic science researchers.Together they discussed the priorities and needs for SCI research. One major take home message was thecritical desire for more studies geared towards investigating approaches which can significantly improve thequality of life of the SCI community beyond home runs like improving motor and sensory function. With this inmind this proposal seeks to understand the mechanisms behind acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) after cervical SCI - where most SCIs occur and which leads to impaired respiratorymotor function. ALI and ARDS significantly impacts those living with SCI by lowering their quality of life anddecreasing their mortality. This is especially relevant now considering the current times of the SARS-CoV-2/COVID-19 pandemic and its impact on lung health even in non-SCI individuals. Undoubtedly this is asignificant issue for this population severely impacting their lives. Towards this goal we propose the followingspecific aims: Specific Aim 1: Test the hypothesis that cervical SCI leads to lung injury and alterations in lungmetabolism. These experiments will help answer questions about the severity temporal dynamics and themechanical inflammatory and metabolic profile of lung injury after cervical SCI. In Specific Aim 2 we will testthe hypothesis that restoring diaphragmatic function after cervical SCI ameliorates ALI. These experiments willhelp determine the role impaired breathing plays in ALI and ARDS development after SCI and can it beprevented or reduced if we restore breathing function. Collectively this proposal will elucidate the extent towhich SCI can negatively impact lung health (mechanically physiologically and metabolically). Moreover wewill uncover the extent to which promising experimental therapeutic approaches can reverse or amelioratethese conditions. These are critical experiments which can help realize the overall goal of improving thequality of life and mortality of the SCI population.

project_terms:
2019-nCoV;Acute;Acute Lung Injury;Address;Adult Respiratory Distress Syndrome;Animal Model;Animals;Basic Science;Breathing;COVID-19 pandemic;Cells;Cervical;Cervical spinal cord injury;Cessation of life;Chondroitin Sulfate Proteoglycan;Chronic;Clinical;Communities;Deterioration;Development;Disease;Edema;Environment;Excision;Extracellular Matrix;Female;Goals;Health;Histology;Home;Human;Hypoxia;Immune;Impairment;Individual;Inflammation;Inflammatory;Injury;Intervention;Investigational Therapies;Ipsilateral;Knowledge;Laboratories;Lateral;Lung;Mechanical Ventilators;Mechanics;Metabolic;Metabolism;Mind;Motor;Natural regeneration;Neutrophil Infiltration;Paralysed;Periodicity;Physiological;Play;Population;Quality of life;Recovery;Research;Research Personnel;Respiratory Diaphragm;Respiratory Paralysis;Role;Running;Science;Sensory;Severities;Spinal Cord;Spinal Cord Plasticity;Spinal cord injury;Testing;Therapeutic;Time;Tissues;United States National Institutes of Health;comorbidity;cytokine;experimental study;health management;improved;injured;lung development;lung injury;male;meetings;metabolic profile;metabolomics;mortality;motor recovery;pre-clinical;prevent;respiratory;restoration;treatment strategy

public_health_relevance:
Project NarrativePublic Relevance: Alongside a loss of motor and sensory function after spinal cord injury (SCI) a multitude of other healthissues negatively impacting the quality of life and increasing mortality presents itself. One major comorbidityafter SCI is acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS). Theexperiments outlined in this proposal seeks to address this major issue and investigate approaches which canprevent or ameliorate ALI or ARDS following SCI.


application_id: 10204279
project_number: 1R56NS117587-01
administering_ic: NINDS
award_notice_date: 2020-08-27
opportunity_number: PA-19-056
application_type: 1
activity_code: R56
ic: NS
serial_number: 117587
program_official: KUMSA, DOE WONDWOSSEN
project_start_date: 2020-09-01
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZRG1-ETTN-P(81)S]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-09-01
project_title:
Continuous and Longitudinal Monitoring of Cerebral Blood Flow and Metabolism in Freely Moving Rodents

project_abstract:
ABSTRACTMeasurements of cerebral blood flow (CBF) and cerebral metabolic rate of oxygen consumption (CMRO2) inresponse to brain activity allows investigation of underlying excitatory and inhibitory neural responses and holdsthe key to optimizing novel therapies for neurological disorders and cerebrovascular diseases. Rodents (miceand rats) have been helping scientists investigate human diseases for well over a century and still make up 95%of the animal models used today. Major limitations with these rodent models are that cerebral hemodynamics ismeasured mostly in anesthetized animals and at limited time points. However anesthesia impacts cerebralhemodynamics profoundly and interferes with studies of behavioral health cognitive function and sleep disorder.A few methods available for cerebral hemodynamic monitoring in conscious rodents require invasive craniotomywith installation of various opto-electrode/ultrasound probes onto the brain which restrains animals head orbody during measurements. Supported by NIH (R21) we have recently developed an innovative noninvasivelow-cost fiber-free near-infrared diffuse speckle contrast flowmetry (DSCF) probe which affixes on the headsof anesthetized rodents and awake humans for continuous monitoring of CBF. The goal of this proposal is toextend optimize and validate this novel technology toward a dual-wavelength multi-channel diffuse specklecontrast flow-oximetry (DSCFO) system for simultaneous regional mapping of CBF cerebral oxygenation andCMRO2 in conscious freely moving rodents. DSCFO uses small near-infrared laser diodes at differentwavelengths as point sources and a tiny CMOS camera as a 2D detector array to detect spatial dynamic lightscattering by intrinsic motions of red blood cells (i.e. CBF) and light attenuations by oxy- and deoxy- hemoglobinabsorptions ([HbO2] and [Hb]). Combination of CBF [HbO2] and [Hb] enables derivation of CMRO2 based onestablished models. The 2D camera array enables 2D mapping of cerebral responses over two hemispheresand at different depths of the rodent head. Importantly connections between the DSCFO probe and control unitare all electrical wires/cables (i.e. fiber-free) thereby offering the promise for continuous cerebral monitoring infreely moving subjects. After calibrating and optimizing the DSCFO system using head-simulating phantoms andvalidation in anesthetized rodents against established techniques we will evaluate its performance forcontinuous and longitudinal cerebral monitoring in conscious freely moving rodents with or without ischemicstroke insult. While we explore stroke-induced cerebral outcomes in this project the DSCFO technology isapplicable for studying other neurological disorders and cerebrovascular diseases. In combination with ourongoing R21 studies in human subjects completion of this study in rodents will generate a unique noninvasivefast low-cost multiscale and multimodal brain mapping tool for both neuroscience research and clinicalapplications. Ultimately the levels/variations and combination of CBF [HbO2] [Hb] and CMRO2 may serve asbiomarkers for assessing brain health and outcomes of cerebral pathological conditions and interventions.

project_terms:
Adult;Algorithms;Anesthesia procedures;Animal Behavior;Animal Model;Animals;Behavioral;Biological Markers;Biomedical Research;Blood Vessels;Brain;Brain Mapping;Carbon Dioxide;Cerebrovascular Circulation;Cerebrovascular Disorders;Cerebrum;Complex;Conscious;Consumption;Craniotomy;Data Analyses;Data Reporting;Derivation procedure;Devices;Diffuse;Elderly;Electric Stimulation;Electrodes;Erythrocytes;Eye;Fiber;Flowmetry;Glucose;Goals;Head;Hemoglobin;Homeostasis;Human;Impaired cognition;Infarction;Inhalation;Injections;Intervention;Investigation;Ischemic Stroke;Lasers;Lead;Light;Measurement;Measures;Mental Depression;Metabolic;Metabolism;Methods;Modeling;Monitor;Motion;Motor;Movement;Mus;Neurons;Neurosciences;Neurosciences Research;Operative Surgical Procedures;Optics;Outcome;Output;Oxygen;Oxygen Consumption;Oxygen saturation measurement;Pathologic;Performance;Radiation Toxicity;Rattus;Rodent;Rodent Model;Scientist;Sensory;Sleep;Sleep Disorders;Source;Stimulus;Stress;Stroke;System;Techniques;Technology;Testing;Time;Ultrasonography;United States National Institutes of Health;Validation;Variant;absorption;attenuation;awake;base;behavioral health;behavioral study;brain health;brain tissue;cerebral hemodynamics;cerebral oxygenation;cerebrovascular;clinical application;cognitive function;cost;cost effective;cranium;design;detector;flexibility;human disease;human subject;innovation;light scattering;metabolic rate;miniaturize;multimodality;nervous system disorder;neural circuit;neurovascular coupling;new technology;novel therapeutics;optical sensor;preterm newborn;radiotracer;relating to nervous system;response;sensor;stroke model;stroke outcome;tool;translational neuroscience

public_health_relevance:
PROJECT NARRATIVEA major challenge in measuring cerebral hemodynamic and metabolic change noninvasively on conscious freelymoving subjects is the present available technology. The objective of this project is to develop and test a low-cost fast miniaturized fiber-free optical probe which can be fixed to the head allowing for transcranialmeasurements of cerebral blood flow and metabolism in conscious freely moving rodents (mice and rats). Incombination with our ongoing NIH-R21 studies in human subjects completion of this study in rodents willgenerate a unique noninvasive low-cost fast multiscale and multimodal brain monitoring tool for bothtranslational neuroscience research and clinical applications.


application_id: 10204046
project_number: 5R25GM132961-03
project_title: STEM Through Authentic Research Training (START) Program for Underrepresented Communities
administering_ic: NIGMS
award_notice_date: 2021-07-05
opportunity_number: PAR-17-339
application_type: 5
activity_code: R25
ic: GM
serial_number: 132961
program_official: BECK, LAWRENCE A
project_start_date: 2019-07-01
project_end_date: 2024-06-30
study_section: Special Emphasis Panel[ZRG1-CB-J(56)R]
contact_pi_person_id: 9077753
contact_pi: BRADLEY, LUKE H
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract/ Project SummaryThe increasing importance of technology in contemporary society necessitates a STEM literate population.This represents a challenge for traditionally underrepresented populations (people of color individuals withdisabilities individuals in less affluent communities) impacting upward social mobility. Often members ofthese groups are doubly disadvantaged as the few who become first generation college students often lack aroadmap for success through family near peers and potential mentors. Success for this populationrepresenting a highly motivated group needs to be nurtured to embrace and advance STEM disciplinesbefore they reach their college classrooms. This necessitates the education not only of students but theirteachers providing synergies in teaching and learning to empower students to avail of opportunities perceivedas being beyond their reach. We hypothesize that bridging this expanding gap requires an integrated programbringing together academic social and real-world professional experiences to establish a pipeline linkingsuccess in middle/high school to success for first generation college students and beyond. Such a pipeline willgenerate not only STEM-proficient citizens but also a cadre of near peers to motivate by example. With thiscentral premise we have formed the STEM Through Authentic Research and Training (START) Program totidentify recruit and retaining traditionally underrepresented populations by providing year-round authenticresearch opportunities and professional development for high school students (grades 9-12) and middle andsecondary STEM teachers (grades 5-12). START represents a partnership between the University of Kentuckyproviding opportunities for STEM research The Academies of Lexington a partnership with the FayetteCounty Public Schools- focused on changing the traditional didactic model for STEM instruction the KY-WVLSAMP program an NSF funded consortium led by UK including over 10 diverse academic institutionssupporting undergraduate research aimed at increasing the representation and overall success of traditionallyunderrepresented populations in STEM disciplines. START establishes a natural pipeline to the collegiatelevel by virtue of the alliance with KY-WV LSAMP and its member institutions. Finally we have recruited SpaceTango a Lexington STEM start-up company which builds and integrates systems for scientific and biomedicalresearch under microgravity conditions on the international space station. As such a spectrum of researchopportunities from the molecular and microscopic level in participating UK STEM laboratories to the vastnessof space itself afforded by Space Tango provide an exciting palate of opportunities for traditionallyunderrepresented students and the teachers responsible for their STEM education. We believe that theintegration of real world authentic research opportunities in the context of overall STEM education via a uniquepartnership between academia educational and commercial entities will motivate underrepresented studentpopulations to levels of achievement they often believe are beyond their horizons.

project_terms:
ARNT gene;Academia;Academy;Achievement;Address;Adopted;Agreement;Area;Biomedical Research;Collaborations;Color;Communities;County;Critical Thinking;Development;Disabled Persons;Disadvantaged;Education;Educational process of instructing;Educational workshop;Engineering;Family;First Generation College Students;Fostering;Funding;Future;Future Teacher;Goals;High School Faculty;High School Student;Individual;Institution;Instruction;International;Kentucky;Knowledge;Laboratories;Leadership;Learning;Life;Link;Mentors;Mentorship;Methods;Microgravity;Microscopic;Modeling;Molecular;Palate;Population;Positioning Attribute;Research;Research Training;Resources;STEM career;STEM curriculum;STEM field;STEM research;STEM student;Schools;Science;Science Technology Engineering and Mathematics Education;Scientist;Secondary Schools;Social Mobility;Societies;Students;Support System;System;Techniques;Technology;Training;Training Programs;Underrepresented Populations;Underrepresented Students;Underserved Population;Universities;age group;apprenticeship;beneficiary;career;college;design;experience;high school;improved;innovation;interdisciplinary collaboration;interest;junior high school;literate;member;neglect;novel strategies;peer;peer coaching;programs;real world application;recruit;role model;skills;social;social integration;space station;success;synergism;teacher;undergraduate research;undergraduate student

public_health_relevance:
Project NarrativeThe relative shortage of near peers and relatable mentors for first generation college students andunderrepresented student populations inhibits them from reaching their maximal potential. By establishing apipeline to integrate real world research experiences in an academic and/or STEM-intensive commercialsetting for both students (grades 9-12) and STEM teachers (grades 5-12) we expect to deliver opportunities forSTEM education typically neglected for underserved populations. The STEM Through Authentic ResearchTraining (START) program is designed to integrate academia the secondary education system andcommercial interests toward identifying and nurturing STEM proficient students promoting success at thecollege level and beyond.


application_id: 10203586
project_number: 3P42ES023716-04S1
project_title: Administrative Core
administering_ic: NIEHS
award_notice_date: 2020-06-30
opportunity_number: RFA-ES-15-019
application_type: 3
activity_code: P42
ic: ES
serial_number: 023716
suffix: S1
program_official: CARLIN, DANIELLE J
study_section: ZES1-LKB-K
subproject_number: 5115
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe Administrative Core of the Louisville Superfund Center (LSC) will provide administrative and fiscal supportto all Projects and Cores supported by the Center. The Core will be directed by the Center Director who withassistance from the Program Administrator will facilitate communication and collaboration between individualCores and Projects and provide scientific and logistic oversight to Center activities. The Core will act as a liaisonfor individual Center members in order to best promote collaboration to ensure all Center work effectivelycontributes issues relevant to the SRP and to maximize the dissemination and application of research findingsthrough the Community Engagement Core and the Research Translation Core. To assist in the planning andcoordination of research and core activities the Core personnel will organize scientific work-in-progress sessionsbiweekly meetings relevant focus groups and frequent formal and informal interactions. To integrate cross-disciplinary research the Core will provide leadership and administrative support needed for integration andcoordination of research. The Core will leverage existing resources on campus to optimize the productivity ofthe Center and will seek input from both an Internal Advisory Committee and an External Advisory Committeein evaluating progress and in maintaining the relevance of Center activities to the Superfund Research Programmandate. Core leaders will maintain close contact with NIEHS program officials and with UofL administration.Core administrators will also manage the finances and resources of the Center to optimize usage and appropriateallocation. They will also coordinate the timely development of progress reports and financial statements. Toensure quality management the Core will monitor and facilitate attainment of Center objectives in researchtraining education and community engagement and ensure compliance with state and federal regulations.These activities will minimize administrative burden on Center members promote communication andcollaboration among investigators and facilitate the sharing of reagents tools specimens and data to ensurethe most effective allocation and use of Center funds. The Administrative Core will be the go-to place for studentsand trainees community members public media and press so that all such activities can be appropriatelyfacilitated and coordinated.

project_terms:
Administrator;Advisory Committees;Collaborations;Communication;Communities;Consultations;Core Facility;Counseling;Data;Development;Development Plans;Diabetes Mellitus;Discipline;Disease;Ensure;Environment;Environmental Exposure;Evaluation;Focus Groups;Funding;Future;Goals;Hazardous Chemicals;Heart Diseases;Human Resources;IACUC;Individual;Institutional Review Boards;Leadership;Link;Liver diseases;Logistics;Mentors;Monitor;National Institute of Environmental Health Sciences;Productivity;Progress Reports;Protocols documentation;Quality Control;Reagent;Regulation;Research;Research Personnel;Research Project Grants;Research Training;Resource Sharing;Resources;Scientific Evaluation;Selection Criteria;Signal Recognition Particle;Specimen;Students;Superfund;Time;Training;Training Activity;Training and Education;Translational Research;Universities;Work;cardiometabolism;effectiveness research;experimental study;meetings;member;operation;programs;tool;training opportunity;web site


application_id: 10203585
project_number: 3P42ES023716-04S1
project_title: Environmental Exposure and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2020-06-30
opportunity_number: RFA-ES-15-019
application_type: 3
activity_code: P42
ic: ES
serial_number: 023716
suffix: S1
program_official: CARLIN, DANIELLE J
project_start_date: 2017-09-01
project_end_date: 2022-03-31
study_section: ZES1-LKB-K(S)
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY (Overall)This proposal is to establish a Superfund Center at the University of Louisville. This Center will support researchon the cardiometabolic effects of volatile organic chemicals (VOCs) that are of high relevance to the SuperfundProgram. Center investigators will conduct mode-of-action research to unravel critical pathways of toxicity andto identify toxicological end-points (cardiometabolic changes) of chemicals (VOCs) found at Superfund andrelated sites. Using high throughput metabolomic and mass spectrometry approaches animal experiments andhuman population studies Center investigations will aid in the discovery and validation of novel biomarkers ofboth exposure and cardiometabolic injury that would lay the foundation for future remediation strategies. Thesestudies will employ state-of-the-art tools to develop pollutant atmospheres for animal exposure and to measureunique and sensitive biological endpoints reflective of cardiometabolic injury. In addition work supported by theCenter will lead to the development of new methods and devices for quantifying atmospheric levels of VOCs thatwill employ advanced technologies and offer precise but low-cost measurements of hazardous waste sites. Themajor objectives of the Center are to conduct state-of-the-art research on the cardiometabolic toxicity of VOCsand to determine how they affect cardiometabolic disease (CMD) prevalence and severity in exposedpopulations. These studies will be complemented by mode-of-action mechanistic studies in animals to identifythe molecular and cellular mechanisms that contribute to VOC toxicity. Center investigators will also identifyspecific conditions such as nutritional status and obesity and increase susceptibility to VOC toxicity and testtherapeutic interventions that can attenuate acute and chronic cardiometabolic effects of VOC exposures. Thefindings of these studies will contribute to both the discovery and the validation of sensitive and robust biomarkersthat could be used to assess the extent of exposure metabolism and toxicity. Center investigators will createnew technologies for detecting VOCs at low environmental levels to enable future exposure assessmentactivities. Senior Center members will educate and train junior investigators graduate students and post-doctoralFellows in the field of environmental science and promote relevant community awareness and participation toenhance mutual bidirectional understanding of exposure risk and the health effects of exposure. The findingsand discoveries of the Center will be transferred to affected communities end users in public and private sectorsand other stakeholders. For future use and analysis all samples of human and animal tissues and all datacollected during Center investigations will be stored in a computer-coded biorepository. Collectively Centeractivities will lead to rigorous evaluation and better understanding of the effects of these hazardous chemicalson obesity diabetes and cardiovascular disease.

project_terms:
Action Research;Acute;Advanced Development;Affect;Animal Experiments;Animal Model;Animals;Area;Atmosphere;Attenuated;Awareness;Biological;Biological Markers;Cardiovascular Diseases;Cause of Death;Chemical Exposure;Chemicals;Chemistry;Chronic;Communities;Community Outreach;Complement;Cost Measures;Critical Pathways;Data;Decision Making;Detection;Development;Devices;Diabetes Mellitus;Disease;Disease Pathway;Ecology;Education and Outreach;Ensure;Environment;Environmental Exposure;Epidemic;Epidemiology;Etiology;Evaluation;Exposure to;Fatty Liver;Foundations;Future;Goals;Hazardous Chemicals;Hazardous Substances;Hazardous Waste Sites;Health;Heart Diseases;Human;Incidence;Industrialization;Injury;Investigation;Knowledge;Liver diseases;Mass Spectrum Analysis;Measures;Medical;Metabolism;Methods;Molecular;Monitor;Non-Insulin-Dependent Diabetes Mellitus;Nutritional;Nutritional status;Obesity;Pathway interactions;Population;Postdoctoral Fellow;Predisposition;Prevalence;Private Sector;Public Health;Public Sector;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Research Training;Resources;Risk;Sampling;Science;Severities;Site;Superfund;Techniques;Technology;Testing;Therapeutic Intervention;Time;Tissue Sample;Toxic effect;Toxicity Tests;Toxicology;Training;Training Programs;Translational Research;Universities;Validation;Work;animal tissue;base;biobank;cardiometabolism;computer code;data archive;data management;data sharing;education resources;experience;exposed human population;graduate student;human population study;human tissue;innovation;interest;member;metabolomics;multidisciplinary;new technology;novel marker;obesity development;outreach program;pollutant;programs;remediation;repository;resilience;response;superfund chemical;superfund site;tool;translational medicine;volatile organic compound

public_health_relevance:
RELEVANCEThis proposal is to establish a Center to support research on the health effect of hazardous Superfund chemicals.Work in this Center will help in evaluating the health impact of several hazardous chemicals that are present inthe environment and in understanding how exposure to chemicals could contribute to the risk and developmentof obesity diabetes and heart disease which despite recent medical advances remain the leading causes ofdeath worldwide.


application_id: 10202394
project_number: 5R24AI138963-04
administering_ic: NIAID
award_notice_date: 2021-06-25
opportunity_number: PAR-16-412
application_type: 5
activity_code: R24
ic: AI
serial_number: 138963
program_official: BREEN, JOSEPH J
project_start_date: 2018-07-23
project_end_date: 2022-08-31
study_section: ZAI1-JTS-I(M1)
contact_pi_person_id: 10517640
contact_pi: WATSON, COREY TAYLOR
other_pis: SMITH, MELISSA LAIRD
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-07-01
project_abstract:
Project Summary/AbstractThere is a fundamental gap in our understanding of how germline variation in immunoglobulin (IG) heavy (IGH)and light chain (IGK; IGL) loci in the human population impacts the development of the functional antibody (Ab)response in health and disease. However there is a growing appreciation that IG polymorphism contributes tovariability in the Ab repertoire indicating that the integration of IG genetic data has the potential to inform ourunderstanding of Ab function in various clinical contexts. A critical barrier to progress has been that existinggenomic resources for IG loci are lacking and poorly represent diversity found across human populations. IGregions are structurally complex consisting of large segmental duplications and are among the mostpolymorphic in the genome with large copy number variants (CNVs) elevated nucleotide diversity andpopulation-specific haplotype variants. These complexities have long made IG loci difficult to study at thegenomic and population level using standard high-throughput methods with direct negative impacts on geneticdisease association studies and more recently the analysis of expressed Ab repertoire data. As a result ourknowledge of human IG germline diversity (particularly in non-Caucasians) and its contribution to disease lagsfar behind that of other well studied immune loci. This highlights a direct need for publically available well-characterized IG haplotype references and accurate variant catalogues from diverse ethnic backgrounds tofacilitate the design and integration of more accurate genotyping tools analysis pipelines and their interpretation.To meet this need we have developed several robust approaches which we will utilize here to establish criticalcommunity resources for the IG loci. We will first enumerate up to 16 novel IGH/K/L haplotype referenceassemblies from an existing set of 8 fosmid libraries from individuals of African Asian and European descent.We will also use a novel multi-haplotype informed genotyping pipeline to profile IGH/K/L genetic variation in acohort of 180 familial and unrelated individuals from these same three populations. This will represent the mostcomprehensive population survey of IG germline diversity including descriptions of variable diversity joiningand constant gene variation and locus-wide single nucleotide polymorphisms (SNPs) and CNVs allowing forfine-scale assessment of variant imputation panels for disease association studies. Finally to facilitate theutility of these data as long-term resources all sequences tools/methods and analysis pipelines will be madepublically available. We will work with established databases to ensure all sequences are deposited in both rawand annotated form. This will include the integration of assemblies into future releases of the human genomereference for use by the genomics community as well as updates to existing germline gene/allele databasescritical to expressed Ab repertoire analysis. This project establishes desperately needed genomic resources forthe human IG loci which will better serve the immunology community for years to come. These will stand as afoundation for future efforts to define the role of IG germline variation in Ab function health and disease.

project_terms:
African;Alleles;Antibodies;Antibody Repertoire;Antibody Response;Asians;Autoimmunity;B-Lymphocytes;Biological Assay;Catalogs;Clinical;Communities;Complex;Copy Number Polymorphism;Data;Data Analyses;Data Set;Databases;Deposition;Development;Diploidy;Disease;Ensure;European;Evaluation;Foundations;Future;Genbank;Genes;Genetic;Genetic Diseases;Genetic Polymorphism;Genetic Research;Genetic Variation;Genome;Genomics;Genotype;Haplotypes;Health;Human;Human Resources;IGL@ gene cluster;Immune;Immune System Diseases;Immunogenetics;Immunoglobulins;Immunology;Individual;Infection;Information Systems;International;Knowledge;Libraries;Light;Link;Malignant Neoplasms;Methods;Nucleic Acid Regulatory Sequences;Nucleotides;Outcome;Population;Positioning Attribute;Resolution;Resources;Role;Sampling;Single Nucleotide Polymorphism;Structure;Update;Variant;Work;adaptive immunity;analysis pipeline;cohort;dbSNP;design;direct application;ethnic diversity;genetic association;high standard;human reference genome;immunoglobulin light chain locus;improved;insight;inter-individual variation;novel;novel strategies;personalized medicine;population survey;precision medicine;reference genome;tool;vaccine response

public_health_relevance:
Project NarrativeGenomic resources for the human immunoglobulin loci are lacking and poorly represent diversity amonghuman populations hindering our understanding of the role of antibody genetic variation in health and disease.This project will result in a set of genomic resources that will have transformative impacts on the fields of B cellimmunology and immunogenetics allowing for a better integration of antibody germline data at the genomicand population level. These will have direct applications in genetic association and antibody repertoire profilingstudies with implications for a range of immunological diseases and personalized medicine approaches.


application_id: 10202391
project_number: 5U01AA026980-04
project_title: Alcoholic Hepatitis Network 3/9 University of Louisville
administering_ic: NIAAA
award_notice_date: 2021-06-18
opportunity_number: RFA-AA-18-002
application_type: 5
activity_code: U01
ic: AA
serial_number: 026980
program_official: GAO, PETER
project_start_date: 2018-08-01
project_end_date: 2023-06-30
study_section: ZAA1-JJ(01)R
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTAlcoholic hepatitis (AH) is a leading cause of liver-related morbidity and mortality with a remarkable paucity ofeffective therapeutics. This application represents a coordinated submission of several NIAAA-fundedconsortia that have come together as the Alcoholic Hepatitis Network (AlcHepNet). Collectively the networkwill synergize efforts and expertise to better understand AH and develop novel effective and safe therapies forsevere AH. Buttressing that goal the overarching aims of this new consortium are to: 1) perform studies tobetter understand the pathogenesis and main determinants of outcomes particularly in severe AH; 2) identifynovel targets for therapy of AH and 3) perform phase 2B studies of compounds that are already FDAapproved and available and can be repurposed as safe and effective therapies for severe AH. Under theumbrella of these larger aims the aims of this AlcHepNet proposal are to: Aim 1. Conduct a prospectivemulticenter observational study of patients with AH and suitable controls that serves as thefoundation for conducting novel mechanistic and therapeutic studies. We will consolidate and extend ourlongitudinal database containing 1) clinical and laboratory information and 2) bio-sample repository fromsubjects with AH of varying severity and matched controls. This database will serve three functions: (a) provideunique information on the outcomes and pathobiology of AH (b) support translational research designed toidentify novel targets for treatment and (c) serve as a catalyst to develop systems biology-based informatics-integrated databases that will serve as a resource for all researchers interested in AH; Aim 2. Perform amulticenter prospective randomized phase 2B clinical trial of granulocyte colony stimulating factor G-CSF versus Anakinra (plus zinc) versus standard medical therapy with Prednisone in patients withsevere AH. This aim will test the hypothesis that both active treatment arms with G-CSF and the IL-1 receptorantagonist Anakinra (plus zinc) are superior to the standard of care (i.e. Prednisone) in patients with severeAH. The choice of these agents is based on: 1) literature demonstrating a role for inflammation andinflammasome activation in severe AH 2) several pilot studies demonstrating therapeutic benefit with G-CSFand 3) interim analysis of an ongoing trial suggesting a mortality benefit with Anakinra in patients with AH. Thisphase 2B efficacy trial will be conducted across nine clinical centers and coordinated by two Data CoordinatingCenters (DCCs). The primary endpoint will be mortality at Day 90. The investigators and the AlcHepNet areuniquely positioned to perform the proposed study given the substantial breadth depth and history ofexpertise related to AH clinical trial conduct and related therapeutic development. By testing promisingtherapies for AH and collecting well-annotated patient samples and datasets this proposal will have a strongand lasting impact on the field.!

project_terms:
Adrenal Cortex Hormones;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Biological Specimen Banks;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collection;Conduct Clinical Trials;Consumption;Data;Data Coordinating Center;Data Set;Databases;Development;Disease;Economic Burden;Educational workshop;Eligibility Determination;FDA approved;Foundations;Funding;Future;Goals;Granulocyte Colony-Stimulating Factor;Hepatitis B;Infection;Inflammasome;Inflammation;Informatics;Institution;Interleukin-1 Receptors;Interleukin-1 beta;Label;Laboratories;Life;Light;Literature;Liver;Liver diseases;Medical;Mission;Morbidity - disease rate;National Institute on Alcohol Abuse and Alcoholism;Observational Study;Oral cavity;Outcome;Pathogenesis;Patient Care;Patient Recruitments;Patients;Pentoxifylline;Pharmaceutical Preparations;Phase;Pilot Projects;Positioning Attribute;Predisposition;Prednisone;Public Health;Randomized;Recording of previous events;Research Design;Research Personnel;Resources;Role;Sampling;Severities;Systems Biology;Testing;Therapeutic;Therapeutic Studies;Translational Research;Universities;Validation;Work;Zinc;active method;anakinra;base;catalyst;clinical center;drug testing;effective therapy;efficacy trial;evidence base;improved;insight;interest;liver injury;longitudinal database;meetings;mortality;new therapeutic target;novel;primary endpoint;prospective;receptor;research study;secondary endpoint;standard of care;targeted treatment;therapeutic development;therapeutically effective;translational study;treatment arm

public_health_relevance:
PROJECT NARRATIVEThe Alcoholic Hepatitis Network project AlcHepNet comprised of nine leading partner institutions in the fieldwill examine new and promising treatments for severe liver damage caused by alcohol. Further the networkwill collect and organize patient information associated data and samples that can help shed greater light onthis disease. Combined these two approaches will improve treatment and how we care for patients with thisdevastating liver condition.!


application_id: 10202388
project_number: 5U01AA026936-04
project_title: Lipid metabolites can both potentiate and treat alcoholic hepatitis
administering_ic: NIAAA
award_notice_date: 2021-06-30
opportunity_number: RFA-AA-18-003
application_type: 5
activity_code: U01
ic: AA
serial_number: 026936
program_official: DUNTY, JR, WILLIAM
project_start_date: 2018-09-22
project_end_date: 2023-06-30
study_section: ZAA1-JJ(01)R
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: JOSHI-BARVE, SWATI
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:
Alcoholic Hepatitis (AH) is an important cause of morbidity mortality and health care costs. Only a limitednumber (<25% of those who drink heavily) develop this more advanced liver disease. Thus there must bemodifying factors that either prevent or facilitate disease activity/progression. Dietary fat represents a criticalmacronutrient disease modifier for AH. The American diet has increased dramatically in omega 6-polyunsaturated fat (PUFA) content and has a very imbalanced omega-6:omega-3 ratio. In pre-clinical rodentmodels dietary PUFA enriched in linoleic acid (LA) promotes alcohol-induced liver damage. Mice fed analcohol + high PUFA (LA) diet generate toxic oxidized products of linoleic acid metabolism (OXLAMs) as wellas a highly reactive and toxic aldehyde lipid peroxidation product (i.e. acrolein) which causes ER stress andliver injury. This high PUFA diet plus alcohol in rodents also causes gut dysbiosis and decreases levels of thecritical short chain fatty acid butyrate. We postulate that human subjects with AH will have (i) increasedlevels of the lipid peroxidation product acrolein (toxic aldehyde) (ii) increased levels of OXLAMs and(iii) altered gut flora with decreased fecal levels of butyrate and butyrate producing bacteria all ofwhich correlate with severity of liver injury. We also postulate that certain lipid products (resolvinsbutyrate) will be therapeutic in AH. We address this hypothesis with three specific aims using unique humansamples generated through the NIAAA-funded U01-consortium in AH.Specific Aim #1: Determine whether levels of acrolein metabolites and adducts in serum/urine/tissue areelevated in AH and correlate these levels with biomarkers of gut permeability hepatic cell death/injury anddisease severity.Specific Aim #2: Determine whether serum levels of OXLAMS are elevated in human AH and correlatethose levels with biomarkers of severity of AH hepatocyte death and gut permeability. Determine whetherserum levels of resolvins are decreased in AH and whether resolvin administration to AH blood ex vivodecreases proinflammatory cytokines.Specific Aim #3: Determine fecal levels of short-chain fatty acids (focusing on butyrate) in patients with AHand determine abundance of butyrate-producing bacteria in patients with acute AH and after recovery withabstinence. We will also determine the effects of different doses of butyrate on ex-vivo cytokine production inAH patients.!

project_terms:
Abstinence;Acrolein;Acute Alcoholic Hepatitis;Address;Alcoholic Hepatitis;Alcoholic liver damage;Alcohols;Aldehydes;American diet;Arachidonate 15-Lipoxygenase;Attenuated;Bacteria;Biological Markers;Blood;Butyrates;Cell Death;Cell membrane;Cessation of life;Data;Development;Diet;Diet and Nutrition;Dietary Fats;Disease;Dose;Endotoxemia;Fatty acid glycerol esters;Free Radicals;Funding;Genetic;Health Care Costs;Heavy Drinking;Hepatocyte;Human;Injury;Institution;Intake;Intervention;Intestinal permeability;Investigation;Laboratories;Linoleic Acids;Lipid Peroxidation;Lipids;Liver;Liver diseases;Macronutrients Nutrition;Mediating;Membrane Lipids;Metabolism;Morbidity - disease rate;Mus;National Institute on Alcohol Abuse and Alcoholism;Nutritional;Omega-3 Fatty Acids;Omega-6 Fatty Acids;Oxidative Stress;Oxides;Patient Care;Patients;Play;Polyunsaturated Fatty Acids;Production;Receptor Activation;Recovery;Research;Risk;Rodent;Rodent Model;Role;Sampling;Serum;Severities;Severity of illness;Smoking;Testing;Therapeutic;Tissues;Toll-like receptors;United States;Universities;Urine;Volatile Fatty Acids;adduct;alcohol research;cytokine;dysbiosis;endoplasmic reticulum stress;gut bacteria;gut dysbiosis;gut microbiota;human subject;improved;inflammatory disease of the intestine;liver injury;mortality;mouse model;nutrition;organ injury;oxidation;polyunsaturated fat;pre-clinical;prevent;response;tributyrin

public_health_relevance:
PROJECT NARRATIVEThis translational application related to the Alcoholic Hepatitis Network project AlcHepNet comprised of nineleading partner institutions in the field will examine new and promising treatments for severe liver damagecaused by alcohol. Combined these two approaches will improve treatment and how we care for patients withthis devastating liver condition.!


application_id: 10201841
project_number: 1R15AA028633-01A1
administering_ic: NIAAA
award_notice_date: 2021-06-18
opportunity_number: PAR-18-714
application_type: 1
activity_code: R15
ic: AA
serial_number: 028633
suffix: A1
program_official: KUMAR, SHAILESH
project_start_date: 2021-07-01
project_end_date: 2024-12-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 11434612
contact_pi: YATES, JUSTIN RYAN
other_pis: Not Applicable
congressional_district: 04
department: PSYCHOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Autonomic Nervous System Functioning in Heavy Drinking Adolescents: Interactions with sleep circadian functioning and health

project_abstract:
Project Summary/ AbstractHeavy drinking is highly prevalent in adolescents and young adults and can lead to dangerous behavioral andhealth consequences. Specific mechanisms of risk for escalating drinking in adolescence and young adulthoodare not well understood. The continuous communication between the heart and brain through the ANS iscritical to basic regulatory processes like sleep and circadian rhythms as well as to responses to stressors andrewards in ones environment. In adults with alcohol use disorders poorer ANS functioning (i.e. lower heart-rate variability [HRV] and baroreflex sensitivity [BRS]) are associated with greater reported craving andalcohol-seeking behavior; however it is unclear how ANS functioning relates to heavy drinking below thethreshold of alcohol use disorders in adolescents. The application seeks to examine autonomic nervoussystem (ANS) functioning as indexed by cardiovascular probes and its relationship to alcohol use cravingand cue-reactivity in an adolescent/young adult sample to elucidate a potential mechanism of risk in heavyalcohol users. The central premise of the application is that ANS functioning: 1) is critical to ones ability to self-regulate emotional response and specifically regulate responses to internal and external cues related toalcohol use and 2) is affected acutely and chronically by alcohol use which cascades to negative effects onsleep and circadian functioning. Quantifying the relationship between alcohol use and ANS functioning in lateadolescence is an important first step in understanding other potential implications for prevention andintervention. Accordingly this project will focus on assessing cardiovascular indices of ANS functioning alongwith sleep and circadian functioning and individuals affect and cue-reactivity over one month. To accomplishthese aims the study will enlist late adolescent Heavy Drinkers (HD n = 50; ages 18-20) and age- and sex-matched non-drinking Controls (CON n = 50) in a 4-week study. Resting-state HRV and BRS will bemeasured weekly (5x total) and affect ratings will be gathered daily throughout the 4 weeks while an alcoholcue-reactivity task with simultaneous HRV assessment will be gathered twice (first and last week). The primaryaims of the current protocol are to: 1) identify differences in ANS function and cue-reactivity over a monthbetween HD and CON and 2) quantify the relations between ANS functioning and craving sleep affectand substance use. The candidate will use his training in ANS assessment to test whether HD exhibitdifferences in ANS functioning affect and cue-reactivity related to their alcohol use. Corroborating changes viamultiple modalities (e.g. cardiovascular functioning and self-reported measures) will yield a biopsychosocialperspective on the potential underlying mechanisms. The candidates long-term goals are to identify markers ofrisk for substance use in even younger samples and to leverage the malleability of ANS functioning as apotential target of prevention and intervention efforts.

project_terms:
Acute;Adolescence;Adolescent;Adolescent and Young Adult;Adult;Affect;Affective;Age;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcoholic beverage heavy drinker;Alcohols;Autonomic nervous system;Baroreflex;Biomedical Research;Blood Pressure;Brain;Cardiovascular Physiology;Cardiovascular system;Chronic;Circadian Rhythms;Communication;Cues;Dangerousness;Data;Devices;Emotional;Enrollment;Environment;Exhibits;Feedback;Funding;Future;Goals;Grant;Health;Heart;Heart Rate;Heavy Drinking;Hormones;Individual;Informal Social Control;Institution;Intervention;Kentucky;Lead;Measures;Modality;Monitor;Nerve;Nervous System Physiology;Network Infrastructure;Neurocognitive;Organism;Outcome;Participant;Patient Self-Report;Physical activity;Physiological;Prevention;Process;Protocols documentation;Psychophysiology;Public Health;Reaction;Recovery;Reporting;Research;Resources;Rest;Rewards;Risk;Risk Factors;Risk Marker;Risk-Taking;Role;Sampling;Sleep;Stress;Symptoms;System;Testing;Training;United States National Institutes of Health;Universities;Vulnerable Populations;actigraphy;alcohol consequences;alcohol cue;alcohol effect;alcohol seeking behavior;alcohol use disorder;behavioral health;binge drinking;biological adaptation to stress;biopsychosocial;chronic alcohol ingestion;circadian;craving;cue reactivity;design;drinking;emerging adult;experience;hangover;heart rate variability;indexing;innovation;negative affect;preventive intervention;programs;psychosocial;reduced alcohol use;response;sex;sleep quality;stressor;substance use;success;therapeutic target;trait;underage drinking;young adult

public_health_relevance:
Project NarrativeThe goals of this grant are to assess the consequences of alcohol use on autonomic nervous system (ANS)functioning as a potential risk factor for negative consequences from drinking in adolescents. By examiningchanges in ANS functioning related to alcohol use over the course of a month this project will be able toquantify the relationships among drinking affect craving and cardiovascular functioning. This line of researchwill contribute to public health by identifying targets for prevention and intervention strategies in adolescents.


application_id: 10201814
project_number: 2R15GM117534-02
project_title: Sympathetic regulation of inflammation from sleep fragmentation
administering_ic: NIGMS
award_notice_date: 2021-03-26
opportunity_number: PAR-18-714
application_type: 2
activity_code: R15
ic: GM
serial_number: 117534
program_official: AKACEM, LAMEESE DANA
project_start_date: 2016-09-21
project_end_date: 2025-04-30
study_section: Special Emphasis Panel[ZRG1 MDCN-R (86)]
contact_pi_person_id: 10465930
contact_pi: ASHLEY, NOAH TODD
other_pis: Not Applicable
congressional_district: 02
department: BIOLOGY
primary_duns: 077876258
primary_uei: U5GMACGETKJ1
duns_number: 077876258
uei: U5GMACGETKJ1
fips: US
organization_id: 9186501
organization_name: WESTERN KENTUCKY UNIVERSITY
organization_city: BOWLING GREEN
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 421011001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryPrimary sleep abnormalities (insomnia shift work and obstructive sleep apnea) promote an inflammatoryenvironment and are associated with the development of cardiovascular and metabolic disease. However themechanisms underlying these relationships are poorly understood. The proposed research examines hormonalmechanisms that underlie the inflammatory response to sleep fragmentation (SF) using pharmacologicalapproaches in mice. Previous R15-funded research in our lab examined the effect of sympathetic nervoussystem (SNS) activation upon inflammatory responses to sleep loss. In this renewal application the role thatactivation of the hypothalamic-pituitary-adrenal (HPA) axis plays in modulating inflammation from acute andchronic SF will be investigated. Aim 1 will examine whether glucocorticoids mediate the onset of SF-inducedinflammation and the activation of microglia an important contributor to neuroinflammation. Specifically micewill be adrenalectomized sham-adrenalectomized or adrenalectomized and rescued with exogenousglucocorticoids and then subjected to acute and chronic SF. Pro- and antiinflammatory gene and proteinexpression will be assessed using RT-PCR and multiplex Luminex protein arrays respectively.Immunocytochemistry will be used to assess microglia activation. These findings will be validated throughpharmacological inhibition of glucocorticoid production and binding to glucocorticoid receptors. Instead of aclassic anti-inflammatory effect it is predicted that glucocorticoids will prime SF-induced inflammation. Aim 2will examine the time course of glucocorticoid release and pro-inflammatory responses to acute and chronicSF. Taken together the proposed research will assess the importance of the adrenocortical response inmediating inflammation during sleep loss and provide unique training opportunities for undergraduatesinterested in conducting biomedical research in endocrinology immunology and the neurosciences.

project_terms:
Acute;Adrenal Glands;Adrenal Medulla;Adrenalectomy;Adult;Anti-Inflammatory Agents;Antiinflammatory Effect;Binding;Biomedical Research;Blood;Blood Pressure;Brain;C57BL/6 Mouse;Cardiovascular Diseases;Cardiovascular system;Catecholamines;Chemicals;Child;Chronic;Cytokine Gene;Data;Development;Disease;Endocrinology;Epidemiology;Event;Exposure to;Funding;Gene Expression;General Adaptation Syndrome;Glucocorticoid Receptor;Glucocorticoids;Health;Hormonal;Hypothalamic structure;Hypoxia;Immune response;Immunohistochemistry;Immunology;Incidence;Inflammation;Inflammatory;Inflammatory Response;Laboratories;Lead;Link;Liver;Measurement;Mediating;Metabolic;Metabolic Diseases;Metabolic syndrome;Microglia;Modernization;Morbidity - disease rate;Mus;Neurobiology;Neurosciences;Neurosecretory Systems;Obesity;Obstructive Sleep Apnea;Organ;Outcome;Oxidopamine;Patients;Peripheral;Pharmacology;Phenotype;Physiological;Pituitary Gland;Play;Prevalence;Production;Protein Array;Regulation;Research;Reverse Transcriptase Polymerase Chain Reaction;Role;Serum;Shift-Work Sleep Disorder;Sleep;Sleep Apnea Syndromes;Sleep Deprivation;Sleep Disorders;Sleep Fragmentations;Sleep disturbances;Sleeplessness;Societies;Spleen;Sympathectomy;Sympathetic Nervous System;Testing;Time;Tissues;biological adaptation to stress;cytokine;fighting;hypothalamic-pituitary-adrenal axis;immunocytochemistry;inflammatory milieu;interest;neuroinflammation;novel therapeutic intervention;novel therapeutics;poor sleep;prevent;protein expression;response;shift work;sleep abnormalities;sleep behavior;sleep onset;sleep regulation;training opportunity;undergraduate student

public_health_relevance:
Project NarrativePoor sleep habits and sleep abnormalities caused by insomnia shift work and sleep-disordered breathing arebecoming more prevalent in modern society. Disordered sleep promotes inflammation which is a commonmechanism for the development of cardiovascular and metabolic diseases. Understanding how the stressresponse contributes to the development of inflammation during sleep loss could lead to novel therapeuticinterventions for treating inflammation-dependent disorders such as cardiovascular disease.


application_id: 10201642
project_number: 5T32GM118292-05
project_title: Graduate Training in Integrative Physiology
project_terms: Physiology;Training
administering_ic: NIGMS
award_notice_date: 2021-05-26
opportunity_number: PA-16-152
application_type: 5
activity_code: T32
ic: GM
serial_number: 118292
program_official: CHAO, CHIEN-CHUNG
project_start_date: 2017-07-01
project_end_date: 2022-08-31
study_section: Training and Workforce Development Study Section - A[TWD-A]
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH 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
project_abstract:
Project SummaryThis is a resubmission of a T32 application requesting funding for a new Graduate Training in IntegrativePhysiology training program for 4 predoctoral fellows/year. Training of the predoctoral fellows will be carriedout by participating faculty with proven track records of cross-disciplinary research on a variety of healthissues. The overall goal of the proposed program is to provide broad-based training in modern researchconcepts required to study quantitatively the nature of physiological processes in both healthy and diseasestates which is necessary to drive discovery of new therapeutic strategies for treating the underlying causes ofdiseases affecting multiple organs and systems. The primary objectives are to: 1) provide a comprehensivequantitative training program for early stage trainees in physiology with a particular emphasis oncardiovascular aging neurophysiology and muscle biology research; and 2) promote interdisciplinary learningteams involving basic scientists clinicians and trainees to foster rigorous innovative translational science.Predoctoral fellows will be trained in the practical issues involved in the design and conduct of basic andtranslational research to enhance their future ability to make therapeutic discoveries for diseases of broadetiology as independent investigators. To accomplish this the predoctoral fellows will engage in cutting-edgequantitative physiologically-based research. In addition to specialized didactic coursework they will participatein a comprehensive Experimental Design Workshop and attend weekly seminars and grand roundspresentations focused on cardiovascular aging-related neurological or musculoskeletal diseases. Althoughmost of the trainees are anticipated to pursue careers in laboratory-based discovery research they will alsoreceive training in conveying knowledge to other scientists through grant-writing and communications skillsworkshops. The combination of these training avenues will provide skills to disseminate their knowledge andprovide them with an understanding of how to design and conduct research in a manner that will enable thetranslation of promising therapies into the clinic.

public_health_relevance:
Project NarrativeThis is a resubmission of a new T32 application requesting support for an NIGMS-sponsored Systems andIntegrative Biology Predoctoral Training Program entitled Graduate Training in Integrative Physiology tobe based in the Department of Physiology at the University of Kentucky College of Medicine. The TrainingProgram is designed to train four predoctoral students per year in quantitative multidisciplinary systems-based research approaches to better understand complex diseases that affect multiple physiological systems.


application_id: 10201322
project_number: 1R03CA259670-01
project_title: Statistical methods for cancer progression delineation and subtype identification
administering_ic: NCI
award_notice_date: 2021-03-09
opportunity_number: PAR-20-052
application_type: 1
activity_code: R03
ic: CA
serial_number: 259670
program_official: MILLER, DAVID J
project_start_date: 2021-07-01
project_end_date: 2023-06-30
study_section: Special Emphasis Panel[ZCA1 SRB-2 (J2)]
contact_pi_person_id: 10631406
contact_pi: WANG, CHI
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:
Project Summary Carcinogenesis is a complex process involving somatic mutations in a number of key biological pathwaysand processes. Full study of the temporal order of somatic mutation occurrences is very important tounderstand biological mechanisms of cancer development and to inform new therapeutic targets and treatmentoptions. The first and most recognized example of order of mutations is from colon cancer which is frequentlyinitiated by mutations that affect the Wnt signaling pathway and then progress upon subsequent mutations ingenes involved in MAPK PI3K TGF-beta and p53 signaling pathways. However for many other cancer typestemporal orders of mutations are still largely unknown. Somatic mutation profiling via high throughput DNAsequencing has provided an unprecedented opportunity for using statistical/computational methods to studycancer progression. We and others have developed methods to infer temporal order of somatic mutationsbased on combining mutation profile data from a cohort of patients. However one major limitation of currentmethods is that they only consider presence or absence of mutations in a patients tumor but do not take intoaccount intra-tumoral heterogeneity (ITH). The ITH refers to the presence of multiple cell populations i.e.subclones with distinct mutation profiles within a patients tumor. The ITH which can be inferred from eithersingle-/multi-region bulk sequencing or single cell sequencing is usually characterized by a phylogenetic treewith nodes in the tree indicating different subclones and edges indicating the evolutionary relationships ofsubclones. As a phylogenetic tree describes the temporal order of mutations within an individual patientstumor incorporating such in-depth intra-patient information into the tumor progression analysis across patientsis likely to substantially increase the power and accuracy of the analysis. Another important priority in cancerresearch is to identify molecular subtypes. As cancer is a complex disease patients of the same cancer typemay have very different prognoses and responses to therapy. Further classifying patients into subtypes allowsclinicians to better predict a patients clinical outcomes and design more personalized treatment strategies. Byharnessing omics profiling data statistical/machine learning has emerged as a powerful tool to identifymolecular cancer subtypes. However due to the high complexity of cancer omics data and limited sample sizeit is still challenging to obtain stable and biologically interpretable results. Recently it has been advocated thatincorporating biological knowledge and structure into the construction of statistical/machine learning models isa viable approach to improve the mechanistic interpretability and robustness of the models. To advancecurrent capabilities we propose to develop new statistical methods to better estimate the temporal order ofpathway mutations by integrating ITH pathway and mutational functional annotation information and therebyto classify patients into biologically meaningful subtypes.

project_terms:
Adenocarcinoma Cell;Advocate;Affect;Algorithms;Appalachian Region;Basic Science;Biological;Cancer Cluster;Cancer Patient;Cells;Clinical;Clinical Research;Colon Carcinoma;Complex;Computing Methodologies;DNA sequencing;Data;Development;Disease;Future;Genes;Genomics;High-Throughput DNA Sequencing;Knowledge;Lung Adenocarcinoma;MAP Kinase Gene;Malignant Neoplasms;Malignant neoplasm of lung;Methods;Modeling;Molecular;Mutation;Outcome;Pathway interactions;Patients;Phylogenetic Analysis;Population;Process;Publications;Research;Resolution;Sample Size;Somatic Mutation;Squamous cell carcinoma;Statistical Methods;Structure;The Cancer Genome Atlas;Transforming Growth Factor beta;Trees;WNT Signaling Pathway;anticancer research;base;cancer classification;cancer subtypes;cancer type;carcinogenesis;clinical practice;cohort;design;drug development;genomic data;improved;individual patient;insight;molecular subtypes;new therapeutic target;p53 Signaling Pathway;personalized medicine;response;single cell sequencing;statistical and machine learning;success;tool;treatment strategy;tumor;tumor heterogeneity;tumor progression;tumorigenesis

public_health_relevance:
Project NarrativeThis project aims to develop new statistical methods to delineate temporal order of pathway mutations duringtumorigenesis and identify cancer subtypes with different cancer progression mechanisms. The success of thisproject will enhance our understanding of the biological mechanisms of cancer progression and enable betterclassification of cancer patients into subtypes which can potentially impact drug development and clinicalpractice.


application_id: 10200898
project_number: 5T32NS077889-10
project_title: Neurobiology of CNS Injury and Repair
project_terms: Neurobiology;central nervous system injury;injury and repair
administering_ic: NINDS
award_notice_date: 2021-06-24
opportunity_number: PA-16-152
application_type: 5
activity_code: T32
ic: NS
serial_number: 077889
program_official: KORN, STEPHEN J
project_start_date: 2012-07-01
project_end_date: 2022-06-30
study_section: ZNS1-SRB-N(13)
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACTThis is a renewal application requesting continued funding for a Neurobiology of CNS Injury andRepair T32 Training Program to support 4 predoctoral fellows working toward their Ph.D. degrees.During the first 4 years of the original funding period 11 trainees have been appointed to the 2 yearprogram of which 5 have completed training and their Ph.D.s (3 in Physiology and 2 in Anatomy &Neurobiology). Of those 5 2 are currently postdoctoral fellows 2 have been hired into university facultypositions and 1 has moved on to medical school. Of the other 6 trainees 2 are expected to finish theirPh.D.s during year 5 of the initial funding period. The remaining 4 are anticipated to complete theirdoctorates within the next two to three years. The training of the predoctoral fellows will be mainly carriedout by training faculty whose primary appointments are either within the University of Kentucky (UK)Spinal Cord & Brain Injury Research Center (SCoBIRC) or are the affiliated with it as SCoBIRC FacultyAssociates. Three of the SCoBIRC faculty associates have their primary appointments within the UKSanders-Brown Center on Aging (SBCoA). In addition to their primary appointments the SCoBIRCand/or SBCoA training faculty have their academic appointments in one of three UK College of Medicinebasic science departments: Anatomy & Neurobiology Physiology or Molecular & Cellular Biochemistry.One additional training faculty is from the UK College of Pharmacy Department of PharmaceuticalSciences. The overall goal of the proposed program will continue to be providing broad-based training inmodern research concepts regarding the acute subacute and chronic pathophysiology of SCI TBI andstroke and the identification of potential disease-modifying molecular targets that can drive the discoveryof pharmacological or gene therapeutic strategies by which the devastating effects of these injuries canbe ameliorated. These strategies will include both neuroprotective and neurorestorative approaches.Although it is anticipated that most of the trainees will pursue careers in laboratory-based therapeuticdiscovery research they will also receive training in clinical aspects of the targeted neurologicaldisorders and the practical issues involved in the design and conduct of neurological clinical trials. Toaccomplish this the predoctoral fellows will spend one day/week for a semester shadowing one of 6Clinical Tutors from the Departments Neurosurgery and Physical Medicine & Rehabilitation and willattend weekly grand rounds to gain an understanding of the clinical nature of TBI and SCI upon whichtheir research is focused. This will enhance their ability as independent investigators to not only maketherapeutic discoveries in experimental neurotrauma and stroke injury models but also provide themwith knowledge concerning how to design their basic research in a manner that will more readily enablethe translation of promising therapeutic approaches into clinical studies and therapeutic trials.

public_health_relevance:
PROJECT NARRATIVEThis project will involve the continuation of a training program that prepares 4 predoctoral fellows/year forneurological research careers that are directed at the discovery and translation of novel neuroprotectiveand neurorestorative therapies for the treatment of acute neurotrauma and stroke as well as the chronicneurodegenerative sequelae of traumatic spinal cord and brain injuries. The training will be directed bybasic science and clinical faculty of the University of Kentucky College of Medicine Spinal Cord & BrainInjury Research Center (SCoBIRC) and Sanders-Brown Center on Aging (SBCoA).


application_id: 10200889
project_number: 5R01LM013240-02
project_title: Advanced End-to-End Relation Extraction with Deep Neural Networks
administering_ic: NLM
award_notice_date: 2021-04-07
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: LM
serial_number: 013240
program_official: WANG, YANLI
project_start_date: 2020-07-01
project_end_date: 2024-03-31
study_section: Biomedical Computing and Health Informatics Study Section[BCHI]
contact_pi_person_id: 11081240
contact_pi: KAVULURU, VENKATA NAGA RAMAKANTH
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTRelations linking various biomedical entities constitute a crucial resource that enables biomedical data scienceapplications and knowledge discovery. Relational information spans the translational science spectrum goingfrom biology (e.g. proteinprotein interactions) to translational bioinformatics (e.g. genedisease associations)and eventually to clinical care (e.g. drugdrug interactions). Scientists report newly discovered relations in nat-ural language through peer-reviewed literature and physicians may communicate them in clinical notes. Morerecently patients are also reporting side-effects and adverse events on social media. With exponential growth intextual data advances in biomedical natural language processing (BioNLP) methods are gaining prominence forbiomedical relation extraction (BRE) from text. Most current efforts in BRE follow a pipeline approach containingnamed entity recognition (NER) entity normalization (EN) and relation classication (RC) as subtasks. Theytypically suffer from error snowballing  errors in a component of the pipeline leading to more downstream errors resulting in lower performance of the overall BRE system. This situation has lead to evaluation of differentBRE substaks conducted in isolation. In this proposal we make a strong case for strictly end-to-end evaluationswhere relations are to be produced from raw text. We propose novel deep neural network architectures thatmodel BRE in an end-to-end fashion and directly identify relations and corresponding entity spans in a singlepass. We also extend our architectures to n-ary and cross-sentence settings where more than two entities mayneed to be linked even as the relation is expressed across multiple sentences. We also propose to create twonew gold standard BRE datasets one for drugdisease treatment relations and another rst of a kind datasetfor combination drug therapies. Our main hypothesis is that our end-to-end extraction models will yield supe-rior performance when compared with traditional pipelines. We test this through (1). intrinsic evaluations basedon standard performance measures with several gold standard datasets and (2). extrinsic application orientedassessments of relations extracted with use-cases in information retrieval question answering and knowledgebase completion. All software and data developed as part of this project will be made available for public use andwe hope this will foster rigorous end-to-end benchmarking of BRE systems.

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

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


application_id: 10199950
project_number: 5R01CA215095-05
project_title: Roles of RORalpha in breast cancer development and progression
administering_ic: NCI
award_notice_date: 2021-06-29
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 215095
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2017-07-01
project_end_date: 2023-06-30
study_section: Tumor Microenvironment Study Section[TME]
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Tumor has been described as the wounds that do not heal. The two share some common features such asloss of polarized tissue structure and chronic inflammation. We showed that disruption of tissue polarityinduced macrophage infiltration. However little is known of how disruption of epithelial cell polarity at earlystage of breast cancer development induces macrophage infiltration. We have identified the RAR-relatedorphan nuclear receptor  (ROR) as a potent tumor suppressor by analyzing global gene expression profilesin polarized and non-polarized mammary epithelial cells. Our recent findings show that ROR inhibits ROSgeneration and macrophage infiltration in the syngeneic mouse mammary tumor model. These results suggestthat ROR is a potent suppressor of macrophage infiltration in mammary epithelial cells. We found thatknockdown of ROR significantly induced ROS production in mammary epithelial cells. Reactive oxygenspecies (ROS) are the driver of cancer progression and critical regulator of the NF-B pathway. Based onthese novel findings the central hypothesis of our proposal is that downregulation of ROR in non-polarizedbreast cancer cells increased ROS generation in mitochondria thereby inducing NF-B and macrophageinfiltration. We integrate high-throughput metabolic analysis a novel 3D co-culture system and global geneexpression profiling to delineate mechanisms by which ROR inhibits ROS production and macrophageinfiltration. The long-term goal of this proposal is to define the impact of the ROR/ROS axis in mediatingmammary epithelial cell-macrophage crosstalk and in regulating breast cancer progression. We have proposedfollowing specific aims to test the hypothesis: Aim 1. To elucidate the molecular mechanisms by which RORreduces ROS levels and NF-B activity in polarized mammary epithelial cells; Aim 2. To determine howreduced ROR expression in non-polarized breast cancer cells induces macrophage infiltration and M2polarization; Aim 3. Define the impact of ROR in suppressing breast cancer formation and metastasis. Theproposed study is high impact for its inherent scientific importance and its translational potential. This study willelucidate the molecular mechanism by which disruption of tissue polarity induces macrophageinfiltration/differentiation. Determining roles of ROR in reducing ROS generation and inhibiting NF-Bactivation may identify a novel strategy to inhibit breast cancer development and progression.

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

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


application_id: 10198918
project_number: 5R01DK123712-02
administering_ic: NIDDK
award_notice_date: 2021-03-29
opportunity_number: PAR-19-294
application_type: 5
activity_code: R01
ic: DK
serial_number: 123712
program_official: NGUYEN, KHOA DINH DANG
project_start_date: 2020-06-20
project_end_date: 2024-03-31
study_section: Special Emphasis Panel[ZRG1-EMNR-F(50)R]
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-04-01
project_title:
Preclinical validation of oral therapeutic lead proteins targeting epithelial GM1 ganglioside for ulcerative colitis therapy

project_abstract:
PROJECT SUMMARYCurrently there is no curative medication available for ulcerative colitis (UC) a type of inflammatory boweldisease affecting the innermost mucosal layer of the rectum and the colon. Although mucosal healing is a majortreatment goal many patients fail to achieve mucosal healing with available UC drugs such as anti-inflammatoryimmuno-modulatory and anti-TNF agents. Since epithelial repair is a critical process towards mucosal healingan agent facilitating this process will provide a novel therapeutic strategy differentiating from existing clinical carefor UC. Our therapeutic lead is a variant of the oral cholera vaccine antigen cholera toxin B subunit (CTB) whichwas modified with a C-terminal extension including an endoplasmic reticulum retention motif (CTBSEKDEL). Wehave recently shown that oral administration of CTBSEKDEL but not native CTB facilitates colon epithelial repairand mucosal healing in a dextran sodium sulfate (DSS)-induced acute colitis mouse model. Moreover biweeklyoral administration of CTBSEKDEL significantly reduced tumorigenesis in the azoxymethane/DSS model of colitis-associated cancer. Based on these findings we hypothesize that CTBSEKDEL provides a prototype oral biologicfacilitating mucosal healing in UC. The goal of this translational R01 project is to optimize and validate thetherapeutic potential of CTBSEKDEL in preclinical UC models. Since CTBSEKDEL has already shown feasibility in anacute colitis model we will immediately proceed with further validation in chronic colitis models. In parallel inAim 1 we will create CTBSEKDEL variants with modifications in the C-terminal sequence (CTB(X)H/KDEL) to improvemolecular stability upon spray dry for enteric-coated formulations. We will produce these proteins using aNicotiana benthamiana plant transient overexpression system and screen them based on a series of biochemicaland biophysical assays as well as a mouse acute DSS colitis model. In Aim 2 we will validate the efficacy andsafety of CTBSEKDEL and a selected CTB(X)H/KDEL in two chronic colitis models based on repeated DSS exposurein C57bl/6 mice and piroxicam-exposed IL-10 knockout mice in comparison to an anti-TNF antibody.Therapeutic efficacy and safety will be determined by disease activity index histopathologyimmunohistochemistry and molecular biological analysis of inflammation crypt regeneration epithelial barrierrecovery and fibrosis. In Aim 3 we will employ a human colon explant model to further validate the mucosalhealing potential of CTBSEKDEL and CTB(X)H/KDEL. Colon biopsy and colectomy tissues will be obtained frompatients with different disease history and biological backgrounds. Efficacy will be evaluated based on woundhealing-related gene expression and immunohistochemistry for epithelial proliferation/regeneration markers. Celltype-specific responses will be investigated in colon lamina propria mononuclear cells and colonic organoids.Collectively the project will generate pivotal preclinical data supporting the development of a first-in-class oralbiologic candidate inducing colon epithelial repair for UC treatment towards a Phase I clinical trial.

project_terms:
Acute;Affect;Affinity;Anti-Inflammatory Agents;Antibodies;Azoxymethane;Binding;Biochemical;Biological;Biological Assay;Biological Response Modifier Therapy;Biophysics;Biopsy;C-terminal;C57BL/6 Mouse;Caco-2 Cells;Cells;Cholera Toxin Protomer B;Cholera Vaccine;Chronic;Clinical Trials;Colectomy;Colitis;Colon;Crohn's disease;Data;Detection;Development;Disease;Disease remission;Dose;Dysplasia;E-Cadherin;Endoplasmic Reticulum;Endoscopy;Enteral;Enzyme-Linked Immunosorbent Assay;Epithelial;Epithelial Cells;Excision;Exposure to;Fibrosis;Formulation;Frequencies;Ganglioside GM1;Gene Expression;Genes;Goals;High Pressure Liquid Chromatography;Histopathology;Human;Immune;Immune System Diseases;Immunohistochemistry;Immunologic Surveillance;Immunosuppressive Agents;Impairment;In Vitro;Individual;Inflammation;Inflammatory Bowel Diseases;Interleukin-10;Intestines;Knock-out;Knockout Mice;Lamina Propria;Lead;Malignant Neoplasms;Mass Spectrum Analysis;Modeling;Modification;Molecular;Monitor;Mononuclear;Mucous Membrane;Mus;Natural regeneration;Nicotiana;Oral;Oral Administration;Organoids;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Phase I Clinical Trials;Piroxicam;Plants;Postoperative Complications;Process;Proteins;Recombinants;Recording of previous events;Recovery;Rectum;Refractory;Relapse;Research;Safety;Scanning;Series;Sodium Dextran Sulfate;Specimen;System;TNF gene;Testing;Therapeutic;Therapeutic Agents;Therapeutic Effect;Tissues;Treatment Efficacy;Ulcerative Colitis;Vaccine Antigen;Validation;Variant;analog;base;cell type;clinical care;colitis associated cancer;comparative efficacy;curative treatments;efficacy study;efficacy validation;epithelial injury;epithelial repair;first-in-human;healing;holotoxins;immunoregulation;improved;indexing;infection risk;inflammatory disease of the intestine;inflammatory marker;mouse model;mutant;novel;novel therapeutic intervention;overexpression;pre-clinical;prototype;response;retrograde transport;safety study;screening;tissue culture;tumorigenesis;wound healing

public_health_relevance:
NARRATIVEThe objective of the proposed research is to optimize and validate the therapeutic potential of a novel orallyactive recombinant mucosal healing protein for the treatment of ulcerative colitis. We will test the proteinsefficacy and safety in well-established mouse models of chronic colitis and in ex vivo human colon tissue culture.The proposed research will generate pivotal preclinical feasibility data towards a first-in-human clinical trial.


application_id: 10198872
project_number: 5R01CA247365-03
project_title: Chemical Biology of the Control of Neddylation by DCN1
administering_ic: NCI
award_notice_date: 2021-08-04
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;Bioavailable;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/antagonist;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: 10198855
project_number: 5R01CA168658-08
project_title: Cellular Metabolites regulating cancer cell adaptation
administering_ic: NCI
award_notice_date: 2021-07-09
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 168658
program_official: WILLIS, KRISTINE AMALEE
project_start_date: 2013-05-02
project_end_date: 2024-06-30
study_section: Cellular Signaling and Regulatory Systems Study Section[CSRS]
contact_pi_person_id: 8821411
contact_pi: LEE, YOUNG-SAM
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Cellular metabolites regulating cancer cell adaptation SAICAR is a metabolite accumulates in cancer cells upon glucose starvation or EGF stimulation. Uponaccumulation SAICAR promotes cancer cell survival and proliferation by inducing tumor PKM2. However it isnot yet clear how cancer cells but not normal proliferating cells accumulate SAICAR. We hypothesize that transformation-induced alteration of pentose phosphate pathway is responsible forthe accumulation of SAICAR. In this project we will test this hypothesis while evaluating the importance ofSAICAR accumulation for the growth of tumor in vivo. The outcome of this project include a better understanding on metabolic reprogramming contributes tocancer. In addition the outcome of this project will determine whether SAICAR accumulation can be a potentialtherapeutic target.

project_terms:
Affect;Biochemistry;Bypass;Cell Proliferation;Cell Survival;Cells;Complex;Data;EGF gene;Enzymes;Epidermal Growth Factor Receptor;Feedback;Glucose;Glycolysis;Growth Factor;Hela Cells;Human;Lung Adenocarcinoma;Malignant Neoplasms;Measures;Metabolic;Metabolic Pathway;Mitogens;Mus;Normal Cell;Nucleotide Biosynthesis;Outcome;Pentosephosphate Pathway;Permeability;Phase;Phosphoenolpyruvate;Phosphorylation;Proliferating;Proteins;Receptor Protein-Tyrosine Kinases;Regulation;Science;Small Interfering RNA;Starvation;Testing;Tissues;Tyrosine;Xenograft procedure;cancer cell;cell transformation;dimer;in vitro activity;in vivo;inhibitor/antagonist;inorganic phosphate;nucleotide metabolism;therapeutic target;tumor;tumor growth

public_health_relevance:
PROJECT NARRATIVE SAICAR is a nucleotide biosynthesis metabolite whose accumulation induces the survival and theproliferation of cultured cancer cells. We will determine the mechanism on how cancer cells but not normallyproliferating cells accumulate SAICAR while testing the relevance to tumor growth in vivo. The outcome willdetermine whether the SAICAR accumulation can be a potential therapeutic target.


application_id: 10198235
project_number: 1R35ES032876-01
project_title: Chromosome Instability Drives Metal-Induced Lung Cancer
administering_ic: NIEHS
award_notice_date: 2021-07-26
opportunity_number: RFA-ES-20-009
application_type: 1
activity_code: R35
ic: ES
serial_number: 032876
program_official: CARLIN, DANIELLE J
project_start_date: 2021-08-01
project_end_date: 2029-06-30
study_section: Special Emphasis Panel[ZES1 LWJ-D (R3)]
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_terms:
3-Dimensional;Animals;Attention;Cancer Etiology;Carcinogens;Cell Line;Cells;Cessation of life;Chromosomal Instability;Collection;Colon Carcinoma;Complex;Disease;Environmental Health;Epithelial;Event;Exposure to;Fibroblasts;Funding;Health;Heritability;Human;Individual;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Metal Carcinogenesis;Metal exposure;Metals;Minority;Mutagens;Neoplastic Cell Transformation;Outcome;Population;Public Health;Risk Assessment;Structure;Tobacco;Tobacco use;Translating;United States;carcinogenicity;cell type;chromium hexavalent ion;human subject;improved;induced pluripotent stem cell;insight;interest;malignant breast neoplasm;mixed cell culture;neoplastic;novel;novel strategies;prevent;programs;social stigma;stem cell model;tobacco user;tool


application_id: 10198022
project_number: 5R01HL142969-04
project_title: The role of soluble prorenin receptor in hypertension associated with obesity
administering_ic: NHLBI
award_notice_date: 2021-07-22
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 142969
program_official: VARAGIC, JASMINA
project_start_date: 2018-07-15
project_end_date: 2023-06-30
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 10353675
contact_pi: LORIA, ANALIA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThe epidemic of obesity currently affecting more than 36.5% of the population in the UnitedStates has contributed to a rise in the prevalence of hypertension. We recently found thatobesity stimulated the secretion of the soluble form of the prorenin receptor (PRR) sPRR intoplasma. While examining sPRR protein concentrations in tissues we found an increase ofsPRR protein levels in the liver the adipose tissue and the kidney of control mice fed a high fatdiet compared to mice fed a low fat diet. New preliminary data showed that the infusion of arecombinant mouse sPRR in mice fed a standard diet activated local and circulating RAS byincreasing renal cortical angiotensinogen (AGT) and circulating renin levels. Consistent withthose results our new results demonstrated that elevated plasma sPRR in adipose PRR KOmice is associated with an increase of cortical angiotensin II levels in the kidney. Urinaryvasopressin levels also increased significantly in these mice. Together with our prior work theseresults raise the possibility that sPRR regulates the renin angiotensin system (RAS) and bodyfluid volume. To test this idea 3T3-L1 cells and human HepG2 cells were incubated withincreased concentration of recombinant mouse sPRR. We found that sPRR increased theexpression of AGT gene in 3T3-L1 cells and the secretion of AGT in the media of humanHepG2. In addition the incubation with our sPRR neutralizing antibody decreased AngII levelsin the media of 3T3-L1 cells. Because sPRR infusion in mice increased plasma renin levels wealso investigated whether sPRR regulated the expression of renin in kidney. Interestingly wefound that sPRR binds to the promoter of the renin gene. Thus we propose that obesitystimulates sPRR production leading to hypertension through a mechanism that involves theactivation of the RAS and increases AVP. We will test the hypothesis that tissue-derived sPRRmediates angiotensin II-induced hypertension associated with obesity likely by amplifying thelocal AGT and renin response and increases urinary AVP. We will also investigate whetherblocking sPRR can be used as a treatment for hypertension associated with obesity. Outcomeswill demonstrate whether obesity is regulated through a previously unrecognized pathwayrepresented by upstream control of RAS and AVP by sPRR. Our studies point to a uniquefunctional role for sPRR in hypertension associated with obesity.

project_terms:
3T3-L1 Cells;Adipose tissue;Adrenergic Receptor;Affect;Angiotensin II;Angiotensin-Converting Enzyme Inhibitors;Angiotensinogen;Antihypertensive Agents;Binding;Biological Markers;Blood Pressure;Body Fluids;C57BL/6 Mouse;Calcium Channel Blockers;Cardiovascular Diseases;Cause of Death;Cell secretion;Cells;Chronic;Cleaved cell;Complex;Data;Diet;Drug usage;Fat-Restricted Diet;Fatty acid glycerol esters;Fluid Balance;Genes;Goals;HepG2;Hepatic;High Fat Diet;Human;Hypertension;In Vitro;Incubated;Infusion procedures;Kidney;Knockout Mice;Liver;Losartan;Mediating;Molecular;Mus;Obese Mice;Obesity;Obesity Epidemic;Outcome;Outcome Study;Pathology;Pathway interactions;Patients;Peptides;Pharmaceutical Preparations;Plasma;Population;Prevalence;Production;Recombinants;Renin;Renin-Angiotensin System;Resistant Hypertension;Risk;Role;Severities;Testing;Therapeutic;Tissues;Transcriptional Regulation;Transgenic Mice;United States;Urine;Vasoconstrictor Agents;Vasopressins;Work;antidiuretic;blood pressure regulation;cardiovascular risk factor;hypertension treatment;in vivo;insight;mortality;mouse model;nectin;neutralizing antibody;normotensive;novel;prevent;promoter;prorenin receptor;receptor;response;urinary

public_health_relevance:
PROJECT NARRATIVEObesity is the leading risk factor for cardiovascular diseases and increases all cause of death inUSA and the risk of hypertension. We found a new molecule in the fat liver and kidney that canhelp to cure hypertension associated with obesity.


application_id: 10197041
project_number: 5R21AI142727-02
project_title: Legionella-Polymorphonuclear Leukocytes Interaction
administering_ic: NIAID
award_notice_date: 2021-05-18
opportunity_number: PA-19-053
application_type: 5
activity_code: R21
ic: AI
serial_number: 142727
program_official: ERNST, NANCY L
project_start_date: 2020-06-17
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-B(80)]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
other_pis: URIARTE, SILVIA M
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 SummaryPolymorphonuclear leukocytes (PMNs)/Neutrophils account for 50-60% of peripheral blood leukocytes inhumans and are an essential part of the innate host defense against microbial infections. Quiescent PMNsrespond to high levels of glucose in vitro through a pro-inflammatory response mediated by up-regulation ofaerobic glycolysis. Importantly PMNs respond to hyperglycemia in diabetic patients by releasing pro-inflammatory cytokines. PMNs restrict intracellular growth of Legionella pneumophila (Lp) whose abilityto cause pneumonia is dependent on pathogen proliferation within alveolar macrophages. The Dot/Icm typeIV translocation system of Lp which functions as a molecular syringe injects protein effectors into themacrophage cytosol to evade lysosomal fusion and macrophage restriction of pathogen proliferation. Despitethe Dot/Icm-mediated translocation of effectors into the PMNs cytosol the cells restrict Lp proliferation. Thetwo main powerful antimicrobial machineries of PMNs to control microbial infections are the generation ofreactive oxygen species (ROS) and the antimicrobial agents within the azurophilic and specific granules. Itis not known whether any of the two major PMNs antimicrobial machineries are involved in Lp restriction.The PMNs mount a pro-inflammatory response to Lp in vivo but the mechanism is not known. In contrast tomacrophages our preliminary data show that PMNs rapidly degrade the WT strain of Lp while the Dot/Icmtranslocation-defective mutant survives for at least 4h. We discovered that one of the Dot/Icm-translocatedeffectors of Lp into the cytosol of human PMNs is a Legionella amylase (LamA) which degrades the PMNsglycogen within 30-60 min of infection. Interestingly PMNs fail to degrade the lamA-deficient mutant whichdoes not degrade PMNs glycogen similar to the Dot/Icm translocation-defective mutant. We will test thehypothesis that human PMNs respond to the effect of the translocated LamA effector by engaging theirantimicrobial machineries in response to the cytosolic hyper-glucose generated by the LamA-mediateddegradation of glycogen. To test the hypothesis our specific aims are: Specific Aim I: Engagement of thePMNs antimicrobial machineries in response to the effect of LamA; and Specific Aim II: Pro-inflammatoryactivation of PMNs in response to cytosolic hyper-glucose generated through glycogen degradation by LamA.Upon completion of the proposed studies we will learn the mechanism of the innate immune response ofhuman PMNs to Lp in response to abnormally high levels of cytosolic glucose. Importantly our studies havebroad significance as they will be relevant to mechanisms of innate immunity under diabetic conditions wheredysregulated inflammation is a common persistent occurrence. Our proposed studies are novel as well asmechanistic and would generate a new paradigm in our knowledge of PMNs innate immune responses tobacterial pathogens.

project_terms:
Alveolar Macrophages;Amylases;Animals;Bacteria;Bacterial Infections;Biopsy;Cells;Cytoplasmic Granules;Cytosol;Data;Exposure to;Generations;Glucose;Glycogen;Growth;Host Defense;Human;Hyperglycemia;Immune;In Vitro;Infection;Infection Control;Inflammation;Inflammatory;Inflammatory Response;Innate Immune Response;Knowledge;Learning;Legionella;Legionella pneumophila;Leukocytes;Mediating;Metabolic;Metabolism;Molecular;NADPH Oxidase;Natural Immunity;Patients;Phagolysosome;Phagosomes;Pneumonia;Production;Proliferating;Proteins;Pulmonary alveolar structure;Reactive Oxygen Species;Reporting;Syringes;System;Testing;Up-Regulation;aerobic glycolysis;antimicrobial;antimicrobial drug;cytokine;diabetic;diabetic patient;glycogenolysis;in vivo;innate immune mechanisms;macrophage;microbial;monocyte;mutant;neutrophil;novel;pathogen;pathogenic bacteria;peripheral blood;response

public_health_relevance:
Project NarrativeNeutrophils account for 50-60% of peripheral blood leukocytes in humans and are anessential part of the innate immune defense against bacterial infections. Our proposedstudies will decipher the mechanisms of the intracellular mechanisms that targetLegionella for degradation and the pro-inflammatory activation of human neutrophils uponengulfing the pathogen.


application_id: 10195454
project_number: 1R21LM013683-01
administering_ic: NLM
award_notice_date: 2021-03-31
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: LM
serial_number: 013683
program_official: WANG, YANLI
project_start_date: 2021-04-01
project_end_date: 2021-04-02
study_section: Health Services Organization and Delivery Study Section[HSOD]
contact_pi_person_id: 15800176
contact_pi: SANDHU, HARPAL SINGH
other_pis: LAMBERT, JOSH
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-04-01
project_title:
Identifying existing FDA-approved drugs with clinically protective effects against coronavirus disease 2019 using a big data approach

project_abstract:
Project Summary/AbstractCoronavirus Disease 2019 (COVID-19) is a national and global public health emergency. Because thecausative virus is novel the present options for treatment are extremely limited and an effective vaccinecould be 1-2 years away. Thus there is an urgent need for efficacious therapeutics against the disease.While development of new drugs is under way that process is slow and resource-intensive. In the short-to-medium term a superior strategy is to repurpose already existing drugs to treat the disease. Over100 drugs already approved by the Food and Drug Administration (FDA) have shown in vitro in silicoor theoretical effect against SARS-CoV-2 the virus that causes COVID-19 or the hyperinflammatoryimmune response it provokes. What is unclear is how many of these have a significant protective effecton actual patients as only a tiny fraction of these drugs is in clinical trials. Most of these agents arechronic medications and thus there are millions of Americans who are already using them. The first aimof this study is to assess the degree of protection any of these drugs confers against the seriouscomplications of COVID-19 while adjusting for known risk factors and confounders. The second aim isto search for additional interactions between drugs or combinations of drugs and specific demographicand/or clinical subgroups that could be protective or harmful. The Change Healthcare Database a partof the COVID-19 Research Database contains up-to-date health insurance claims data for about one-third of all Americans. Using this database this study will evaluate the impact of these drugs on the riskof four important outcomes in patients who are COVID-19-positive: need for hospitalization use ofmechanical ventilation shock and death. Results will be risk-adjusted for the risk factors already wellestablished to predict poor outcomes in COVID-19. This study will further mine the data for second- andthird-order interactions between drugs or combinations of drugs and different subpopulations of patientsusing a novel machine learning method called the Feasible Solution Algorithm (FSA). The FSA enablesthe researcher to uncover higher-order statistical interactions in regression models which leads to theidentification of subgroups and complexities that are not always apparent with traditional regressionmodels. If the results show candidate drugs with highly protective effects these can be prioritized forprospective clinical studies. Drugs that show harmful effects can be considered for discontinuation ininfected or high-risk patients.

project_terms:
2019-nCoV;Address;Affect;Age;Algorithmic Analysis;Algorithms;American;Angiotensin-Converting Enzyme Inhibitors;Anticoagulants;Antiplatelet Drugs;Antiviral Agents;Big Data;Biometry;Blood Coagulation Disorders;COVID-19;COVID-19 diagnosis;COVID-19 patient;COVID-19 treatment;Cessation of life;Chronic;Clinical;Clinical Data;Clinical Research;Clinical Trials;Communicable Diseases;Complication;Data;Data Set;Databases;Development;Disease;Drug Combinations;Goals;Health;Health Insurance;Healthcare;Hospitalization;Immune response;In Vitro;Inpatients;Insurance Carriers;Judgment;Logistic Regressions;Mechanical ventilation;Medical;Medicare;Methods;Mineralocorticoid Receptor;Modeling;Outcome;Outpatients;Patients;Pharmaceutical Preparations;Pharmacoepidemiology;Process;Prospective Studies;Protective Agents;Race;Research;Research Personnel;Resources;Risk;Risk Factors;SARS-CoV-2 positive;Shock;Statistical Algorithm;Subgroup;Testing;Therapeutic;Therapeutic Effect;Time;United States Food and Drug Administration;Vaccines;Virus;Vision;Vulnerable Populations;Work;clinically significant;comorbidity;coronavirus disease;cyclooxygenase 1;cytokine release syndrome;demographics;drug candidate;drug development;drug repurposing;global health emergency;high risk;human data;immunomodulatory therapies;improved;in silico;in vivo;inhibitor/antagonist;insurance claims;interest;machine learning algorithm;machine learning method;mortality;multidisciplinary;novel;novel therapeutics;off-label use;pandemic disease;patient subsets;preclinical study;prophylactic;prospective;protective effect;public health emergency;sex

public_health_relevance:
Project NarrativeRepurposing existing drugs to treat coronavirus disease 2019 (COVID-2019) is a muchfaster and more resource-effective approach than developing new drugs de novo. Thisholds promise because over 100 drugs already approved by the Food and DrugAdministration (FDA) have shown in vitro in silico or theoretical activity against SARS-CoV-2 or the immune response it provokes. Using a large health insurance claimsdatabase we will assess the potentially protective effects of each of these drugs onpatients diagnosed with COVID-19 and search for interactions between multiple drugsand specific demographic and clinical subpopulations via a novel statistical algorithm.


application_id: 10194546
project_number: 5R01GM132443-03
project_title: A novel mechanism of immunosuppression in sepsis: Depletion of monocytes and macrophages
administering_ic: NIGMS
award_notice_date: 2021-06-22
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: GM
serial_number: 132443
program_official: ZHAO, XIAOLI
project_start_date: 2019-09-20
project_end_date: 2021-11-30
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8558885
contact_pi: LI, ZHENYU
other_pis: WEI, YINAN
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:
Sepsis is a life-threatening condition that affects more than 1 million patients a year in the United States.Growing evidence indicates that immunosuppression is a major driving force for mortality in sepsis.Macrophages play essential roles in immune response to pathogens. Previous clinical studies have shown thatperipheral monocytes are depleted in septic patients through apoptosis. Recent in vitro studies revealed thatbacterial components flagellin the rod protein of the type III secretion system (T3SS) or LPS inducepyroptosis of macrophages through activation of inflammasome pathways. In this proposal we provideconvincing evidence that both peripheral monocytes and tissue macrophages are depleted due to pyroptosis inmouse sepsis models including the cecal ligation and puncture (CLP) model. We show that intravenousinjection of flagellin or the rod proteins induced depletion of peripheral monocytes and macrophages in tissues.We further demonstrate that depletion of these cells in mice impaired immune response and increasedmortality rate by subsequent challenged with E. coli. Importantly our data indicate that tissue factor releasedfrom pyroptotic monocytes and macrophages triggers disseminated intravascular coagulation (DIC). Thus ourfindings identified monocyte/macrophage depletion as a novel mechanism of immunosuppression and DIC insepsis. The goal of this application is to delineate the underlying mechanisms of monocyte/macrophagedepletion and its contribution to immunosuppression in sepsis. Aim 1 is to delineate the mechanisms ofpyroptotic monocyte and macrophage death during sepsis. The working hypothesis is that inflammasomeactivation and subsequent pyroptosis play a critical role in monocyte/macrophage depletion during sepsis.Mouse models deficient in caspase-1 caspase-11 caspase-1/11 double or GSDMD (whole-body andmacrophage-specific) will be used to elucidate the detailed mechanism of inflammasome activation andpyroptosis in monocyte/macrophage depletion. Aim 2 is to identify the mechanism by which rod protein andflagellin induce pyroptosis leading to monocyte/macrophage depletion. We recently identified an intracellularbinding partner of EprJ the acyl-CoA dehydrogenase family member type 9 (ACAD9) in macrophages. We willuse different approaches to test the hypothesis that the ACAD9-dependent pathway contributes tomacrophage depletion. Aim 3 is to identify the contribution of monocyte/macrophage depletion toimmunosuppression during sepsis. We will use a combination of sepsis models to investigate the role ofmonocyte/macrophage depletion in immunosuppression during sepsis. Peripheral monocyte depletion in septicpatients will also be investigated. Completion of the proposed studies will reveal a novel molecular mechanismof immunosuppression induced by Gram-negative bacteria. Such findings will significantly advance ourunderstanding about the pathogenesis of sepsis and identify new drug targets for this deadly disease.

project_terms:
Affect;Apoptosis;B-Lymphocytes;Bacteria;Binding;CASP1 gene;Caspase;Cell Death;Cell membrane;Cells;Cessation of life;Cleaved cell;Clinical Research;Data;Dendritic Cells;Disease;Disseminated Intravascular Coagulation;Effector Cell;Escherichia coli;Family member;Flagellin;Goals;Gram-Negative Bacteria;Gram-Negative Bacterial Infections;Immune;Immune response;Immunosuppression;Impairment;In Vitro;Infection;Inflammasome;Inflammatory;Lead;Life;Modeling;Molecular;Morbidity - disease rate;Mus;N-terminal;Pathogenesis;Pathway interactions;Patients;Peripheral;Phagocytosis;Play;Proteins;Reporting;Research Project Grants;Rod;Role;Rupture;Sepsis;T-Cell Depletion;Testing;Thromboplastin;Tissues;Type III Secretion System Pathway;United States;Work;acyl-CoA dehydrogenase;cecal ligation puncture;driving force;insight;intravenous injection;macrophage;monocyte;mortality;mouse model;new therapeutic target;novel;pathogen;release factor;response;septic patients

public_health_relevance:
Project NarrativeCumulative data indicate that immunosuppression is a major driving forcefor morbidity and mortality in sepsis. This research project seeks tounderstand the mechanism of monocyte and macrophage depletion which maycontribute to sepsis-associated immunosuppression. Completion of the work willprovide new insights into molecular mechanism of immunosuppression by Gram-negative bacteria that could be targeted to treat this deadly disease.


application_id: 10194498
project_number: 5R21ES031712-02
project_title: Translational Control in Cr(VI) Carcinogenesis
administering_ic: NIEHS
award_notice_date: 2021-05-13
opportunity_number: PA-19-053
application_type: 5
activity_code: R21
ic: ES
serial_number: 031712
program_official: TYSON, FREDERICK L
project_start_date: 2020-06-16
project_end_date: 2024-05-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 10534129
contact_pi: SHE, QING-BAI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYCr(VI) is a common and well-recognized environmental carcinogen that causes lung and other cancers in human.Despite considerable research effort to understand the molecular and cellular mechanisms of Cr(VI)carcinogenesis crucial facets of these mechanisms remain largely unknown; identification of the key molecularregulators and processes the mechanisms of action and strategies for prevention are urgently needed.Remarkable progress has been made that highlights the functional importance of mRNA translation and proteinsynthesis in cancer development and progression. However translational control of Cr(VI) carcinogenesis hasnot yet been investigated. We recently demonstrated that chronic low dose Cr(VI) exposure in human lungbronchial epithelial cells can induce cancer stem cell (CSC)-like properties cell transformation and tumorformation through upregulation of histone-lysine methyltransferases including G9a SUV39H1 and EZH2.Notably we found that chronic Cr(VI) exposure can activate mTOR kinase leading to phosphorylation(inactivation) of the translational repressor 4E-BP1 and thereby promote the recruitment of capping mRNAs andribosomal subunits to the eIF4F translation initiation complex (eIF4E+eIF4G+eIF4A) for active translation inpolysomes. Furthermore we found that on chronic Cr(VI) exposure the EZH2 mRNA is actively translated inpolysomes with no changes in its transcriptional level. Importantly targeted inhibition of mTOR kinase can inhibittranslation of EZH2 mRNA in polysomes and result in growth inhibition of Cr(VI)-transformed cells. Based onthese findings the central hypothesis of the proposed study is that the activation of cap-dependent mRNAtranslation machinery by mTOR kinase is required to selectively upregulate key oncoproteins that confer Cr(VI)-induced tumorigenesis. To test this hypothesis two specific aims are proposed. Aim 1 will define the role ofmTOR-activated translation machinery in Cr(VI)-induced tumorigenesis using a combination of molecularcellular biochemical and pharmacologic approaches as well as genetically engineered mouse models withclinical association schemes. Aim 2 will characterize the molecular mechanism of mTOR-activated cap-dependent translation in Cr(VI) carcinogenicity using a polysome profiling approach to systematically identify aset of key mRNAs that are selectively recruited to polysomes and translated in Cr(VI)-transformed humanbronchial epithelial cells followed by characterization of their functional importance in Cr(VI)-inducedtumorigenicity. Our proposed study will investigate the innovative concept that Cr(VI) induces carcinogenesisthrough dysregulation of the mTOR/4E-BP1-mediated translation initiation process. Elucidating this process willprovide novel insights into the biology and clinical relevance of translational regulation in Cr(VI) carcinogenesis.This research will have the added benefit of identifying Cr(VI)-induced translationally-regulated targets forpotential preventive or interventional therapy.

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

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


application_id: 10193064
project_number: 1R01CA251478-01A1
project_title: Local Flavor Policies to Enhance Equity in Tobacco
administering_ic: NCI
award_notice_date: 2021-04-08
opportunity_number: PAR-18-675
application_type: 1
activity_code: R01
ic: CA
serial_number: 251478
suffix: A1
program_official: RODITIS, MARIA LEIA
project_start_date: 2021-04-08
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZRG1 RPHB-N (56)]
contact_pi_person_id: 11156218
contact_pi: ROSE, SHYANIKA W
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Advertising;Affect;Area;California;Cigarette;Code;Color;Communities;County;Data;Data Collection;Data Set;Databases;Ecological momentary assessment;Education;Electronic cigarette;Ensure;Ethnic Origin;Exposure to;Goals;Home;Income;Individual;Kentucky;Laws;Link;Longitudinal cohort;Longitudinal trends;Low income;Malignant Neoplasms;Malignant neoplasm of lung;Marketing;Menthol;Modeling;Neighborhoods;Outcome;Participant;Persuasive Communication;Policies;Population;Protocols documentation;Public Policy;Race;Research;Resources;Respondent;Risk;Sales;Smokeless Tobacco;Socioeconomic Status;Statistical Data Interpretation;Structure;Testing;Time;Tobacco;Tobacco use;United States Food and Drug Administration;Universities;Variant;Vulnerable Populations;Youth;attributable mortality;cancer health disparity;cancer risk;cigarette smoking;cigarillos;cohort;cost;demographics;disparity reduction;emerging adult;evidence base;follow-up;health disparity;health equity;implementation framework;innovation;low socioeconomic status;neighborhood disadvantage;public policy on tobacco;racial difference;reduce tobacco use;theories;tobacco advertising;tobacco exposure;tobacco flavor;tobacco products;tobacco user;trend;young adult


application_id: 10191056
project_number: 5R01NS079507-08
administering_ic: NINDS
award_notice_date: 2021-03-31
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 079507
program_official: LEENDERS, MIRIAM
project_start_date: 2012-09-30
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZRG1-MDCN-M(91)S]
contact_pi_person_id: 9358186
contact_pi: BAUER, BJOERN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-04-01
project_terms:
Agonist;Arachidonate 5-Lipoxygenase;Attenuated;Automobile Driving;Blood - brain barrier anatomy;Blood capillaries;Brain Diseases;Cell Adhesion Molecules;Characteristics;Chronic;Clinical;Data;Data Reporting;Development;Disease;Endothelium;Epilepsy;Extracellular Matrix Proteins;Extravasation;FPR2 gene;Feedback;Functional disorder;Funding;Glutamates;Goals;Human;Inflammation;Intervention;Knockout Mice;Knowledge;LOX gene;Lead;Leukocytes;Leukotrienes;Link;Matrix Metalloproteinases;Mediating;Mission;Modeling;Molecular Target;Mus;National Institute of Neurological Disorders and Stroke;Neurons;Neurotransmitters;PTGS2 gene;Pathway interactions;Patients;Prostaglandins;Proteins;Public Health;Publishing;Rattus;Research;Research Personnel;Seizures;Signal Transduction;Symptoms;Testing;Therapeutic;Therapeutic Intervention;Tight Junctions;United States National Institutes of Health;base;cerebral capillary;clinical translation;cyclooxygenase 2;evidence base;expectation;glutamatergic signaling;improved;in vivo;individual patient;innovation;lipoxin A4;mouse model;nervous system disorder;neuroinflammation;neurovascular;new therapeutic target;novel;novel therapeutic intervention;repaired;therapy design;vascular inflammation


application_id: 10189617
project_number: 5U18FD006179-05
administering_ic: FDA
award_notice_date: 2021-06-01
opportunity_number: PA-12-194
application_type: 5
activity_code: U18
ic: FD
serial_number: 006179
program_official: CERIC, OLGICA
project_start_date: 2017-08-01
project_end_date: 2022-05-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 14767081
contact_pi: LOYNACHAN, ALAN
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
arra_indicator: N
budget_start_date: 2021-06-01
project_abstract:
Gaskill 2017 Project Summary/AbstractThe objective of this Food and Drug Administration (FDA) Veterinary Laboratory Response Network (Vet-LRN)Cooperative Agreement Program is to provide increased sample analysis capabilities for the FDA throughpartnership with Vet-LRN laboratories in the event of animal food or drug related illness or other large scaleanimal food/feed emergency events requiring surge capacity testing of implicated diagnostic or animal foodsamples. Testing will include microbiological and chemical analysis of samples such as animalfood/feed/drugs environmental samples related to animal food/feed/drug production and/or animal diagnosticnecropsy or clinical samples. In the event of a large-scale biological or chemical contamination affecting animalfood or drug products the UKVDL will perform selected analyses of diagnostic samples collected and suppliedto the laboratory by FDA or other government agencies. Federal or State surveillance assignments will also bea source of samples for analyses.The overall goal of the cooperative agreement is to complement develop improve and use university stateand federal veterinary diagnostic laboratory testing capabilities. The program will also be used to implementstandardized analysis through the usage of standardized methods equipment analytical worksheets andelectronic reporting. Training and proficiency testing will be provided for each method and Qualitymanagement systems will be enhanced. Small scale method development and method validation projects willbe performed as directed by the Vet-LRN Program Office. Funding will be used for supplies equipmentmaintenance and personnel time.

public_health_relevance:
Gaskill 2017 Project NarrativeThis FDA Vet-LRN Cooperative Agreement Program will strengthen the overall food safety system bydeveloping increased capacity and capabilities to detect adulteration which could affect animals raised forhuman consumption or companion animals consuming ingredients used in both animal and human foodproducts.


application_id: 10189602
project_number: 5U18FD006155-05
project_title: CVM Vet-LRN Veterinary Diagnostic Laboratory Program
administering_ic: FDA
award_notice_date: 2021-06-01
opportunity_number: PAR-17-141
application_type: 5
activity_code: U18
ic: FD
serial_number: 006155
program_official: CERIC, OLGICA
project_start_date: 2017-08-01
project_end_date: 2022-05-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 15010137
contact_pi: REED, DEBBIE CAROL
other_pis: Not Applicable
congressional_district: 01
department: VETERINARY SCIENCES
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractExpanded national laboratory capacity to respond to animal food/drug related illnessesor other large-scale animal food/feed emergency events requiring surge capacity testingof implicated diagnostic or animal food samples is required to ensure food safety inhumans. Food safety directly affects the food chain through biological and chemicalcontaminants in animal feedsThe Breathitt Veterinary Center is a fully accredited (AAVLD) animal disease diagnosticlaboratory strategically located in Western Kentucky.The objective of this grant application is to support activity by the Breathitt VeterinaryCenter in the FDA CVM Vet-LRN Veterinary Diagnostic Laboratory Program. The FDAVet-LRN grant program is a mutually beneficial opportunity in which the laboratoryreceives support to advance its scientific scope and the FDA CVM adds to the nationallaboratory capacity. Funding provided through a cooperative agreement will be used toprovide equipment supplies training and proficiency testing requested by the FDA Vet-LRN on an annualized basis for a five-year period.The Specific Aims of this proposal are:1) To strengthen coordination of veterinary diagnostic laboratory efforts as related to thesafety of the food supply;2) To train equip and proficiency test technicians to perform such testing as isnecessary to ensure the safety of the food supply;3) To participate in the Vet LIRN Whole Genome Sequencing Project by providingbacterial samples as a Source Laboratory.

public_health_relevance:
Project NarrativeAgriculture is Kentuckys number one industry contributing almost $6 billion to thestates economy annually. Livestock and livestock product sales generate 65% of thetotal agricultural revenues. The Murray State University Breathitt Veterinary Center(BVC) is an animal disease diagnostic laboratory dedicated to protecting the valuableassets of the region by providing the fastest most accurate and most dependableanimal disease diagnostic services possible. Located in Hopkinsville Kentucky theBVC with a staff of 40 is housed in a new 77000 square foot facility 53000 squarefeet of which are dedicated to veterinary diagnostics.The facility is centrally located to serve a 200 mile radius including Western KentuckySouthern Indiana and Illinois and Northwestern Tennessee. The BVC professional staffincludes nine members with Doctorates in Veterinary Medicine and/or Masters and PhDdegrees in the fields of Pathology Microbiology Virology Immunology and Toxicologyand Public Health. The professional staff is supported by laboratory bench personneleach of who hold a minimum of a Bachelors degree and several have Masters degrees.The laboratory provides full administrative secretarial/clerical and maintenance staff insupport of diagnostic and research activities. The BVC is accredited for all species bythe American Association of Veterinary Laboratory Diagnosticians (AAVLD) throughDecember 2019.The BVC is a member of the USDA National Animal Health Laboratory Network(NAHLN) the Centers for Disease Control Laboratory Response Network (LRN) andthe FDA VetLaboratory Response Network (VetLRN). The centers scope of activityincludes the scientific disciplines of Pathology Microbiology Molecular DiagnosticsClinical Pathology Toxicology Serology and Virology. The BVC processes 24000+diagnostic cases per year to include over 200000 tests.The FDA CVM VetLRN desires to expand the national laboratory capacity to provideincreased sample analyses in the event of animal food or drug related illnesses or otherlargescale animal food/feed emergency events requiring surge capacity testing ofimplicated diagnostic or animal food samples.Objective: The objective of this grant application is to provide a cooperative agreementbetween the FDA CVM VetLRN and the BVC whereby the BVC will participate in theVetLRN Veterinary Diagnostic Laboratory Program. The FDA CVM VetLRN grantprogram is a mutually beneficial opportunity in which the FDA CVM VetLRN adds to thenational laboratory capacity and the BVC receives support to advance its scope ofactivity. Funding provided through the cooperative agreement will be used to provideequipment supplies training and proficiency testing under the aegis of the VetLRNVeterinary Diagnostic Program on an annualized basis for a five year period.


application_id: 10188701
project_number: 1K22CA258678-01
project_title: Admixture mapping of mosaic copy number alterations for identification of cancer drivers
administering_ic: NCI
award_notice_date: 2022-04-12
opportunity_number: PAR-18-467
application_type: 1
activity_code: K22
ic: CA
serial_number: 258678
program_official: JAKOWLEW, SONIA B
project_start_date: 2022-04-15
project_end_date: 2025-03-31
study_section: Special Emphasis Panel[ZCA1 RTRB-R (J1)]
contact_pi_person_id: 12387511
contact_pi: JAKUBEK SWARTZLANDER, YASMINKA ALEKSANDRA
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:
PROJECT SUMMARY/ABSTRACTBackground: Somatic mosaicism arises due to the clonal expansion of a cell with an acquired mutation whichleads to genetically distinct sub-populations of cells in an organism derived from a single zygote. As a cloneproliferates its subclones can accumulate further molecular changes that seed cancer. A better understandingof acquired point mutations and copy number changes in these clonal expansions can help elucidate theearliest stages of cancer development. Studies of tissues from healthy individuals have found that those withclonal mosaicism in blood specifically copy number alterations (CNAs) have a ~10-fold higher risk ofdeveloping hematological malignancies thus underscoring the translational potential of mosaicism studies forthe development of improved risk assessment and cancer prevention strategies. Research up to now hasmainly focused on persons of European ancestry. My own preliminary results show differences in the genomiclandscape of CNAs between individuals of African American or Latino ancestry when compared withEuropeans. Understanding these differences and the underlying molecular mechanisms is critical in order toinclude these still under-researched populations in translational mosaicism studies for early detection andprevention of hematological and potentially other cancers. Proposed Research: Aim 1 is to address the greatneed for comprehensive studies of mosaicism in American minority populations through a large-scale analysesof CNAs in African American and Latino whole genome sequencing (WGS) data sets. This approach willenable a robust comparison of mosaicism profiles across populations; WGS will allow for joint analysis ofCNAs and somatic point mutations to gain insights into mechanisms that underlie different rates and subtypesof hematological malignancies across populations. Aim 2 is to develop novel methods to combine CNA andhaplotype level ancestry data for detection of variants associated with increased mosaicism rates. I will usethese methods to identify genetic variants that are associated with mosaicism and with increased cancer risk inLatinos and African Americans. Candidate: I have led projects to discover and analyze acquired CNAs inthousands of non-malignant tissues  first of their kind studies for pathologically normal and premalignanttissues  as well as in cancer tissues that complement these. This expertise and my established track record inthe development of computational methods for human/cancer genomics will ensure the successful completionof these aims. As larger volumes of normal tissues are molecularly profiled I will be able to extend methodsdeveloped in Aim 2 to additional normal tissue types and conduct integrative omics analyses. I will follow upthis work and the associated publications with an R01 proposal focused on translational applications of mosaicmutations in normal tissues as markers for cancer risk assessment early detection and prognosis. The K22award will be fundamental as I launch my independent investigator career offering management and grantwriting training helping to hone my skills as a mentor/PI and establish a long-term funded research program.

project_terms:
Address;Admixture;African;African American;African American population;African ancestry;American;Blood;Cell Fraction;Cells;Cessation of life;Clonal Expansion;Complement;Computing Methodologies;DNA Sequence Alteration;Data;Data Set;Development;Disease;Early Diagnosis;Ensure;European;Frequencies;Funding;Genes;Genetic;Genetic Population Study;Genetic Variation;Genetic study;Genomic Segment;Genomics;Goals;Grant;Haplotypes;Hematologic Neoplasms;Hematology;Human;Incidence;Individual;Inherited;Japanese;Japanese Population;Joints;K22 Award;Latino;Latino Population;Link;Loss of Heterozygosity;Malignant Neoplasms;Maps;Mentors;Methodology;Methods;Minority Groups;Modeling;Molecular;Molecular Profiling;Mosaicism;Mutation;Non-Malignant;Normal tissue morphology;Organism;Pathologic;Pattern;Persons;Point Mutation;Population;Population Genetics;Prevention;Prevention strategy;Prognosis;Proliferating;Publications;Recurrence;Reporting;Research;Research Personnel;Risk Assessment;Sampling;Screening for cancer;Single Nucleotide Polymorphism;Statistical Methods;Testing;Tissues;Training;Translations;Underrepresented Populations;Variant;Work;Writing;admixture mapping;ancestry analysis;cancer biomarkers;cancer genomics;cancer prevention;cancer risk;cancer seeding;career;detection method;follow-up;genetic variant;genome sequencing;genome wide association study;genomic variation;high risk;improved;innovation;insight;leukemia;method development;multi-ethnic;novel;premalignant;programs;skills;study population;translational applications;translational potential;variant detection;whole genome;zygote

public_health_relevance:
PROJECT NARRATIVEClonal mosaicism in the blood has not been comprehensively investigated in African American and Latinopopulations. We will assess this biomarker of cancer risk in these populations through the development ofnovel methodology that will enhance integrative analysis of mosaic mutations germline variation and ancestry.A better understanding of mosaicism in these under-studied populations will allow for more targeted cancer riskassessment and early detection.


application_id: 10188500
project_number: 5R01DE026963-04
project_title: P. gingivalis genes essential for tobacco smoke survival
administering_ic: NIDCR
award_notice_date: 2021-06-23
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DE
serial_number: 026963
program_official: MCNEALY, TAMARA L
project_start_date: 2017-09-01
project_end_date: 2025-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-C(02)M]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abscess;Adult;Alveolar Bone Loss;Anaerobic Bacteria;Award;Bacteria;Basic Science;Biological;Biological Assay;Biological Process;Blood Vessels;Cells;Chronic;Cigarette;Clinical;Communicable Diseases;Complex;Consumption;Data;Databases;Developed Countries;Diabetes Mellitus;Disease;Dose;Economic Burden;Environment;Epidemiology;Epithelial;Epithelial Cells;Essential Genes;Exhibits;Exposure to;Financial cost;Funding Mechanisms;Future;Gene Deletion;Genes;Genome;Gingiva;Growth;Health;Homologous Gene;Immune;Immune response;In Vitro;Infection;Inflammation;Libraries;Lung diseases;Modeling;Mouth Diseases;Mus;National Institute of General Medical Sciences;New Zealand;Nicotine;Oral;Oral cavity;Patients;Peptide Hydrolases;Periodontal Diseases;Periodontitis;Physiology;Population;Porphyromonas gingivalis;Predisposition;Premature Birth;Prevention;Refractory;Research;Resistance;Resources;Scandinavia;Smoke;Smoker;Smoking;Standardization;Stress;Subcutaneous abscess;System;Testing;Tissues;Tobacco;Tobacco smoke;Tobacco smoking behavior;Tooth structure;Toxin;Treatment Protocols;Variant;Vascular Diseases;Virulence;Work;base;biological adaptation to stress;cigarette smoke;cigarette smoke-induced;fitness;immune resistance;in vivo;infection rate;insight;mouse model;mutant;non-smoker;novel;novel vaccines;oral cavity epithelium;pathogen;periodontopathogen;success;therapeutic target;tobacco regulation;tobacco smoke exposure;trait;transcriptome;transcriptome sequencing;transposon sequencing


application_id: 10188396
project_number: 5R01AI090048-10
project_title: Novel aminoglycoside adjuvants and stand-alone agents to combat tuberculosis
administering_ic: NIAID
award_notice_date: 2021-05-14
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AI
serial_number: 090048
program_official: XU, ZUOYU
project_start_date: 2011-08-01
project_end_date: 2023-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-S(02)M]
contact_pi_person_id: 8970083
contact_pi: GARNEAU-TSODIKOVA, SYLVIE
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTTuberculosis (TB) is the deadliest global infection (1.4 million deaths in 2015) having recently surpassedHIV/AIDS. ~250000 of these deaths were from multidrug-resistant (MDR) TB with only ~50% success intreatment of MDR-TB. Unless new strategies to combat or prevent emergence of drug-resistant TB arefound the global spread of MDR-TB will be an epidemic of epic proportions. Kanamycin A (KAN) is anantibiotic of last resort used to treat MDR-TB. Resistance to KAN signifies extensively drug-resistant(XDR) TB which is nearly incurable. One-third of KAN-resistant TB is caused by upregulation of theacetyltransferase Eis in Mycobacterium tuberculosis (Mtb) caused by mutations in the eis promoter. Weinvestigated the mechanism of Eis and discovered and validated several Eis inhibitor scaffolds in theprevious funding period. In Aims 1 and 2 of this application we propose to develop a novel strategy tocombat and forestall KAN resistance in TB. These Aims are focused on the preclinical development ofthese Eis inhibitors for their ultimate use as a combination therapy with KAN against MDR-TB. In Aim 3we propose to determine the mechanism(s) of the anti-Mtb activity of novel compounds that werediscovered to inhibit Eis and potently inhibit Mtb bacteria without KAN ultimately to develop them astherapeutics against both drug-resistant and drug-resistant TB.

project_terms:
AIDS/HIV problem;Acetyltransferase;Adjuvant;Adjuvant Therapy;Aminoglycosides;Anti-Bacterial Agents;Antibiotics;Antitubercular Agents;Area;Bacteria;Biochemical;Biological;Biological Assay;Cells;Cessation of life;Chemicals;Combined Modality Therapy;Complex;Consultations;Coupled;Crystallization;Development;Drug resistance;Drug resistance in tuberculosis;Epidemic;Evaluation;Exhibits;Extreme drug resistant tuberculosis;Funding;Future;Genotype;Genus Mycobacterium;Human;In Vitro;Infection;Kanamycin;Kanamycin A;Knock-out;Laboratories;Lead;Measurement;Mediating;Modeling;Multidrug-Resistant Tuberculosis;Mutation;Mycobacterium tuberculosis;Mycobacterium tuberculosis H37Rv;Pathogenicity;Permeability;Pharmaceutical Chemistry;Pharmaceutical Preparations;Property;Reporting;Resistance;Resort;Safety;Solubility;Structure;Testing;Therapeutic;Toxic effect;Tuberculosis;Up-Regulation;analog;clinical development;combat;cytotoxicity;design;drug-sensitive;experience;extensive drug resistance;genome sequencing;infection burden;inhibitor/antagonist;innovation;interest;macrophage;mouse model;mutant;novel;novel strategies;pre-clinical;preclinical development;preclinical study;prevent;promoter;research clinical testing;resistance mechanism;scaffold;structural biology;success;synergism

public_health_relevance:
NARRATIVETuberculosis (TB) kills 1.4 million annually worldwide and is currently the deadliest infection with~250000 of these deaths resulting from multidrug-resistant (MDR) TB for which the treatment successrate is only 50%. This project is focused on developing innovative kanamycin adjuvants (Eis inhibitors)for their use with kanamycin to forestall and combat MDR-TB. Additionally the project is focused onelucidating the mechanism and development of other novel anti-TB agents to kill the pathogenicmycobacteria without the need of using KAN ultimately to develop these agents as therapeutics againstboth drug-resistant and drug-resistant TB in the US and worldwide.


application_id: 10186728
project_number: 5R21DC018878-02
project_title: Watching cellular dynamics in the taste bud
administering_ic: NIDCD
award_notice_date: 2021-05-12
opportunity_number: PA-19-053
application_type: 5
activity_code: R21
ic: DC
serial_number: 018878
program_official: SULLIVAN, SUSAN L
project_start_date: 2020-06-10
project_end_date: 2023-05-31
study_section: Chemosensory Systems Study Section[CSS]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: A unique feature of the peripheral taste system is that the receptor cells die and are replaced.This requires a constant rewiring of the peripheral system. In order for a new taste receptor cellto form a synapse with an existing neuron it must first come into contact with the correct type ofneuron. Here our goal is to understand the cellular dynamics involved in this process. Wehypothesize that since many receptor cells are replaced within 10 days this cellular influxshould be accompanied by cellular migration of taste bud cells and/or remodeling by the arbor.To test this hypothesis we will combine genetic labeling with intra vital two-photon microscopyto examine plasticity in the taste bud over a 10 day period. Aim 1 will examine the migration ofprecursors into the taste bud as they mature. Aim 2 will measure the growth and retraction ofindividual nerve branches. These studies will be first to examine taste bud plasticity with directobservation of changes over time in a live animal. Future studies will use this approach to helpidentify roles of molecular factors underlying the formation of new connections in the taste bud.

project_terms:
Adult;Anatomy;Animals;Axon;Cell Differentiation process;Cell Maturation;Cell division;Cells;Chemicals;Chronic;Dose;Epithelial;Evaluation;Event;Fiber;Food;Fungiform Papilla;Future;Genetic;Genotype;Goals;Growth;Image;Individual;Label;Length;Location;Longevity;Maps;Measures;Mitotic;Molecular;Monitor;Morphology;Movement;Mus;Nerve;Nerve Fibers;Nervous system structure;Neurons;Pattern;Peripheral;Peripheral Nerves;Pharmaceutical Preparations;Process;Property;Receptor Cell;Resolution;Role;Structure;Structure of geniculate ganglion;Surface;Synapses;System;Tamoxifen;Taste Bud Cell;Taste Buds;Taste Perception;Testing;Time;Tongue;Width;cell motility;chemotherapy;in vivo;in vivo imaging;in vivo two-photon imaging;migration;precursor cell;stem cells;taste system;tongue papilla;two photon microscopy

public_health_relevance:
Project NarrativeHere we propose to develop an in vivo imaging paradigm permitting evaluation of taste receptorcell differentiation/migration and taste neuron plasticity in live animals over time. This paradigmis ideally suited to determine the specific impact of drugs and conditions (includingchemotherapies) that potentially disrupt taste receptor cell turnover and the ability of receptorcells to connect with nerve fibers.


application_id: 10186610
project_number: 3U01DA043908-02S1
project_title: Development of Novel Therapeutics for Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2020-06-18
opportunity_number: PA-18-591
application_type: 3
activity_code: U01
ic: DA
serial_number: 043908
suffix: S1
program_official: ACRI, JANE
project_start_date: 2018-08-01
project_end_date: 2021-07-31
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
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:
The current proposal is a request for a supplement to U01 DA043908 Development of Novel Therapeutics forMethamphetamine Abuse on which I serve as PI. Methamphetamine (METH) use disorder is linked to direhealth and societal consequences and its use has markedly increased in the United States. Effectivetreatments for METH use disorder are not available. METH interacts with the vesicular monoamine transporter-2 (VMAT2) promoting dopamine (DA) release into the cytosol and reversal of the DA transporter to increaseextracellular DA resulting in abuse liability. This project focuses on VMAT2 as a novel therapeutic target withthe overall goal of obtaining a treatment for METH use disorder. Phase 1b studies with lobeline the initial leadwere completed; bitter taste short half-life and the requirement for multiple daily doses were expected toreduce compliance. Lobeline was modified to obtain GZ-793A which had the desired pharmacology but wasfound to have off-target hERG interaction and potential cardiotoxicity. Iterative optimization of GZ-793Aresulted in GZ-11608 and JPC-077 which were potent and selective inhibiting VMAT2 function and METH-evoked DA release in vitro. Importantly these compounds had greatly reduced hERG activity anddemonstrated our ability to further modify the molecule to eliminate off-target interactions. These analogs alsospecifically decreased METH self-administration and METH-induced reinstatement in rats at doses that did notalter food reinforcement. Tolerance did not develop upon repeated dosing. These analogs also protectedagainst or did not exacerbate METH-induced striatal DA neurotoxicity. Despite this favorable pharmacologicprofile these analogs had low oral bioavailability (F% = 3% in rats). The current project (U01 DA043908)produced optimized GZ-11608 analogs. Again we met the milestones and identified a very promisingcompound STK-5-25 that has a Ki = 19 nM at VMAT2 no detectable hERG interaction >4 h stability in ratmicrosomes and F% = 30% in rats. The current lead STK-5-25 has an aniline moiety on one of the rings whichcan be associated with idiosyncratic liver toxicity with bioconversion to a reactive metabolite although we havenot observed changes in liver enzymes in rats. Our plan for the requested supplemental funds is to substitutenitrogenous heterocycles in place of the aniline as a final optimization strategy for a candidate and backup forIND enabling studies in 3 species. To do this we will employ a Contract Research Organization (CRO) tosynthesize 50-100 compounds during the last few months of the active award period. Compounds will beevaluated in in vitro pharmacological assays to inform the prioritization of synthesis during the active period ofthe current award. Evaluation in pharmacokinetic and behavioral assays will proceed during the no costextension period. Thus I am requesting that NIDA provide supplemental funding so that we can finalize theoptimization of our lead compound and come back with a new GOMD application to bring us to IND submissionwith the goal of developing a pharmacotherapy for methamphetamine use disorder.

project_terms:
Acute;Affinity;Aniline;Award;Back;Behavioral Assay;Biological Assay;Biological Availability;Cardiotoxicity;Chemical Structure;Clinical Research;Corpus striatum structure;Cues;Cytosol;Development;Disease;Dopamine;Dose;Drug Kinetics;Enzymes;Evaluation;Exhibits;FDA approved;Food;Formulation;Funding;Goals;Half-Life;Health;Hepatotoxicity;In Vitro;Lead;Link;Liver;Lobeline;Metabolism;Methamphetamine;Microsomes;Molecular Bank;National Institute of Drug Abuse;Oral;Oral Administration;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Phase;Psychological reinforcement;Rattus;Relapse;Research;Research Contracts;Scourge;Self Administration;Slice;Societies;Synaptic Vesicles;Taste Perception;Therapeutic;Toxic effect;Treatment Efficacy;United States;analog;base;cost;dopamine transporter;drug discovery;effective therapy;extracellular;innovation;methamphetamine abuse;methamphetamine use;neurotoxicity;new therapeutic target;novel;novel therapeutics;scaffold;small molecule;therapeutic development;uptake;vesicular monoamine transporter 2

public_health_relevance:
Methamphetamine use disorder is linked to dire health and societal consequences and its use has markedlyincreased in the United States. The current request to supplement U01 DA043908 Development of NovelTherapeutics for Methamphetamine Abuse is to allow us to perform the final optimization of our lead compoundby substituting an aniline moiety with nitrogenous heterocycles to obtain a candidate and backup for INDenabling studies.


application_id: 10186445
project_number: 6U60OH008483-15M003
project_title: Kentucky Occupational Safety and Health Surveillance
administering_ic: NIOSH
award_notice_date: 2020-06-03
opportunity_number: PAR-14-275
application_type: 6
activity_code: U60
ic: OH
serial_number: 008483
suffix: M003
project_start_date: 2005-07-01
project_end_date: 2021-06-30
study_section: ZOH1-GGB(52)
contact_pi_person_id: 7931539
contact_pi: BUNN, TERRY LEE
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Kentucky (KY) ranks as the 14th-worst state for fatal occupational injury rates and 7th-worst for nonfatal occupational injuries and illnesses. The overall KY Occupational Safety and Health Surveillance (KOSHS) expanded program KOSHS fundamental. Occupational Health Indicator [OHI] and Fatality Assessment Control and Evaluation [FACE] component programs) focuses on population-based and case-based surveillance of work-related injuries/illnesses in KY a southeastern HHS Region 4 state. Specific aims are to perform population-based occupational injury and illness surveillance using 21 NIOSH-recommended OHI 6 Ky-specific OHI FACE and other surveillance data including new data source evaluation; perform case based occupational injury and illness surveillance through FACE on-site investigations and high adult blood lead level follow-up investigations; conduct epidemiological analyses of work-related injury and illness surveillance & investigation data; establish & maintain partnerships and collaborations that integrate KOSHS results with partners' intervention and outreach activities; participate in the KOSHS advisory committee and attend semiannual grantee meetings; disseminate occupational injury and illness data & research results through annual reports OHI data submission to NIOSH newsletters website postings NIOSH State-based Occupational Health Clearinghouse presentations publications NIOSH and CDC alerts MMWR Workplace Solutions & social media; & perform a process impact & outcome evaluation of the overall KOSHS expanded program. Novel industries and occupations targeted in the KOSHS application include highway incident management & truck transportation injury epidemiology studies & fatality investigations online truck driver safety training modules & towing and truck driver tool kits. KOSHS will also have an innovative emphasis on work-related severe traumatic injuries TBIs and concussions. Advanced statistical methodologies such as probabilistic data linkage and multiple imputation will be used and surveillance data quality improvement studies will be performed. Innovative integration of the KOSHS program with NIOSH Total Worker Health(tm) (TWH) Safe Communities CDC-funded Violence and Injury Prevention Program and National Safety Council is planned.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This proposed project is relevant to public health by 1) identifying industries occupations and worker populations at high risk for work injuries and illnesses; 2) identifying risk factors trends and emerging issues; and 3) identifying gaps in andimproving occupational injury and illness surveillance systems. When injury prevention knowledge is attained by the worker injuries will decrease and the economic costs of injuries will decrease because there will be fewer worker compensation claims.


application_id: 10185144
project_number: 3UL1TR001998-04S1
project_title: Kentucky Center for Clinical and Translational Science
administering_ic: NCATS
award_notice_date: 2020-06-29
opportunity_number: PAR-15-304
application_type: 3
activity_code: UL1
ic: TR
serial_number: 001998
suffix: S1
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2021-05-31
study_section: ZTR1-SRC(99)
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Contact PD/PI: Kern Philip APROJECTSUMMARYTheUniversityofKentucky(UK)CenterforClinicalandTranslationalScience(CCTS)hascreatedanintegratedhomeforclinicalandtranslationalresearchtopromotescientificprogressanddiscoveriesateveryphaseofthetranslationalcontinuum.TheCCTShasfundamentallytransformedtheresearchenvironmentnotonlyatUKbutthroughoutCentralAppalachiathroughthedevelopmentofastrongresearchnetworktheAppalachianTranslationalResearchNetwork(ATRN)withintegratedresearchpartnershipsincludingotherCTSAhubs.Whencombinedwithanin-depthunderstandingoftheuniqueandserioushealthchallengesfacedbyCentralAppalachianresidentstheUKCCTSispositionedtoleadlocalregionalandnationalresearcheffortsthatfocusonthesignificanthealthdisparitiesinthispopulation.OuroverarchinggoalasaCTSAhubistocontinuetochampioninnovationinthefullspectrumofclinicalandtranslationalresearchwhileeducatingtheworkforceofthefutureengagingourcommunitiesinbiomedicalscienceandworkingwiththenationalnetworktoadvancecohesivemulti-centerclinicaltrialswhichwillultimatelyelevatethehealthandqualityoflifeofthepopulaceofCentralAppalachia.SpecificallytheUKCCTSwill:1)Leadinstitutionalinnovationinthedeliveryofefficienteffectiveclinicalandtranslationalresearch.2)Developadiverseworkforceacrossmultipledisciplinesthatadvancestranslationalresearchandexcelsinteam-basedscience.3)MeettheuniqueneedsofCentralAppalachianresidentsbyextensivelyengagingandcollaboratingwithourregionalruralandcommunity-basedpartners.4)Catalyzeinnovativeresearchincludingnoveldrugdevelopmentandinformaticsmethodologieswithparticularfocusonbringinginnovationtospecialpopulationsandacrossthelifespan.5)CreateanefficientclinicaltrialsnetworkcenteredatUKandextendingintoourpartnerhealthcaresystemsthatwillbeanessentialandleadingcomponentoftheCTSAconsortiuminvolvingparticipantsthroughoutafourstateregionofruralCentralAppalachia.TheUKCCTSbenefitsfromacollaborativeenvironmentfoundononlyafewuniversitycampuses.UKhas16collegeswith11involvedintheUKCCTS(includingsixbiomedicalcolleges)ononecentralcampus.ThisphysicalproximityofouracademicandhealthcarecommunitiesalongwithacultureofcollaborationcreatesacloselyknitunifiedacademiccommunityandpositionstheUKCCTStodemonstratetheimpactofcollaborativetranslationalresearchandleadershipinteamscience.OureffortshavealreadybeensuccessfulattransformingthecultureoftheUKacademicmedicalcentertoonethatmorekeenlyappreciatesscholarshipinnovationandtranslationalscience.Wenowplantobuildonthesestrengthstoadvancetranslationalsciencetothenextlevelwithfurtherdevelopmentofourclinicaltrialnetworksdevelopmentofnovelinformaticsprogramsandcontinueddevelopmentoftheworkforcethroughouttheregion.TheseeffortswillbenefitthemedicallyunderservedresidentsofCentralAppalachiaandwillsignificantlycontributetothenationalCTSAprogram.  1 Project Summary/Abstract Page 287Contact PD/PI: Kern Philip A

project_terms:
Abbreviations;Academic Medical Centers;Affect;Agriculture;Appalachian Region;Arts;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Clinical Trials Network;Collaborations;Communities;Data;Development;Discipline;Diverse Workforce;Education;Engineering;Environment;Fostering;Future;Goals;Health;Healthcare;Healthcare Systems;Home environment;Informatics;Institutes;Institution;Interdisciplinary Study;Kentucky;Lead;Leadership;Longevity;Medical center;Methodology;Mission;Multi-Institutional Clinical Trial;Participant;Patient Recruitments;Personal Satisfaction;Phase;Population;Positioning Attribute;Quality of Care;Quality of life;Research;Research Training;Role;Rural;Rural Community;Rural Population;Scholarship;Science;Solid;Target Populations;Translational Research;Trust;Universities;West Virginia;Workforce Development;base;biomedical informatics;catalyst;clinical center;cohesion;collaborative environment;college;data management;data warehouse;drug development;food environment;health care service organization;health disparity;healthcare community;improved;innovation;medical schools;medically underserved;named group;novel;novel therapeutics;programs;rural area;success

public_health_relevance:
PROJECT NARRATIVEThe University of Kentucky (UK) Center for Clinical and Translational Science (CCTS) is strategicallypositioned in Central Appalachia to catalyze efforts to connect the populace of this medically underservedregion with significant health disparities to the national CTSA network. The UK CCTS is recognized locallyand regionally for affecting change and building robust partnerships across the CTSA network in CentralAppalachia and at UK creating an efficient platform for clinical and translational research and training all toimprove quality of care health and well-being for the rural populations of this region.1Project Narrative Page 288


application_id: 10184711
project_number: 1R21DA053324-01
administering_ic: NIDA
award_notice_date: 2021-08-03
opportunity_number: PAR-19-064
application_type: 1
activity_code: R21
ic: DA
serial_number: 053324
program_official: DUFFY, SARAH Q
project_start_date: 2021-09-01
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZDA1 SXM-M (09)]
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: 2021-09-01
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;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;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;prescription opioid;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: 10183340
project_number: 5R01NS097722-05
project_title: Neurovascular astrocyte dysfunction in VCID
administering_ic: NINDS
award_notice_date: 2021-06-10
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 097722
program_official: CORRIVEAU, RODERICK A
project_start_date: 2017-08-01
project_end_date: 2022-05-31
study_section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT]
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia behindAlzheimer's disease (AD). In addition VCID is a frequent co-morbidity with AD complicating the diagnosis andtreatment of AD for a significant proportion of AD patients. Despite its prevalence VCID remains relativelyunderstudied compared to AD and little is known about the molecular mechanisms underlying the cognitivedysfunction resulting from cerebrovascular disease. In part this is due to the multiple pathological processesdisrupting neurovascular networks that can result in VaD. We have previously shown that astrocytic end-feet are significantly impacted in the presence ofcerebral amyloid angiopathy (CAA) with decreased contact of astrocytic end-feet with the vasculature. Furtherthese morphological changes in the astrocyte were associated with decreased expression of aquaporin 4Kir4.1 and BK channels at the astrocytic end-feet. We have developed a model of VCID through the inductionof hyperhomocysteinemia (HHcy). We have shown that this model in wildtype mice is associated with multiplemicrohemorrhages reduced blood flow neuroinflammation and cognitive impairment. We now have intriguingpreliminary data that indicates these same pathological changes in the astrocytes that we observed with CAAalso occur in our HHcy model of VCID. In this research proposal we will use the HHcy model of VCID. We will test the hypothesis thatastrocyte end-foot disruption contributes to neuronal dysfunction and that the activation of MMP9 inthe HHcy model is critical to the disruption of the astrocytic end-feet. We have developed 3 specific aims.Aim 1. Test the hypothesis that astrocytic end-foot disruption leads to neuronal dysfunction and impairedpotassium homeostasis.Aim 2. Test the hypothesis that MMP9 is an essential mediator of astrocyte end-foot detachment from thecerebrovasculature with VCID.Aim 3. Test the hypothesis that astrocytic end-foot disruption is a common pathological characteristic ofcerebrovascular pathologies of VCID.

project_terms:
Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease patient;Astrocytes;Autopsy;Basal lamina;Biochemical;Blood flow;Brain;Cerebral Amyloid Angiopathy;Cerebrovascular Circulation;Cerebrovascular Disorders;Cerebrovascular system;Characteristics;Data;Dementia;Diagnosis;Dystroglycan;Electrophysiology (science);Environment;Enzymes;Extracellular Matrix;Family;Functional disorder;Gene Expression;Glial Fibrillary Acidic Protein;Histologic;Homeostasis;Human;Hyperhomocysteinemia;Impaired cognition;Impairment;Inhibition of Matrix Metalloproteinases Pathway;Interleukin-1 beta;Knockout Mice;MMP9 gene;Matrix Metalloproteinase Inhibitor;Matrix Metalloproteinases;Measures;Mediator of activation protein;Methods;Modeling;Molecular;Morphology;Neuroglia;Neuronal Dysfunction;Neurons;Pathologic;Pathologic Processes;Pharmacology;Pilot Projects;Potassium;Prevalence;Proteins;Research Proposals;Role;TNF gene;Testing;Time;Tissues;Wild Type Mouse;aquaporin 4;behavioral outcome;cerebrovascular pathology;comorbidity;foot;human tissue;large-conductance calcium-activated potassium channels;mouse model;neuroinflammation;neurovascular;protein expression;vascular cognitive impairment and dementia

public_health_relevance:
Project NarrativeVascular contributions to cognitive impairment and dementia (VCID) is the second leading cause of dementiabehind Alzheimer's disease (AD) and frequently occurs as a co-morbidity with AD. Astrocytes are glial cellsthat are critical for both controlling blood flow in the brain and maintaining an optimal environment for theneurons to function properly. We will determine the involvement of astrocytes in the progression of VCID.


application_id: 10181998
project_number: 1R01CA259580-01
project_title: Defining the Critical Function and Regulation of NNMT in Breast Cancer Progression and Metastasis
administering_ic: NCI
award_notice_date: 2021-03-05
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: CA
serial_number: 259580
program_official: WATSON, JOANNA M
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acetylation;Aging;Anchorage-Independent Growth;Animal Model;Brain;Breast Cancer Cell;Breast cancer metastasis;CRISPR library;Cancer Biology;Cancer Cell Growth;Cell Nucleus;Cell model;Clinical;Code;Complex;Cytoplasm;Data;Development;Diabetes Mellitus;Diagnosis;Disease;Drug resistance;Environment;Enzymes;Event;Exhibits;Extravasation;FOXC1 gene;Family;Gatekeeping;Genetic Transcription;Goals;Homeostasis;Human;In Vitro;Knock-out;Lung;Malignant Neoplasms;Mammary gland;Mediating;Metabolic;Metabolic Pathway;Metabolism;Methyltransferase;Mitochondria;NADH;NADP;Neoplasm Metastasis;Niacinamide;Nicotinamide N-Methyltransferase;Nicotinamide adenine dinucleotide;Oncogenic;Oxidation-Reduction;Oxidative Stress;Pathologist;Pathway interactions;Pharmaceutical Preparations;Pharmacotherapy;Positioning Attribute;Prognosis;Prognostic Marker;Proliferating;Property;Reactive Oxygen Species;Regimen;Regulation;Research;Respiration;Rodent;Role;Signal Pathway;Site;Specimen;Suspensions;Talents;Testing;Therapeutic;Transcriptional Regulation;Up-Regulation;Vertebral column;Xenograft Model;arginine methyltransferase;base;breast cancer progression;coactivator-associated arginine methyltransferase 1;druggable target;experimental study;extracellular;in vivo;inhibitor/antagonist;innovation;knock-down;malignant breast neoplasm;mammary gland development;metabolomics;mouse model;multidisciplinary;novel therapeutic intervention;oxidative damage;patient derived xenograft model;prevent;screening;stem-like cell;success;therapeutically effective;therapy resistant;transcription factor;tumor growth;tumor progression;uptake


application_id: 10180196
project_number: 1R01CA258421-01
project_title: Gold-derived therapeutic compounds for disease application
administering_ic: NCI
award_notice_date: 2021-08-04
opportunity_number: PA-20-185
application_type: 1
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;design;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;response;scaffold;small molecule;targeted agent;targeted treatment;therapeutic target;tool;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor xenograft;uptake


application_id: 10179595
project_number: 1R01NS121193-01
project_title: Functional Diversity of Reactive Astrocytes in Spinal Cord Repair
administering_ic: NINDS
award_notice_date: 2021-03-24
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: NS
serial_number: 121193
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 9380335
contact_pi: CHEN, MEIFAN
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:
Area;Astrocytes;Attenuated;Axon;CSF1 gene;Cells;Chest;Chronic;Cicatrix;Corticospinal Tracts;Data;Diffuse;Distal;Functional disorder;Genetic;Glial Fibrillary Acidic Protein;Goals;Hindlimb;Human;Injury;Knock-out;Knowledge;Lateral;Lesion;Leucine Zippers;Location;Macrophage Colony-Stimulating Factor;Maintenance;Mediating;Microglia;Microinjections;Modeling;Molecular;Motor;Mus;Outcome;Paralysed;Pathologic;Pathway interactions;Phenotype;Phosphotransferases;Primary Lesion;Recovery;Regulation;Research;Role;Sensory;Site;Spinal;Spinal Cord;Spinal cord injury;Tamoxifen;Testing;Therapeutic;Tissues;Translating;Traumatic CNS injury;United States;Work;astrogliosis;axon growth;axonal degeneration;axonal sprouting;base;cellular targeting;central nervous system injury;disability;genetic manipulation;in vivo;injury and repair;injury recovery;insight;macrophage;monocyte;novel;overexpression;promoter;relating to nervous system;repair strategy;repaired;response to injury;restoration;spinal cord repair;targeted treatment;tool;translational approach


application_id: 10179359
project_number: 5R01DK074816-12
project_title: RORalpha and Hepatic Zonal Regulation
administering_ic: NIDDK
award_notice_date: 2021-06-25
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 074816
program_official: BURGESS-BEUSSE, BONNIE L
project_start_date: 2007-09-01
project_end_date: 2023-06-30
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 1879406
contact_pi: SPEAR, BRETT
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The restricted expression of specific hepatic genes in pericentral or periportal regions ofthe adult liver a phenomenon known as zonal regulation is a fascinating aspect of liverbiology. Elegant studies in the past 10 years have uncovered the role of the b-cateninsignaling pathway in controlling zonal expression. Our recent studied using a novelmouse model system developed by us indicates that the retinoic acid-related orphanreceptor alpha (RORa) also plays a role in controlling zonal gene expression.Furthermore studies in other tissues have shown that RORa contributes to thedifferentiation and proliferation of stem cells but this property has not been evaluated inthe liver. We propose to use genetically modified mice and contemporary high-throughput genomic technologies to explore the role of RORa in the function and stemcell properties of pericentral hepatocytes. Since many hepatotoxins including ethanoland pharmaceuticals such as acetaminophen specifically damage pericentralhepatocytes a better understanding of the mechanisms controlling gene expression inand the self-renewing properties of this subpopulation of hepatocytes will help developstrategies to reduce hepatocyte injury in humans.

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

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


application_id: 10178025
project_number: 5R25ES027684-05
project_title: Summer Research in Environmental Health Sciences
administering_ic: NIEHS
award_notice_date: 2022-05-04
opportunity_number: PAR-15-184
application_type: 5
activity_code: R25
ic: ES
serial_number: 027684
program_official: HUMBLE, MICHAEL C
project_start_date: 2017-05-01
project_end_date: 2022-12-14
study_section: ZES1-LKB-J(R)1
contact_pi_person_id: 1883439
contact_pi: SWANSON, HOLLIE ISABEL
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractThe overall goal of this proposal is to develop and implement a 10-week summer program(Summer Undergraduate Research in Environmental Health Sciences (SURES) that willimmerse upper-level undergraduates in environmental health science research. The program isdesigned to introduce students to the highly interdisciplinary and collaborative nature ofenvironmental health science research that is focused on solving key global health problems.An additional focus is preparing underprivileged and under-represented students for successfulcareers in relevant fields. The SURES program will leverage the substantial and ongoingefforts at the University of Kentucky driven to enhance the undergraduate experience with therobust environmental health science research programs of involved faculty mentors. Studentswill be recruited from the Commonwealth of Kentucky with an emphasis on those from theAppalachian region. The SURES program will commence with a week-long session thatintroduces students to research laboratory safety and scientific ethics. The students will thenexperience hands-on research by performing experiments in the laboratories of their chosenmentors. Professional development and a sense of belonging to the environmental healthsciences community will be built via student participation in weekly breakfasts lunches net-working opportunities tours of research facilities and social activities including movie nightswhere films depicting environmental issues will be viewed and discussed. The SURES programwill culminate in a poster session attended by the faculty staff and students of the participatingdepartments. Dissemination of the approaches used in this program and their outcomes willbuild upon the expansion of the traditional environmental health sciences research training fromthe graduate and post-doctoral level to the undergraduates at a national level.

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

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


application_id: 10176379
project_number: 5R01AI127970-05
project_title: Mechanisms of successful vaccine adjuvants
administering_ic: NIAID
award_notice_date: 2021-05-14
opportunity_number: PAS-15-055
application_type: 5
activity_code: R01
ic: AI
serial_number: 127970
program_official: JOFFE, AARON MICHAEL
project_start_date: 2017-06-26
project_end_date: 2023-05-31
study_section: Special Emphasis Panel[ZRG1-IMM-U(90)S]
contact_pi_person_id: 1941645
contact_pi: MITCHELL, THOMAS C.
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryAdjuvant options for subunit vaccine design are extremely limited. Apart from alum just two adjuvants areapproved for use in the US: squalene and the combination adjuvant system AS04 which combinestraditional alum with a partial agonist of TLR4 monophosphoryl lipid A (MPL). MPL adjuvant is notablebecause it is the first and only purified TLR agonist in a licensed vaccine in the US was tested extensivelyfor safety and efficacy in large clinical trials and shows promise as an adjuvant in ambitious vaccineprojects such as the RTSS/AS01 vaccine to prevent malaria. Alum+MPLA is currently the best example wehave of a clinically successful adjuvant but the factors that make it successful are poorly understood.Moreover MPL is a heterogeneous mixture of lipid A structures in which a hexa-acylated structure isthought to be the active component but the functions of other components have never been tested inhuman immune cells. Preliminary studies support the hypothesis that MPL adjuvant contains animmunomodulatory inhibitor of human TLR4 that constrains endotoxic responses with less impact onadaptive priming. This project will identify the inhibitor determine if and how it has differential effects onMyD88- vs TRIF-signaling and evaluate synthetic analogues of MPL with amplified properties as adjuvants.

project_terms:
Adjuvant;Agonist;CD8-Positive T-Lymphocytes;Cell Culture Techniques;Cells;Cervarix;Chemicals;Clinical;Clinical Trials;Communicable Diseases;Dendritic Cells;Development;Dose;Epitopes;Goals;HLA A*0201 antigen;Human;Immune;Immune response;Immune system;Immunization;Individual;Inflammatory;Knowledge;Learning;Lipid A;Malaria;Modeling;Mus;Oryctolagus cuniculus;Outcome;Pathway interactions;Pattern;Peripheral Blood Mononuclear Cell;Persons;Preparation;Preventative vaccination;Property;Public Health;Research;Research Personnel;Safety;Signal Pathway;Signal Transduction;Squalene;Structure;Subunit Vaccines;System;T cell response;TLR4 gene;Testing;Therapeutic;Tissues;Tonsil;Toxic effect;Transgenic Organisms;Vaccinated;Vaccine Adjuvant;Vaccine Design;Vaccines;Work;aluminum sulfate;analog;clinical development;cytokine;human pathogen;immunoregulation;improved;inhibitor/antagonist;mimetics;neutrophil;next generation;novel;novel vaccines;peripheral blood;preclinical study;predictive modeling;prevent;research study;response;success;vaccine access;vaccine safety

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


application_id: 10175754
project_number: 3R01AR071398-04S1
project_title: Diversity Supplement: Mechanistic Assessment of Blood Flow Restricted Training for an ACL Injury
administering_ic: NIAMS
award_notice_date: 2020-09-25
opportunity_number: PA-20-166
application_type: 3
activity_code: R01
ic: AR
serial_number: 071398
suffix: S1
program_official: WASHABAUGH, CHARLES H
project_start_date: 2017-07-22
project_end_date: 2022-06-30
study_section: Musculoskeletal Rehabilitation Sciences Study Section[MRS]
contact_pi_person_id: 10137938
contact_pi: NOEHREN, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Abstract:Anterior cruciate ligament reconstruction surgery results in protracted quadriceps weakness that is associatedwith altered biomechanics and heightened risk of subsequent injuries. Little progress has been made inimproving quadriceps strength in the past 15-20 years. Alterations in the morphological and cellularcomposition of the vastus lateralis muscle promote muscle weakness following an anterior cruciate ligamentreconstruction. These features are not responsive to traditional physical therapy techniques. A promisingemerging treatment blood flow restriction training (BFRT) has been shown to address these same alterationsin healthy subjects; however it has never been tested in those with an injury. Pilot data in the current proposalshows that BFRT can lead to a significant increase in muscle strength following an anterior cruciate ligamentinjury. This project seeks to mechanistically determine the ability of BFRT to address underlying musclecellular deficits following anterior cruciate ligament reconstruction compared to usual care. Goals in the currentproposal are as follows: aim 1 will determine if BFRT is able to significantly improve knee mechanics andquadriceps strength following an anterior cruciate ligament reconstruction compared to usual care. Aim 2 willuse advanced magnetic resonance imaging techniques to assess improvements in quadriceps morphologyafter training with BFRT. Lastly aim 3 will identify BFRT-mediated improvements in cellular deficits in thequadriceps as the result of BFRT training versus usual care. The expected outcomes will show for the first timethat BFRT is an effective mechanistic treatment for normalizing quadriceps strength within individuals followingan anterior cruciate ligament reconstruction.

project_terms:
Address;Affect;Area;Atrophic;Automobile Driving;Biological;Biomechanics;Blood flow;Cell Nucleus;Cell Respiration;Cell model;Clinical;Clinical Trials;Data;Disadvantaged;Dose;Elderly;Exposure to;Faculty;Fiber;Fibrosis;Funding;Genetic Transcription;Goals;Human;Imaging Techniques;Impairment;In Vitro;Individual;Injury;Intake;Intestines;Kidney;Knock-out;Lead;Learning;Liver;MADH3 gene;Magnetic Resonance Imaging;Measures;Mediating;Mitochondria;Molecular;Morphology;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle Weakness;Muscular Atrophy;National Institute of Arthritis and Musculoskeletal and Skin Diseases;Nutritionist;Operative Surgical Procedures;Outcome;Parents;Participant;Pathway interactions;Patients;Persons;Physical therapy;Proteins;Publishing;Reconstructive Surgical Procedures;Research;Research Personnel;Research Project Grants;Respiration;Risk;Role;Signal Transduction;Skeletal Muscle;Succinate Dehydrogenase;Techniques;Testing;Time;Tissues;Training;Transforming Growth Factor beta;Vitamin D;Vitamin D Deficiency;Vitamin D supplementation;Vitamin D3 Receptor;Work;anterior cruciate ligament injury;anterior cruciate ligament reconstruction;anterior cruciate ligament rupture;experience;improved;innovation;knee mechanics;mRNA Expression;member;muscle strength;new therapeutic target;parent grant;quadriceps muscle;receptor binding;receptor expression;response;skills;treatment as usual;vastus lateralis;young adult

public_health_relevance:
The attached supplement application is to support junior faculty member and clinical nutritionist Jean Fry PHDRDN to gain clinical trial management and molecular skills. The proposed research projects seek to elucidateunderlying mechanisms driving vitamin Ds integral role in molecular pathways in affecting skeletal musclefibrosis and oxidative metabolism. Dr Fry who meets criteria as a person from a disadvantaged backgroundproposes to learn new skills and complete the proposed work with the guidance of two experiencedindependent investigators who are both currently funded by NIAMS.


application_id: 10175637
project_number: 3U18FD006408-03S1
project_title: Kentucky's FSMA Human Foods Preventive Controls Implementation Expansion Submission
administering_ic: FDA
award_notice_date: 2020-08-31
opportunity_number: PAR-20-091
application_type: 3
activity_code: U18
ic: FD
serial_number: 006408
suffix: S1
program_official: KEPPLEY, LAURIE
project_start_date: 2018-09-01
project_end_date: 2021-06-30
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
project_abstract:
Project AbstractThe Commonwealth of Kentucky is applying for federal funds to conduct activities that willenable the Food Safety Program of the Kentucky Department for Public Healths Division ofPublic Health Protection and Safety to adopt and implement the risk-based Preventive Controlsfor Human Food regulation (PCHF Rule) as described in the Code of Federal Regulations (21CFR 117). Currently the state has adopted by reference 21 CFR 117 by incorporation into TheKentucky Food Processing Packaging Storage and Distribution Operations Regulation (902 KAR45:160) which establishes procedures and requirements for food processing packagingstorage and distribution operations in Kentucky. This state regulation mirrors the specific FDArequirements for food firms food plant requirements regarding plan review construction andmaintenance water supply plumbing sewage disposal toilet facilities hand washing facilitiesand food transportation. In 2017 902 KAR 45:160 also incorporated the FDAs Food SafetyModernization Act (FSMA) Final Rule on Preventive Controls for Human Food. However full-scope implementation of the PCHF Rule by the Food Safety Program has been limited by theavailability of qualified auditors in the state as well as by insufficient technical resources fordata processing and information sharing.The Food Safety Branch intends to use these funds to hire and train two state auditors (withintwo years) to conduct Phase III inspections of food manufacturing facilities to meet FDAstandards. The auditors will be auditing the state inspectors. In addition a computerapplication database called KY First will be enhanced to communicate with the FDAs system(NSFDX) and result in reducing the amount of time staff use for data entry.

public_health_relevance:
Project NarrativeThe Food Safety Branch intends to use awarded funds to hire and train two state auditors(within two years) to conduct Phase III inspections of food manufacturing facilities to meet FDAstandards. The auditors will be auditing the state inspectors. In addition a computerapplication database called KY First will be enhanced to communicate with the FDAs system(NSFDX) and result in reducing the amount of time staff use for data entry.


application_id: 10175004
project_number: 5R01HL141356-04
project_title: Mitochondrially Targeted Therapies for Sepsis Induced Diaphragm Dysfunction
administering_ic: NHLBI
award_notice_date: 2021-05-21
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 141356
program_official: ZHOU, GUOFEI
project_start_date: 2018-07-01
project_end_date: 2023-05-31
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 6210708
contact_pi: CALLAHAN, LEIGH A
other_pis: SCHRODER STUMPF, ELIZABETH A
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Severe ICU acquired diaphragm dysfunction is present in the majority of mechanically ventilated MICUpatients. Importantly recent work indicates that patients with weak diaphragms have a much longerrequirement for mechanical ventilation and a markedly higher mortality. As a result therapies that increasediaphragm function have the potential to improve MICU patient outcomes. These recent studies also suggestthat a major risk factor for ICU acquired diaphragm weakness is infection. Infections elicit a marked increasein diaphragm mitochondrial free radical production and these free radicals contribute to weakness andfatigue. The present proposal therefore will test the hypothesis that pharmacological therapiesdesigned to either inhibit mitochondrial free radical generation or induce mitochondrial repair willprevent and/or reverse sepsis mediated diaphragm dysfunction. This theory will be tested in fourgroups of studies:Aim 1 studies will test the hypothesis that sepsis induced diaphragm dysfunction can be reduced by usingagents which inhibit mitochondrial free radicals. Experiments will utilize the cecal ligation puncture sepsismodel (CLP) and compare diaphragm function in sham operated CLP CLP plus drug and sham plus druggroups. Drugs to be tested include mitoTEMPOL SKQ1 and necrostatin.Aim 2 studies will test the hypothesis that administration of activators of mitochondrial biogenesis canimprove infection induced diaphragm dysfunction. Sepsis will again be produced with CLP and we willexamine the ability of three treatments (i.e. AICAR+PQQ PQQ and AICAR+GW1506) to prevent CLPinduced diaphragm dysfunction.Aim 3 studies will evaluate the mechanisms by which Aim 1 and Aim 2 drugs produce their effects onmuscle cells. These experiments will also test the hypothesis that these agents induce release of myokineswhich have autocrine effects to attenuate cytokine induced muscle cell damage.Aim 4 studies will test the hypothesis that myokine administration can be used as a pharmacologicaltreatment to attenuate sepsis induced diaphragm dysfunction in animals. Myokines to be tested include irisinand other proteins found in Aim 3 studies to block cytokine induced muscle cell damage in vitro.

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

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


application_id: 10174989
project_number: 5R01HD097675-03
project_title: Neurotensin: A Novel Mediator of Ovulation
administering_ic: NICHD
award_notice_date: 2021-06-30
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: HD
serial_number: 097675
program_official: TAYMANS, SUSAN
project_start_date: 2019-09-06
project_end_date: 2024-05-31
study_section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: DUFFY, DIANE M
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: 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:
A womans fertility is dependent on the cascade of events leading up to ovulation. Defects in this ovulatoryprocess result in 25% of all female infertility cases supporting the paramount role of ovulation in reproductivesuccess and providing a strong premise to explore mediators of the ovulatory process. We propose thatneurotensin is one of these pivotal regulators of the ovulatory process. Ovulation is set in motion by the preovulatory LH surge which increases ovarian intrafollicular mediatorsthat act to bring about oocyte release. Our novel and exciting preliminary data indicate that neurotensin (NTS)a small neuropeptide is a key intrafollicular mediator of ovulation. This is based upon our findings that NTS isone of the most differentially-expressed genes in the granulosa cells of the human ovulatory follicle up to15000 fold after the ovulatory gonadotropin surge. Likewise LH also rapidly and significantly increases NTSmRNA in granulosa cells from rodent and monkey ovulatory follicles. Importantly injection of a neurotensinantibody into monkey preovulatory follicles blocked oocyte release resulting in luteinized unruptured folliclesconsistent with failure of ovulation. Similarly mice lacking NTS expression form luteinized unruptured folliclesfollowing LH/hCG administration and a NTS receptor antagonist inhibits oocyte release in a novel in vitromodel of mouse ovulation. Yet other than our preliminary data nothing is known regarding the temporalexpression of NTS receptors or the function of NTS in ovulation and female fertility. These questions will beaddressed in this proposal through a collaborative approach utilizing the exceptional backgrounds technicalexpertise and models of the Project Leaders. We will make use of a high-impact translational model wherethe granulosa and theca from human periovulatory follicles will be collected prior to and at three designatedtimes after hCG (early late and postovulatory) to complement in vivo and in vitro studies performed with miceand monkeys. The regulation of NTS and NTS receptor expression in the ovulatory follicle will be illuminatedand compared across women monkeys and mice in Aim 1. The ovulatory functions stimulated by NTS ingranulosa theca cumulus and endothelial cells of the follicle will be elucidated in Aim 2. The actions of NTSon ovulation as well as other key reproductive processes will be revealed in mice and monkeys using micelacking NTS expression NTS receptor antagonists and NTS-neutralizing antibodies in Aim 3. A major strengthof this proposal is the collaborative interactions between Dr. Curry and Dr. Duffy to address the function of NTSand its receptors in periovulatory events across multiple species including exceptional human ovarian tissuesand in vivo studies of non-human primates an animal model with high relevance to human reproductivefunction. Thus there is an exceptional degree of significance in understanding the basic tenets of oocyterelease which provides a fundamental platform to either improve outcomes for infertile women or converselyprovide targets to prevent oocyte release for female contraception.

project_terms:
Address;Agonist;Animal Model;Antibodies;Bioinformatics;Cell physiology;Complement;Data;Defect;Development;EGF gene;Endothelial Cells;Evaluation;Event;Failure;Fc Receptor;Female Contraceptive Agents;Female infertility;Fertility;Fertilization;Future;Gene Expression Profiling;Genes;Gonadotropins;Histologic;Human;Human Chorionic Gonadotropin;In Vitro;Infertility;Injections;LH Receptors;Luteinization;Mediating;Mediator of activation protein;Messenger RNA;Modeling;Monkeys;Motion;Mus;Neuraxis;Neuropeptides;Neurotensin;Neurotensin Receptors;New Agents;Oocytes;Ovarian;Ovarian Follicle;Ovarian Tissue;Ovary;Ovulation;Pathway interactions;Play;Pregnancy;Pregnancy Outcome;Process;Progesterone;Prostaglandins;Receptor Signaling;Regulation;Reproductive Process;Reproductive system;Rodent;Role;Rupture;Signal Transduction;System;Technical Expertise;Testing;Time;Vascular Endothelial Cell;Wild Type Mouse;Woman;angiogenesis;base;cell type;collaborative approach;differential expression;experimental study;female fertility;granulosa cell;implantation;improved outcome;in vitro Model;in vivo;mouse model;neutralizing antibody;nonhuman primate;novel;oocyte quality;paracrine;prevent;receptor;receptor expression;reproductive function;reproductive success;response;theca cell;translational model

public_health_relevance:
The present study explores the role of neurotensin in the ovulatory process. Neurotensinincreases prior to ovulation in mice monkeys and women and a loss of neurotensin results inovarian follicles that do not ovulate. The proposed studies will elucidate the role that thisexquisite system plays in the coordinated processes of follicular rupture and oocyte releasewhich will aid in the understanding of the regulation of human fertility.


application_id: 10174960
project_number: 5R01GM129532-04
project_title: Visceral fat gamma delta T cells in sepsis pathogenesis
administering_ic: NIGMS
award_notice_date: 2021-05-24
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: GM
serial_number: 129532
program_official: ZHAO, XIAOLI
project_start_date: 2018-09-01
project_end_date: 2023-05-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 10399494
contact_pi: STARR, MARLENE ELENA
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTSepsis pathophysiology involves activation of both pro- and anti-inflammatory responses along with alterationsin thrombotic and metabolic pathways. We previously revealed that genes for several inflammatory andthrombotic mediators are highly expressed in visceral adipose tissues during sepsis; however what causes thefat tissue to be so reactive and whether adipose-derived factors are mediators of sepsis is currently not known.Our preliminary data using both a preclinical mouse model of sepsis as well as patient-derived samplessuggest that visceral fat is the major source of plasminogen activator inhibitor type 1 (PAI-1) a pro-thromboticfactor which is implicated in the pathogenesis of sepsis and multi-organ failure. In addition we recently foundthat gamma delta ()-T cells a subset of innate-like T cells are surprisingly abundant in visceral fat tissue.These findings have led to our hypothesis that these cells are responsible for PAI-1 overproduction by adiposetissues during sepsis and contribute to the development of organ injury. The major goals of this project are (1)to demonstrate that -T cells are key regulators of PAI-1 production in visceral fat tissue and (2) to establishthat visceral fat-derived PAI-1 promotes organ injury during sepsis. To achieve these goals a series of ex vivoadipose explant culture experiments utilizing tissues from several transgenic mouse strains will be performedand visceral fat tissues will be surgically removed or transplanted from wild-type to PAI-1 knockout mice.Completion of this project will establish the concept that overproduction of PAI-1 from visceral fat contributes tothe pathophysiology of sepsis-associated organ injury and reveal key mechanisms for PAI-1 overproduction.This information will aid in the development of future therapeutic strategies to reduce sepsis severity.

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

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


application_id: 10174602
project_number: 5R01AG019223-15
project_title: Ceramide and acute phase proteins elevation during aging
administering_ic: NIA
award_notice_date: 2021-05-26
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 019223
program_official: OROSZ, ANDRAS
project_start_date: 2002-08-01
project_end_date: 2023-05-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 6730250
contact_pi: NIKOLOVA-KARAKASHIAN, MARIANA N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract(Some of the leading causes of death among the elderly are a number of chronic conditions associated withpersistent low-grade inflammation in which IL-1 has a central role. One of the paths by which low-gradeinflammation contributes to aging-associated diseases is by interfering with the ability of the host to maintainhomeostasis. The experiments from the previous funding period provided evidence for a novel pathway bywhich inflammation may deteriorate a major regulatory mechanism. Specifically we found that IL-1 increasesthe levels of glucocorticoid receptor an effect especially potent in aged animals leading to an augmentedresponse to glucocorticoids. This proposal investigates the mechanisms and impact of IL-1 control ofglucocorticoid -dependent functions in the elderly. The proposed studies will do that in the context of fatty livera condition of paramount health importance for public health which is frequent in the elderly and in somecases may progress to non-alcoholic fatty liver disease. In aim 1 a series of in vitro studies will identify themechanisms for IL-1-induced increases in GR levels and delineate some of the functional consequences inhepatocytes. A candidate approach paralleled by an unbiased genome wide analyses using ChipSeq andmRNA arrays will determine the degree of IL-1 impact on GR-dependent transcriptional regulation of geneexpression in the liver. Specific aim 2 is dedicated to investigating the impact IL-1 has on GR responses invivo using a diet-induced mouse model of steatosis and metabolic syndrome. The magnitude of IL-1 responsein hepatocytes will be modulated in vivo or in vitro by targeting a key component of its signaling cascadenSMase2. The consequences on lipogenesis gluconeogenesis and insulin sensitivity will be main readouts.Glucocorticoid hypersensitivity underlies many aging-associated disease. The chronic used of glucocorticoidsfor the treatment of inflammation is associated with significant side effects particularly in the elderly. Thereforeby uncovering the mechanisms that regulate glucocorticoid response in the liver during aging the proposedstudies have the potential to discover both basic mechanisms of aging as well as novel approaches tomanage unwanted side effects of chronic use of glucocorticoids.

project_terms:
Acute-Phase Proteins;Affinity;Aging;Agonist;Alzheimer's Disease;Animals;Cause of Death;Cell Aging;Cell physiology;Cells;Ceramides;ChIP-seq;Chronic;Clinical;Complex;Diet;Disease;Dose;Drug Prescriptions;Elderly;Enzymes;FOXO1A gene;Fatty Liver;Funding;Gene Delivery;Gene Expression Regulation;Genes;Genetic;Glucocorticoid Receptor;Glucocorticoids;Gluconeogenesis;Goals;Grant;Health;Hepatic;Hepatocyte;Histologic;Homeostasis;Hypersensitivity;IGFBP1 gene;IRAK1 gene;In Vitro;Incidence;Infection;Inflammation;Inflammation Mediators;Inflammatory;Insulin Signaling Pathway;Interleukin-1 beta;Lead;Link;Liver;MAPK8 gene;Medical;Messenger RNA;Metabolic syndrome;Minor;Morbidity - disease rate;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Organ;Organism;Oxidation-Reduction;Pain;Pathway interactions;Pattern;Pharmacology;Phosphorylation;Play;Population;Process;Progress Reports;Protein Phosphatase 2A Regulatory Subunit PR53;Public Health;Rattus;Receptor Signaling;Regulation;Research;Role;Series;Signal Transduction;Sphingomyelinase;Stress;Testing;Transcriptional Regulation;Trauma;Ubiquitination;Work;adenoviral-mediated;aged;experimental study;genome-wide;genome-wide analysis;in vivo;in vivo evaluation;insulin sensitivity;lipid biosynthesis;mouse model;non-alcoholic fatty liver disease;novel;novel strategies;response;senescence;side effect;stressor;transcription factor;transcriptome sequencing

public_health_relevance:
Project narrativeSome of the leading causes of death among the elderly are a number of chronic conditions associated withpersistent low-grade inflammation. Uncovering new aging-specific factors that influence the onset ofinflammation is of uttermost significance for the over health and medical treatment of the elderly. The proposedstudies are concentrated on steatosis the hepatic manifestation of metabolic syndrome which is a commondisease of the aged.


application_id: 10174084
project_number: 1U19FD007082-01
project_title: KY Environmental Food Microbiology and WGS Incorporation and Expansion.
administering_ic: FDA
award_notice_date: 2020-09-08
opportunity_number: PAR-20-105
application_type: 1
activity_code: U19
ic: FD
serial_number: 007082
project_start_date: 2020-09-01
project_end_date: 2025-06-30
study_section: Special Emphasis Panel[ZFD1 ORA-K (01)]
subproject_number: 5688
contact_pi_person_id: 16381471
contact_pi: JOHNSON, BETH D
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PAR-20-15 4/16/20 Project 045-Summary: KY Environmental Food Microbiology and WGS Incorporation and Expansion The Kentucky Division of Lab Services has had the capability for Whole Genome Sequencing (WGS) since November of 2017 with the purchase of our own Illumina MiSeq analyzer. Since that time we have been able to implement WGS for environmental microbiological food samples to complement testing performed on clinical samples in outbreak situations. This has resulted in faster action taken with more accurate information for potential linkage of food pathogens implicated in outbreaks. We intend to add WGS to our ISO17025 scope of accreditation this fall. We have been able to purchase advanced equipment such as the Qubit and the QiaCube. We have also been trained to use and allowed access to the Hamilton Library Preparation Robot which we (Env. Micro) have already validated for use with the microbiology food lab isolates. Division of Lab Services is the only State Public Health lab in KY and we are heavily relied upon to provide the most up to date and reliable testing options in all areas of public health but especially in environmental testing. We continually reach out to other public health labs offering assistance on backlogged samples and have established relationships with some FDA/FERN labs as well as USDA labs for sequencing of not only food isolates but agricultural water and animal sample isolates. We have sequenced approximately 142 Listeria isolates for the FDA and 85 Salmonella isolates for the USDA. DLS has been contributing data to Genome Trakr since 2018 and is active in the Genome Trakr network meetings calls and trainings. Our lead analyst has gone through the Galaxy Trakr training. Currently metadata is being submitted to Genome Trakr via email and sequencing projects are shared through BaseSpace. Strain name and NCBI accessions (BioSample and SRR) are used to confirm that the isolate sequences have been uploaded to the NCBI Pathogen Detection Browser. The goal is that DLS will develop the capability to submit metadata and sequences in real-time to NCBI directly using the NCBI submission portal in coordination with FDA/CFSAN. We rely greatly on Federal funding to sustain the majority of Regulatory food/commodity testing as well as improving our lab space adding new test methods and instrumentation and in some cases qualified analyst retention. 1

public_health_relevance:
Project 045-KY WGS Expansion Narrative: PAR-20-15 4/16/20 KY WGS Expansion  DLS has collaborated with the Kentucky Food Safety Branch since 2012 in achieving conformance with Standard 10 Laboratory Support for MFRPS as well as finally achieving full Laboratory ISO17025:2017 accreditation in November 2018. We have performed testing on roughly 240 regulatory samples annually on their behalf. As testing methods become more advanced and the increase in the diversity of food supply sources the amount of regulatory oversight must also increase. Funding this proposal will ensure that the food lab can independently continue with WGS on local regulatory samples outbreak investigations as well as samples from other agencies when needed. All sample results will be reported through the enhanced web submission ORAPP and shared with the FDA through Genome Trakr.


application_id: 10173581
project_number: 5R01AG055449-05
project_title: Contributions of Alzheimer's Pathology and Cerebrovascular Factors to Cognitive Aging
administering_ic: NIA
award_notice_date: 2021-04-27
opportunity_number: PAR-15-357
application_type: 5
activity_code: R01
ic: AG
serial_number: 055449
program_official: WAGSTER, MOLLY V
project_start_date: 2017-09-15
project_end_date: 2023-04-30
study_section: Special Emphasis Panel[ZRG1-BDCN-A(55)R]
contact_pi_person_id: 7993908
contact_pi: GOLD, BRIAN TIMOTHY
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL 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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Alzheimer's disease is associated with the accumulation of pathological markers [amyloid-beta(A) and tau] brain atrophy and a progressive loss of memory functions. However a significantproportion of individuals with AD pathology do not develop cognitive impairment indicatingcontributions of other factors to clinical AD. Increasing evidence suggests that factors stronglylinked with brain aging such as cerebrovascular alterations and declines in executive functioncontribute to clinical AD. This link is not straightforward though as the effects of AD pathologyand vascular alterations can be moderated by cognitive reserve and brain resilience. Our recentresults suggest that levels of A and tau in cerebrospinal fluid (CSF) and cerebrovasculardeclines associated with white matter hyperintensities (WMHs) are differentially related topatterns of executive function in cognitively normal older adults. In addition our results suggestthat some of the patterns appear modifiable based on positive lifestyle variables. This proposalseeks to define the interplay between AD pathology cerebrovascular-related alterations andcognitive reserve that distinguish normal brain aging from AD-like cognitive declines. Wepropose to study of 120 cognitively normal older adults using measures of CSF A p-tau and t-tau neuroimaging measures including event-related fMRI multiple structural imaging measures.Structural neuroimaging measures will include volumetric measures FLAIR imaging forquantification of WMH volumes and diffusion tensor imaging for quantification of regionallydistributed white matter abnormalities. A subset of participants will complete the same CSF andimaging measures approximately 3 years later. We aim to (1) dissociate effects of AD pathologyand brain aging on functional compensation (2) identify the separate and synergistic effects ofAD pathology and cerebrovascular markers on cognitive declines over time and (3) identifyreserve factors that moderate relationships between vascular and AD pathology markers oncognition. We will test hypotheses that AD pathology and cerebrovascular factors synergisticallyinteract to predict AD-like cognitive declines. We will also test the hypothesis that reservefactors will offset the effects of some of these pathological and vascular changes on cognitivefunctions via mechanisms of brain maintenance or plastic functional brain reorganization oflarge-scale brain functional networks in some older adults.

project_terms:
Affect;Aging;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimers disease biomarker;Amyloid beta-42;Amyloid beta-Protein;Biological Markers;Blood Vessels;Brain;Brain region;Brain scan;Cerebrospinal Fluid;Clinical;Cognition;Cognitive;Cognitive aging;Development;Diffusion Magnetic Resonance Imaging;Elderly;Event;Financial compensation;Functional Magnetic Resonance Imaging;Goals;Health;Hippocampus (Brain);Image;Impaired cognition;Individual;Intercept;Intervention;Life Style;Linear Regressions;Link;Magnetic Resonance Imaging;Maintenance;Measures;Memory Loss;Modeling;Neurocognitive;Neuropsychological Tests;Outcome Study;Participant;Pathologic;Pathology;Pathway interactions;Pattern;Performance;Regression Analysis;Running;Short-Term Memory;Structure;System;Testing;Time;Visit;White Matter Hyperintensity;aging brain;base;behavior measurement;brain health;cerebral atrophy;cerebrovascular;clinical development;cognitive function;cognitive performance;cognitive reserve;executive function;frontal lobe;gray matter;hippocampal atrophy;indexing;lifestyle factors;neuroimaging;neuromechanism;prevent;rate of change;resilience;response;tau Proteins;tau-1;white matter

public_health_relevance:
Overall this project will begin to disentangle the relative contributions of Alzheimer's pathologyand brain aging to the development of clinical Alzheimer's disease and identify factors that maypromote optimal cognitive aging.


application_id: 10172976
project_number: 5G08LM013185-03
project_title: Integrating Information Resources to Promote Environmental Health Literacy in Appalachian Kentucky
administering_ic: NLM
award_notice_date: 2021-05-10
opportunity_number: RFA-LM-19-001
application_type: 5
activity_code: G08
ic: LM
serial_number: 013185
program_official: DENNIS, ALLISON FRANCES
project_start_date: 2019-09-09
project_end_date: 2023-05-31
study_section: ZLM1-ZH-G(01)
contact_pi_person_id: 11057059
contact_pi: HOOVER, ANNA GOODMAN
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTHealth disparities in Appalachian Kentucky have been well-documented with many chronic healthconditions disproportionately experienced across the region linked to environmental contributors.Deteriorating infrastructure inappropriate waste disposal and risks related to mining agricultureand other occupational activities underscore the need for this at-risk population to receive cleartimely and accessible information about potential environmental health threats to supportimportant decisions about preventive and protective actions. Unfortunately creating easilyunderstandable resources and tools can prove especially challenging in a region whereeducational attainment falls well below national averages with nearly one-quarter of adults overage 25 lacking high school diplomas and only about one-fifth holding an associate's degree orhigher. Therefore improving environmental health literacy (EHL) in the region is critical. EHL usesinformation and methods from health social and environmental sciences to promoteunderstanding of the relationship between environmental exposures and human health. Suchunderstanding can spur individual and/or community actions to minimize unnecessary exposuresand mitigate illness related to unavoidable exposures. To this end it is critical that existinginformation resources be evaluated integrated improved and made more accessible to helpimprove EHL and inform environmental health decisions. To address these needs ourmultidisciplinary team will deploy stakeholder-engaged research strategies to achieve thefollowing Specific Aims: 1) evaluate existing environmental health-related risk maps currentlyavailable from academic government and non-profit organizations to determine resourceaccessibility navigability understandability and perceived utility for Appalachian Kentuckians; 2)conduct needs assessments to identify additional information and appropriate framing required toimprove understandability and utility of environmental health-related risk maps for AppalachianKentuckians; 3) use information gathered in Aims 1 and 2 to enhance maps through the inclusionof critical health-related information in accessible formats as well as through potential changesto the visualizations themselves to improve understandability; and 4) leverage stakeholder-partnerships developed through the study to disseminate revised maps and additionalenvironmental health resources through community organizations thereby promoting EHL acrossthe region.

project_terms:
Address;Adult;Affect;Age;Agriculture;Appalachian Region;Associate Degree;Chronic;Communities;Community Actions;Decision Making;Development;Diabetes Mellitus;Ecology;Educational Status;Environmental Exposure;Environmental Health;Face;Goals;Government;Health;Health Resources;Health Sciences;Human;Hypertension;Incidence;Individual;Industry;Information Resources;Infrastructure;Interdisciplinary Study;Kentucky;Link;Maps;Methods;Mining;Morbidity - disease rate;Needs Assessment;Nonprofit Organizations;Obesity;Occupational;Occupational Exposure;Personal Satisfaction;Population;Populations at Risk;Preventive;Refuse Disposal;Research;Resources;Risk;Social Sciences;Time;Visualization;community organizations;evidence base;experience;falls;health disparity;health literacy;high school;improved;model development;mortality;multidisciplinary;population health;prevent;socioeconomics;tool

public_health_relevance:
PROJECT NARRATIVEHealth disparities in Appalachian Kentucky have been well-documented and are driven by manyfactors including challenging socioeconomic conditions and low levels of educational attainmentexacerbated by environmental concerns about deteriorating infrastructure inappropriate wastedisposal and risks related to mining agriculture and other occupational activities. This studystrives to mitigate these disparities by building regional environmental health literacy through thedevelopment integration refinement and provision of timely understandable and accessibleinformation about potential environmental health threats and evidence-based preventive andprotective actions. A multidisciplinary research team will deploy stakeholder-engaged researchstrategies to achieve the following Specific Aims: 1) evaluate existing environmental health-related risk maps currently available from academic government and non-profit organizations todetermine resource accessibility navigability understandability and perceived utility forAppalachian Kentuckians; 2) conduct needs assessments to identify additional information andappropriate framing required to improve understandability and utility of environmental health-related risk maps for Appalachian Kentuckians; 3) use information gathered in Aims 1 and 2 toenhance maps through the inclusion of critical health-related information in accessible formatsas well as through potential changes to the visualizations themselves to improveunderstandability; and 4) leverage stakeholder-partnerships developed through the study todisseminate revised maps and other environmental health resources through communityorganizations thereby promoting EHL across the region.


application_id: 10172928
project_number: 5R01GM127495-04
project_title: Exercise-enhanced resolution of inflammation
administering_ic: NIGMS
award_notice_date: 2021-05-11
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: GM
serial_number: 127495
program_official: NELSON, SHAKIRA M
project_start_date: 2018-09-01
project_end_date: 2023-05-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 11169883
contact_pi: HELLMANN, JASON L
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract:Frequent physical activity improves cardiovascular health and prolongs life span whereas physical inactivity isassociated with premature mortality and global burden of chronic disease. The salutary effects of exercise have beenextensively documented in the literature. Exercise promotes skeletal muscle growth cardiac hypertrophy and tissueangiogenesis and it improves cardiovascular disease (CVD) risk factor profile. Nevertheless the beneficial effects ofexercise extend beyond reduction in CVD risk factors (blood pressure lipids) involving mechanisms and processes thatremain largely unknown. This lack of mechanistic understanding underlying the salubrious effects of exercise limits itsoptimization in healthy individuals and hinders extension of its benefits to obese and diabetic individuals who thoughare most likely to gain from exercise cannot exercise or remain impervious to its benefits. Some investigators havesuggested that CVD risk factor-independent effects of exercise may relate to a decrease in inflammation. Inflammationis a carefully orchestrated systemic response targeted to degrade offending components clear tissue debris promotehealing and restore homeostasis. While escalation of inflammation leading to inflammatory cell invasion and cytokineproduction has been extensively studied less is known about how inflammation is resolved. Recent work has shownthat resolution of inflammation is mediated by specialized pro-resolving lipid mediators (SPMs) that limit neutrophilextravasation quell inflammatory signaling and promote macrophage phagocytosis. SPMs are necessary and sufficientto resolve inflammation by binding to cognate G-protein coupled receptors (GPCRs). We propose that the beneficialeffects of exercise relate to its ability to promote resolution of inflammation by stimulating the synthesis of pro-resolvingSPMs. Our preliminary data show that exercise-adapted mice display enhanced SPM synthesis accelerated neutrophilclearance and increased macrophage phagocytosis suggesting that exercise exerts beneficial effects on resolution ofinflammation. We also find that catecholamines which are transiently elevated by exercise activate SPM biosynthesisin macrophages and increase 5-lipoxygenase (5-LO) and 12/15-lipoxygenase (15-LO) enzymes that synthesize SPMs.These observations link processes activated by exercise to key components of inflammation-resolution and have led usto formulate the hypothesis that exercise-mediated production of catecholamines increases pro-resolving lipid mediatorsynthesis and enhances resolution of inflammation. The specific aims are: (1) Determine the effect of exercise onresolution; (2) Delineate the contribution of catecholamines in mediating the effect of exercise on resolution ofinflammation; (3) Elucidate the role of SPMs in exercise-enhanced resolution. Results of this project will generate newinsights into how exercise regulates inflammation; which processes mediate the beneficial effects of exercise; and howexercise affects the resolution of acute and chronic inflammation. Collectively these results would generate new knowledgeabout the processes by which exercise improves cardiometabolic health and inflammation-resolution. This knowledge couldlead to the development of new therapeutic interventions to enhance the benefits of exercise or simulate its salutary effectsin individuals resistant or recalcitrant to its beneficial effects or those unable to exercise.

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

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


application_id: 10172892
project_number: 5R01DK121695-03
project_title: Macrophage Migration Inhibitory Factor mediates bladder pain
administering_ic: NIDDK
award_notice_date: 2021-06-07
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: DK
serial_number: 121695
program_official: KIRKALI, ZIYA
project_start_date: 2019-07-01
project_end_date: 2023-06-30
study_section: Special Emphasis Panel[ZRG1-DKUS-B(90)]
contact_pi_person_id: 8093598
contact_pi: VERA, PEDRO L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078344581
primary_uei: JCSKALYM8HU6
duns_number: 078344581
uei: JCSKALYM8HU6
fips: US
organization_id: 10030991
organization_name: LEXINGTON BIOMEDICAL RESEARCH INSTITUTE
organization_city: LEXINGTON
organization_state: KY
organization_type: Research Institutes
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Our long-term goal is to discover novel therapeutic targets for pelvic pain. Pelvic painbladder pain specifically is also the cardinal symptom of interstitial cystitis/bladder painsyndrome (IC/BPS) where most patients show no underlying bladder infection pathology orinjury. The local and central mechanisms that mediate pelvic pain are not fully understood.There is an urgent need to correct this knowledge gap so as to develop effective noveltherapeutic targets for chronic pelvic pain. Our overall objective in this application is to determine the mechanisms of MIF-mediated bladder hyperalgesia. Our central hypothesis is that MIF mediates bladderhyperalgesia through local (bladder) and central (spinal) mechanisms. We plan to test our central hypothesis by pursuing the following three specific aims: 1. Identify urothelial MIF receptors that mediate bladder hyperalgesia.Based on the published data referred to above our working hypothesis is that released MIFacts at urothelial MIF receptors to elicit urothelial HMGB1 release and bladder hyperalgesia. 2. Identify downstream targets of MIF/HMGB1 that mediate bladder hyperalgesia. Ourworking hypothesis based on our published and preliminary evidence is that blockingdownstream signaling pathways activated by MIF/HMGB1 will prevent bladder hyperalgesia. 3. Identify spinal mechanisms that mediate persistent bladder hyperalgesia.Based on our preliminary data our working hypothesis is that increased production andrelease of spinal MIF activates increased release of spinal HMGB1 to maintain bladder pain. In order to accomplish these aims we will conduct studies using rodent models ofbladder pain and in vitro studies using human urothelial cells. We will examine organ-leveland spinal-level mechanisms of bladder pain while focusing on treating persistent bladderpain. We will also identify novel lumbosacral peptides/proteins associated with persistentbladder pain. Succesful completion of these studies is expected to have a positive impactbecause it is probable that the identified components of the mechanism will provide newperipheral and/or central targets for therapeutic interventions in conditions of bladder pain.

project_terms:
Acute;Binding;Bladder;Bladder Injury;Cyclophosphamide;Cystitis;Data;Goals;HMGB1 Protein;Human;Hyperalgesia;In Vitro;Infection;Infective cystitis;Inflammation;Inflammatory;Injury;Interstitial Cystitis;Knowledge;Mediating;Microglia;Migration Inhibitory Factor;Organ;Outcome;Pain;Pathology;Patients;Pelvic Pain;Peptides;Peripheral;Production;Proteins;Publishing;Research;Rodent Model;Signal Pathway;Signal Transduction;Spinal;Spinal Cord;Symptoms;TLR4 gene;Testing;Therapeutic;Therapeutic Intervention;Urothelial Cell;Urothelium;Work;base;bladder pain;chronic pelvic pain;cytokine;inhibitor/antagonist;interstitial;new therapeutic target;novel;prevent;protease-activated receptor 4;radiation cystitis;receptor;targeted treatment;therapeutic target

public_health_relevance:
The proposed studies will contribute to fundamental knowledge about the mechanisms ofbladder pain and identify novel potential therapeutic targets for patients with InterstitialCystits/Bladder Pain Syndrome.


application_id: 10171923
project_number: 5R01NS097781-05
project_title: Altered Motor Function & Force Feedback After Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2021-04-03
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 097781
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2017-04-01
project_end_date: 2025-03-31
study_section: Special Emphasis Panel[ZRG1-BDCN-N(91)S]
contact_pi_person_id: 1904515
contact_pi: HOWLAND, DENA R.
other_pis: NICHOLS, T. RICHARD
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Extensor muscles of the hind limbs are actively involved in weight support and walking activities.These muscles are extensively linked by inhibitory force dependent pathways which contributeto the successful execution of a range of functional behaviors including locomotion. Thesereflex pathways are thought to arise from Golgi tendon organs and are believed to regulate limbstiffness and promote inter-joint coordination during movements. Weightings of these linkagesvary across control decerebrate animals when quiescent but obey a proximal to distal gradientduring stepping on a treadmill. This finding indicates the strength and distribution of these reflexpathways are subject to modulation in a task-dependent manner. Our preliminary data inanimals suggest that spinal cord hemisection alters the normal distribution and a dominantdistal-to-proximal inhibitory gradient emerges. Animals with this lesion do not exhibit clasp-knifeinhibition a phenomenon mediated by receptors other than Golgi tendon organs and that resultsfrom bilateral injury to the dorsal half of the spinal cord. Changes in the strength and distributionof force feedback that we have observed is correlated with diminished limb stiffness and poorweight acceptance during locomotor tasks  both of which are problems seen in humans withspinal cord injuries (SCIs). These findings provide new insight into potential mechanismscontributing to disruption of motor function following injury. Our guiding hypothesis is: SCI-induced force-feedback dysregulation results in strong inhibition directed towardproximal muscles and contributes to inadequate limb stiffness during weight supportphases of movement. The current application has evolved from collaborative work across twoestablished laboratories bringing together expertise in SCI plasticity force feedback and motorcontrol. The proposed studies are designed to understand and map changes in force feedbackcontrol following SCI characterize associated changes in gait subphases where inhibitory forcefeedback is thought to be most active across diverse locomotor tasks and determine whichwhite matter tracts may modulate spinal circuitry responsible for force feedback. Datagenerated in the proposed projects will be compared with an existing laboratory databasecontaining force feedback findings from control decerebrate preparations. Overall findings fromthese studies will explicate the impact of disrupting this intralimb control system onperformance provide critical mechanistic insight likely to be essential for design of the mosteffective rehabilitation programs for those with SCIs and other neurological disorders and laygroundwork for development of a new method for testing force feedback in humans

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

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


application_id: 10170923
project_number: 3R21DC017247-03S1
project_title: Supplement for Mechanotransduction-Dependent Remodeling of the Stereocilia Cytoskeleton
administering_ic: NIDCD
award_notice_date: 2020-06-09
opportunity_number: PA-18-591
application_type: 3
activity_code: R21
ic: DC
serial_number: 017247
suffix: S1
program_official: FREEMAN, NANCY
project_start_date: 2018-07-01
project_end_date: 2021-06-30
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 12084410
contact_pi: VELEZ ORTEGA, ALEJANDRA CATALINA
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACT Stereocilia are the sensory machinery of the inner ear sensory hair cells. We found that the stability ofthese actin-filled projections depends on the constant influx of calcium through the mechano-electricaltransduction (MET) channels that are located at the tips of stereocilia (Velez-Ortega et al. eLife 2017).We found that the blockage of MET channels or the breakage of their gating tip links leads to theshortening of stereocilia; but once the blockage is removed or the tip links regenerate stereocilia areable to regrow. Based on the changes in stereocilia height in response to variations in the resting METcurrent I hypothesized that the stereocilia actin cytoskeleton exhibits activity-dependent plasticity. Aim 2 of the parent grant (R21 DC017247) has been studying the contribution of myosin XV isoformsin the MET-dependent regulation of stereocilia height using several myosin XV mutant mice. Our resultsthus far indicate that the two types of mammalian auditory hair cells (inner vs. outer hair cells) havedifferent molecular mechanisms driving the MET-dependent changes in the stereocilia cytoskeleton. Inaddition we have observed interesting MET-dependent changes to the resting tilt of the hair bundle thatcould arise from changes at the level of the stereocilia rootlets and/or the cuticular plate. The goal of this Administrative Supplement is to obtain resources (for personnel and supplies) thatwould allow us to perform focused ion beam scanning electron microscopy (FIB-SEM) imaging to (i)answer some questions that traditional SEM imaging has not been able to address due to the difficulty inobtaining accurate 3D measurements of the extremely short stereocilia in some myosin XV mutants; andusing the same FIB-SEM data sets to (ii) further explore the mechanotransduction-dependentrearrangements of the stereocilia rootlets and/or cuticular plate. In addition this supplement would allowDr. Velez-Ortega to spend less time on the bench performing experiments and instead more time ondata analysis and manuscript preparation. This `shift' in the focus of Dr. Velez-Ortega's effort wouldminimize a decrease in the progress of the parent grant due to the upcoming birth of her child in the Fallof 2020.

project_terms:
3-Dimensional;Actins;Address;Administrative Supplement;Affect;Antibodies;Architecture;Area;Auditory;Automobile Driving;Buffers;Calcium;Cells;Childbirth;Cilia;Cochlea;Cytoskeleton;Data Analyses;Data Set;Exhibits;Goals;Growth;Hair;Hair Cells;Hearing;Height;Human Resources;Image;Ions;Label;Labyrinth;Lead;Link;Maintenance;Manuscripts;Measurement;Molecular;Morphology;Motor;Mus;Mutant Strains Mice;Mutation;Myosin ATPase;Natural regeneration;Noise-Induced Hearing Loss;Outer Hair Cells;Plasmids;Preparation;Protein Isoforms;Proteins;Regulation;Resources;Rest;Role;Scanning Electron Microscopy;Sensory;Sensory Hair;Shapes;Testing;Time;Variant;age related;base;beta Actin;depolymerization;experimental study;falls;gamma Actin;hearing impairment;mechanotransduction;microscopic imaging;mutant;new therapeutic target;parent grant;polymerization;prevent;response;treadmill

public_health_relevance:
PROJECT NARRATIVE Our sense of hearing relies on the survival of a limited number of inner ear sensory cells throughoutour entire lifetime. This supplement will provide clues about the molecular machinery regulating thestability and shape of the inner ear sensory apparatus. The identification of these molecular players mightuncover novel therapeutic targets to prevent the loss of stereocilia in some types of age-related or noise-induced hearing loss.


application_id: 10170755
project_number: 3P30AG028383-15S1
project_title: UK-ADRC neuroimaging supplement: LATE and PART
administering_ic: NIA
award_notice_date: 2020-08-27
opportunity_number: PA-18-591
application_type: 3
activity_code: P30
ic: AG
serial_number: 028383
suffix: S1
program_official: ELLIOTT, CERISE
project_start_date: 2006-07-15
project_end_date: 2023-06-30
study_section: ZAG1(M1)
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: GOLD, BRIAN TIMOTHY
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACT  OVERALL (Adapted from Abstract of parent grant UK-ADC)This is a proposal for a University of Kentucky Alzheimers Disease Research Center (UK-ADRC)neuroimaging supplement. This purpose of the supplement is to provide neuroimaging data on the UK-ADRCsdeeply phenotyped clinical cohort to the NIHs recently funded initiative Standardized Centralized Alzheimer'sand Related Dementias Neuroimaging (SCAN). In addition a secondary purpose of this supplement is toidentify neuroimaging correlates of two AD-mimics: limbic-predominant age-related TDP-43 encephalopathy(LATE) and primary age-related tauopathy (PART). The UK-ADRC is an experienced and collaborative ADRCoriginally funded in 1985. Our principal mission is to serve as the focal point for all AD-related activities at UKand this region of the United States by providing an environment and core resources that catalyze innovativeresearch outreach education and clinical programs. Our signature resources include: 1) a cognitively normalgroup of ~500 subjects followed longitudinally with all committed to brain autopsy upon death; 2) a strongprogram in clinical-neuropathological correlations and short postmortem interval autopsies; 3) an establishedprogram studying preclinical biomarkers of AD using neuroimaging and biofluids; 4) an integrated centralizeddatabase and innovative biostatistical expertise to characterize clinical and biological transitions; and 5) asuccessful and close partnership with the African-American community and increased participation ofunderrepresented individuals in our longitudinal cohort and ADRC-affiliated research studies and clinical trials.The overall scientific emphasis of the UK-ADRC continues to be on our interrelated themes: Transitions &Translation. Our well-characterized longitudinal cohort and historically strong neuropathology programfocused on normal aging preclinical disease states and early cognitive transitions have been central to oursuccess in defining early pathogenic mechanisms underlying the transitions from normal cognitive aging toimpairment. The depth of expertise and collaborative nature of our investigators have also resulted insubstantial progress on translation of that knowledge into new targets and novel therapeutic strategies. TheUK-ADRC provides an infrastructure and environment that focuses on these integrated themes and advancesAD research education outreach and clinical programs through highly interactive and effective components:Administrative Core Clinical Core Data Management and Statistics Core Neuropathology Core Outreach andRecruitment Core Biomarker Core and Research Education Component. The UK-ADRC will make resourcesfrom these Cores available to support the success of this ADRC neuroimaging supplement.

project_terms:
Address;African American;Alzheimer's Disease;Alzheimer's disease related dementia;Amyloid;Autopsy;Biological;Biological Markers;Biometry;Brain;Brain imaging;Cerebrovascular Disorders;Cessation of life;Characteristics;Clinical;Clinical Trials;Clinical assessments;Cognitive;Cognitive aging;Collection;Communities;Data;Data Set;Degenerative Disorder;Dementia;Development;Disease;Education;Education and Outreach;Elderly;Environment;Fostering;Funding;Genetic;Goals;High Prevalence;Image;Impairment;Individual;Infrastructure;Kentucky;Letters;Liquid substance;Longitudinal cohort;Magnetic Resonance Imaging;Mission;Nature;Participant;Pathogenicity;Pathologic;Pathology;Pattern;Phenotype;Protocols documentation;Research;Research Personnel;Resources;Scanning;Spectrum Analysis;Standardization;Tauopathies;Time;Translations;United States;United States National Institutes of Health;Universities;age related;aged;aging population;base;biomarker development;biomarker discovery;central database;clinical development;clinical phenotype;cohort;data management;education research;experience;hippocampal atrophy;human old age (65+);in vivo;innovation;knowledge translation;limbic-predominant age-related TDP-43 encephalopathy;longitudinal analysis;machine learning algorithm;neurochemistry;neuroimaging;neuroimaging marker;neuropathology;new therapeutic target;normal aging;novel marker;novel therapeutics;outreach;parent grant;pre-clinical;preclinical study;programs;recruit;research study;statistics;success;tau Proteins;vascular cognitive impairment and dementia;white matter

public_health_relevance:
NARRATIVEThis supplement will fill a critical gap in the field by focusing on the development of neuroimaging biomarkersof two common AD mimics: LATE and PART. By imaging subjects who are A negative and without significantcerebrovascular disease we will identify MRI patterns characteristic of these AD mimics. We will share the UKSCAN neuroimaging data combined with our deep clinical biofluid and genetic phenotyping of theselongitudinally followed subjects to stimulate additional research on AD mimics across the ADRC network.


application_id: 10169248
project_number: 5R01AI153275-02
administering_ic: NIAID
award_notice_date: 2021-04-09
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AI
serial_number: 153275
program_official: DUPUY, LESLEY CONRAD
project_start_date: 2020-05-21
project_end_date: 2025-04-30
study_section: Virology - A Study Section[VIRA]
contact_pi_person_id: 10849785
contact_pi: SOKOLOSKI, KEVIN JOSEPH
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: 2021-05-01
project_terms:
Address;Affect;Alphavirus;Alphavirus Infections;Antiviral Agents;Antiviral Therapy;Arthritis;Attenuated;Binding;Biology;Brain;Cell Line;Cessation of life;Chikungunya virus;Clinical;Defect;Development;Disease;Disease Outbreaks;Environment;Event;Failure;Gene Expression;Genomics;Growth;Histologic;Immune response;Impairment;In Vitro;Individual;Infection;Innate Immune Response;Integration Host Factors;Interferons;Internal Ribosome Entry Site;Invertebrates;Joints;Kinetics;Link;Modeling;Molecular;Molecular Analysis;Morbidity - disease rate;Nature;Nucleocapsid;Pathogenesis;Pathologic;Process;Production;Proteins;Proteomics;Public Health;RNA;RNA chemical synthesis;Reporting;Research;Role;Ross river virus;Sindbis Virus;Structure;Techniques;Testing;Therapeutic;Vaccines;Venezuelan Equine Encephalitis Virus;Viral;Viral Encephalitis;Viral Genes;Viral Pathogenesis;Virion;Virulence;Virus Diseases;Virus Replication;Wild Type Mouse;Work;base;combinatorial;defined contribution;effective therapy;exhaustion;expectation;genomic RNA;improved;in vivo;innovation;knowledge base;mortality;mutant;negative affect;neuroinflammation;novel;particle;pathogen;response;tissue culture;tissue/cell culture;transcriptomics;vector-borne pathogen;viral RNA


application_id: 10169210
project_number: 5R01AG055359-05
project_title: Mechanisms mediating severity of acute pancreatitis in the aged
administering_ic: NIA
award_notice_date: 2021-06-03
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 055359
program_official: WILLIAMS, JOHN
project_start_date: 2017-09-01
project_end_date: 2023-05-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8163817
contact_pi: SAITO, HIROSHI
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe objective of this project is to understand the mechanisms leading to the development of severe acutepancreatitis (sAP) a life-threatening illness with high mortality characterized by necrotizing pancreas severesystemic inflammation coagulation multiple organ dysfunction syndrome (MODS). AP is a particularly seriousdisease among the elderly as both incidence and the likelihood for progression to sAP increases dramaticallywith advancing age. Despite recognition of this clinical problem little is known regarding the underlyingbiological mechanisms of this disease or why progression to sAP is more common among elderly patients. Werecently developed an aged mouse model of AP in which only aged mice exhibit sAP that parallels clinicalobservations including prolonged systemic inflammation coagulation MODS and fatality. Our observationswith this mouse model include a dramatic age-dependent increase in tissue damage and cytokine geneexpression within visceral adipose tissue and elevated levels of free fatty acids in the ascitic fluid. Collectivelythese findings suggest that visceral adipose tissues are key mediators promoting the progression of AP to sAPin the aged. The central hypothesis of this project is that aged animals are more prone to develop sAP due topronounced visceral adipose tissue inflammation caused by leakage of pancreas-derived digestive enzymesinto the peritoneum from the damaged pancreas. AP-induced adipose tissue inflammation results in release offree fatty acids inflammatory cytokines and pro-thrombotic factors all promoting MODS. Our hypothesis willbe tested in the following three specific aims: To determine features of visceral adipose tissue inflammation inaged animals with sAP (Aim 1); To demonstrate that increased visceral adipose tissue inflammation promotesthe progression of AP to sAP in the aged (Aim 2); and To develop strategies to prevent the progression of APto sAP in aged animals by suppressing adipose tissue inflammation (Aim 3).

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

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


application_id: 10168957
project_number: 7R03DA045881-03
project_title: Glutamatergic mechanisms underlying nicotine addiction and relapse following nicotine reduction
administering_ic: NIDA
award_notice_date: 2020-06-08
opportunity_number: PA-18-590
application_type: 7
activity_code: R03
ic: DA
serial_number: 045881
program_official: KAUTZ, MARY A
project_start_date: 2018-09-30
project_end_date: 2022-08-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 9706320
contact_pi: GIPSON-REICHARDT, CASSANDRA D
other_pis: Not Applicable
congressional_district: 06
department: FAMILY 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:
PROJECT SUMMARY/ABSTRACT Nicotine abuse and addiction represent a substantial burden to public health. Nicotine an active alkaloidin tobacco is responsible for addiction to tobacco-containing products such as cigars cigarettes andvaporized liquid e-cigarettes. Given the immense negative health impact of nicotine addiction as well as therecent surge in popularity of nicotine-containing e-cigarettes there is a great need for innovative research onthe neurobiological underpinnings of nicotine addiction and relapse. In 2009 federal regulation of nicotinecontent was established by the Family Smoking Prevention and Tobacco Control Act in the United States toreduce addiction to cigarette smoking. Specifically reduction of nicotine content in tobacco products is acontrol strategy intended to decrease smoking dependence that reduces nicotine content over time (althoughnot to zero) resulting in gradual reduction of intake and dependence. However nicotine addiction and relapserates remain high and the ability of nicotine reduction strategies to effectively reduce tobacco and nicotineaddiction is unknown. Our preliminary results illustrate the utility of an efficient and sensitive behavioraleconomics (BE) protocol for the examination of elasticity of nicotine demand and nicotine motivation.Importantly this model utilizes a daily within-session nicotine dose-reduction protocol with conditioned cuesassociated with different doses of nicotine. These cues can then be used to evaluate cue-induced nicotineseeking to different doses to nicotine as well as the neurobiological sequelae that occur in nicotine-motivatedbehavior. Nicotine produces cellular adaptations in brain regions associated with drug reward such as thenucleus accumbens. However the neurobehavioral mechanisms underlying nicotine relapse vulnerability arerelatively unknown. Nucleus accumbens core (NAcore) glutamatergic mechanisms are involved in nicotinerelapse including rapid transient increased synaptic strength (measured as increased AMPA currents frommedium spiny neurons). In the proposed studies we will determine if nicotine reduction strategy can inhibitcue-induced nicotine seeking as well as aberrant NAcore synaptic plasticity. In Specific Aim 1 we will examineindividual differences in nicotine demand elasticity in male and female rats using an abbreviated BE protocoland determine the ability of abrupt nicotine reduction to inhibit cue-induced nicotine seeking using areinstatement paradigm. In Specific Aim 2 we will determine if nicotine reduction can inhibit reinstatement-associated NAcore plasticity. In these ways the proposed studies will uncover the neurobiological basis of theeffects of decreasing nicotine dose and will identify potential neurobiological targets in glutamate signaling forlater manipulation that may increase sensitivity to changes in price and dose and could be beneficial for futureregulatory purposes. Through these efforts we will accomplish our overarching goal of determining efficacy ofnicotine reduction to promote nicotine use cessation and reduced relapse vulnerability.

public_health_relevance:
PROJECT NARRATIVENicotine addiction is associated with long-lasting brain changes that cause heightened relapsevulnerability even after extended drug abstinence. Importantly nicotine reduction is a tobaccocontrol strategy to promote nicotine abstinence. The proposed research has the potential to revealnovel neurobiological mechanisms of nicotine reduction which could contribute to thedevelopment of novel therapeutic options aimed at reversing nicotine-induced alterations in thebrain as well as guiding nicotine and tobacco regulatory policy.


application_id: 10166806
project_number: 5R01CA243529-02
administering_ic: NCI
award_notice_date: 2021-05-27
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: CA
serial_number: 243529
program_official: CHEN, WEIWEI
project_start_date: 2020-06-01
project_end_date: 2025-05-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 9351620
contact_pi: TSODIKOV, OLEG V
other_pis: LEGGAS, MARKOS ;ROHR, JURGEN T
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-06-01
project_terms:
Affect;Animal Model;Antineoplastic Agents;Binding;Biochemical;Biological;Biological Assay;Biophysics;Bone Tissue;Cell model;Cells;Child;Clinical;Clinical Treatment;Clinical Trials;Collaborations;Combined Modality Therapy;Complement;Complex;Crystallization;DNA;DNA Binding;DNA Binding Domain;DNA Sequence;Data;Development;Drug Design;Drug Kinetics;EWS-FLI1 fusion protein;Elements;Enhancers;Evaluation;Ewings sarcoma;FLI1 gene;Family;Foundations;Genetic Transcription;Goals;Higher Order Chromatin Structure;Human;In Vitro;Investigational Therapies;Kinetics;Liver;Malignant Bone Neoplasm;Metabolism;Microsatellite Repeats;Modeling;Molecular;Molecular Biology;Molecular Structure;Mus;Natural Products;Oncogenic;Patients;Pharmaceutical Preparations;Pharmacology;Pharmacology Study;Phase I/II Clinical Trial;Plasma;Plicamycin;Preclinical Testing;Property;Proteins;Public Health;Reporter;Reporting;Roentgen Rays;Route;Shunt Device;Side;Site;Specificity;Structure;Testing;Therapeutic;Toxic effect;Translating;Tube;Xenograft Model;analog;base;cancer cell;cancer diagnosis;cytotoxic;cytotoxicity;design;drug candidate;drug clearance;effective therapy;experience;improved;inhibitor/antagonist;insight;lead candidate;mouse model;neoplastic cell;novel;patient derived xenograft model;programs;screening;soft tissue;transcription factor;transcriptional reprogramming;tumor;tumorigenesis;young adult


application_id: 10165838
project_number: 5R01NS092552-04
project_title: Contribution of adult neurogenesis to epileptogenesis and recovery after TBI
administering_ic: NINDS
award_notice_date: 2021-05-04
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 092552
program_official: CHURN, SEVERN BORDEN
project_start_date: 2018-06-01
project_end_date: 2021-07-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
other_pis: SAATMAN, KATHRYN E
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryMore than one million people are treated medically each year in the United States after sustaining a braininjury and traumatic brain injury (TBI) is often accompanied by the delayed development of posttraumaticepilepsy (PTE) for which there are few effective therapies. Although clinical association between TBI andepilepsy is well documented treatments designed to prevent PTE have been largely unsuccessful. Among themost promising antiepileptogenic treatments reported to date center on inhibition of the mammalian(mechanistic) target of rapamycin (mTOR) pathway. mTOR is activated after TBI and seizures and it's activityregulates a variety of cellular activities including growth and proliferation especially in developing neurons.Inhibiting mTOR activity has shown promise for altering the progression of epileptogenesis in rodent models ofepilepsy including PTE but several caveats have also been acknowledged specifically: Suppression ofmTOR post-TBI has been proposed to prevent epileptogenesis whereas mTOR activation has been proposedas a means of improving cognitive recovery after TBI in patients. The mechanisms by which mTORmodulation exerts its anti-epileptogenic effects are not known and the contribution of newborn neurons andsynaptic reorganization in the dentate gyrus to epileptogenesis and cognition are controversial. PreventingPTE is hampered by these fundamental knowledge gaps. This proposal will use the controlled cortical impact(CCI) model of TBI which results in cell loss increased neurogenesis and synaptic reorganization in thedentate gyrus and delayed development of spontaneous seizures (i.e. epileptogenesis) to study the impact ofnewborn neurons on synaptic excitability changes in the dentate gyrus. The effects of both negative andpositive regulation of mTOR on epileptogenesis and cognitive recovery will also be determined in the context ofneurogenesis after brain injury. The overarching hypotheses are that adult born neurons contribute to synapticreorganization after TBI and that mTOR activity-dependent regulation of neurogenesis alters epileptogenesisand post-TBI cognitive recovery. A combination of electrophysiological histological and behavioral techniquesutilizing optogenetic and chemogenetic modification of adult born neurons will be used to address three aims:1) Determine the functional synaptic organization of adult born DGCs after TBI; 2) Determine effects of mTORmodulation on neurogenesis and synaptic connectivity in the dentate gyrus after TBI; and 3) Determine howadult born DGCs contribute to functional recovery and seizures after TBI. A mechanistic understanding of howadult born neurons contribute to DGC circuitry and how mTOR modulation alters the circuitry of these neuronsafter CCI will be developed in the context of both cognitive recovery after TBI and development of PTE. Abetter understanding of the contribution of adult born neurons to recovery and epileptogenesis after TBI willfacilitate the development of treatments to prevent PTE.

project_terms:
Address;Adult;Affect;Antiepileptogenic;Behavior;Behavioral;Brain;Brain Injuries;Cells;Cessation of life;Clinical;Cognition;Coupled;Development;Disease;Disease Progression;Down-Regulation;Electrophysiology (science);Epilepsy;Epileptogenesis;FRAP1 gene;Growth;Hippocampus (Brain);Histologic;In Vitro;Injury;Knowledge;Medical;Modeling;Modification;Mus;Neurons;Newborn Infant;Outcome;Pathway interactions;Patients;Post-Traumatic Epilepsy;Recovery;Recovery of Function;Regulation;Reporting;Risk;Rodent Model;Role;Seizures;Sirolimus;Site;Structure;Synapses;Techniques;Temporal Lobe Epilepsy;Testing;Therapeutic;Time;Traumatic Brain Injury;Traumatic Brain Injury recovery;United States;Up-Regulation;adult neurogenesis;base;behavioral outcome;cognitive development;cognitive function;cognitive recovery;controlled cortical impact;dentate gyrus;effective therapy;experimental study;functional outcomes;granule cell;improved;injury recovery;mossy fiber;mouse model;neural network;neurogenesis;newborn neuron;optogenetics;prevent;therapeutic target;therapy design;therapy development

public_health_relevance:
Project Narrative.After brain injury synaptic reorganization specifically involving newborn neurons in the dentate gyrus may beinvolved in the development of posttraumatic epilepsy and the increase in adult neurogenesis after brain injuryis modulated by increasing or decreasing mTOR function. The function of adult born neurons after brain injuryis incompletely described hampering development of potential post-injury therapies based on mTORmodulation. Experiments in this proposal will examine how neurons born after brain injury integrate intohippocampal circuitry and contribute to post-injury recovery or pottraumatic epilepsy in order to better exploitthe promising mTOR therapeutic pathway to both improve recovery and prevent development of epilepsy afterbrain injury.


application_id: 10165681
project_number: 5R01DA043938-05
project_title: Cardiovascular Immune and Psychosocial Benefits of Reduced Cocaine Use
administering_ic: NIDA
award_notice_date: 2022-05-18
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DA
serial_number: 043938
program_official: MANDLER, RAUL N
project_start_date: 2017-09-01
project_end_date: 2024-11-30
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTPromoting reductions in problem behaviors is common in medical practice wherein at-risk individuals arecounseled to make moderate sustainable changes in lifestyle. Reducing the percentage of heavy drinkingdays in individuals with alcohol use disorder is an accepted intervention target in alcohol addiction treatmentyet for other drug use disorders complete abstinence remains the standard for demonstrating treatmentefficacy. Interventions that promote reductions in drug use should improve biopsychosocial outcomes. Littleresearch has been conducted to demonstrate benefits of reduced drug use however. Demonstrating thebenefits of reduced cocaine (COC) use would significantly advance treatment development by challengingexpectations for outcomes from possible interventions. COC use produces a number of biopsychosocialdetriments (e.g. cardiovascular toxicity disrupted immune function increased psychiatric comorbidities) thatcould be ameliorated by COC use reduction. No studies have prospectively or comprehensively evaluated thispossibility to date although preliminary data support this hypothesis. To fill this critical knowledge gap wepropose a randomized controlled 12-week trial in which financial incentives will be used to reduce COC use.Subjects will be randomly assigned to one of three groups (n=66 completers/ group): 1) high value financialincentives for COC abstinence in which frequency of COC use is expected to be substantially reduced orcompletely eliminated 2) low value financial incentives for COC abstinence in which frequency of COC use isexpected to be reduced or 3) a non-contingent control group in which frequency of COC use is expected toremain stable. This study aims to demonstrate that reduced COC use improves physiological and biochemicalindicators of cardiovascular and immune fitness as well as psychosocial function. The overarching hypothesisis that individuals assigned to the active treatment conditions will display improvements in biopsychosocialdomains compared to individuals assigned to the non-contingent control group. A dose-response is alsoexpected whereby individuals assigned to the high value condition will display greater reductions in COC useand consequently greater improvements relative to the low value condition. This research will advance thefield by: 1) using multifaceted health outcomes to provide prospective evidence supporting reduced drug useas a viable endpoint for COC treatment development 2) identifying biochemical indicators of healthimprovements associated with reduced COC use and 3) laying the foundation for a paradigm-shifting definitionof COC treatment success thereby challenging expectations for outcomes in behavioral and pharmacologicalintervention development. These innovations will accelerate identification of promising treatments for cocaineuse disorder resulting in a sustained and powerful impact on scientific and clinical practice.

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

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


application_id: 10164725
project_number: 5T32CA160003-10
project_title: Oncology Research Training for Surgeon-Scientists
project_terms: Oncology;Research Training;Scientist;Surgeon
administering_ic: NCI
award_notice_date: 2021-06-23
opportunity_number: PA-16-152
application_type: 5
activity_code: T32
ic: CA
serial_number: 160003
program_official: LIM, SUSAN E
project_start_date: 2011-07-01
project_end_date: 2023-06-30
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACTThe primary focus of our training program at the University of Kentucky (UK) is to provide intensive andinterdisciplinary basic science research training to qualified individuals in the various surgical disciplines toprepare them to become independent scientists and incorporate state-of-the-art techniques learned duringtheir training period into a successful academic career. Moreover these trainees will be prepared to be activeparticipants in multidisciplinary teams which are required for the optimal treatment of the complex cancerpatient. Our two-year training program represents a collaboration between the Markey Cancer Center (MCC)and the academic clinical departments at UK and benefits greatly from the experience and collegiality of theprogram and associate directors who have worked together for many years and have led other successfultraining programs for clinician-scientists and basic researchers. The primary training faculty is composed ofboth basic and clinical-scientists who are collaborative and multidisciplinary; each primary faculty mentor is arecognized expert in his or her field and has a long record of research productivity in the training of younginvestigators from the US and abroad. The diversity of our training program is further enhanced by theinclusion of seasoned adjunct faculty mentors who will provide additional clinical and biostatistical expertise.Also we have designed a pipeline mechanism to provide the time and instruction for promising junior facultymembers to further hone their mentoring skills so that they can become effective primary mentors in the future.In addition to an intensive research experience the trainees take formal courses (eg grant writing skills ethicsand biostatistics) and are mentored in the fine points of preparing abstracts scientific papers andpresentations and writing successful grant applications. Furthermore the trainees participate in regularlyscheduled MCC departmental and Center for Clinical and Translational Science (CCTS) seminars andlectures. All of our trainees are required to complete coursework for a Master's degree in Clinical andTranslational Science (CTS). In addition the option of obtaining a PhD is available and encouraged (of notetwo former trainees have successfully completed requirements for their PhD degrees and one current trainee isenrolled in the program). The requirement to successfully complete either a Master's or PhD further adds depthand breadth to the program and increase interactions with other scientists on campus through the requiredsupervisory or thesis committees. We are concerned with the alarming decrease in the number of clinician-scientists; this decrease is most apparent in the diminishing number of those in the various surgical specialties.We are passionate motivated and committed to the training of future academic surgeons.

public_health_relevance:
NARRATIVEThe number of clinician scientists and in particular surgeon scientists is decreasing at an alarming rate; thisreduction will negatively impact the ability and rapidity to translate basic discoveries made in cancer researchto the patient. Our training program representing a collaboration between the Markey Cancer Center and theacademic clinical departments (Departments of Surgery and Pathology and Laboratory Medicine and theDivision of Gynecologic Oncology) at the University of Kentucky is focused on the interdisciplinary training offuture clinician scientists in the various surgical specialties and disciplines. The overall objective of thisprogram is to train clinician scientists in the skills and expertise in basic science and translational research tobe competitive in the academic arena and to be active participants in multidisciplinary cancer teams which arerequired for the care of the complex cancer patient.


application_id: 10164716
project_number: 5R01AI145335-03
administering_ic: NIAID
award_notice_date: 2021-05-11
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AI
serial_number: 145335
program_official: O'NEIL, MICHAEL T
project_start_date: 2019-06-17
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZRG1-IDM-U(02)]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY P.
other_pis: PATWARDHAN, ABHIJIT R.
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-06-01
project_title:
Quantitative Approaches for Drug Testing in Chronic Toxoplasmosis: Leveraging New Insights Into Bradyzoite Biology Within Tissue Cysts In Vivo

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

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

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


application_id: 10164703
project_number: 5R03AG067611-02
project_title: Functional Censored Quantile Regression for Investigating Heterogeneous Effects in Survival Data
administering_ic: NIA
award_notice_date: 2021-03-19
opportunity_number: PA-19-052
application_type: 5
activity_code: R03
ic: AG
serial_number: 067611
program_official: CHATTERJI, MINKI
project_start_date: 2020-05-15
project_end_date: 2022-01-31
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: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractFunctional biomarkers that are in the form of curves images and objects are often collected in biomedical studiesnowadays due to the rapid advances in data acquisition technology. In recent research there has been growingawareness that the underlying association between the functional biomarkers and outcomes may be prone toconsiderable heterogeneity. Those heterogeneous associations often shed insight on scientic discoveries andentail signicant implications but tend to be overlooked by many existing functional data analysis procedures witha narrow focus on the response mean. Our proposal aims at offering researchers alternative tools to explore thecomprehensive information of the relationship between functional biomarkers and survival time. In contrast to statistical models that presume constant effects of covariates quantile regression (QR) ac-commodates varying effects and may reveal more detailed dependence structure of outcomes on covariates.Regretfully QR for functional data has barely been studied. The objective of this proposal is to make the QRframework applicable for investigating the regression heterogeneity in functional survival data to develop reliableand efcient estimation approaches and to obtain sharp inference on the effects of functional biomarkers. Wewill propose a local functional censored QR (FCQR) method to evaluate the impacts of functional biomarkerson the survival time at a single or multiple pre-specied quantile levels and develop a related signicance test fortesting the impact of functional biomarkers (Aim 1). Then we will develop a global FCQR method to investigatethe varying effects of functional biomarkers on the survival time over a region of quantile levels which will provideresearchers with a comprehensive picture about the covariates-response association. In addition two inferenceprocedures including a bootstrap resampling method for estimating the standard errors and the martingale-basedmodel diagnostics will be developed (Aim 2). Moreover we will extend the local FCQR method to longitudi-nal measurements of functional biomarkers for dynamic prediction of residual life (Aim 3). Also we will developstatistical software that efciently implements the proposed methods. The innovation of our proposal is at least three-fold. Firstly it will produce reliable and efcient FCQR toolsthat facilitate the identication and evaluation of new valuable functional biomarkers. Secondly the successfulcompletion of my proposal can signicantly advance the theory of QR and semi/non-parametric statistics andfurther broaden their applications in lots of biomedical research. Thirdly our proposed methods will also serveas a exible platform for examining the heterogeneity in functional data. They can be readily extended to otherpublic health applications.

project_terms:
Address;Awareness;Big Data;Biological Markers;Biomedical Research;Brain Injuries;Cancer Patient;Characteristics;Collaborations;Collection;Community Health;Computer software;Data;Data Analyses;Dependence;Diagnostic;Disease;Evaluation;Event;Gaussian model;Goals;Hematological Disease;Hemodialysis;Hemoglobin;Heterogeneity;Image;Life;Literature;Long-Term Survivors;Magnetic Resonance Imaging;Malignant Neoplasms;Measurement;Measures;Medical;Mental Health;Methods;Modeling;Modernization;Nonparametric Statistics;Outcome;Patients;Physicians;Procedures;Prognosis;Property;Public Health;Public Health Applications Research;Reporting;Research;Research Personnel;Research Project Grants;Residual state;Seminal;Severity of illness;Specific qualifier value;Statistical Methods;Statistical Models;Structure;Technology;Testing;Time;Visit;Work;base;cancer recurrence;data acquisition;discrete time;flexibility;follow-up;innovation;insight;interest;prognostic value;response;success;theories;tool;vector

public_health_relevance:
NarrativeThis proposal will not only promote the use of quantile regression as an excellent platform to examine the het-erogeneous covariate-response association but also advance the functional data analysis. Robust and exiblefunctional censored quantile regression methods along with statistical software will be developed for exploringthe evolving effects of functional biomarkers on censored survival time. This project will impact public healthcommunity by allowing researchers to more efciently and thoroughly evaluate the functional biomarkers for thepurposes of disease prognosis.


