# projects

application_id: 9980987
project_number: 5R01HL142973-03
administering_ic: NHLBI
award_notice_date: 2020-08-05
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 142973
program_official: VARAGIC, JASMINA
project_start_date: 2018-08-20
project_end_date: 2022-07-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: GUO, ZHENHENG
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-08-01
project_title:
A novel mechanism by which smooth muscle BMAL1 regulates IL-6 and sexual dimorphism of abdominal aortic aneurysm

project_abstract:
PROJECT SUMMARYAbdominal aortic aneurysm (AAA) is a vascular disease affecting millions of Americans that accounts for15000 deaths per year in the United States. Currently open or endovascular surgery is the only therapeuticoption for AAA as no drug has been approved for treatment of this devastating disease highlighting an urgentneed for new mechanistic understandings of AAA. We recently reported that administration of mineralocorticoidreceptor (MR) agonists Aldo or deoxycorticosterone acetate (DOCA) plus salt but not Aldo DOCA or saltalone to 10-month-old C57BL/6 male mice potently induces AAA and our preliminary data demonstrated thatadministration of angiotensin II (Ang II) plus salt but not Ang II alone to 10-month-old C57BL/6 male mice alsopotently induces AAA. While the mechanism remains elusive our preliminary data show that Aldo- or Ang II-salt-induced AAA occurs only or mostly in male but not in female or orchidectomized (orx) male mice. Toelucidate the mechanism that underlies sexual dimorphism of AAA we identified several genes that wereselectively upregulated by Aldo-salt in aorta in male but not in female or orx male mice. Among these genescircadian clock BMAL1 and inflammatory cytokine interleukin 6 (IL-6) are particularly promising as BMAL1 hasnot been previously implicated in AAA despite wide recognition that aortic dissection and aneurysmal ruptureare characterized by circadian variation and as IL-6 has been associated with human AAA by recent largegenome-wide association studies (GWAS). Our preliminary data show that selective deletion of BMAL1 fromsmooth muscle (SM) completely abolished DOCA-salt-induced AAA and IL-6 upregulation. In addition wefound that treatment of mice with a novel small molecule inhibitor targeting the IL-6 signaling significantlydiminished Aldo-salt-induced AAA. Based on these provocative preliminary data and the literature thattestosterone (T) promotes AAA whereas estrogen (E2) protects against AAA we hypothesize that T and E2critically regulate sexual dimorphism in Aldo- or Ang II-salt-induced AAA via SM-BMAL1 and IL-6signaling and further that targeting IL-6 signaling represents a novel therapeutic strategy againstAAA. Two specific aims test this central hypothesis: Aim1. To determine whether sex hormone is crucial forAldo- or Ang II-salt to activate BMAL1 in aorta and thereby result in sexual dimorphism in Aldo- or Ang II-salt-induced AAA. Aim2. To define the mechanism by which IL-6 is transcriptionally regulated by SM-BMAL1 and totarget IL-6 signaling as a novel therapeutic strategy against Aldo- or Ang II-salt-induced AAA. To achieve theseaims we will administer Aldo- or AngII-salt and/or T or E2 to 10-month-old normal or castrated C57BL/6 maleor female mice SM-BMAL1-KO IL-6R-KO and wild-type control mice to induce SM-BMAL1 and IL-6 signalingand AAA. The proposed studies will shed new mechanistic insight into a novel role of BMAL1 and IL-6signaling in sexual dimorphism of AAA. Moreover the results will provide preclinical evidence that targeting IL-6 signaling represents a novel therapeutic strategy against AAA.

project_terms:
ARNTL gene;Abdominal Aortic Aneurysm;Accounting;Acetates;Affect;Age;Agonist;Aldosterone;American;Angiotensin II;Animal Model;Aorta;Cardiovascular Diseases;Cessation of life;Country;Data;Deoxycorticosterone;Disease;Dissection;Estrogens;Female;Genes;Genetic Transcription;Goals;Gonadal Steroid Hormones;Heart failure;Human;Hypertension;Inflammatory;Interleukin 6 Receptor;Interleukin-6;Left Ventricular Hypertrophy;Link;Literature;Mediating;Mineralocorticoid Receptor;Mus;Myocardial Infarction;Operative Surgical Procedures;Pharmaceutical Preparations;Pharmacotherapy;Plasma;Play;Prevalence;Reporting;Rheumatoid Arthritis;Role;Rupture;Serum;Sex Differences;Signal Transduction;Smooth Muscle;Sodium Chloride;Stroke;Testing;Testosterone;Therapeutic;Transcriptional Regulation;United States;Up-Regulation;Variant;Vascular Diseases;Woman;base;circadian;circadian pacemaker;cytokine;effective therapy;genome wide association study;insight;male;men;mortality;neutralizing antibody;new therapeutic target;novel;novel therapeutics;pre-clinical;salt intake;sexual dimorphism;sham surgery;small molecule inhibitor

public_health_relevance:
PROJECT NARRATIVEAbdominal aortic aneurysm (AAA) is a vascular disease with greater prevalence in men than in women overthe age of 60 and a high mortality rate (65% to 85%) related to aneurysmal rupture accounting for about 2% ofall deaths in Western countries. The goals of this application are to use new animal models that we recentlydeveloped to elucidate the mechanisms responsible for sex difference of AAA and identify new therapeutictargets to develop new drugs for treatment of AAA.


application_id: 9980938
project_number: 5R25GM125680-03
project_title: Interactive Mentoring to Enhance Research Skills (IMERS)
administering_ic: NIGMS
award_notice_date: 2020-08-26
opportunity_number: PAR-17-070
application_type: 5
activity_code: R25
ic: GM
serial_number: 125680
program_official: SESMA, MICHAEL A
project_start_date: 2018-09-01
project_end_date: 2023-08-31
study_section: ZGM1-TWD-7(IP)
contact_pi_person_id: 8535385
contact_pi: FRAZIER, DONALD T
other_pis: SPEAR, BRETT
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTIn an era of increasingly competitive biomedical funding as well as recognized needs for bolder efforts tofacilitate inclusion of disparate perspectives in 21st century discoveries that impact human health theimportance of successful grant-seeking skills and behaviors is clear. Recent findings of underrepresentation ofminority scientists in award of biomedical research grants underscore the importance of this skill set for facultyat institutions with significant enrollments of underrepresented students. Similarly the role of research projectfunding as a pipeline for student development as next-generation researchers places even greater importanceon the need for skills training in research mentoring. To address these two integrated needs the University ofKentucky (UK) proposes Interactive Mentoring to Enhance Research Skills (IMERS) as a workshop series toprovide interactive grant-writing training for faculty cohorts from minority-serving institutions (MSIs) across theUnited States. The IMERS training in NIH-focused grantsmanship will be coupled with professionaldevelopment on research education mentoring for participating faculty. The program based on a well-established long-running conference grant program directly addresses issues of diversity in biomedicalresearch. The proposed expansion to a research education program reflects two new priorities: a newprofessional development intervention to train participants in skills and strategies to effectively mentor studentsin research and direct engagement of a research-active program faculty to serve in mentor and outreach roles.IMERS will continue a grantsmanship training model that incorporates guided writing participatory training andactive learning. The core event is a three-day grant-writing workshop to be held on the UK campus for twodifferent faculty cohorts (25 participants per event) each year. Off-site regional or institution-specific eventsprovide opportunities for complementary outreach and a continuum of mentored support. Specific aims are to:1) engage participants in hands-on active-learning style grant-writing training for selected faculty poised tosubmit NIH proposals ranging from developmental/exploratory to R01s; 2) to provide targeted training ineffective laboratory-based research training and mentorship strategies; and 3) to provide mentored post-workshop proposal development support from a broad community of funded research mentors and researchdevelopment professionals. The proposed PI-centered IPERT provides an integrated model of skillsdevelopment mentoring and outreach that collectively feature guided proposal development support usingparticipants' own developing research narratives. In addition the mentoring components span initial hands-onmentoring during group workshop sessions proposal-specific one-on-one consultations with mentors andsubsequent post-workshop support. Expected outcomes are to facilitate individual faculty skills development inresearch and research education for faculty from MSIs with limited research development resources.

project_terms:
Active Learning;Address;Award;BRAIN initiative;Behavior;Biomedical Research;Communities;Consultations;Coupled;Development;Discipline;Diverse Workforce;Educational workshop;Enrollment;Event;Extramural Activities;Faculty;Foundations;Funding;Future;Goals;Grant;Health;Human;Individual;Institution;Kentucky;Laboratories;Malignant Neoplasms;Mentors;Mentorship;Minority;Minority-Serving Institution;Mission;Modeling;Motivation;Outcome;Participant;Personal Satisfaction;Productivity;Research;Research Personnel;Research Project Grants;Research Support;Research Training;Resource Development;Role;Running;Science;Scientific Advances and Accomplishments;Series;Site;Statistical Data Interpretation;Students;Teacher Professional Development;Time;Training;Training and Education;Underrepresented Minority;Underrepresented Students;United States;United States National Institutes of Health;Universities;Writing;base;career;cohort;data management;demographics;design;education research;experience;extended reality;faculty research;innovation;interest;minority scientist;minority undergraduate;next generation;outreach;post-doctoral training;precision medicine;programs;research and development;skill acquisition;skills;skills training;student mentoring;student training;success;symposium;therapy development;training opportunity

public_health_relevance:
PROJECT NARRATIVEDiversity in the biomedical workforce is essential to the ability to enlist the power of divergent perspectives togenerate discovery-driven innovations in biomedical research. The proposed program is designed to facilitatethe success of researchers at minority-serving institutions in competing for extramural funding and inimplementing effective mentored research education activities for their students thereby exerting a substantialimpact on the health and well-being of our citizens.


application_id: 9980916
project_number: 5R01HS025148-03
administering_ic: AHRQ
award_notice_date: 2020-07-28
opportunity_number: PA-14-291
application_type: 5
activity_code: R01
ic: HS
serial_number: 025148
program_official: SANDMEYER, BRENT
project_start_date: 2018-09-30
project_end_date: 2022-07-31
study_section: Healthcare Systems and Values Research[HSVR]
contact_pi_person_id: 6985670
contact_pi: WATERS, TERESA 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
budget_start_date: 2020-08-01
project_title:
Impact of Medicare Value Programs on Inpatient Quality Indicators (IQIs) and Patient Safety Indicators (PSIs)

project_abstract:
The penalties and bonuses assessed under Medicare's hospital Pay for Performance (P4P) programs focus anunprecedented amount of attention on a limited set of performance metrics; this intense emphasis may createunintended consequences for areas outside the focus of these programs. Medicare will assess about $878million in penalties against hospitals under the Hospital Readmission Reduction Program (HRRP) and HospitalAcquired Conditions Reduction Program (HACRP) this year and an additional $1.8 billion will be withheld frominpatient payments covered by the Hospital Value Base Purchasing (HVBP) program to be used later for value-based incentive payments. The size of these incentives along with the precedent they set for future value-based programs make in-depth study of their impact absolutely critical. We propose to see how introduction ofthese programs may have affected a range of quality and safety areas especially areas outside the focus ofthe programs using AHRQ's inpatient quality indicators (IQIs) and patient safety indicators (PSIs).Q1: How have Medicare's hospital P4P programs affected metrics outside the programs' focus?Hypothesis #1: Quality and safety metrics for areas outside the focus of Medicare's hospital P4P programshave deteriorated or improved more slowly compared to time periods prior to program introduction.Hypothesis #2: Quality metrics not clinically related to focus areas have been most affected.Using interrupted time series we will examine the impact of P4P introduction on IQIs and PSIs that capturequality and safety for patients that fall outside the program focus. We also propose fuzzy difference-in-differences (f-DID) analysis to compare metrics within and outside the program focus.Q2: Does the magnitude of penalties or bonuses affect how a particular hospital's metrics change inresponse to P4P? Hospitals with large penalties may divert resources to improve their metrics in focus areasleaving fewer resources to address quality and safety in other areas. This may be especially acute forfinancially troubled hospitals. Hypothesis #3: Hospitals facing large penalties will demonstrate greaterdeterioration/improvement attenuation in metrics outside P4P focus compared to those with low/no penalties.Q3: How have Medicare's hospital P4P programs affected metrics for non-Medicare patients? Hospitalsmay find it unethical impractical or unprofitable to treat Medicare patients differently from other patients. If sowe may observe spillover to other patients. Hypothesis #4: Metrics outside P4P focus have also deterioratedfor non-Medicare patients or improved more slowly compared to time periods prior to program introduction.Combining 2007-2016 HCUP State Inpatient Databases (SID) from 14 states with publicly reported penaltiesand bonuses American Hospital Association (AHA) Medicare hospital Area Health Resource File (AHRF) andcensus data to address study questions. Our analyses will identify and quantify potential unintended effects ofHACRP HRRP and HVBP on areas and populations outside the focus of these programs.

public_health_relevance:
The penalties and bonuses assessed under Medicare's current hospital Pay for Performance (P4P) programsfocus an unprecedented amount of attention on a limited set of performance metrics; this intense emphasismay create unintended consequences for areas that lie outside the focus of these programs. We propose tosee how the introduction of these hospital P4P programs may have affected a range of quality and safetyareas especially areas outside the focus of the programs using AHRQ's inpatient quality indicators (IQIs) andpatient safety indicators (PSIs). Our timely analyses will identify and quantify potential unintended effects ofHospital Readmission Reduction Program (HRRP) Hospital Acquired Condition Reduction Program (HACRP)and Hospital Value Based Purchasing (HVBP) program on areas and populations outside the focus of theseprograms.


application_id: 9980610
project_number: 7R21CA208206-03
administering_ic: NCI
award_notice_date: 2019-08-14
opportunity_number: PA-13-288
application_type: 7
activity_code: R21
ic: CA
serial_number: 208206
program_official: VOLLINGER, ROBERT
project_start_date: 2017-04-15
project_end_date: 2020-03-31
study_section: Community Influences on Health Behavior Study Section[CIHB]
contact_pi_person_id: 11156218
contact_pi: ROSE, SHYANIKA W
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-09
project_title:
Exposure to flavored tobacco advertising and associations with future use in young adults: implications for health equity

project_abstract:
PROJECT SUMMARYA potential ban on flavored tobacco products is a policy option to reduce tobacco product initiation by youth and youngadults. However few studies examine its potential to reduce disparities in vulnerable populations due to tobaccoadvertising exposure perceptions of flavored products and differential use.The purpose of this study is to addresshow targeted marketing of FTPs may influence perceptions of susceptibility to and initiation of tobacco in a vulnerablepopulation(recruited from 3 wards within Washington DC with the highest smoking rates % African American andlowest SES)(VP) vs. a non-vulnerable population (non-VP) of young adults in Washington DC. It will address thepotential of a policy ban or restrictions on flavored tobacco products to reduce tobacco and ultimately cancerdisparities and enhance equity in the distribution of tobacco marketing risk.The current study will build on theElaboration Likelihood Model (ELM) a model of cognitive processing of how advertising results in persuasion. TheELM suggests that one way tobacco advertising works is by linking tobacco to `peripheral cues' positive attributesincluding flavoring that may contribute to positive appraisal and lower harm perceptions of flavored products. Across asample of n = 256 VP and non-VP young adult non-tobacco users this multi-level study (store- and individual-level)will build on the ELM to examine differences in real-world exposure to FTP advertising emphasizing point of sale(POS) exposure using 14 days of ecological momentary assessment (EMA). It will examine the influence of exposureon self-reported perceptions of FTPs (lower harm more appeal). Participants will be assessed at 2-weeks and 6-months post-baseline to examine differential impacts of FTP advertising and attitudes on susceptibility intentions andtobacco use patterns (for FTPs and non-FTPs) as a function of VP group status. POS exposure will be validated byphotographs of tobacco advertising in stores visited by respondents. Our specific aims are to (1)Identify the frequencyof FTP and non-FTP advertising and number and types of products characterized by FTP descriptors (e.g. mentholcherry) in tobacco retailers visited by VP and non-VP young adults (2)Compare differences in harm perceptions andappeal of FTP vs non-FTP advertisements and descriptors across VP and non-VP young adults and (3) Examine thepredictive utility of FTP advertising and descriptor exposure on susceptibility intentions to use and initiation of FTPs(and non-FTPs) at 6-month follow-up across VP and non-VP young adults. This unique approach to triangulate dataat the store and individual cognitive level will yield timely information given the increase in use of FTPs and the need toidentify new policies and approaches to combat tobacco disparities in vulnerable groups. Achieving the aims of thisR21 will establish whether these associations exist and provide the foundation for a larger study developinginterventionscorrecting FTP misperceptions promoting FTP de-normalizationamong young adults and examiningthe likely impact of local policies to restrict FTP availability and advertisingparticularly in vulnerable communities. Thisstudy can also provide a basis for examining targeted marketing of other harmful products at POS.

public_health_relevance:
PROJECT NARRATIVEThis project seeks to address a potential cause of tobacco use and ultimately cancer disparities by examiningtargeted advertising of flavored tobacco products in vulnerable populations compared with a non-vulnerablepopulation of young adults in Washington DC. It also explores a potential solution through examination of arestriction or ban on flavored tobacco products (FTP) as a way to reduce disparities. This project links level ofexposure to FTP advertising and descriptors to: perceptions of harm and attractiveness of FTPs susceptibility tousing FTPs and initiation of FTP use and differences in these relationships across vulnerable group status.


application_id: 9980605
project_number: 7R03CA219737-03
administering_ic: NCI
award_notice_date: 2019-08-21
opportunity_number: PAR-16-416
application_type: 7
activity_code: R03
ic: CA
serial_number: 219737
program_official: HARTMAN, ANNE
project_start_date: 2017-07-15
project_end_date: 2020-05-31
study_section: ZCA1-SRB-5(M1)
contact_pi_person_id: 11156218
contact_pi: ROSE, SHYANIKA W
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-09
project_title:
Predicting menthol cigarette and flavored cigar smokers responses to menthol or flavored tobacco restrictions: results from experimental auctions

project_abstract:
PROJECT SUMMARYRestrictions on the availability of menthol cigarettes and flavored tobacco products can reduce smoking prevalenceand lead to reduced cancer risk. However these public health impacts can only occur if substantial proportions ofmenthol cigarette and flavored cigar smokers quit or if they cannot quit switch completely to lower harm products.Federal state and local policy makers and tobacco control advocates are considering a range of different mentholcigarette/flavored tobacco product restrictions. Understanding how best to structure policies to promote positivechanges among current flavored tobacco users is a critical need. Additionally self-reported measures of behavioralintention in response to policy may be subject to social desirability as well as lack of information about true effects ofpolicy change. The proposed study uses experimental auctions a behavioral economics paradigm to better predictmenthol cigarette and flavored cigar smokers behavioral intentions in response to various menthol cigarette/flavoredtobacco product policy options. The current tobacco product marketplace has expanded and there are a range ofpotential substitute products available to consumers. Given this expanded marketplace and variety of policy optionsthis study (1) uses menthol cigarette and flavored cigar smokers existing demand for a variety of potential productsubstitutes to estimate their likely policy response and (2) identifies factors associated with likely positive behavioralresponses of quitting or switching to a lower harm product among menthol cigarette and flavored cigar users. Drawingon behavioral economics theory the current study recruits 150 menthol cigarette and 150 flavored cigar users fromthe Washington DC area using an experimental auction paradigm to determine existing demand for a range ofpotential alternative products including menthol non-menthol and flavored cigarettes little cigars and e-cigarettesand nicotine gum under different policy restriction scenarios. Results can inform potential Federal state and localregulatory decisions about restrictions on menthol and flavored tobacco products and developing public healthmessages to better communicate and frame the benefits of potential menthol/flavored tobacco product policy changeto users. Findings will help the PI establish an independent research career in cancer control research and will providepreliminary data for an R01 of behavioral response to policy. This study will help policymakers and advocates toshape the types of policy options and communication strategies most likely to maximize public health benefits forcancer control.

public_health_relevance:
PROJECT NARRATIVEThe Federal government states and localities are considering policies to restrict the availability of mentholcigarettes and flavored tobacco products. These policies have the potential to have a significant public health andcancer control benefit if they are structured to encourage menthol cigarette and flavored cigar smokers to quit orswitch to less harmful products. The proposed study uses a behavioral economics experimental auction approachto better predict menthol cigarette (n=150) and flavored cigar smokers' (n=150) behavioral intentions if faced withmenthol cigarette/flavored tobacco restrictions. It will also examine individual factors associated with beneficialresponses to policy in order to better identify the types of policies that may be beneficial as well as ways to frameand communicate the benefits of policy change to flavored tobacco users.


application_id: 9980487
project_number: 5P01HL078825-14
project_title: Project 4 - Metabolic Regulation of Myocardial Repair
administering_ic: NHLBI
award_notice_date: 2020-07-25
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6153
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-09-01
project_abstract:
ABSTRACTResults of several preclinical studies and clinical trials suggest that cell therapy improves cardiac function aftermyocardial infarction; however high variability marginal efficacy and our poor understanding of themechanisms by which cell therapy works have precluded its clinical translation. One major knowledge gap is alack of understanding of how host metabolism impinges on the efficacy of cell therapy. This is importantbecause a pervasive feature of heart failure is insulin resistance a condition known to affect glucose transportin the myocardium as well as the function of circulating and tissue-resident stem cells. This dysfunction isfurther exacerbated by frank diabetes a condition inordinately common in HF patients. Therefore identificationof the metabolic factors that determine the efficacy of cell therapy is required to optimize cell therapy for HFpatients. In this project we will examine how diabetes affects cardiac repair induced by transplantation ofcardiac mesenchymal cells (CMCs) or paracrine factors derived therefrom. Our preliminary data indicate thatin contrast to CMCs isolated from non-diabetic mice CMCs isolated from diabetic mice fail to improve thefunction of the infarcted heart. The diabetic CMCs show elevated rates of glycolysis associated with expressionof Pfkfb3 which in cardiac progenitor cells increases glycolysis by augmenting phosphofructokinase activityand appears to diminish their proliferation and survival. In addition we find that these changes involve not onlyglycolytic mediators such as PFKFB3 but mitochondrial effectors such as sirtuin 1 (Sirt1) as well. Building onthese observations we propose to test the hypothesis that diabetes compromises the therapeutic efficacy ofCMCs by chronically increasing glycolysis which alters paracrine mechanisms that mediate cardiac repair andthat Sirt1 improves the repair capacity of CMCs by augmenting mitochondrial activity and thereby decreasingglycolysis. To test this hypothesis we will i) determine how diabetes affects CMC-mediated myocardial repairii) elucidate how glycolysis affects CMC repair competence and iii) develop strategies to improve CMC therapyin diabetes. This project will provide fundamental knowledge regarding how metabolic disease affects celltherapy and how mesenchymal cells adapt to nutrient stress. In addition these studies will illuminatemechanisms by which metabolism regulates paracrine factor secretion thereby generating novel biologicalunderstanding of cell-cell communication. Collectively the knowledge garnered from this project will facilitatethe optimization of cell therapy protocols and provide critical direction to ongoing clinical trials.

project_terms:
Affect;Autologous;Biological;Cardiac;Cause of Death;Cell Communication;Cell Proliferation;Cell Survival;Cell Therapy;Cell Transplantation;Cell secretion;Cells;Characteristics;Chronic;Clinical;Clinical Trials;Collaborations;Competence;Data;Defect;Diabetes Mellitus;Diabetic mouse;Family suidae;Functional disorder;Glucose;Glycolysis;Heart;Heart Transplantation;Heart failure;Hyperglycemia;Immune;Impairment;In Vitro;Insulin Resistance;Intervention;Knowledge;Mediating;Mediator of activation protein;Mesenchymal;Metabolic;Metabolic Diseases;Metabolic Pathway;Metabolism;Mitochondria;Modeling;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Nutrient;Outcome;Paracrine Communication;Patients;Pharmacology;Process;Property;Protocols documentation;Recovery of Function;Regulation;Role;SIRT1 gene;Stress;Testing;Tissues;Treatment Efficacy;Up-Regulation;Work;cardiac repair;clinical translation;comorbidity;cytokine;diabetic;diabetic patient;glucose metabolism;glucose transport;heart function;improved;improved functioning;improved outcome;in vivo;insight;ischemic cardiomyopathy;loss of function;negative affect;non-diabetic;novel;overexpression;paracrine;pre-clinical;preclinical study;repaired;response;senescence;stem cells

public_health_relevance:
PROJECT NARRATIVEHeart failure is a prevalent cause of death and a large proportion of heart failure patients are diabetic. In thisproject we will examine how diabetes impairs cardiac mesenchymal cell therapy and delineate ways toimprove cell therapy for diabetic patients with heart failure.


application_id: 9980485
project_number: 5P01HL078825-14
project_title: Project 3 - Cell Therapy and Remodeling
administering_ic: NHLBI
award_notice_date: 2020-07-25
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6152
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-09-01
project_abstract:
Despite the dearth of mechanistic insights into precisely how cell therapy works preclinical studies commonlyreport a reduction in fibrosis. Thus to understand how cell therapy limits remodeling we must first appreciatehow reparative cells interact with the stromal compartment. In the normal heart fibroblasts are essential inmaintaining the extracellular matrix. Following infarction fibroblasts assume an active role in acute woundhealing. Although this phenotypic activation is necessary for the acute post-ischemic injury responsefibroblasts become chronically activated which contributes to post-ischemic pathology. Project 3 will elucidatewhether and how cardiac mesenchymal cells (CMCs) interact with the recipient heart and will identify CMC-mediated changes in fibroblast activation. Because the post-MI heart is characterized by a shift in the balanceof hyaluronan (HA) metabolism in which more HA is produced than is degraded HA accumulation maycontribute to persistent fibroblast activation and support unresolved inflammation. Furthermore we reason thatcell therapy effects myocardial repair by restoring balance to dysregulated HA metabolism which is largelypropagated by activated fibroblasts. We will perform proof-of-concept studies to show whether and how HAmetabolizing enzymes in reparative cells may regulate their competence in in vivo models of post-ischemicmyocardial repair. We will identify specific receptor-ligand interactions that confer reparative competence totherapeutic cells. Although the aforementioned goals are worthy of pursuit on their own we argue they shouldbe examined further through a translational lens because preclinical studies of reparative cells use healthyanimals as cell donors; however clinical trials of autologous cells use heart failure (HF) patients as bothdonors and recipients. This preclinical/clinical dichotomy creates a sizeable translational barrier. Becausesignificant changes occur in the stromal compartment following infarction reparative cells derived therefromlikely differ from nave reparative cells. Indeed our preliminary data indicate that heart failure-derived CMCslack reparative competence which may stem from their inability to properly metabolize post-MI stromalcomponents such as HA. We will identify and correct defects in incompetent heart failure-derived CMCs.Thus our central hypothesis holds that reparative cells attenuate ventricular remodeling through recognition ofand response to specific stromal components which are lost in CMCs derived from failing hearts. We will testthis hypothesis through these synergistic aims: 1) Elucidate the impact of CMCs on fibroblast activation; 2)Determine how CMCs interact with the recipient heart to limit maladaptive remodeling; 3) Identify and rescuedefective mechanisms in heart failure-derived reparative cells. Thus we will show for the first time how CMCsshape the post-MI stroma to limit fibroblast activation. We will also identify reasons for reparativeincompetence in heart failure-derived CMCs and restore their competence by rescuing their capacity tometabolize HA. Collective insights from Project 3 will fundamentally change future cell therapy studies.

project_terms:
Acute;Address;Affect;Animals;Attenuated;Autologous;Binding;CD44 Antigens;CD44 gene;Cardiac;Cell Shape;Cell Therapy;Cell Transplantation;Cells;Chronic;Clinical;Clinical Trials;Collaborations;Competence;Data;Defect;Environment;Enzymes;Equilibrium;Event;Extracellular Matrix;Extravasation;Family suidae;Fibroblasts;Fibrosis;Future;Goals;Heart;Heart failure;Hyaluronan;Hyaluronidase;Infarction;Inflammation;Inflammatory;Injections;Leukocytes;Ligands;Logic;Mediating;Mesenchymal;Metabolism;Modeling;Mus;Muscle;Muscle Cells;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myofibroblast;Pathology;Patients;Phenotype;Positioning Attribute;Process;Production;Recording of previous events;Reporting;Response Elements;Role;Severities;Signal Transduction;Source;Stromal Cells;Testing;Therapeutic;Time;Ventricular Function;Ventricular Remodeling;Work;acute wound;clinical translation;effective intervention;gain of function;improved;in vivo Model;innovation;insight;interest;ischemic injury;lens;novel;paracrine;pre-clinical;preclinical study;programs;receptor;repaired;response;response to injury;stem;synergism;transdifferentiation;wound healing

public_health_relevance:
Cell therapy is a promising approach to limit the severity of heart failure. Unfortunately we have limitedunderstanding of precisely how cell therapy works to limit heart failure. This project will test new ideas related tohow cell therapy interacts with the failing heart to bring about repair of the muscle.


application_id: 9980484
project_number: 5P01HL078825-14
project_title: Project 2 - Role of Inflammation in CMC-Induced Myocardal Repair
administering_ic: NHLBI
award_notice_date: 2020-07-25
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6151
contact_pi_person_id: 11176762
contact_pi: WYSOCZYNSKI, MARCIN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-09-01
project_abstract:
The mechanism by which cell therapy improves cardiac function remains unclear. Although injected cellsminimally differentiate into cardiomyocytes or vessels and only a small fraction survive long term in therecipient common beneficial effects are observed regardless of injected cell type: improvement in pumpfunction reduction of fibrosis and enhanced angiogenesis. These results are consistent with the idea that celltherapy recruits endogenous repair mechanisms which however have not been identified. The immunesystem has been implicated in a variety of sterile diseases including processes regulating myocardial damageand repair. Although unresolved inflammatory processes controlled by infiltrating and tissue-resident immunecells worsen heart failure depletion of macrophages in the infarcted myocardium leads to LV rupture anddeath. Thus immune cells appear to play diametrically opposite roles in the heart. Macrophages have beenshown to be required for spontaneous regeneration of neonatal mammalian myocardium after injury andrecent findings implicate them as direct contributors to cell therapy-mediated myocardial repair. Neverthelesshow immune cells regulate myocardial repair and what determines their harmful versus salutary actionsremains unknown. Furthermore the impact of cell therapy on reparative immune cells has not yet been studiedin the heart. Our preliminary data show that injection of cardiac mesenchymal cells (CMCs) into the infarctedheart promotes accumulation of reparative macrophages. Thus the central hypothesis of this proposal is thatCMCs facilitate recruitment of monocytes and activation of reparative macrophages which are essentialendogenous mediators of repair. By generating detailed flow cytometric analyses of immune cell populationsfollowing CMC administration we will not only resolve the time course of immune cell recruitment but alsodetermine how inflammation is eventually extinguished in the heart after cell therapy. To elucidate themechanism whereby CMCs regulate inflammatory processes in monocyte-derived macrophages we willdetermine how these cells regulate NFB-p65 subunit expression with emphasis on horizontal transfer ofmiRNAs to macrophages through CMC-derived EVs. Finally using macrophage genetic fate mapping andgenetically modified CMCs we will elucidate the role of monocyte-derived macrophages in CMC-inducedmyocardial repair. This project will be the first systematic analysis of how cell therapy modulates immune cells a mechanism that has been relatively understudied. The results will provide novel insights not only into themechanisms regulating cell therapy-mediated myocardial repair but also into how endogenous reparativeactivities of macrophages are recruited. We will also determine whether EVs recapitulate the salutary effects ofCMCs on immune cells. Thus these studies have far-reaching implications for our understanding of how theimmune system regulates myocardial homeostasis in general.

project_terms:
Affect;Bone Marrow;Cardiac;Cardiac Myocytes;Cardiovascular system;Cell Therapy;Cells;Cessation of life;Clinical;Clinical Research;Coculture Techniques;Data;Diabetes Mellitus;Disease;Fibrosis;Gene Expression;Genetic;Heart;Heart failure;Homeostasis;Homo;Immune;Immune response;Immune system;In Vitro;Infiltration;Inflammation;Inflammatory;Injections;Injury;Knowledge;Left;Left Ventricular Function;Left ventricular structure;Mediating;Mediator of activation protein;Mesenchymal;MicroRNAs;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Natural regeneration;Nature;Neonatal;Outcome;Patients;Phenotype;Play;Population;Process;Proliferating;Pump;Role;Rupture;Signal Transduction;Spleen;Sterility;Surface;TNFRSF5 gene;Testing;Time;Tissues;Transgenic Organisms;Ventricular;angiogenesis;base;cardiac repair;cell type;extracellular vesicles;heart function;immunomodulatory therapies;improved;in vivo;inhibitor/antagonist;insight;macrophage;monocyte;myocardial damage;novel;p65;preclinical study;programs;recruit;repaired;response;synergism

public_health_relevance:
PROJECT 2 NARRATIVEThe immune system is an important component of myocardial repair after myocardial infarction. In this projectwe will examine how CMC treatment affects the immune system and delineate strategies to improve celltherapy for patients with heart failure.


application_id: 9980483
project_number: 5P01HL078825-14
project_title: Project 1 - Repeated Cell Therapy for Heart Failure: A New Paradigm
administering_ic: NHLBI
award_notice_date: 2020-07-25
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6150
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-09-01
project_abstract:
The therapeutic benefits of cell-based treatments have often been regarded as modest borderline or nil. As aresult clinical translation has not occurred and considerable uncertainty and skepticism surround the conceptof cell therapy. A major factor limiting the benefits of cell therapy (regardless of cell type) is the poorengraftment of the cells which disappear rapidly after transplantation; because of this we propose thatadministering one dose of cells cannot be considered an adequate test of efficacy. However almost allpreclinical and clinical studies of cell therapy performed heretofore have based their assessment of efficacy onthe outcome of one cell administration. Our work in the current PPG has shown that 3 doses of c-kitPOScardiac progenitor cells (CPCs) are strikingly (~3 times) more effective than 1 dose in improving LV function.Building on this prior work we will test the idea that the problem of poor engraftment can be overcome byrepeated cell administrations. We have recently discovered a new population of cells cardiac mesenchymalcells (CMCs) that appear to be more suitable for widespread use and to have greater therapeutic potentialthan CPCs. Consequently we will focus this proposal on CMCs. The overall goal of Project 1 is tothoroughly evaluate the therapeutic effectiveness and mechanism of action of repeated doses ofCMCs. Our central hypothesis is that repeated administrations of CMCs dramatically increase the beneficialeffects of cell therapy not only in mice but also in large preclinical animal models (pigs) and in the presence ofmajor co-morbidities (diabetes) via mechanisms that involve the cumulative effects elicited by repetitive burstsof extracellular vesicle (EV) release resulting in cumulative favorable modulation of the inflammatory andfibrotic response to CMC transplantation. The specific Aims are: 1) To establish the most effective protocols foradministering repeated doses of CMCs or CMC-derived EVs. We will determine how the effects of repeateddoses can be maximized by varying the number of doses and the interval between doses and the impact ofdiabetes. 2) To generate data necessary for Phase I clinical trials of repeated CMC or EV therapy in patientswith heart failure. Using a preclinical porcine model we will assess the effects of repeated administrations ofCMCs or EVs and identify the optimal doses. 3) To elucidate the mechanism of action of repeated doses ofCMCs and EVs including their effect on the inflammatory and fibroblast response to infarction. Throughoutthese studies the effects of EVs will be compared with those of CMCs to determine whether cell-free EVtherapy recapitulates the benefits of CMC therapy. This Project will test two potentially disruptive ideas: i) theconcept that the full effects of cell or EV therapy require repeated doses would constitute a major paradigmshift with potentially vast implications for the entire field of reparative medicine; ii) the concept that theeffects of cell therapy can be reproduced with cell-free administration of EVs would revolutionize the field.These studies will lay the groundwork necessary for first-in-human trials of repeated CMC/EV administration.

project_terms:
Ablation;Advocate;Animal Model;Cardiac;Cell Therapy;Cell Transplantation;Cells;Chronic;Clinical Research;Clinical Trials;Collaborations;Data;Diabetes Mellitus;Diabetic mouse;Dose;Engraftment;Family suidae;Fibroblasts;Genetic;Goals;Heart;Heart Transplantation;Heart failure;Immune response;Infarction;Inflammatory;Left Ventricular Remodeling;Mesenchymal;Metabolic;Modeling;Mus;Myocardial Infarction;Myocardial Ischemia;Myocardium;Outcome;Patients;Phase I Clinical Trials;Population;Proteins;Protocols documentation;Research;Research Design;Route;Testing;Therapeutic;Therapeutic Effect;Time;Transplantation;Treatment Efficacy;Uncertainty;Vesicle;Work;base;cell type;clinical translation;clinically relevant;comorbidity;efficacy testing;extracellular vesicles;first-in-human;heme oxygenase-1;improved;in vivo;inflammatory modulation;ischemic cardiomyopathy;mouse model;novel;overexpression;pre-clinical;preclinical study;reparative medicine;response;stem cells;therapeutic effectiveness;transcriptome;vesicular release

public_health_relevance:
Project 1 will determine whether repeated doses of cardiac mesenchymal cells exert cumulativebeneficial effects that make them much more effective than a single dose. It will also determinewhether cell-free administration of vesicles secreted by the cells can reproduce the effects ofthese cells. These studies will lay the groundwork necessary for first-in-human trials; if either ofthese ideas proves correct it would constitute a major paradigm shift with potentially vastimplications that would revolutionize the entire field of reparative medicine.


application_id: 9980482
project_number: 5P01HL078825-14
project_title: Core D - Pathology and Flow Cytometry Core
administering_ic: NHLBI
award_notice_date: 2020-07-25
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6149
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-09-01
project_abstract:
The function of the Flow Cytometry and Pathology (Core D) is to provide each Project with the expertiseequipment and facilities required for the flow cytometric analyses cell sorting and pathological analyses thatare needed for studies of cardiac mesenchymal cells (CMCs) and extracellular vesicles (EVs). Accurateidentification characterization and quantitation of cells in a complex heterogeneous population are technicallydemanding and require specialized and expensive equipment and personnel. One of the major advantages ofthis Program Project is that it will make available to all four Projects the facilities and techniques of flowcytometry and cell sorting which otherwise would not be affordable to any Project in isolation. Flow cytometry-based analysis for the identification of specific cell populations changes in cell commitment or phenotype andcharacterization of cell functions such as cell cycle viability or signal transduction will be crucial to allProjects. A central common facility that performs these technically challenging analyses is thereforeindispensable to achieve the goals of the Program Project. Besides the obvious advantages of efficiency andcost savings the Core will also enable four investigators with diverse and complementary backgrounds (Drs.OToole Moore Li and Ratajczak) to combine their technical and biological expertise in order to ensure thatthe proposed work is successfully executed. The Core will offer the Program Project investigators the ability toidentify and characterize specific cell types from complex populations. It will also offer the facilities andexpertise necessary to perform the comprehensive histopathologic/immunohistochemical analyses required forthis Program. The uniform histopathologic analyses conducted by the Core in a blinded and rigorouslystandardized fashion will make it possible to compare results of different experiments within the same Projectand among different Projects.Core D will be the continuation of the Flow Cytometry Core in the current funding cycle (led by Dr. OToole)and of the intense and productive ongoing collaboration in flow cytometry and pathology between Dr. OTooleand the other PPG investigators. The function of Core D is to provide all four Projects with the expertiseequipment facilities reagents procedures and analyses needed for flow cytometry sorting and pathologywork. Specifically the Core will i) perform the flow cytometric analyses and cell sorting procedures required forstudies of CMCs and EVs ii) perform tissue processing histopathology and immunohistochemistry of cardiacsamples and iii) make available to the four Projects the tremendous experience and expertise of the Corepersonnel.

project_terms:
American Heart Association;Antibodies;Biochemistry;Biography;Biological;Blinded;Bone Marrow;Budgets;Calibration;Cardiac;Cell Culture Techniques;Cell Cycle;Cell Separation;Cell Therapy;Cell physiology;Cells;Centers of Research Excellence;Collaborations;Collection;Complex;Computer software;Confocal Microscopy;Core Facility;Cost Savings;Data Analyses;Diabetes Mellitus;Doctor of Medicine;Doctor of Philosophy;Ensure;Equipment;Experimental Designs;Financial compensation;Flow Cytometry;Funding;Goals;Heart;Heart failure;Histology;Histopathology;Human Resources;Immunofluorescence Microscopy;Immunohistochemistry;Inflammatory;Institutes;International;Investigation;Laboratories;Maintenance;Mesenchymal;Molecular Biology Techniques;Myocardial Ischemia;Myocardial tissue;Obesity;Pathologic;Pathology;Phenotype;Population;Population Heterogeneity;Procedures;Protocols documentation;Reagent;Regulation;Research Personnel;Rodent Model;Running;Sampling;Signal Transduction;Sorting - Cell Movement;Stains;Standardization;Supervision;Techniques;Tissue Sample;Tissues;Tobacco;Training;United States National Institutes of Health;Universities;Work;addiction;analytical tool;base;cell type;experience;experimental study;extracellular vesicles;instrument;light microscopy;member;operation;programs;skills;stem;stem cell biology;stem cells;tissue processing

public_health_relevance:
The Flow Cytometry and Pathology Core will provide each Project with the expertiseequipment and facilities required for the study and separation of cells by flow cytometry and forthe pathological analyses of tissue samples obtained from the heart after cell therapy. The Corewill ensure that the analyses of cells and tissues are done expertly efficiently and consistently


application_id: 9980481
project_number: 5P01HL078825-14
project_title: Core C - Cell Biology Core
administering_ic: NHLBI
award_notice_date: 2020-07-25
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6148
contact_pi_person_id: 8307878
contact_pi: LI, QIANHONG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-09-01
project_abstract:
The Cell Biology Core will be a critical resource to this PPG. It will provide the four Projects with access to awide array of reagents procedures and analyses including fully characterized cardiac mesenchymal cells(CMCs) and CMC-derived extracellular vesicles (CMC-EVs hereafter referred to as EVs) isolated from miceand pigs assays of CMC function in vitro and characterization of EVs (e.g. arrays of EV-related non-codingRNAs particle size analysis protein assays). Specifically the Core will i) isolate CMCs from mouse and pighearts; ii) perform comprehensive CMC characterization including proliferation population doubling timemorphometric analysis (cell length and area) clonogenicity analysis of marker expression secretomeanalysis and gene profiling; iii) isolate EVs from mouse and pig CMCs; iv) perform characterization of EVsincluding particle size analysis validation of markers expression and RNA and protein profiling; v) isolate cellsutilizing multiple markers; vi) assess cell viability; vii) determine changes in cell signaling; and viii) quantify cellsat each phase of the cell cycle. The individual Projects do not have the facilities or expertise needed to isolateand characterize CMCs consistently or to perform the extensive EV characterizations. Consolidation of allCMC/EV work into a Core facility will decrease the costs of supplies and equipment because the Core willmake bulk purchases of supplies (thereby reducing expenses) and because waste and unnecessaryduplication of supplies reagents and equipment will be eliminated with the maintenance of centralized stocksand inventories. Consolidating CMC/EV work into a Core facility is also time-effective because the techniquesinvolved in this work are very labor intensive and require dedicated skilled personnel. Core C will makeavailable to the four Projects the tremendous experience and expertise of the Core personnel in thepreparation and analysis of CMCs and EVs. The Core staff a strong team of dedicated individuals under theimmediate supervision of the Core Leader will provide consistency and reproducibility of analysis. This iscrucial because it will ensure that all four Projects will use CMCs isolated and expanded the same waythereby making the results comparable. A single source of CMCs and EVs with rigorous standardization toensure consistency will result in transplantation of uniform CMC and EV populations in all four Projects andthus is extremely important for the integration and comparison of results from each of the Projects. This willmake it possible to compare results of different experiments within the same Project and among differentProjects. In summary the Core will ensure quality control and by eliminating duplication of effort and maximizingthe use of personnel and supplies will enable an efficient use of resources.

project_terms:
Area;Biochemical;Biography;Bioinformatics;Biological Assay;Biological Markers;Biology;Bone Marrow;Budgets;Cardiac;Cell Culture Techniques;Cell Cycle;Cell Survival;Cell Therapy;Cell physiology;Cells;Cellular biology;Collaborations;Core Facility;Data Analyses;Databases;Disease model;Doctor of Medicine;Doctor of Philosophy;Ensure;Equipment;Equipment and Supplies;Equipment and supply inventories;Experimental Designs;Family suidae;Flow Cytometry;Foundations;Funding;Gene Expression;Gene Expression Regulation;Gene Transfer;Genes;Grant;Heart;Human;Human Resources;Immunology;In Vitro;Individual;Institutes;International;Leadership;Length;Maintenance;Mesenchymal;Methods;MicroRNAs;Molecular;Molecular Biology;Molecular and Cellular Biology;Mus;Myocardial Ischemia;Particle Size;Pathway Analysis;Phase;Population;Preparation;Procedures;Production;Proteins;Protocols documentation;Quality Control;RNA;Rattus;Reagent;Reproducibility;Research;Research Personnel;Resources;Role;Signal Transduction;Solid;Source;Span 20;Standardization;Structure of thyroid parafollicular cell;Supervision;Techniques;Time;Training;Transplantation;United States National Institutes of Health;Universities;Untranslated RNA;Work;biomarker validation;cost;experience;experimental study;extracellular vesicles;large datasets;progenitor;protein profiling;skills;stem;stem cell biology;stem cells;success;vector;wasting

public_health_relevance:
The Cell Biology Core will provide the four Projects with a uniform source of cardiacmesenchymal cells (CMCs) and CMC-derived extracellular vesicles. It will provide uniformassays of CMC function in vitro and characterization of EVs.


application_id: 9980480
project_number: 5P01HL078825-14
project_title: Core B - Mouse Surgery and Physiology
administering_ic: NHLBI
award_notice_date: 2020-07-25
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6147
contact_pi_person_id: 8251726
contact_pi: GUO, YIRU
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-09-01
project_abstract:
The function of the Surgery and Physiology Core (Core B) is to provide the expertise equipment and facilitiesneeded for all of the in vivo murine and porcine studies. Specifically Core B will be responsible for all surgicaland cardiac catheterization procedures (coronary artery occlusion/reperfusion delivery of cardiacmesenchymal cells [CMCs] delivery of CMC-derived extracellular vesicles [EVs] and endomyocardialbiopsies) echocardiographic analyses invasive hemodynamic studies magnetic resonance imaging studiesand maintenance and genotyping of transgenic and knockout mouse lines. Accurate physiologicalmeasurements and surgical procedures in mice represent technically demanding tasks that cannot and shouldnot be attempted in every laboratory but rather should be performed by a group of dedicated investigatorswho focus on studies in mice and thereby acquire extensive experience with this difficult model. Similarlystudies in large animals such as the pig are complex expensive and technically challenging and requireexperienced and skilled investigators and staff. One of the main advantages of this Program Project is that itprovides all four Projects with access to complex and technically challenging in vivo mouse and pig models ofmyocardial infarction (MI) and cell therapy expert physiology and surgery and state-of-the-art techniques thatotherwise would not be available to these investigators. This is a major benefit to all investigators. Core Bconsists of a team of skilled highly-experienced investigators who have worked together cohesively for manyyears focusing exclusively on murine and porcine studies (Dr. Guo has performed >31000 surgical proceduresin mice and Dr. Tang >600 procedures in pigs) have developed and perfected murine and porcine models ofMI and cell therapy utilizing state-of-the-art facilities and equipment and have collaborated extensively with theother investigators in this PPG. An important feature of Core B is that it will use a new technique for deliveringCMCs  percutaneous intraventricular infusion in the mouse which was recently developed in our lab.Compared with standard intramyocardial injection percutaneous intraventricular infusion offers the advantageof enabling repeated cell administrations in the same mouse with very low mortality. Another feature is that allechocardiographic hemodynamic and MRI analyses will be performed off-line by blinded observers. Thecapacity of the Core has been tested during the current funding cycle. In the past 5 years the Core hassuccessfully assisted all four Projects resulting in a total of 27 full-length original papers and has performed atotal of 4654 procedures in 5029 mice (including 2964 transgenic/knockout mice provided by our transgenicfacility). These procedures include 2029 coronary occlusion/reperfusion protocols 1060 injections of cells orvehicle 333 implantations of minipumps for BrdU/IdU delivery 1396 echocardiograms and 291 invasivehemodynamic studies. These numbers eloquently illustrate the research output that the Core can produce.

project_terms:
Animal Disease Models;Animals;Biography;Biopsy;Blinded;Breeding;Bromodeoxyuridine;Budgets;Cardiac;Cardiac Catheterization Procedures;Cardiovascular Physiology;Cardiovascular system;Catheterization;Catheters;Cell Therapy;Cells;Collaborations;Complex;Coronary Occlusions;Data Analyses;Data Collection;Development;Doctor of Medicine;Doctor of Philosophy;Echocardiography;Equipment;Family suidae;Funding;Future;Genotype;Heart failure;Human Resources;Injections;Intraventricular Infusion;Knock-out;Knockout Mice;Laboratories;Left Ventricular Function;Left Ventricular Remodeling;Length;Magnetic Resonance Imaging;Maintenance;Measurement;Mesenchymal;Modeling;Mus;Myocardial Infarction;Myocardial Ischemia;Operative Surgical Procedures;Output;Paper;Physiological;Physiology;Pressure Transducers;Procedures;Protocols documentation;Quality Control;Radiology Specialty;Reperfusion Therapy;Research;Research Personnel;Study of magnetics;Supervision;Techniques;Testing;Transgenic Mice;Transgenic Organisms;Translational Research;Universities;Work;cohesion;coronary artery occlusion;experience;experimental study;extracellular vesicles;heart function;heart imaging;hemodynamics;imaging program;imaging scientist;imaging study;implantation;in vivo;molecular imaging;mortality;mouse model;pressure;programs

public_health_relevance:
The function of the Surgery and Physiology Core is to provide the expertise equipment andfacilities needed for all of the in vivo studies in mice and pigs. Specifically Core B will beresponsible for all surgical and cardiac catheterization procedures and all echocardiographichemodynamic (catheterization) and magnetic resonance imaging studies in these animalmodels of disease.


application_id: 9980479
project_number: 5P01HL078825-14
project_title: Administrative Core
administering_ic: NHLBI
award_notice_date: 2020-07-25
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6146
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-09-01
project_abstract:
Core A will provide scientific budgetary administrative logistic and biostatistical oversight to all aspects ofthe Program Project. The Core will facilitate communication among investigators and sharing of reagentstools specimens and data; will ensure appropriate allocation of funds to each Project and appropriate use ofthese funds; will provide clerical support; will coordinate the Projects with subcontracted institutions; willorganize regular investigator meetings; and will provide biostatistical assistance. Dr. Bolli Core Leader will beresponsible for the overall coordination integration and administration of the Program Project for theappropriate utilization of the funds for compliance with institutional and federal regulations for the scientificproductivity of the Program and for any issues related to the Program. The Principal Investigator will beassisted by the other members of the Executive Committee which will be composed of the four ProjectLeaders and the four Core Leaders. The Principal Investigator and the executive Committee will meet on amonthly basis to discuss the scientific progress data problems and future directions for the four Projects.Scientific responsibilities include (1) providing leadership in maintaining the focus of the investigators (2)providing statistical assistance and (3) weekly meetings of all Program Project Investigators. Administrativeand financial responsibilities include (1) implementing guidelines for PPG support (2) administering thebudget according to NIH guidelines (3) monitoring budgets for each Project and Core and (4) ensuringcompliance with the institutional and NIH regulations. The Biostatistician working in the Core will be Dr. MaiyingKong. She will attend the monthly meetings of the Executive Committee review the experimental dataanalyze them calculate group sizes and ensure that all studies are performed with rigor. Indeed an importantaspect of this Program Project is that in all in vivo studies proposed in this Project we will adhere strictly to theprocedures that we used in the CAESAR Consortium. Specifically: i) all animals will be allocated to treatmentgroup randomly (randomization will be performed by Dr. Kong); ii) all investigators will be blinded to treatmentallocation until the final data analysis is released by Dr. Kong; iii) exclusion criteria will be established a prioribefore the experiments are started not during or after the experiments; iv) group sizes will be determined apriori before the experiments are started (based upon power analysis by Dr. Kong) and will not be changedduring or after the experiment; v) the experiments will be carried out until the predetermined sample sizes areachieved without any knowledge of interim results. After the predetermined sample sizes are achieved alldata will be given to Dr. Kong where they will be unblinded and analyzed by appropriate statistical methods.These are the same procedures that we have used successfully in CAESAR for the past six years. Use ofthese methods will ensure rigor and greatly reduce the chance of spurious or misleading results.

project_terms:
Animals;Basic Science;Biography;Biological Markers;Biometry;Biostatistics Core;Blinded;Budgets;Cardiac;Cardiology;Cardiotonic Agents;Cardiovascular system;Cell Therapy;Cells;Clinical Trials;Communication;Data;Data Analyses;Effectiveness;Ensure;Environment;Exclusion Criteria;Faculty;Family suidae;Funding;Future;Goals;Grant;Growth;Guidelines;Human Resources;Individual;Infrastructure;Institutes;Institution;Knowledge;Laboratories;Laboratory mice;Leadership;Logistics;Medicine;Mesenchymal;Methods;Mission;Molecular;Monitor;Myocardial Ischemia;National Heart Lung and Blood Institute;Personality;Principal Investigator;Procedures;Productivity;Protocols documentation;Randomized;Reagent;Regulation;Research;Research Personnel;Research Project Grants;Resources;Sample Size;Scientist;Services;Specimen;Standardization;Statistical Methods;Therapeutic Studies;Time;United States National Institutes of Health;Work;base;cardioprotection;experience;experimental study;in vivo;meetings;member;multidisciplinary;next generation;power analysis;pre-clinical;preclinical study;programs;student training;tool;treatment group


application_id: 9980476
project_number: 5P01HL078825-14
project_title: Protection of Ischemic Myocardium
administering_ic: NHLBI
award_notice_date: 2020-07-25
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2004-12-01
project_end_date: 2022-08-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP(JH)]
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
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:
Clinical translation of cell therapy has been hindered by i) lack of understanding of basic mechanisms and ii)borderline or inconsistent results in clinical trials. The overarching objective of this renewal application is todirectly address these two problems; specifically to advance our understanding of the mechanism of action ofcell therapy and to develop strategies that optimize its therapeutic efficacy. We will focus on cardiacmesenchymal cells (CMCs) a promising new population of heart-derived cells that we have recentlydiscovered and that appears to be particularly suitable for clinical translation. Four closely inter-related andinter-dependent Projects will address different facets of this theme. Project 1 (Bolli) will carefully evaluate theuse of repeated treatments to maximize therapeutic benefit including translational studies in a preclinicalporcine model. The central hypothesis is that repeated administrations of CMCs dramatically increase thebeneficial effects of cell therapy via repetitive bursts of extracellular vesicle (EV) release. Project 2(Wysoczynski) will elucidate the role of immune cells in mediating the beneficial effects of cell therapy and testthe hypothesis that CMCs and EVs facilitate recruitment of monocytes and activation of reparativemacrophages which are endogenous mediators of repair. Project 3 (Jones) will illuminate the role of thestromal compartment (including fibroblast activation and hyaluronan metabolism) in the reparative actions ofCMCs and EVs and identify and correct defects in CMCs rendered incompetent by heart failure (HF). Theoverarching hypothesis is that CMCs attenuate remodeling by favorably enhancing hyaluronan metabolismwhich is defective in HF. Project 4 (Bhatnagar) will determine how diabetes affects CMC-mediated myocardialrepair and how CMC therapy can be optimized for the diabetic heart. The central hypothesis is that diabetescompromises the therapeutic efficacy of CMCs by increasing glycolysis which alters paracrine mechanismsand that Sirt1 improves CMC repair capacity by decreasing glycolysis. Thus all four Projects focus cohesivelyon CMCs. These Projects will be supported by four Cores that will provide expertise in mouse and pig surgerycell transplantation CMC culture and phenotyping pathology flow cytometry and cell sorting. This highly-focused PPG will be led by investigators who have collaborated productively for many years. Their long historyof collaboration has resulted in closely integrated Projects that are ideally suited for a PPG. Throughout thefour Projects the effects of CMCs will be systematically compared with those of EVs. These will be the firststudies to systematically examine the effects of repeated doses and the role of immune and stromal cellsglycolysis and Sirt1 in the salubrious effects of cell therapy; thus the results will be entirely new. The pigstudies (3 Projects) will lay the groundwork for translational investigations of CMC therapy in patients with HF.This PPG may generate disruptive new knowledge including two new therapeutic paradigms (repeatedtreatments and use of cell-free EV products) either of which in itself would revolutionize cell therapy.

project_terms:
Address;Affect;Animal Model;Animals;Attenuated;Autologous;Cardiac;Catabolism;Cell Culture Techniques;Cell Separation;Cell Therapy;Cell Transplantation;Cells;Chronic;Clinical Trials;Collaborations;Competence;Data;Defect;Diabetes Mellitus;Diabetic mouse;Dose;Engraftment;Event;Family suidae;Fibroblasts;Flow Cytometry;Funding;Glycolysis;Goals;Heart;Heart failure;Hyaluronan;Immune;Immune response;Infarction;Inflammation;Intervention;Investigation;Knowledge;Left Ventricular Remodeling;Mediating;Mediator of activation protein;Mesenchymal;Metabolic;Metabolism;Mitochondria;Modeling;Molecular;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Operative Surgical Procedures;Paracrine Communication;Pathology;Patients;Phenotype;Population;Property;Recording of previous events;Regulation;Research Design;Research Personnel;Role;SIRT1 gene;Stromal Cells;Study models;Testing;Therapeutic;Therapeutic Effect;Therapeutic Intervention;Time;Translations;Treatment Efficacy;Treatment Protocols;cardiac repair;cell type;clinical application;clinical translation;cohesion;comorbidity;diabetic;effective therapy;extracellular vesicles;first-in-human;heart function;immunomodulatory therapies;improved;improved outcome;inflammatory modulation;insight;ischemic injury;macrophage;monocyte;non-diabetic;novel;novel therapeutics;paracrine;pre-clinical;preclinical study;programs;recruit;repaired;reparative medicine;response;stem;tool;translational study;vesicular release;virtual

public_health_relevance:
The goal of this application is to study cardiac mesenchymal cells (CMCs) a promising newpopulation of heart-derived cells that we have recently discovered and that appears to beparticularly suitable for clinical application. The overall objective of this renewal application is toadvance our understanding of the mechanism of action of CMCs and to develop strategies thatoptimize their efficacy for treating heart failure caused by a heart attack (myocardial infarction).The results of these studies will lay the groundwork for first-in-human clinical trials of CMCs.


application_id: 9980359
project_number: 5F30DE028166-03
project_title: Regulation of ZEB1 by Porphyromonas gingivalis in gingival epithelial cells
administering_ic: NIDCR
award_notice_date: 2020-08-04
opportunity_number: PA-18-673
application_type: 5
activity_code: F30
ic: DE
serial_number: 028166
program_official: FRIEDEN, LESLIE A
project_start_date: 2018-09-01
project_end_date: 2022-08-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 14903180
contact_pi: FITZSIMONDS, ZACKARY R
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryOral cancer is the 11th most frequently diagnosed cancer in the world and due to its late diagnosis it has anapproximately 50% survival rate after 5 years. Metastasis is meditated through Epithelial to MesenchymalTransition (EMT) which is the process by which epithelial cells lose their tight junctions and apical/basal polarityand shift to a more invasive mesenchymal phenotype giving the cancer cells systemic access through invasionof the bloodstream. EMT is mediated through several transcriptional factors however we will focus on ZEB1.Porphyromonas gingivalis is an oral obligate anaerobe that when present shifts the host/microbe relationshipfrom synergy to a more dysbiotic environment which contributes to periodontal disease. P. gingivalis has beenshown to invade gingival epithelial cells and once inside the cells can inhibit apoptosis ramp up the cell cycleand more recently by our lab has been shown to upregulate ZEB1. Although we are beginning to understand thepotential oncogenic role of P. gingivalis we do not currently know how ZEB1 is regulated by P. gingivalis ingingival epithelial cells. Our preliminary data suggests that this regulation is occurring through SMAD signalingregulation and through the long non-coding RNA ZEB1-AS1. SMAD signaling is a branch of the TGF-b signalingpathway which during embryonic development is responsible for producing mesenchymal cells from the initialepithelium. SMAD signaling occurs by phosphorylation of SMAD2/3 by the TGF-b receptor followed by theformation of a transcriptional regulatory trimer by SMAD2/3 and SMAD4 and finally nuclear localization andupregulation of ZEB1. Additionally ZEB1 can bind to SMAD2/3 and SMAD4 to form a ZEB1/SMAD trimer toregulate ZEB1 transcription. We have found that P. gingivalis upregulates the regulatory SMAD3 which suggestsP. gingivalis is able to intercept this pathway to upregulate ZEB1. We have also found that P. gingivalisupregulates ZEB1-AS1 which has been shown in hepatocarcinoma and esophageal squamous cell carcinomato directly upregulate ZEB1 and our preliminary data supports this as knocking down ZEB1-AS1 leads toabrogation of ZEB1 regulation by P. gingivalis in gingival epithelial cells. We will investigate mechanisms ofregulation by ZEB1-AS1 including direct promotion of gene expression in the nucleus through binding to P300and/or control of ZEB1 mRNA stability. EMT regulation is a complex process that involves integration of severalhost signaling pathways so we also suspect that ZEB1-AS1 will be integrated with SMAD signaling by potentiallyacting as a scaffold for SMAD3. Developing a better understanding of P. gingivalis mediated EMT will lay thefoundation for future studies to target these regulatory mechanisms for diagnosis and treatment and ultimatelyreduce the 50% chance of survival current patients have 5 years after diagnosis.

project_terms:
Amanitins;Anaerobic Bacteria;Apical;Apoptosis;Binding;Biopsy;Blood Circulation;Cancer Patient;Cell Cycle;Cell Cycle Progression;Cell Nucleus;Cells;Co-Immunoprecipitations;Complex;Data;Development;Diagnosis;E-Cadherin;E1A-associated p300 protein;Embryonic Development;Environment;Epidemiology;Epithelial;Epithelial Cells;Epithelium;Esophageal Squamous Cell Carcinoma;Family;Foundations;Future;Gene Expression;Genes;Genetic Transcription;Germ Cells;Gingiva;Homeobox;Human;Immunofluorescence Immunologic;Immunohistochemistry;Immunoprecipitation;Intercept;Invaded;Knowledge;Laboratories;Lead;Literature;Luciferases;MADH2 gene;MADH3 gene;MADH4 gene;MADH6 gene;MADH7 gene;MMP9 gene;Malignant Neoplasms;Measures;Mediating;Mesenchymal;MicroRNAs;Migration Assay;Molecular;N-Cadherin;Neoplasm Metastasis;Nuclear;Oncogenic;Oral;Oral cavity;Pathway interactions;Patients;Periodontal Diseases;Periodontitis;Phenotype;Phosphorylation;Plasmids;Play;Porifera;Porphyromonas gingivalis;Primary carcinoma of the liver cells;Process;Property;Quantitative Reverse Transcriptase PCR;RNA;RNA Synthesis Inhibitors;Ramp;Regulation;Role;Sampling;Signal Pathway;Signal Transduction;Speed;Survival Rate;TGF Beta Signaling Pathway;Testing;Tight Junctions;Time;Tongue Neoplasms;Transcription Coactivator;Transforming Growth Factor beta Receptors;Translating;Untranslated RNA;Up-Regulation;Western Blotting;Zinc Fingers;arm;cancer cell;cancer diagnosis;differential expression;dysbiosis;epithelial to mesenchymal transition;expression vector;genetic corepressor;host-microbe interactions;human tissue;knock-down;mRNA Expression;mRNA Stability;malignant mouth neoplasm;mouth squamous cell carcinoma;new therapeutic target;novel;novel diagnostics;novel therapeutics;outcome forecast;overexpression;prevent;promoter;recruit;response;scaffold;synergism;transcription factor;tumor

public_health_relevance:
Project NarrativeOral Cancer is the eleventh most frequently diagnosed cancer in the world and has approximately a 50% survivalrate 5 years post diagnosis. In this project we will study the intricate molecular interplay between Porphyromonasgingivalis and gingival epithelial cells and how this can lead to an environment conducive to cancer. This projecthas the potential to identify novel contributors to oral cancer and could potentially lead to novel therapeutics inthe future.


application_id: 9979792
project_number: 5R37CA229337-03
project_title: Adoption of Smoke-free Laws and Voluntary Policies in Rural Communities in Southern States
administering_ic: NCI
award_notice_date: 2020-07-31
opportunity_number: PAR-17-217
application_type: 5
activity_code: R37
ic: CA
serial_number: 229337
program_official: REYES-GUZMAN, CAROLYN
project_start_date: 2018-08-01
project_end_date: 2021-07-31
study_section: Special Emphasis Panel[ZRG1-RPHB-N(56)R]
contact_pi_person_id: 11363954
contact_pi: FALLIN-BENNETT, AMANDA
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 NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractSmoking remains high in Americas rural southern population despite rapid declines in other regions of the U.S.in recent decades. While 58.3% of U.S. citizens are covered by comprehensive smoke-free (SF) laws only16.7% of citizens living in the East South Central or the South Atlantic regions are protected. Current bestpractices for SF law advocacy have not been effective in closing the gaps in coverage for rural southernresidents. Meanwhile adoption of voluntary policies (e.g tobacco-free schools public housing outdoorspaces) have accelerated nationwide. The presence of voluntary policies may increase readiness for SF policyadoption or they may derail SF law adoption in rural municipalities in southern states. Our study is innovativebecause we will incorporate a political theory Kingdons Multiple Streams framework to guide SF law adoptionresearch in a region with tobacco use disparities. The Specific Aims are to: 1) determine the differencesbetween rural municipalities with and without SF laws in regard to community readiness problem indicators(e.g. smoking prevalence) focusing events and feedback; politics (e.g. consensus building); policy factors(e.g. anticipated constraints); and policy entrepreneurs (e.g. strength of tobacco control) controlling forpopulation size and other demographic factors; 1a) compare the number and type of voluntary smoke- andtobacco-free policies (e.g % tobacco-free schools public housing outdoor spaces) in rural municipalities withand without SF laws; and 2) describe facilitators and barriers in the sociopolitical environment that impactadvocacy strategies the policy window (e.g. the tipping point for policy adoption) and enactment of SF laws inrural municipalities with and without SF laws. We will use a mixed methods case-control design to conducttelephone and online surveys to assess policy adoption factors with local advocates (N = 150-250) and electedofficials (N = 150) from 50 municipalities (cities towns or villages) (25 cases; 25 controls) nested within fourstates: Alabama Kentucky Mississippi and South Carolina. Case municipalities will have enacted a SF lawwithin the past 3 years; controls will be matched with cases in each state based on community population sizeand rurality. Using qualitative methods we also will conduct in-depth interviews with community leaders citizenactivists and policymakers in case municipalities with the most recent SF law and their matched controls fromeach state (two communities per state; 10-15 key informants per community). Participants will be asked todescribe factors affecting SF policy adoption and asked to comment on key events that may have contributedto or inhibited policy adoption. A Community Advisory Board consisting of 8 leaders in tobacco control and SFlaw adoption in rural areas and representing the four southern states will guide all aspects of the study. Thisstudy will shift the current research paradigm to a new way of understanding SF law adoption in rural southernmunicipalities. Tobacco-related health disparities will continue to lead to poor health outcomes and enormoussocietal costs in rural southern municipalities until we can advance the science of SF policy adoption.

project_terms:
Address;Adopted;Adoption;Advocacy;Advocate;Affect;Alabama;Area;Cities;Communities;Complex;Consensus;Demographic Factors;Environment;Event;Feedback;Fostering;Future;Goals;Government;Health;Intervention;Interview;Kentucky;Laws;Lead;Methods;Mississippi;Modeling;Municipalities;Outcome;Participant;Policies;Policy Developments;Politics;Population;Population Sizes;Psychosocial Factor;Public Health;Public Housing;Published Comment;Qualitative Methods;Readiness;Research;Rural;Rural Community;Schools;Science;Smoke;Smoking;Social Change;Social Justice;South Carolina;Stream;Surveys;Telephone;Tobacco;Tobacco smoke;Tobacco use;Work;Workplace;base;case control;design;evidence base;experience;health disparity;improved;informant;innovation;reduce tobacco use;rural America;rural area;rurality;self reliance;smoke-free policy;smoking prevalence;social norm;societal costs;success;theories;tobacco control;tobacco-free;treatment group

public_health_relevance:
NarrativeSmoking rates remain high in rural southern areas in part because of regional disparities in smoke-free laws.Current best practices have not been effective in closing gaps in coverage. This study will shift the currentresearch paradigm to a new way of understanding smoke-free policy adoption in rural southern communities.


application_id: 9979035
project_number: 1R21ES030334-01A1
project_title: Alternative splicing in arsenical skin carcinogenesis
administering_ic: NIEHS
award_notice_date: 2020-07-13
opportunity_number: PA-19-053
application_type: 1
activity_code: R21
ic: ES
serial_number: 030334
suffix: A1
program_official: HUMBLE, MICHAEL C
project_start_date: 2020-07-14
project_end_date: 2022-06-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Project SummaryChronic exposure to arsenic most commonly through contaminated drinking water plagues over 200 millionindividuals in over 70 countries including the USA. Arsenic is a multi-organ toxicant and chronic arsenicexposure causes several chronic diseases including cancer in multiple organs skin cancer being the mostcommon. While several mechanisms are postulated to be responsible for arsenic-induced carcinogenesis aclear picture is yet to emerge. It is well known that chronic arsenic exposure radically changes thetranscriptomic and proteomic signatures but the underlying mechanism for such sweeping global changesare not yet clearly understood. Differential alternative splicing plays a role in carcinogenesis and may be atplay in arsenic-induced carcinogenesis. We employed state-of-the-art RNA-Seq analysis ina well-established model of arsenic-induced skin cancer (HaCaT cells exposed continuously to 100 nM sodiumarsenite for 32 weeks) in a longitudinal study to understand the global changes in splicing occurring during thetransformation process. Our data indicate >600 differential alternative splicing events occurred at each of thetime points studied (7 19 28 weeks of exposure). This differential splicing program by dramatically changingthe proteome could be a key player in the arsenic-induced transformation of skin cells. The present proposalaims to examine the contribution of significant differential splicing events at each time point towards theprocess of carcinogenesis. We will specifically scrutinize if the significant splicing events predicted by ourtranscriptomic studies can be correlated with protein isoform expression profiles. Furthermore we also aim tostudy if predicted significantly different spliced isoforms that take place in the 5' or 3' UTR of transcripts canbe correlated to expression profile in the mature mRNA samples from exposed and unexposed cells. Theoutcomes from this study will further our understanding of how alternative splicing shapes the cellular eventstaking place before during and after the time the HaCaT cells become malignant. In addition our study willlook to elaborate the mechanistic basis of how one change in an upstream regulatory alternative splicing factorcan cause genome-wide synchronized alternative splicing changes by signal amplification through successivesteps leading to altered proteome and ultimately adverse health effects.

project_terms:
3' Untranslated Regions;5' Untranslated Regions;Affect;Alternative Splicing;Area;Arsenic;Arsenicals;Arsenites;Attention;Automobile Driving;Biogenesis;Biological;Biological Process;Cell Cycle Regulation;Cell physiology;Cells;Chronic;Chronic Disease;Complex;Country;DNA Repair;DNA damage checkpoint;Data;Disease;Etiology;Event;Exposure to;Expression Profiling;Gene Expression;Gene Expression Regulation;Genome Components;Global Change;Health;Human;Individual;Lead;Longitudinal Studies;Malignant - descriptor;Malignant Neoplasms;Mass Spectrum Analysis;Messenger RNA;MicroRNAs;Mitotic;Modeling;Oncogenic;Organ;Outcome;Outcome Study;Oxidative Stress;PLK1 gene;Paint;Pathway Analysis;Pathway interactions;Phenotype;Play;Post-Transcriptional Regulation;Process;Production;Protein Isoforms;Proteins;Proteome;Proteomics;RNA Splicing;Regulation;Research;Reverse Transcriptase Polymerase Chain Reaction;Role;Sampling;Shapes;Signal Transduction;Skin;Skin Cancer;Skin Carcinogenesis;Squamous cell carcinoma;System;Testing;Time;Transcript;arsenic-induced carcinogenesis;base;biological adaptation to stress;carcinogenesis;contaminated drinking water;differential expression;genome-wide;keratinocyte;programs;proteomic signature;public health relevance;response;sodium arsenite;toxicant;transcription factor;transcriptome;transcriptome sequencing;transcriptomics;tumorigenesis;well water

public_health_relevance:
Public Health Relevance Statement/ Project NarrativeThis study will lead to a better understanding of the mechanisms at play by which chronic arsenic exposureleads to human skin cancer in human and will generate markers of early and late response to arsenicexposure. This study will contribute to the understanding of how one or a few cellular events lead to globalcoordinated alternative splicing events through amplification of splicing signal cascades.


application_id: 9978812
project_number: 5R01EY021769-08
project_title: Vertebrate photoreceptor development and regeneration
administering_ic: NEI
award_notice_date: 2020-07-31
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: EY
serial_number: 021769
program_official: NEUHOLD, LISA
project_start_date: 2012-08-01
project_end_date: 2023-07-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 10184513
contact_pi: MORRIS, ANN C
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYInherited retinal dystrophies such as retinitis pigmentosa (RP) are a leading cause of blindness forwhich there is currently no cure. One potential treatment for retinal degenerative diseases is cell-based transplantation therapy whereby precursor cells are transplanted into the diseased eye toreplace the lost photoreceptors. While this is an exciting possibility several challenges to theimplementation of transplantation therapies must be overcome including the inefficient integration ofphotoreceptor precursors into the recipient retina and the difficulty of obtaining sufficient numbers ofphotoreceptor precursors for clinical application. To improve protocols for the in vitro culture of suchcells we must have a better understanding of the transcriptional networks that promote specificationof photoreceptor precursors. One of the long-term goals of our laboratory is to contribute to theseefforts by studying photoreceptor development and regeneration in the zebrafish. The zebrafish isespecially useful for studying photoreceptor biology because its retina contains numerous conesubtypes in addition to rods. Furthermore unlike mammals the zebrafish retina is able to regenerateneurons in response to experimental damage. The experiments described in this proposal will definethe role of three transcription factors -- Sox Sox11 and Her9 -- during retinal neurogenesis throughthe application of gene targeting and molecular genetic approaches. Our specific aims are as follows:Specific Aim I: Determine the role of Sox4 and Sox11 in photoreceptor differentiation. Using newlygenerated loss-of-function mutants in this aim we will 1) determine whether there is a dosage effectof Sox4/11 activity on rod photoreceptor number; 2) use state-of-the-art time-lapse imaging todetermine when and where Sox4 expression is required to achieve proper rod photoreceptordevelopment; 3) determine precisely how Sox4/11 regulate Hh and Bmp signaling; and 4) identify themolecular targets of Sox4/11. Specific Aim II: Determine the cause and extent of photoreceptordefects in the zebrafish her9 mutant. In this aim we will 1) determine the mechanism forphotoreceptor defects in her9 mutants; 2) determine whether loss of Her9 impairs vision; 3) identifythe upstream signaling pathway(s) that regulate her9 expression in the retina; and 4) determinewhether Her9-mediated VEGF expression in the avascular zebrafish retina regulates retinalprogenitor cell proliferation and differentiation. Completion of our proposal will bridge important gapsin our understanding of the molecular mechanisms of vertebrate photoreceptor differentiation andreveal underlying principles relevant to the development of approaches for the treatment of humanretinal degenerative disease.

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


application_id: 9978489
project_number: 1R21DA049130-01A1
project_title: Glutamergic Mechanisms in Opioid and Cocaine Co-Use
administering_ic: NIDA
award_notice_date: 2020-09-16
opportunity_number: PAR-18-084
application_type: 1
activity_code: R21
ic: DA
serial_number: 049130
suffix: A1
program_official: ANANTHAN, SUBRAMANIAM
project_start_date: 2020-09-30
project_end_date: 2022-08-31
study_section: Special Emphasis Panel[ZRG1 BBBP-X (03)]
contact_pi_person_id: 9706320
contact_pi: GIPSON-REICHARDT, CASSANDRA D
other_pis: STOOPS, WILLIAM WALTON
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
project_terms:
Acetylcysteine;Animals;Attenuated;Biological Markers;Brain;Chemosensitization;Chronic;Clinical;Cocaine;Cues;Dendritic Spines;Dependence;Development;Disease;Dose;Drug Controls;Drug Use Disorder;Drug usage;Food;Glutamate Transporter;Glutamates;Heroin;Homosynaptic Depression;Human;Individual;Intake;Intervention;Intravenous;Knowledge;Laboratories;Magnetic Resonance Spectroscopy;Maintenance;Measures;Methods;Modeling;Motivation;N-Methylaspartate;Neurons;Nucleus Accumbens;Opioid;Opioid agonist;Oral;Oxycodone;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Phase;Phased Innovation Awards;Physical Dependence;Physiological;Placebos;Proteins;Protocols documentation;Proxy;Public Health;Randomized;Reporting;Self Administration;Specific qualifier value;Stimulus;Synapses;Synaptic plasticity;System;Time;United States;Up-Regulation;Withdrawal;Work;cocaine exposure;cocaine use;comorbidity;comparison group;experience;glutamatergic signaling;improved outcome;incentive salience;meetings;motivated behavior;multiple drug use;neurobiological mechanism;neuromechanism;novel;novel therapeutics;opioid use;opioid use disorder;opioid withdrawal;overdose risk;polysubstance abuse;pre-clinical;protein expression;relating to nervous system;sex


application_id: 9978283
project_number: 1R03HD097075-01A1
project_title: MicroRNAs as Mediators of Birth Defects
administering_ic: NICHD
award_notice_date: 2020-03-26
opportunity_number: PA-18-481
application_type: 1
activity_code: R03
ic: HD
serial_number: 097075
suffix: A1
program_official: TOYAMA, REIKO
project_start_date: 2020-04-01
project_end_date: 2022-03-31
study_section: Developmental Biology Study Section[CHHD-C]
contact_pi_person_id: 1861667
contact_pi: GREENE, ROBERT M
other_pis: PISANO, M. MICHELE
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Project Summary/Abstract: Orofacial clefts are amongst the most prevalent birth defects occurring in ~1/800 live births worldwide.Despite progress identifying genetic and environmental risk factors for orofacial clefting causes of the majorityof isolated cleft cases  particularly clefts of the palate  continue to elude our complete comprehension. Agreater depth of understanding of the molecular underpinnings of orofacial development is therefore essentialfor the development of diagnostic preventative and therapeutic strategies. The discovery of vast conserved stretches in the human genome of non-coding regulatory RNAs suchas microRNAs (miRNAs) has revealed a previously unrecognized layer of genomic information of significanceto human health and disease. Studies proposed in the current application enter this new and challengingscientific arena to examine the function of miRNAs in orchestrating the complex morphogenetic mechanismsand gene expression programs underlying formation of the mammalian secondary palate. These studies which are a logical extensions of our published comprehensive profile of miRNAsexpressed in the developing facial processes and palate will investigate the functions of carefully selectedmiRNAs in mammalian palatal ontogenesis. Loss/gain of function strategies and in situ hybridization will beemployed to systematically determine the biological functions and spatio-temporal expression patterns duringdevelopment of the secondary palate. Results from these studies will elucidate miRNA functionality in specificaspects of mammalian palatal morphogenesis growth and cellular differentiation. The immediate impact of theproposed research will be delineation of miRNA candidate genes that can be interrogated for human variantsassociated with an increased risk of human isolated cleft palate.

project_terms:
Affect;Animal Model;Apoptosis;Biological Process;Breathing;Candidate Disease Gene;Cell Culture Techniques;Cell Proliferation;Cell physiology;Cells;Chondrogenesis;Cleaved cell;Cleft Palate;Complex;Comprehension;Congenital Abnormality;DNA;DNA Sequence;Data;Development;Developmental Process;Diagnostic;Disease;Elements;Embryonic Development;Embryonic Palate;Environmental Risk Factor;Enzymes;Epigenetic Process;Epithelial;Epithelium;Etiology;Extracellular Matrix;Face;FaceBase;Failure;Family;Fetus;Future;Gene Activation;Gene Expression;Gene Silencing;Genetic;Genetic Determinism;Genetic Risk;Genome;Genomics;Growth;Health;Hearing;Heritability;Histones;Human;Human Genome;In Situ Hybridization;Individual;Instruction;Investigation;Link;Live Birth;MSX1 gene;Medial;Mediator of activation protein;Mesenchymal;Mesenchymal Differentiation;MicroRNAs;Molecular;Morphogenesis;Mus;Mutant Strains Mice;Nasal cavity;Oral cavity;Organ Culture Techniques;Palate;Pattern;Phenotype;Play;Pregnancy;Primordium;Process;Production;Publishing;RNA;Regulator Genes;Research;Risk;Role;Secondary Palate;Signal Transduction;Signaling Molecule;Speech;Stretching;Syndrome;System;Therapeutic;Time;Tissues;Transforming Growth Factor beta;Ubiquitin;Untranslated RNA;Variant;base;cell motility;craniofacial;epigenome;feeding;gain of function;genetic association;homologous recombination;loss of function;methyl group;orofacial;orofacial cleft;orofacial development;programs;repository;spatiotemporal;success

public_health_relevance:
Project Narrative:Orofacial clefting represents one of the most common of birth defects. Failure of the palate (roof of themouth) to develop properly during gestation results in continuity between the oral and nasal cavitiescausing problems in feeding breathing speech and hearing in affected individuals. Causes of cleftpalate are poorly understood. This research proposes to investigate recently discovered elements in thehuman epigenome  microRNAs  that may play critical roles in palate development and clefting.


application_id: 9978279
project_number: 1R03AG067611-01A1
project_title: Functional Censored Quantile Regression for Investigating Heterogeneous Effects in Survival Data
administering_ic: NIA
award_notice_date: 2020-05-14
opportunity_number: PA-19-052
application_type: 1
activity_code: R03
ic: AG
serial_number: 067611
suffix: A1
program_official: PHILLIPS, JOHN
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
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;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;outcome forecast;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.


application_id: 9978219
project_number: 7K23MH111977-03
project_title: Enhancement of extinction learning using transcranial direct current stimunation
administering_ic: NIMH
award_notice_date: 2019-09-03
opportunity_number: PA-18-590
application_type: 7
activity_code: K23
ic: MH
serial_number: 111977
program_official: CHAVEZ, MARK RAY
project_start_date: 2017-09-11
project_end_date: 2022-08-31
study_section: Adult Psychopathology and Disorders of Aging Study Section[APDA]
contact_pi_person_id: 10570976
contact_pi: ADAMS, THOMAS G
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThis application for a mentored patient-oriented research career development award will provide the applicant a clinical psychologist with a strong background in experimental psychopathology and cognitive-behavioraltherapy and growing expertise in non-invasive brain stimulation  with advanced training mentored researchexperience and protected research time. This will facilitate the applicant's long-term goal: to reduce the mentalhealth burden associated with pathological fear and anxiety by developing novel treatments and augmentationstrategies. The candidate proposes: 1) a training plan to gain expertise in translational clinical neuroscience: I)neurobiology and cognitive neuroscience II) neuroimaging and III) non-invasive brain stimulation; 2) amentoring and consultation team with expertise in these three areas; 3) two mentored research projects thatwill test whether transcranial direct current stimulation (tDCS) can enhance neural and cognitivemechanisms underlying exposure-based treatments for pathological fear and anxiety.The negative valence systems of acute threat (fear) potential threat (anxiety) and sustained threat are amongthe most clinically important research domain constructs. Psychiatric disorders characterized by pathologicalfear and anxiety are common and often disabling. Despite their limitations exposure therapies are among themost efficacious treatments for these disorders. Extinction learning is thought to be a core mechanism oftherapeutic exposure. Extinction learning is mediated by a well-defined circuit encompassing the medialprefrontal cortex amygdala and hippocampus. This raises the exciting possibility that direct engagement of thiscircuitry might enhance the response to therapeutic exposure. tDCS is a neuromodulation technology that canaugment synaptic plasticity learning and memory. The proposed studies will employ an experimentaltherapeutics framework to assay mechanisms of action behind therapeutic exposure and evaluate whether tDCSengages these mechanisms.Study 1 will enroll 62 healthy volunteers to test whether tDCS applied to the mPFC can augment spontaneousmPFC activity (Aim 1) functional engagement of extinction circuitry during extinction learning and recall (Aim 2)and classically-conditioned extinction learning (Aim 3). Study 2 will enroll 32 patients diagnosed with obsessive-compulsive disorder (OCD) who will complete a novel behavioral paradigm that encapsulates the core featuresof exposure therapy for OCD to test whether tDCS applied to the mPFC enhances exposure-relevant extinctionlearning (Aim 4).Pathological fear and anxiety directly affect more than one out of every four Americans. Existing treatments arefrequently inadequate and need to be improved. The proposed studies will evaluate the ability of tDCS to engageneural and cognitive targets that underpin therapeutic exposure for disordered anxiety. This synergy mayimprove treatment outcomes for individuals suffering from pathological fear and anxiety.

project_terms:
Acute;Affect;American;Amygdaloid structure;Anxiety;Anxiety Disorders;Area;Base of the Brain;Behavioral Paradigm;Biological Assay;Brain;Clinical;Cognitive;Cognitive Therapy;Consultations;Data;Development;Diagnosis;Disease;Distress;Encapsulated;Enrollment;Exercise;Exposure to;Extinction (Psychology);Frequencies;Fright;Functional Magnetic Resonance Imaging;Future;Galvanic Skin Response;Goals;Hippocampus (Brain);Individual;Intervention;Investigational Therapies;Knowledge;Lead;Learning;MRI Scans;Measures;Medial;Mediating;Membrane Potentials;Memory;Mental Health;Mental disorders;Mentored Patient-Oriented Research Career Development Award;Mentors;Methods;Minority;Monitor;Mood Disorders;Negative Valence;Neurobiology;Neurosciences;Obsessive-Compulsive Disorder;Pathologic;Patients;Population;Post-Traumatic Stress Disorders;Prefrontal Cortex;Prevention;Procedures;Psychologist;Psychopathology;Psychotherapy;Refractory;Research;Research Project Grants;Rest;Ritual compulsion;Scanning;Signal Transduction;Stimulus;Symptoms;Synaptic plasticity;System;Technology;Testing;Therapeutic;Time;Training;Treatment outcome;anxious;base;behavior test;clinical efficacy;cognitive neuroscience;conditioned fear;conditioning;experience;healthy volunteer;improved;improved outcome;in vivo;indexing;learning extinction;neuroimaging;neuroregulation;novel;partial response;recruit;relating to nervous system;response;symptomatology;synergism;treatment of anxiety disorders

public_health_relevance:
PROJECT NARRATIVE The proposed studies aim to use transcranial direct current stimulation (tDCS)  a non-invasiveneuromodulatory technology  to augment resting brain activity and plasticity within fear extinction circuitryenhance extinction of classically-conditioned fear and improve learning within the context of therapeuticexposure. Results from these studies may lead toward the development of novel methods that can improve theefficacy and efficiency of therapeutic exposure for multiple forms of disordered fear and anxiety includingobsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD).


application_id: 9978095
project_number: 5R25GM133328-02
project_title: UofL Bridges to Baccalaureate(ULBB)
administering_ic: NIGMS
award_notice_date: 2020-06-30
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_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;Underserved 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;university student


application_id: 9978015
project_number: 5UG1DA050069-02
project_title: Kentucky Women's Justice Community Opioid Innovation Network (WJCOIN)
administering_ic: NIDA
award_notice_date: 2020-04-17
opportunity_number: RFA-DA-19-025
application_type: 5
activity_code: UG1
ic: DA
serial_number: 050069
program_official: MULFORD, CARRIE FRIED
project_start_date: 2019-07-15
project_end_date: 2024-04-30
study_section: ZDA1-HXO-H(05)R
contact_pi_person_id: 14909213
contact_pi: STATON, MICHELE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Benefits and Risks;Caring;Climate;Clinical;Clinical Research;Communities;Cost Analysis;Criminal Justice;Death Rate;Development;Drug abuse;Drug usage;Effectiveness;Exposure to;Funding;Goals;Health Services Accessibility;High Risk Woman;Hybrids;Imprisonment;Intervention;Jail;Justice;Kentucky;Lead;Leadership;Life;Link;Maintenance;Methods;Modeling;National Institute of Drug Abuse;Opioid;Outcome;Overdose;Perception;Pharmaceutical Preparations;Physicians;Positioning Attribute;Public Health;Quality of Care;Randomized;Readiness;Recording of previous events;Recovery;Relapse;Reporting;Research;Research Personnel;Rewards;Safety;Savings;Self Medication;Services;Site;System;Time;Treatment Cost;United States National Institutes of Health;Universities;Woman;arm;base;community reentry;compare effectiveness;comparison group;cost;cost effectiveness;cost-effectiveness ratio;effectiveness implementation trial;experience;follow-up;high risk;improved;incremental cost-effectiveness;innovation;innovative technologies;intervention cost;member;men;opioid epidemic;opioid exposure;opioid injection;opioid mortality;opioid use disorder;overdose death;pain sensitivity;peer;prescription opioid;programs;recidivism;safety outcomes;telehealth;treatment as usual


application_id: 9977357
project_number: 7R01DA018151-15
project_title: Investigation of Neoclerodanes as Novel Opioid Ligands
administering_ic: NIDA
award_notice_date: 2019-08-22
opportunity_number: PA-18-590
application_type: 7
activity_code: R01
ic: DA
serial_number: 018151
program_official: HILLERY, PAUL
project_start_date: 2019-08-01
project_end_date: 2021-02-28
study_section: Special Emphasis Panel[ZRG1-MDCN-B(05)M]
contact_pi_person_id: 7842243
contact_pi: PRISINZANO, THOMAS EDWARD
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Addiction to cocaine and methamphetamine highly addictive psychostimulants is associated with substantial neuropsychiatric co-morbidity and also enhances transmission of HIV-1 hepatitis B and C and thus causes massive public health costs. There are currently no FDA-approved treatments for psychostimulant addiction. Growing evidence shows that that  opioid (KOP) receptors (and their endogenous high-efficacy agonist neuropeptides the dynorphins) are involved in the modulation of major abuse-related effects of psychostimulants and particularly relapse. The plant-derived hallucinogen salvinorin A (a neoclerodane) from the mint Salvia divinorum is a structurally unique KOP-agonist. Reference KOP-r agonists and salvinorin A can decrease certain psychostimulant-induced effects but these desirable actions are accompanied by undesirable effects including the aforementioned hallucinations sedation and dysphoria/aversion. Selected novel semi-synthetic neoclerodanes from the previous period of this Project have potential as "lead" pharmacotherapeutic agents for psychostimulant addiction as shown by their in vitro and in vivo profiles in translational modelsincluding a reduced burden of undesirable behavioral effects. The central hypothesis of this proposal is that iterative structural modification of these neoclerodane "leads" will generate novel opioid receptor ligands with the potential to treat psychostimulant addiction relapse and co-morbid neuropsychiatric disorders. The Specific Aims of this proposal are (1) optimize the activity of novel neoclerodanes including innovative synthetic trans-decalin analogs at KOP receptors; (2) determine and optimize the in vivo activity of novel neoclerodanes as KOPr ligands in mice and for their ability to decrease cocaine-induced effects; and (3) determine and optimize the activity of novel neoclerodanes prioritized from Aims 1 and 2 in translational non- human primate models. The proposed research is innovative because neoclerodanes are a unique class of opioid receptor ligands. The design synthesis evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with opioid receptors. This information is expected to facilitate the identification of clinically useful KOP-r targeted medications for the treatment of drug addiction.

project_terms:
Affinity;Agonist;Anxiety;Behavioral;Biological Assay;Biological Markers;Central Nervous System Diseases;Chemicals;Clinical;Cocaine;Comorbidity;Development;Dose;Drug Addiction;Dynorphins;Effectiveness;Evaluation;FDA approved;Funding;Generations;Genus Mentha;Goals;HIV-1;Hallucinations;Hallucinogens;Health Care Costs;Hepatitis B;Hepatitis C;In Vitro;Investigation;Laboratories;Lead;Ligands;Literature;Mediating;Mental Depression;Methamphetamine;Modeling;Modification;Motor Activity;Mus;Neuropeptides;Neurosecretory Systems;Opioid;Opioid Receptor;Parents;Pharmaceutical Preparations;Pharmacology;Plants;Post-Traumatic Stress Disorders;Preparation;Progress Reports;Property;Psychostimulant dependence;Public Health;Relapse;Reporting;Research;Research Personnel;Rewards;Salvia;Sedation procedure;Signal Transduction;Structure;Terpenes;Testing;Toxic effect;Work;addiction;analog;base;decalin;design;dysphoria;experience;improved;in vivo;innovation;kappa opioid receptors;nanomolar;neoclerodane;neuropsychiatric disorder;neuropsychiatry;nonhuman primate;novel;pharmacophore;preference;psychostimulant;public health relevance;receptor;salvinorin A;stress related disorder;targeted treatment;translational model;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This project seeks develop neoclerodane-derived  opioid (KOP) receptor ligands with pharmacotherapeutic potential in psychostimulant addiction and relapse as well as neuropsychiatric disorders (including anxiety depression and stress-related disorders such as PTSD). The design synthesis and evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with opioid receptors. This information is expected to facilitate the identification of clinically usefu opioid- targeted drugs for the treatment of drug addiction and major neuropsychiatric disorders.


application_id: 9977341
project_number: 1K08NS112580-01A1
administering_ic: NINDS
award_notice_date: 2020-06-19
opportunity_number: PA-19-117
application_type: 1
activity_code: K08
ic: NS
serial_number: 112580
suffix: A1
program_official: KOENIG, JAMES I
project_start_date: 2020-07-01
project_end_date: 2025-06-30
study_section: NST-1 Study Section[NST-1]
contact_pi_person_id: 8204899
contact_pi: MILLER, BRANDON A
other_pis: Not Applicable
congressional_district: 06
department: NEUROSURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Reversing inflammatory macrophage activation as treatment for neonatal intraventricular hemorrhage and hydrocephalus

project_abstract:
Neonatal Intraventricular hemorrhage (IVH) originates from the underdeveloped germinal matrix a siteof cell rapid cell division adjacent to the lateral ventricles of the brain. IVH leads to post-hemorrhagichydrocephalus (PHH). Within the same time frame that neonatal IVH occurs the neonatal brain is also rapidlyproducing the cells needed for myelination. Oligodendrocytes the myelin-forming cells of the brain are derivedfrom oligodendrocyte progenitor cells (OPCs). OPCs are fragile cells - exquisitely sensitive to many factors thatare present across multiple neurological diseases such as excitotoxicity inflammatory cytokines and oxidativestress. Across a wide spectrum of neurological diseases neuroinflammation causes OPC loss and failure ofmyelination. Infiltrating brain macrophages are implicated in many forms of neonatal brain injury. Macrophagesare activated by many different stimuli in CNS injury and disease including blood products released into theventricular space. Understanding the role of macrophages after IVH is critical to improving outcomes asmacrophage activation mediates white matter injury in other forms of neonatal brain injury. Azithromycin is a commonly prescribed antibiotic that is safe in neonates. Besides its antibioticproperties azithromycin is also anti-inflammatory and shifts macrophage activation into an anti-inflammatoryphenotype that actually promotes tissue recovery rather than injury. Azithromycin has been used in a variety ofanti-inflammatory applications including preclinical work in spinal cord injury where it improves tissue sparingand neurological function. Importantly azithromycin has already undergone rigorous clinical trials in neonatesfor inflammation-induced lung injury. This study will pharmacologically block infiltrating macrophages inIVH/PHH and test azithromycins ability to protect OPCs from macrophage-induced injury in a rat model ofneonatal IVH. I will use a combination of in vivo and in vitro experiments to examine macrophage activationOPC death and myelination with and without azithromycin treatment. My in vivo work will allow us to useneurobehavioral outcomes to assess the efficacy of azithromycin while my in vitro model will allow for in-depthmechanistic studies of macrophage-OPC interaction. This project will support Dr. Millers training in studies ofneuroinflammation and neurotherapeutics. If successful this project will pave the way for clinical studies ofazithromycin for improving neurological outcome after neonatal IVH.

project_terms:
Activation Analysis;Adult;Affect;Animals;Anti-Inflammatory Agents;Antibiotics;Antibodies;Azithromycin;Birth;Bone Marrow;Brain;Brain Injuries;Bromodeoxyuridine;Cell Communication;Cell Death;Cell Maturation;Cell Survival;Cell division;Cells;Central Nervous System Diseases;Cerebral Ventricles;Cerebrum;Child;Childhood Injury;Clinical;Clinical Research;Clinical Trials;Cognitive deficits;Data;Development;Dichloromethylene Diphosphonate;Disease;Failure;Goals;Hematogenous;Hemoglobin;Hemorrhage;Hydrocephalus;Immunochemistry;Immunohistochemistry;In Vitro;Infiltration;Inflammation;Inflammatory;Injections;Injury;Interruption;Intraventricular;Liquid substance;Macrophage Activation;Maps;Measures;Mediating;Medical;Messenger RNA;Microglia;Modeling;Myelin;Myelin Basic Proteins;Myelogenous;NF-kappa B;Neonatal;Neonatal Brain Injury;Nervous System Physiology;Neurological outcome;Nucleic Acids;Oligodendroglia;Outcome;Oxidative Stress;Oxides;Peripheral;Pharmaceutical Preparations;Pharmacology;Phenotype;Premature Birth;Premature Infant;Process;Production;Property;Rattus;Recovery;Role;Site;Spinal cord injury;Stimulus;TNF gene;Testing;Therapeutic;Time;Tissues;Training;Ventricular;Western Blotting;Work;blood product;brain cell;cell type;central nervous system injury;chemokine;cytokine;disability;excitotoxicity;experimental study;functional improvement;improved;improved outcome;in vitro Model;in vivo;intraventricular hemorrhage;lateral ventricle;lung injury;mRNA Expression;macrophage;monocyte;myelination;neonatal brain;neonate;nervous system disorder;neurobehavioral;neuroinflammation;oligodendrocyte progenitor;pre-clinical;preservation;protein expression;recruit;repaired;response;self renewing cell;stem cells;white matter;white matter injury

public_health_relevance:
Many premature infants suffer brain injury due to bleeding within the fluid-filled spaces of the brain that occursshortly after birth. Currently there is no medical therapy to reduce brain injury in these children. This study willexamine the causes of this neonatal brain injury and test therapies to reduce the injury.


application_id: 9976832
project_number: 2R01NS079507-07A1
administering_ic: NINDS
award_notice_date: 2020-06-12
opportunity_number: PA-19-056
application_type: 2
activity_code: R01
ic: NS
serial_number: 079507
suffix: A1
program_official: LEENDERS, MIRIAM
project_start_date: 2012-09-30
project_end_date: 2025-03-31
study_section: Special Emphasis Panel[ZRG1 MDCN-M (91)]
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
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;novel therapeutics;repaired;therapy design;vascular inflammation


application_id: 9976790
project_number: 7K01AA024519-05
project_title: Neurobiological factors underlying sex differences in risk for alcohol abuse
administering_ic: NIAAA
award_notice_date: 2019-09-11
opportunity_number: PA-18-590
application_type: 7
activity_code: K01
ic: AA
serial_number: 024519
program_official: MATOCHIK, JOHN A
project_start_date: 2019-07-12
project_end_date: 2021-02-28
study_section: Neuroscience and Behavior Study Section[AA-4]
contact_pi_person_id: 9711222
contact_pi: WEAFER, JESSICA J
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Substance abuse has been traditionally considered a male-oriented problem and as a consequence research on risk factors specific to women has been minimal. However the gender gap in substance abuse is closing rapidly and findings from both animal and human studies suggest that females are actually more vulnerable to drug use than males. As such there is an urgent need to identify sex differences in risk factors for alcoho and drug abuse in order to develop sex-specific prevention and treatment efforts. One clear candidate risk factor is poor inhibitory control. Recent studies suggest that the ovarian hormone estradiol is associated with poor inhibition and that among heavy young adult drinkers women have poorer inhibitory control than men both in terms of baseline levels of inhibition and sensitivity to the disinhibiting effects of alcohol. The studies proposed here will determine the neural and hormonal mechanisms underlying this sex difference by addressing two specific aims: 1) to determine the degree to which circulating sex hormones menstrual cycle phase and sex influence brain activation during response inhibition and 2) to determine the degree to which circulating sex hormones and menstrual cycle phase influence alcohol effects on brain activation during response inhibition in women. For both aims brain activation during response inhibition will be assessed using functional magnetic resonance imaging (fMRI) during performance of the stop signal task which reliably activates right-lateralized prefrontal regions implicated in inhibitory control. Women will be tested in the late follicular and mid-luteal phasesof the menstrual cycle and serum levels of sex hormones (estradiol progesterone and testosterone) will be assessed. For Aim 2 alcohol (60mg%) and saline will be administered intravenously during fMRI of stop signal task performance. It is hypothesized that estradiol will be inversely related to brain activation during response inhibition such that women will have less activation than men and be more sensitive to the effects of alcohol particularly in the late follicular phase when estradiol is high. Completion of this research plan in conjunction with thecareer development plan including mentor-directed training formal coursework and workshops will provide training in three critical domains: 1) fMRI; 2) fMRI during IV alcohol infusion; and 3 neuroendocrinology. Results from these studies will lay the foundation for an R01 application to longitudinally examine the degree to which biologically-based sex differences in inhibitory control are a cause or consequence or both of heavy drinking. The proposed training plan will provide the unique skill set necessary to conduct the next steps in this line of research and pave the way for establishing an independent program of research aimed at determining the behavioral neural and hormonal determinants of sex differences in risk for alcohol and drug abuse.

project_terms:
Address;Affect;Alcohol abuse;Alcohols;Animals;Behavioral;Biological;Brain;Data;Development;Development Plans;Drug abuse;Educational workshop;Emotional;Estradiol;Female;Financial Hardship;Foundations;Functional Magnetic Resonance Imaging;Gender;Goals;Gonadal Steroid Hormones;Heavy Drinking;Hormonal;Human;Impairment;Individual;Infusion procedures;Intravenous;Laboratories;Link;Luteal Phase;Menstrual cycle;Mentors;Neurobiology;Neuroendocrinology;Ovarian hormone;Performance;Pharmaceutical Preparations;Phase;Prevention;Prevention strategy;Progesterone;Research;Risk;Risk Factors;Saline;Serum;Sex Differences;Signal Transduction;Societies;Source;Substance abuse problem;Task Performances;Testing;Testosterone;Training;Wit;Woman;alcohol effect;alcohol response;alcohol risk;base;behavior measurement;career development;drug use vulnerability;male;men;neurobiological mechanism;programs;proliferative phase Menstrual cycle;public health relevance;relating to nervous system;response;sex;skills;sobriety;treatment strategy;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE   Results from these studies will provide information regarding biologically-based sex differences in inhibitory control a clear risk factor for alcohol abuse. This project will help to identify se-specific sources of risk and ultimately it is hoped that this line of research will lead to sex-specific prevention and treatment efforts for alcohol and drug abuse.


application_id: 9976445
project_number: 5P30AG028383-15
project_title: University of Kentucky Alzheimer's Disease Core Center - Biomarker Core
administering_ic: NIA
award_notice_date: 2020-06-09
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_end_date: 2023-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 5033
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
project_abstract:
ABSTRACT The University of Kentucky Alzheimer's Disease Center (UK-ADC) was founded in 1985 prior to theadvent of biomarker initiatives that continue to grow in size and scope. We propose the development of aBiomarker Core to enrich the UK-ADC and provide an infrastructure that will allow us to contribute significantlyto the discovery of antemortem biomarkers. The UK-ADC has focused on the early transitions from normalcognitive aging to the development of cognitive impairment. The shift of focus in the AD field to earlier pre-clinical stages of disease ideally positions our center which has had a focus on subjects with normal cognitionand early detection and tracking of changes associated with degenerative disease states for the last 30 years.As a result our center has collected over 700 plasma samples 100 CSF samples and 250 MRI batteries fromcognitively intact individuals. Further we have over 350 plasma samples 150 CSF samples and 300 MRIbatteries from individuals with mild cognitive impairment. In establishing a biomarker core we will build aninfrastructure that allows us to analyze distribute and track these valuable current and future biomarkersamples. The infrastructure will also provide the means for us to support intramural extramural and nationalbiomarker initiatives such as NACC ADGC/NCRAD ADNI ADCS/ATRI and other NIH/NIA initiatives. We willalso establish a trial-ready biomarker-characterized subject cohort facilitating enrollment into intramural andextramural clinical translational studies to eliminate recruitment and screen fail bottlenecks. Finally our centerhas been at the forefront of research on AD-mimics including hippocampal sclerosis (HS-Aging) primary age-related tauopathies (PART) cerebral age-related TDP-43 and sclerosis (CARTS) and vascular contributions tocognitive impairment and dementia (VCID). As such the addition of a biomarker core will allow us to continueto contribute to these fields and the rapidly growing interest in biomarker development in these areas. Overallthe bolus of support for our new biomarker core will allow us the increased infrastructure needed to supportNIH/NIA initiatives and our researchers needs in the 21st century and beyond.

project_terms:
Aging;Algorithms;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimers disease biomarker;Amyloid;Amyloid beta-Protein;Area;Autopsy;Awareness;Biological;Biological Markers;Biometry;Blood;Bolus Infusion;Budgets;Cataloging;Catalogs;Cerebrum;Clinical;Cognition;Cognitive;Cognitive aging;Collection;Communities;Complex;Consensus;Consent;Data;Degenerative Disorder;Dementia;Development;Diagnosis;Disease;Early Diagnosis;Enrollment;Extramural Activities;Funding;Future;Image;Impaired cognition;Individual;Inflammatory;Infrastructure;International;Intervention Studies;Investigation;Kentucky;Letters;Liquid substance;Longitudinal cohort;Magnetic Resonance Imaging;Modeling;Pathologic;Pathway interactions;Pharmaceutical Preparations;Plasma;Policies;Positioning Attribute;Positron-Emission Tomography;Procedures;Protocols documentation;Research;Research Personnel;Research Project Grants;Resources;Risk;Sampling;Sclerosis;Stress;Tauopathies;Translational Research;United States National Institutes of Health;Universities;Validation;Work;age related;base;biomarker development;biomarker discovery;clinical development;clinical phenotype;cognitive development;cohort;comparative;cost;data sharing;hippocampal sclerosis;interest;mild cognitive impairment;neuroimaging;neuropathology;novel;novel marker;pre-clinical;programs;protein TDP-43;recruit;stem;translational study;vascular cognitive impairment and dementia


application_id: 9976442
project_number: 5P30AG028383-15
project_title: Research Education Component (RL5)
administering_ic: NIA
award_notice_date: 2020-06-09
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_end_date: 2023-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 6813
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
project_abstract:
Project Summary/Abstract: Research Education ComponentThe Research Education Component (REC) of the UK-ADC offers a variety of educational and trainingprograms aimed at enhancing the training of a workforce to meet the nations biomedical behavioral andclinical needs in Aging and Alzheimers disease (AD)-related research. The overall goal of all the educationalefforts of the REC is to build a trained workforce with the knowledge and skills to:  accelerate the pace of scientific research and translate basic science discoveries more rapidly into information and interventions that address specific aspects of AD with the aim of minimizing its symptoms or delaying its progression (researchers)  provide high-quality care and information to individuals treating the normal aging population and those with cognitive impairment or more advanced dementia (healthcare professionals).Consistent with the Transitions and Translation theme of our ADC we place a major emphasis on thepromotion and education of translational researchers and provision of a collaborative environment and trainingopportunities designed to facilitate their career growth. Over the next funding cycle we will continue to offermulti-faceted learning formats and programs to educate healthcare professionals and to promote thedevelopment of future leaders in AD research. These include our CME educational series on dementiatelemedicine caregiver training programs for healthcare professionals the annual Markesbery Symposium onAging and Dementia Sanders-Brown Center on Aging (SBCoA) monthly seminar program Medical StudentGeriatrics Enrichment Program Geriatrics Clinical Selective for medical students NeurodegenerativeDisorders Selective for Neurology residents formal didactic course education and one-on-one mentoring ofstudents fellows residents and faculty as well as extramural researchers in the region. Our different learningformats provide opportunities for trainees to: attain information ideas or concepts; learn through demonstrationand observation; practice skills techniques and thinking processes; and increase in-depth understanding. Inaddition to continuing these existing highly successful educational programs we propose to expand ourtraining opportunities through two new initiatives. First we plan to develop a training program called AD101:From Bench to Bedside aimed at enhancing the clinical research expertise of basic translational scientists.Second we plan to pilot a new primary care provider training program for dementia screening that can be usedin the setting of the Medicare Annual Wellness visit for detection of possible cognitive impairment. Our programincludes highly motivated ADC Core faculty who bring a variety of specialized expertise to our educationalprograms strong interactions with educational partners to provide multiple learning opportunities and a highlycollaborative environment and strong institutional support. These substantial program strengths will support theREC in attainment of its goals.

project_terms:
Address;Administrator;Advanced Practice Nurse;Aging;Alzheimer disease prevention;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Basic Science;Behavioral;Behavioral Symptoms;Caring;Chronic Disease;Clinical;Clinical Research;Communities;Coupling;Dementia;Detection;Development;Discipline of Nursing;Disease;Early Diagnosis;Education;Educational Activities;Extramural Activities;Faculty;Family;Funding;Future;Geriatrics;Goals;Growth;Health;Health Professional;Home Health Aides;Human;Impaired cognition;Individual;Intervention;Kentucky;Knowledge;Learning;Medical Students;Medicare;Neurobehavioral Manifestations;Neurodegenerative Disorders;Neurology;Occupational Therapist;Physician Assistants;Physicians;Primary Care Physician;Process;Psychologist;Quality of Care;Registered nurse;Research;Research Personnel;Research Support;Resources;Scientist;Series;Social Workers;Specialist;Students;Symptoms;Techniques;Telemedicine;Testing;Thinking;Training;Training Programs;Translating;Translational Research;Translations;Universities;Visit;Work;advanced dementia;aging population;bench to bedside;care providers;career;caregiver education;caregiving;clinical care;collaborative environment;design;education research;interest;next generation;normal aging;novel;physical symptom;prevent;profession allied to medicine;programs;research study;screening;senior faculty;skills;student mentoring;success;symposium;training opportunity;translational scientist


application_id: 9976439
project_number: 5P30AG028383-15
project_title: Core E: Outreach and Recruitment Core
administering_ic: NIA
award_notice_date: 2020-06-09
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_end_date: 2023-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 6812
contact_pi_person_id: 9662252
contact_pi: SCHMITT, FREDERICK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
project_abstract:
Project Summary/Abstract: Outreach and Recruitment CoreThe Outreach and Recruitment (OR) Core functions as a key link between the UK-ADC and the local and statecommunities. OR Core programs and activities have created and will maintain an educated local communityeager to receive updated information on AD and to participate in our Centers research. Through OR Coreefforts the UK-ADC will continue to work with both the Commonwealth of Kentucky and UK partners indirecting state and institutional responses to meeting dementia health care needs and increasing healthliteracy in the elderly. Over the past five years the OR Core has taken the lead in developing innovativepartnerships and products to support research participation by African Americans the largest minority group inKentucky. We will continue to emphasize recruitment and retention of research participants at the earlieststages of the cognitive continuum (Cognitively Normal and MCI). These efforts involve engaging theseparticipants in the ADC longitudinal cohort as well as agreement to brain donation in support of theNeuropathology Core willingness to engage in clinical studies and therapeutic trials that support the ClinicalCore and donation of antemortem biospecimens (plasma DNA CSF and neuroimaging) that support allCores. In the next cycle we will maintain and further build on these efforts and partnerships through thefollowing specific aims:Aim 1. Recruit and retain individuals into our longitudinal cohort ADC-affiliated research studies and nationalinitiatives with a special focus on recruitment and retention of African Americans.Aim 2. Increase community awareness of AD and related disorders through the promotion of health literacythat further enhances recruitment and retention of minority participants in research.Aim 3. Evaluate the effectiveness of our outreach recruitment and educational activities with both qualitativeand quantitative metrics of success.Aim 4. Support and collaborate with the other Cores to reach UK-ADC goals.The OR Core plays a critical role in the UK-ADC and works closely with the other Cores to support recruitmentand retention activities for research protocols clinical trials and national initiatives; increase communityawareness of AD and maintain a strong presence in the African-American community; support educationalinitiatives for the lay community in collaboration with key partners. These functions are vital to the UK-ADCmission to catalyze outstanding and innovative research outreach education and clinical programs.

project_terms:
Address;African American;Aging;Agreement;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Autopsy;Awareness;Biological Markers;Brain;Catchment Area;Clergy;Clinical;Clinical Research;Clinical Trials;Cognitive;Collaborations;Communication;Communities;Community Actions;Consent;DNA;Data Collection;Database Management Systems;Databases;Dementia;Development;Disease;Education;Educational Activities;Effectiveness;Elderly;Enrollment;Event;Extramural Activities;Failure;Fostering;Future;Goals;Health Promotion;Healthcare;Individual;Intervention Trial;Kentucky;Lead;Link;Longitudinal cohort;Minority;Minority Groups;Minority Participation;Mission;Outcome Measure;Participant;Plasma;Play;Poa plant;Program Development;Protocols documentation;Recording of previous events;Recruitment Activity;Reporting;Research;Research Activity;Research Support;Resources;Role;System;Therapeutic Trials;Time;Translational Research;Translations;Universities;Update;Work;cohort;dementia care;dementia risk;demographics;design;education research;effectiveness evaluation;health literacy;healthcare community;innovation;meetings;member;minority communities;neuroimaging;neuropathology;outreach;parity;participant retention;programs;recruit;research study;response;success;volunteer;willingness


application_id: 9976438
project_number: 5P30AG028383-15
project_title: Core D: Neuropathology Core
administering_ic: NIA
award_notice_date: 2020-06-09
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_end_date: 2023-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 6811
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
project_abstract:
Project Summary/Abstract: Neuropathology CoreThe overall objective of the Neuropathology Core of the University of Kentucky Alzheimers Disease Center(UK-ADC) is to support research on normal brain aging presymptomatic Alzheimers disease (pAD) mildcognitive impairment (MCI) early and late AD mixed dementia syndromes and other dementing disorders.Autopsies will be performed by our Rapid Autopsy Team on longitudinally followed subjects from our ClinicalCore. We will perform short post-mortem interval autopsies in relation to our clinical cohort and we willmaintain a high autopsy rate. This Core is optimally tailored to help address important research questions.The Core will provide brain tissue specimens CSF and synaptosomes for investigators at UK other ADCsand outside investigators. The Core will also provide consensus conference determined diagnosesquantitation of neurofibrillary tangles (NFT) neuritic plaques and diffuse plaques from 8 brain regions A 1-40and 1-42 quantitation Braak staging CERAD and NIA-Reagan Institute staging on all autopsied cases toinvestigators. This brain bank has been operating continuously for over three decades with a strong trackrecord so special care will be taken to ensure diagnostic excellence consistency and continuity. The Corewill maintain a tissue bank of the above specimens and frozen serum plasma buffy coats and CSF from livingpatients. Special emphasis will be placed on defining the neuropathological findings in the brains of the oldestold (>85 years) and providing investigators with specimens from cognitively intact control subjects with no Adeposition and sparse tau pathology (successful cerebral aging) and also cognitively intact subjects withabundant plaques and neurofibrillary tangles. Providing these samples will contribute to clinical-pathologicalcorrelation studies and cutting-edge research that include sponsored studies related to AD genomics oxidativestress hippocampal sclerosis dementia with Lewy bodies amyloid precursor protein processing Downsyndrome and neuroinflammation. Frequent consensus conferences will be held with the Clinical Core andBiostatistics Core to help define clinical-pathological diagnoses on all autopsied subjects. This Core is stronglyintegrated with other Cores of the UK-ADC and exploits unique opportunities to conduct clinical-pathologicalcorrelative studies on longitudinally followed subjects. Through these methods we will better understandnormal brain aging and the transition to dementia with the focused goal of contributing to therapeutic orpreventive measures. The Neuropathology Core complements the other Cores of the UK-ADC to provide extremely essentialdiagnoses and tissue samples that are required for many cutting-edge researchers at the University ofKentucky and elsewhere. We will build on our track record of excellence using innovative tools related to brainautopsies neuropathological diagnoses tissue banking and state-of-the-art clinical-pathological correlation.

project_terms:
Address;Aged 80 and over;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimer's disease patient;Amyloid beta-Protein;Area;Autopsy;Biological;Biological Markers;Biological Specimen Banks;Biometry;Biostatistics Core;Brain;Brain Diseases;Brain imaging;Brain region;Caring;Catalogs;Cerebrospinal Fluid;Cerebrum;Clinical;Clinical Trials;Cognition Disorders;Cognitive;Collaborations;Complement;Consensus;Correlation Studies;Correlative Study;DNA;Data;Databases;Dementia;Diagnosis;Diagnostic;Disease;Down Syndrome;Ensure;Freezing;Frontotemporal Lobar Degenerations;Genetic study;Genomics;Goals;Impaired cognition;Individual;Infrastructure;Institutes;Investigation;Kentucky;Laboratory Research;Lesion;Lewy Body Dementia;Medical Genetics;Memory;Methodology;Methods;Mission;Nerve Degeneration;Neurofibrillary Tangles;Oxidative Stress;Pathologic;Pathology;Patients;Plasma;Preparation;Preventive measure;Protocols documentation;Publishing;Research;Research Personnel;Research Support;Resources;Running;Sampling;Senile Plaques;Serum;Services;Specimen;Staging;Standardization;Synaptosomes;Syndrome;Tauopathies;Therapeutic;Thinness;Time;Tissue Banks;Tissue Sample;Tissues;Universities;Work;abeta deposition;age related;age related neurodegeneration;aging brain;amyloid precursor protein processing;blood product;brain tissue;cerebrovascular pathology;clinical center;cohort;data management;digital;experience;genome wide association study;hippocampal sclerosis;innovation;meetings;mild cognitive impairment;mixed dementia;neuroinflammation;neuropathology;normal aging;novel;pre-clinical;protein TDP-43;religious order study;symposium;synucleinopathy;tau Proteins;tool


application_id: 9976434
project_number: 5P30AG028383-15
project_title: Core C: Data Management and Statistical Core
administering_ic: NIA
award_notice_date: 2020-06-09
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_end_date: 2023-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 6810
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
project_abstract:
Program Summary/Abstract: Data Management and Statistical CoreThe Data Management and Statistical (DMS) Core can be conceptualized as the lynchpin for integration of theADC Cores and is vital to the success of the UK-ADC. Its critical roles include managing a large centralizeddatabase consulting with ADC-affiliated researchers and working to develop and apply innovative statisticalmethodology for data analysis. Data management efforts focus on collecting and storing high quality data.This focus begins with the leadership and vision and attention to detail provided by the DMS Core. This corehas an enviable track record of timely and accurate reporting of a high volume of data to NACC. Furtherweekly Core meetings are popular with UK-ADC investigators who find that the expert advice provided by ourseasoned investigators improves their success in pilot studies grant applications and publications. The Corealso participates as a full partner to the research mission of the UK-ADC emphasizing transitions andtranslations. One such partnership with the Clinical and Neuropathology Cores relates to clinico-pathologicalmodels of mixed dementias. A key element of this DMS Core is the well-established track record of developingnovel methodology to analyze data collected at the UK-ADC and from other cohorts with a focus on elderlysubjects transitions to MCI and eventually dementia. The Core also provides training for students enrolled inthe graduate programs in Gerontology Public Health Epidemiology and Biostatistics Psychology andStatistics. It is committed to developing younger faculty to become productive ADC investigators. In keepingwith the mission of the UK-ADC faculty in this Core also contribute to the dementia research community atlarge through service on external advisory committees study sections manuscript reviews and data safetymonitoring boards. The DMS Core will continue these critical responsibilities through the following specificaims.1: Create and maintain a web-based integrated data warehouse for ADC Cores and projects.2: Provide expertise on experimental design and statistical analysis.3: Support the clinical neuropathological and educational/outreach missions of the ADC.4: Contribute to the activities of the dementia community at large through service and research.

project_terms:
Adopted;Advisory Committees;Alzheimer's Disease;Alzheimer's Disease Core Center;Applications Grants;Area;Attention;Biological Markers;Biometry;Cerebrospinal Fluid;Clinical;Clinical Trials;Clinical Trials Data Monitoring Committees;Cognitive;Collaborations;Communities;Consult;Data;Data Analyses;Data Collection;Data Element;Databases;Dementia;Elderly;Enrollment;Epidemiology;Evaluation;Event;Experimental Designs;Extramural Activities;Faculty;Funding;Future;Generations;Genetic;Gerontology;Growth;Health Services Research;Image;Kentucky;Leadership;Literature;Manuscripts;Mentors;Methodology;Methods;Mission;Modeling;Neuroepidemiology;Online Systems;Paper;Participant;Pathologic;Pathology;Phase;Pilot Projects;Psychology;Public Health;Publications;Records;Reporting;Research;Research Design;Research Personnel;Research Support;Risk Factors;Role;Scanning;Seasons;Secure;Services;Statistical Data Interpretation;Study Section;System;Tablets;Time;Training;Translational trial;Translations;Universities;Ursidae Family;Vision;central database;cohort;data management;data warehouse;direct application;doctoral student;improved;innovation;interest;meetings;member;mixed dementia;neuropathology;novel;outreach;programs;recruit;statistics;student training;success


application_id: 9976432
project_number: 5P30AG028383-15
project_title: Core B: Clinical Core
administering_ic: NIA
award_notice_date: 2020-06-09
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_end_date: 2023-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 6809
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
project_abstract:
Project Summary/Abstract: Clinical CoreThe Clinical Core of the UK-ADC maintains a well-characterized community-based cohort focused onnormal aging and early transitional disease states and follows individuals longitudinally until brain autopsy.We maintain a mandatory autopsy requirement for all subjects (with the exception of our Minority GatewayClinic where autopsy is promoted but not required) allowing major contributions in the area of clinical-pathological correlative studies definition of early preclinical and pre-dementia disease state pathologyand basic translational research. The UK-ADC Clinical Core emphasizes: 1) collection of demographicclinical genetic and autopsy data from large numbers of subjects readily available as potential researchsubjects for current and future research needs 2) provision of non-autopsy biospecimens includingantemortem imaging and CSF biomarkers in a sub-cohort of subjects and 3) efforts to further advance thediscovery and development of novel therapeutics for AD. We are major contributors to nationalcollaborative initiatives such as NACC ADCS ADNI NCRAD and ADGC. Our research cohort is stronglymotivated to participate in research as evidenced by 304 unique active (living) subjects who haveparticipated in clinical studies over the report period. The Clinical Core has supported 40 grants and affiliatedprojects focused on specific research questions beyond standard UK-ADC data collections culminating in 64direct and 18 indirect publications supported by Core activities. Antemortem biomarker collections over thecurrent funding cycle include 361 clinical and 267 standardized research MRI scans 229 CSF collections and90 A-PET scans in order to more fully characterize our normal control and early transitional (MCI) cohort.Another major strength of our center lies in our robust minority outreach and engagement. Our efforts inconjunction with the OR Core have led to above-par for local and regional area minority engagement in ADCand affiliated studies. We have effectively engaged minority subjects in perceived invasive and therapeuticresearch efforts at a level of participation that has previously been considered untenable by most ADCs andnon-NIA funded centers nationally (37.6% unique minority subjects engaged in interventional trials). Theseefforts and successes will continue in the next five years under the harmonized and integrated Clinical Coreefforts that have proven successful at the UK-ADC. We will continue to play a leading role in clinicaltranslational research and development of potential novel therapeutic strategies to prevent or modifypathogenesis of AD and related disorders. Overall the Clinical Core will continue to provide an infrastructureand environment that will continue to contribute to our success in advancing multidisciplinary innovative ADresearch supporting our center theme of Transitions & Translation.

project_terms:
Alzheimer's Disease;Alzheimer's Disease Core Center;Amyloid beta-Protein;Area;Autopsy;Basic Science;Biological Markers;Blood;Brain;Cessation of life;Clinic;Clinical;Clinical Research;Clinical Trials;Cognitive;Collaborations;Collection;Communities;Correlative Study;Data;Data Collection;Data Set;Dementia;Development;Disease;Education and Outreach;Environment;Extramural Activities;Foundations;Funding;Genetic Markers;Grant;Heart;Image;Impairment;Individual;Industry;Infrastructure;Intervention Trial;Kentucky;Leadership;Longitudinal cohort;MRI Scans;Magnetic Resonance Imaging;Medical Genetics;Minority;Minority Participation;Mission;Pathogenesis;Pathologic;Pathology;Pharmaceutical Preparations;Phase;Play;Population;Positron-Emission Tomography;Publications;Reporting;Research;Research Personnel;Research Project Grants;Research Subjects;Research Support;Role;Schedule;Specimen;Standardization;Therapeutic Human Experimentation;Tissues;Translational Research;Translations;United States National Institutes of Health;Universities;Work;active lifestyle;base;clinical center;cohort;data management;innovation;meetings;minority communities;minority subjects;multidisciplinary;normal aging;novel therapeutics;operation;outreach;pre-clinical;prevent;programs;research and development;success;therapeutic development


application_id: 9976429
project_number: 5P30AG028383-15
project_title: Core A: Administrative Core
administering_ic: NIA
award_notice_date: 2020-06-09
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_end_date: 2023-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 6808
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
project_abstract:
Project Summary/Abstract: Administrative CoreThe ultimate goal of the UK-ADC is to catalyze innovative and outstanding AD research while ensuring a morerapid rate of progress toward new therapies to delay or prevent AD so that our human volunteers patients andcaregivers become the beneficiaries of our advances in knowledge. The Administrative Core provides thefoundation infrastructure leadership overall direction strategic planning and integration of all ADCcomponents to more rapidly achieve this goal. We support and facilitate research aimed at elucidating thepathogenic mechanisms underlying the transitions from normal cognitive aging to the development ofcognitive impairment with a long-term goal of enabling more effective translation of this mechanisticknowledge to intervention strategies. The UK-ADC functions in a multidisciplinary integrated collaborative andsupportive environment that catalyzes high-quality AD research within the UK community region nation andbeyond. Our major emphases continue to support our traditional strengths in neuropathologic discoveries andprovision of normal and MCI autopsy tissue to support basic translational research as well as our maturingprogram in antemortem biomarker assessment of predementia-stage subjects. The UK-ADC also enhanceseducation and outreach within UK and in the community. We have developed a trusting partnership with theAfrican-American community that has resulted in successful outreach programs and educational products aswell as increasing minority participation in research studies. We have innovative programs focused on qualityof care and support for people with dementia and their caregivers. We offer multi-faceted educational andtraining programs to healthcare professionals and researchers that are aimed at enhancing the training of aworkforce to meet the nations biomedical behavioral and clinical needs in AD-related research. Oursuccessful Pilot Project program leveraged support from university partners to be able to fund 6 additional pilotprojects beyond the 10 funded by the ADC grant. The UK-ADC also reaches beyond Kentucky to enhance ADresearch education and clinical practice on a national level through its interactions with other ADCs as wellas other regional and national institutions including the Alzheimers Association NIA and industry. TheAdministrative Core will continue to support the ability of our UK-ADC to serve as a vital resource for theuniversity community state region and nation through the following specific aims.Aim 1: Provide leadership and an organizational framework for management and coordination of all ADCactivities to ensure optimal resource utilization to meet the overall goals of the ADC.Aim 2: Promote our translational mission and enhance research education and scientific interactions.Aim 3: Contribute to and interact with other ADCs and other national collaborative activities and increasevisibility in the local and national community.

project_terms:
Advisory Committees;African American;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Autopsy;Behavioral;Biological Markers;Caregivers;Clinical;Clinical Trials;Cognitive aging;Collaborations;Communication;Communities;Dementia;Education;Education and Outreach;Ensure;Ethics;Evaluation;Faculty Recruitment;Fostering;Foundations;Funding;Future;Goals;Grant;Growth;Health Professional;Human Volunteers;Impaired cognition;Industry;Infrastructure;Institution;Intervention;Kentucky;Knowledge;Leadership;Medical;Minority Participation;Mission;Pathogenicity;Patients;Pilot Projects;Policies;Productivity;Quality of Care;Research;Research Activity;Research Personnel;Resources;Strategic Planning;Tissues;Training;Training Programs;Translational Research;Translations;Trust;Universities;University resources;beneficiary;career;caregiver education;clinical practice;cognitive development;collaborative environment;innovation;multidisciplinary;novel therapeutics;outreach;outreach program;prevent;programs;research study;supportive environment;training opportunity;translational scientist


application_id: 9976410
project_number: 5P30AG028383-15
project_title: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2020-06-09
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
program_official: ELLIOTT, CERISE
project_start_date: 2006-07-15
project_end_date: 2023-06-30
study_section: ZAG1-ZIJ-G(M1)
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: 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
arra_indicator: N
project_abstract:
Project Summary/Abstract: OverallThis application seeks to renew the University of Kentucky Alzheimers Disease Core Center (UK-ADC) anexperienced and collaborative ADC originally funded in 1985. Our principal mission is to serve as the focalpoint for all AD-related activities at UK and this region of the United States by providing an environment andcore resources that catalyze innovative research outreach education and clinical programs. Our signatureresources include: 1) a cognitively normal group of ~500 subjects followed longitudinally with all committed tobrain autopsy upon death; 2) a strong program in clinical-neuropathological correlations and short postmorteminterval autopsies; 3) a maturing program studying the early preclinical biological emergence of pathology thatmay lead to dementia states with an increasing focus on antemortem imaging and CSF biomarker collection;4) an integrated centralized database and innovative biostatistical expertise to characterize clinical andbiological transitions; and 5) a successful and close partnership with the African-American community andincreased participation of underrepresented individuals in our longitudinal cohort and ADC-affiliated researchstudies and clinical trials. The overall scientific emphasis of the UK-ADC continues to be on our interrelatedthemes: Transitions & Translation. Our well-characterized longitudinal cohort and historically strongneuropathology program focused on normal aging preclinical disease states and early cognitive transitionshave been central to our success in defining early pathogenic mechanisms underlying the transitions fromnormal cognitive aging to impairment. The depth of expertise and collaborative nature of our investigators havealso resulted in substantial progress on translation of that knowledge into new targets and novel therapeuticstrategies. The UK-ADC will continue to provide the infrastructure and resources to focus on these integratedthemes and advance innovative AD research through the pursuit of four overarching specific aims.Aim 1. Facilitate and enhance basic translational and clinical research in AD and related dementias.Aim 2. Provide the necessary resources and interactive environment to support and create new opportunitiesfor innovative research.Aim 3. Maintain and grow educational opportunities and community partnerships to promote awarenessincrease participation in research and provide an innovative and interdisciplinary training environment.Aim 4. Contribute to the national efforts to advance AD research education and care.The UK-ADC provides an infrastructure and environment that focuses on these integrated themes andadvances AD research education outreach and clinical programs through six highly interactive and effectivecomponents: Administrative Core Clinical Core Data Management and Statistics Core Neuropathology CoreOutreach and Recruitment Core and Research Education Component.

project_terms:
African American;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimer's disease related dementia;Area;Autopsy;Awareness;Basic Science;Biological;Biological Markers;Biometry;Brain;Caring;Cessation of life;Clinical;Clinical Research;Clinical Trials;Cognitive;Cognitive aging;Collaborations;Collection;Communities;Community Outreach;Dementia;Disease;Education;Education and Outreach;Environment;Funding;Goals;Health Professional;Image;Impaired cognition;Impairment;Individual;Industry;Infrastructure;Intervention;Kentucky;Lead;Longitudinal cohort;Mission;Nature;Neurodegenerative Disorders;Outcome;Pathogenicity;Pathology;Pilot Projects;Research;Research Personnel;Research Support;Resources;Risk;Training;Translating;Translational Research;Translations;United States;Universities;Work;aging brain;biomarker development;central database;clinical practice;cognitive development;cohesion;collaborative environment;community partnership;comorbidity;data management;education research;experience;healthcare community;innovation;knowledge translation;neuropathology;new therapeutic target;next generation;normal aging;novel therapeutics;outreach;pre-clinical;prevent;programs;recruit;research study;statistics;success

public_health_relevance:
NARRATIVE: OVERALLThe University of Kentucky Alzheimers Disease Center facilitates and supports research efforts to identify theearly manifestations of disease and the pathogenic mechanisms underlying the transitions from normal agingto the development of cognitive impairment with an overall goal of more rapid translation of that knowledgeinto new therapies to delay or prevent AD. We are also dedicated to training the next generation ofresearchers and to educating the lay and healthcare community to increase awareness of AD and relateddisorders and the importance of research and research participation.


application_id: 9975573
project_number: 1R43AR077338-01
administering_ic: NIAMS
award_notice_date: 2020-04-22
opportunity_number: RFA-AR-20-003
application_type: 1
activity_code: R43
ic: AR
serial_number: 077338
program_official: WANG, XIBIN
project_start_date: 2020-05-01
project_end_date: 2022-09-30
study_section: Special Emphasis Panel[ZAR1 YL (M2)]
contact_pi_person_id: 16416375
contact_pi: GUNN, JOSHUA ADAM
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 079118862
primary_uei: EFHKV1BNKWN9
duns_number: 079118862
uei: EFHKV1BNKWN9
fips: US
organization_id: 10048065
organization_name: ETHOS RESEARCH AND DEVELOPMENT, LLC
organization_city: NEWPORT
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 410711803
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-05-01
project_title:
Development of a urinary biomarker panel and software-based solutions to optimize treatment strategies for Systemic Juvenile Idiopathic Arthritis.

project_abstract:
AbstractSystemic Juvenile Idiopathic Arthritis (SJIA) is a rare auto-inflammatory condition characterizedby prolonged synovial inflammation that can lead to structural joint damage. Roughly 15-30% ofSJIA patients develop a complication called macrophage activation syndrome (MAS) which iscaused by excessive activation and proliferation of T cells along with macrophages. Patientswith recurrent MAS can develop interstitial lung disease (LD) with features of pulmonaryalveolar proteinosis caused by dysfunction of alveolar macrophages. Once lung disease isdiagnosed in children with SJIA fatality occurs in 57% of patients within two years ofdiagnosis. Identifying abnormal pathologies that occur early in disease progression and arespecific to subtypes of SJIA is imperative in order to improve the standard of care for patientsand prolong patient life. Ethos R&D proposes to develop a 2-part assay consisting ofbiomarkers related to inflammatory and non-inflammatory pathologies that are perturbed inpatients with SJIA that can be analyzed from urine samples by high-performance liquidchromatography tandem mass spectrometry (LC-MS/MS). Along with the biomarker assayEthos R&D will develop a software-based solution report according to biomarker analysis thatwill communicate recommended adjuvant therapies for physicians parents and patients.Through collaboration with clinicians at CCHMC we will be able to determine the specificity of aurine-based test panel by analyzing subtypes of patients with SJIA (active SJIA SJIA with MASSJIA with lung disease) as compared to healthy controls (patient siblings). Such a technologycould provide life-changing standard of care for SJIA patients.

project_terms:
Adjuvant Therapy;Alveolar Macrophages;Biochemical;Biologic Development;Biological;Biological Assay;Biological Markers;Biological Response Modifier Therapy;Caring;Child;Client;Climacteric;Clinical;Collaborations;Community Developments;Complication;Computer software;Country;Data;Development;Diagnosis;Diagnostic;Dietary intake;Disease;Disease Progression;Environment;Food;Functional disorder;High Pressure Liquid Chromatography;Home environment;Individual;Industry;Inflammatory;Injections;Interleukin-1;Interstitial Lung Diseases;Kynurenine;Laboratories;Lead;Life;Lung diseases;Macrophage activation syndrome;Mass Spectrum Analysis;Measures;Medical;Medical center;Methods;Micronutrients;Modeling;Modernization;Multivariate Analysis;Nutrient;Nutritional;Parents;Pathology;Patient Care;Patients;Pattern;Pediatric Hospitals;Phase;Physicians;Preparation;Provider;Pulmonary Alveolar Proteinosis;Recurrence;Relapse;Reporting;Research Personnel;Sampling;Services;Siblings;Small Business Innovation Research Grant;Source;Specificity;Structure;Synovitis;T-Cell Proliferation;Technical Expertise;Techniques;Technology;Testing;Urine;autoinflammatory;base;biomarker panel;biosignature;cytokine;drug development;hospital laboratories;improved;industry partner;innovation;instrumentation;joint injury;macrophage;micronutrient deficiency;patient response;patient subsets;personalized medicine;protein intake;research and development;research clinical testing;response;sample collection;software development;standard of care;success;systemic juvenile idiopathic arthritis;tandem mass spectrometry;tool;treatment optimization;treatment response;treatment strategy;urinary

public_health_relevance:
Project NarrativeResearchers and physicians from both the drug development community and clinicalenvironment require more understanding of abnormal pathologies associated with systemicjuvenile idiopathic arthritis (SJIA) to improve modern standards of care. Utilizing LC-MS/MSmethods to identify unique profiles of SJIA provides for rapid reliable and scalable techniquesthat can be implemented in clinical evaluations of patients. By measuring urinary metabolitesassociated with a specific disorder and adding this information to a multivariate analysis modelfor each patient researchers will be able to categorize and treat patients according to objectivebiochemical information and improve personalized treatment strategies.


application_id: 9975470
project_number: 1R21AG067438-01
administering_ic: NIA
award_notice_date: 2020-04-21
opportunity_number: PAR-19-071
application_type: 1
activity_code: R21
ic: AG
serial_number: 067438
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2020-05-01
project_end_date: 2023-04-30
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 8899488
contact_pi: STAMM, STEFAN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-05-01
project_title:
Understanding the influence of FTDP-17 mutation on human tau circular RNA formation and function to develop treatment options

project_abstract:
53 currently known mutations in the human microtubule associated protein tau gene (MAPT) cause frontotemporal dementia characterized by behavioral disturbances cognitive impairment and parkinsonism. These mutations have been described as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). The dominant mutations affect men and woman equally and have an average onset of 49 years of age. We recently reported that human MAPT generates two human-specific circular RNAs caused by back-splicing of exon 12 to either exon 7 or 10.Intriguingly 46 of the 53 known FTDP-17 mutations are located in these circular RNAs. The FTDP-17 mutations V337M and K317M introduce a start codon in tau 12->10 circRNA which lacks a start codon in all reading frames. Highly unexpectedly transfection experiments with reporter genes showed that the circular RNAs are translated in HEK293 cells. This suggests that the V337M and K317M mutations act by generating a protein from the tau 12->10 circular RNA. The 12->10 circRNA contains 288 nt and no stop codon. Since 288 nt/3 = 96 amino acids the presence of V337M and K317M leads to a rolling circle translation creating tau polymers. We observed one to three rounds of translation i.e. a protein predicted of 96-288 amino acids in both mutants. The tau circ12->7 RNA is weakly expressed but has its own start codon and again we observe translation using reporter gene systems. We postulate that other FTDP-17 mutations influence translatability stability and/or location of the tau circ12->7 RNA and its protein products. We will test the hypothesis that FTDP-17 mutations act through tau circular RNAs by generating peptides that promote the formation of neurofibrillary tangles (NFT) in two specific aims. First we willcharacterize the influence of FTDP-17 mutation on translatability of the tau 12->10 and 12->7 circRNAsinvestigate the translational initiation and possible contributions to NFT formation. In the second Aim we willInvestigate the influence of tau circular RNAs harboring FTDP-17 mutations on neurons and zebrafish andexplore treatment options. These experiments are highly innovative as they are one of the first demonstration of a translation of a natural circular RNA in a rolling circle mechanism. The translation is completely unexpected as the circular RNAs lack a trimethyl guanosine cap and a known ribosomal entry site and thus according to current `textbookknowledge should not be translated. The findings are significant as they could provide a new model for themolecular mechanism that generates tau aggregates in FTDP-17. Although the FTDP-17 mutations are rarethey can be considered `experiments of nature' which will help understand the more frequent tau pathology inAlzheimer's disease.

project_terms:
Affect;Affinity Chromatography;Age-Years;Alzheimer's Disease;Amino Acid Sequence;Amino Acids;Back;Behavior;Behavioral;Binding;Brain;Budgets;Cells;Cessation of life;Chromosome 17;Complex;Data;Drug Targeting;Exons;FTD with parkinsonism;Fishes;Frontotemporal Dementia;Genes;Genetic Diseases;Guanosine;Human;Impaired cognition;Initiator Codon;Internal Ribosome Entry Site;Investigation;K-18 conjugate;Knowledge;Link;Location;MAPT gene;Maps;Mass Spectrum Analysis;Mediating;Microtubules;Modeling;Molecular;Mutation;Nature;Neurofibrillary Tangles;Neurons;Nucleotides;Oligonucleotides;Open Reading Frames;Parkinsonian Disorders;Pathology;Peptides;Personality;Physiological;Polymers;Proteins;RNA;RNA Splicing;Reading Frames;Reporter Genes;Reporting;Sampling;Seeds;Site;Structure;Subgroup;Symptoms;Syndrome;System;Tauopathies;Temporal Lobe;Terminator Codon;Testing;Textbooks;Transfection;Translating;Translations;Woman;Zebrafish;circular RNA;drug testing;experimental study;frontal lobe;induced pluripotent stem cell;innovation;knock-down;mRNA Precursor;men;molecular modeling;mutant;neurofibrillary tangle formation;neuron loss;overexpression;polypeptide;prevent;tau Proteins;tau aggregation;tau mutation

public_health_relevance:
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a genetic disease thatresembles Alzheimers disease. Almost all mutations causing FTDP-17 affect a part of the microtubuleassociated protein tau pre-mRNA that forms circular RNAs. We will investigate the influence of FTDP-17mutations on the function of these circular RNAs to develop treatment options.


application_id: 9973591
project_number: 1R01DE028916-01A1
project_title: Biosynthesis structure and function of cell wall in Streptococcus mutans
administering_ic: NIDCR
award_notice_date: 2020-04-08
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: DE
serial_number: 028916
suffix: A1
program_official: MCNEALY, TAMARA L
project_start_date: 2020-04-08
project_end_date: 2025-03-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 8869391
contact_pi: KOROTKOVA, NATALIA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Adherence;Affect;Anabolism;Analytical Chemistry;Antibiotics;Antimicrobial Resistance;Autolysin;Autolysis;Bacteremia;Bacteria;Biochemical;Biogenesis;Biology;Carbohydrates;Cell Wall;Cell division;Cell physiology;Cell surface;Cellular Morphology;Charge;Chemical Structure;Collaborations;Defect;Dental caries;Development;Divalent Cations;Drug Design;Drug Targeting;Enzymatic Biochemistry;Enzymes;Etiology;Future;Genetic;Glucose;Glycerol;Goals;Gram-Positive Bacteria;Human;In Vitro;Infection;Infective endocarditis;Knowledge;Lead;Light;Link;Mass Spectrum Analysis;Mechanics;Methods;Microbial Biofilms;Microscopy;Modeling;Modification;Molecular;Molecular Genetics;Molecular Structure;Morphology;NMR Spectroscopy;Oral cavity;Outcome;Outcomes Research;Pathogenesis;Pathway interactions;Peptidoglycan;Permeability;Phenotype;Phospholipase A2;Phospholipids;Play;Polysaccharides;Predisposition;Preparation;Process;Property;Proteins;Publishing;Rattus;Regulation;Reporting;Research;Resistance;Rhamnose;Role;Septal Region;Serotyping;Side;Signal Transduction;Spatial Distribution;Streptococcus;Streptococcus mutans;Streptococcus pyogenes;Structure;Surface;Techniques;Testing;Transferase;Treatment Efficacy;Vertebral column;Virulence;Work;antimicrobial;antimicrobial drug;base;carbohydrate biosynthesis;carbohydrate structure;cell envelope;drug development;extracellular;improved;inorganic phosphate;insight;lipoteichoic acid;mutant;nanomechanics;neutrophil;novel;novel strategies;pathogen;quorum sensing;recruit;targeted treatment;therapeutic target


application_id: 9973149
project_number: 5R01CA196634-06
project_title: Improving chemotherapy of castration-resistant prostate cancer
administering_ic: NCI
award_notice_date: 2020-09-01
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 196634
program_official: FORRY, SUZANNE L
project_start_date: 2019-01-15
project_end_date: 2021-06-30
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Title: Improving chemotherapy of castration-resistant prostate cancerAbstractBecause prostate cancer (PCa) requires androgen for development androgen ablation (castration) is theprimary treatment for patients with late stage PCa. However recurrent tumors arise within 2 years whereasandrogen receptor (AR) signaling has been inappropriately restored and the disease enters a stage calledcastration-resistant prostate cancer (CRPC). Docetaxel is the standard treatment for CRPC patients withlimited success. Therefore it is urgent to understand mechanisms of docetaxel so novel avenues can bedeveloped to increase its efficacy. It was recently found that the nuclear localization of AR is microtubuledynamics dependent and that the anti-tumor effect of docetaxel in CRPC is largely due to its inhibition of ARnuclear import. However the detailed molecular mechanisms behind these intriguing observations are stillelusive. The long-term goals of this study are to provide novel approaches to overcome docetaxel resistanceof CRPC. Polo-like kinase 1 (Plk1) a critical regulator in many cell cycle events is elevated in PCa and linkedto tumor grades. The objective here is to define the role of Plk1 in activating AR signaling and to examinewhether its inhibition can enhance the efficacy of docetaxel in CRPC. Clip-170 and p150Glued two regulators ofmicrotubule dynamics were recently identified as novel Plk1 substrates. The central hypothesis of the proposalis that Plk1-associated activity towards Clip-170 and p150Glued increases microtubule dynamics resulting inconstitutive activation of AR signaling and development of docetaxel resistance. This hypothesis will be testedby pursuing three specific aims  (1) to test how Plk1 phosphorylation of Clip-170 and p150Glued contributes todocetaxel resistance in CRPC cells; (2) to analyze whether Plk1-associated kinase activity contributes todocetaxel resistance in CRPC in mice; and (3) to ask whether a combination of Plk1 inhibition and docetaxelis a novel avenue for treatment of CRPC. These complementary aims will be accomplished using biochemicalanalyses of signaling intermediates and employing genetic strategies with inducible PCa mouse modelsculture systems and PCa xenograft methodologies. The rationale for the research is that it will be the first toprobe the importance of Plk1 to the AR signaling and to examine how Plk1 induces docetaxel resistance inCRPC. This contribution is significant because it will (i) define the molecular mechanism by which Plk1activates AR; (ii) genetically evaluate how Plk1 cooperates with loss of PTEN signaling; and (iii) validate Plk1as a critical therapeutic target to enhance the efficacy of docetaxel. The research is innovative as it approachesthe disease from a novel Plk1 signaling pathway challenging the traditional view that Plk1 functions solely toregulate mitotic events. These studies are poised to provide a new paradigm for improved patient therapies byidentifying the key regulator of the AR signaling that is critical for generating and maintaining the CRPCphenotype.

project_terms:
Ablation;Affect;Agreement;Androgen Receptor;Androgens;Apoptosis;Binding;Biochemical;Cancer Patient;Castration;Cell Cycle;Cell Nucleus;Cells;Clinical;Clinical Research;Clip;Cytoplasm;Data;Development;Disease;Event;Fostering;Genetically Engineered Mouse;Goals;Health;Human;In Vitro;Interphase;Investigation;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Methodology;Microtubule Depolymerization;Microtubule Stabilization;Microtubules;Mission;Mitotic;Molecular;Mus;Nuclear;Nuclear Import;Nuclear Receptors;Outcome;PLK1 gene;PTEN gene;Patient-Focused Outcomes;Patients;Pharmacology;Phenotype;Phosphorylation;Phosphorylation Site;Phosphotransferases;Public Health;RNA Splicing;Receptor Activation;Receptor Signaling;Recurrent tumor;Research;Resistance;Resistance development;Role;Signal Pathway;Signal Transduction;System;Testing;Therapeutic;Time;Transactivation;Tumor-Derived;Variant;Work;Xenograft Model;Xenograft procedure;antitumor effect;beta Tubulin;cancer cell;castration resistant prostate cancer;chemotherapy;design;docetaxel;event cycle;genetic approach;improved;innovation;mouse model;mutant;novel;novel strategies;overexpression;predictive marker;prevent;prostate cancer cell;prostate cancer progression;receptor function;response;standard care;success;therapeutic target;tumor


application_id: 9972589
project_number: 1R01HL148443-01A1
project_title: Mechanisms of cardiac remodeling triggered by gestational diabetes
administering_ic: NHLBI
award_notice_date: 2020-04-29
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: HL
serial_number: 148443
suffix: A1
program_official: TJURMINA, OLGA A
project_start_date: 2020-05-01
project_end_date: 2024-04-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 9983033
contact_pi: DESPA, SANDA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Acids;Age-Months;Agreement;Beta Cell;Blood;Calcineurin;Cardiac;Cardiac Myocytes;Cardiovascular Diseases;Cardiovascular system;Complex;Data;Deposition;Development;Female;Functional disorder;Genetic Transcription;Gestational Diabetes;Heart;Heart Diseases;Heart Hypertrophy;Histone Deacetylase;Hormones;Human;Hyperglycemia;Hypertrophy;Impairment;Individual;Injections;Insulin;Insulin Resistance;Life;Measurement;Mediating;Mediator of activation protein;Membrane;Metabolic;Modeling;Molecular;Mothers;Muscle Cells;Myocardial dysfunction;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pancreas;Pancreatic Hormones;Participant;Pathologic;Pathology;Pathway interactions;Pharmacological Treatment;Pharmacology;Poloxamer 188;Postpartum Period;Prediabetes syndrome;Pregnancy;Property;Prospective Studies;Rattus;Recombinants;Reporting;Risk;Role;Signal Transduction;Structure;Structure of beta Cell of islet;Testing;Transgenic Organisms;Woman;Work;base;blood treatment;calmodulin-dependent protein kinase II;design;diabetic;experimental study;glycemic control;heart dimension/size;heart disease risk;heart function;in vivo;insight;insulin secretion;islet amyloid polypeptide;male;neonate;novel therapeutic intervention;novel therapeutics;nuclear factors of activated T-cells;offspring;population based;pregnant;programs;pup


application_id: 9971810
project_number: 1R01DA048892-01A1
project_title: DAT- Integrated Outpatient Treatment of Opioid Use Disorder and Injection-Related Infections
administering_ic: NIDA
award_notice_date: 2020-09-24
opportunity_number: PA-19-055
application_type: 1
activity_code: R01
ic: DA
serial_number: 048892
suffix: A1
program_official: FITZ-RANDOLPH, MARCY ESTHER
project_start_date: 2020-09-30
project_end_date: 2024-08-31
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 14788426
contact_pi: FANUCCHI, LAURA
other_pis: LOFWALL, MICHELLE RENEE
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Abstinence;Address;Adoption;Alcohol consumption;Ambulatory Care;Antibiotic Therapy;Antibiotics;Buprenorphine;Catheters;Client satisfaction;Clinical;Counseling;Criminal Justice;Development;Dose;Drug usage;Effectiveness;Effectiveness of Interventions;Endocarditis;Enrollment;Evidence based treatment;Future;Health Care Costs;Health Care Sector;Health Services;Healthcare Systems;Home environment;Hospitalization;Hospitals;Illicit Drugs;Infection;Injections;Inpatients;Intervention;Interview;Intravenous;Investigation;Length of Stay;Medical;Medical Care Team;Methadone;Modeling;National Institute of Drug Abuse;Nosocomial Infections;Observational Study;Outcome;Outpatients;Participant;Patient Self-Report;Patient-Focused Outcomes;Patients;Peripheral;Persons;Pharmaceutical Preparations;Phase;Pilot Projects;Population;Productivity;Provider;Quality-Adjusted Life Years;Randomized;Randomized Clinical Trials;Regimen;Research;Resources;Risk;Running;Sampling;Schedule;Self Administration;Supervision;Testing;Time;Tobacco Use Disorder;Urine;Work;addiction;buprenorphine treatment;clinical practice;cost;cost effective;cost effectiveness;economic evaluation;health care model;health care service organization;health care settings;health economics;illicit drug use;illicit opioid;improved;injection drug use;innovation;opioid epidemic;opioid use;opioid use disorder;primary outcome;response;safety and feasibility;secondary outcome;standard of care;treatment as usual


application_id: 9971576
project_number: 5R01HL142710-03
project_title: Regulation of Coronary Blood Flow
administering_ic: NHLBI
award_notice_date: 2020-07-06
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 142710
program_official: OH, YOUNGSUK
project_start_date: 2018-07-20
project_end_date: 2023-06-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 10920880
contact_pi: NYSTORIAK, MATTHEW A
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe goal of this project is to gain a better understanding of mechanisms that underlie metabolic couplingbetween myocardial oxygen demand and oxygen supply via changes in coronary blood flow to the heart.Redox-sensitive voltage-gated potassium channels (i.e. Kv1.x) in coronary vascular smooth muscle (CVSM)are known to be essential to the enhancement of myocardial blood flow (MBF) in response to increasedcardiac workload. How Kv1 channel activity is enhanced in CVSM in response to metabolic signals from anactive myocardium is unknown. Here we propose an essential role for metabolic regulation of Kv1 channelactivity by the tetrameric assembly of cytosolic auxiliary Kv subunits which are members of the aldo-ketoreductase (AKR) superfamily and bind oxidized and reduced pyridine nucleotides (e.g. NAD(H)) with highaffinity. Our preliminary data are consistent with the global hypothesis that interactions between NAD(H) andKv1 and Kv2 impart precise control over the coupling between regional MBF with cardiac oxygen demand.In Aim 1 we will delineate the role of coronary Kv subunits in the regulation of the metabolic hyperemiaresponse. To do this we will use non-invasive myocardial contrast echocardiography (MCE) to measure MBFas a function of cardiac workload in anesthetized WT and Kv-null animals upon administration ofnorepinephrine (NE). The cell-specific contribution of Kv1 and Kv2 in CVSM to metabolic hyperemia will beexamined in double transgenic animals with inducible smooth muscle-specific expression of Kv in nullbackground animals. In vitro electrophysiology and myography will test the relative roles for Kv in altering thevoltage-dependence of Kv1 activation and inactivation and metabolic vasodilation respectively. In Aim 2 wewill elucidate the mechanism of Kv-mediated metabolic coupling. We will measure using electrophysiologythe relative functional contribution of Kv subunits to regulation of Kv1 activity upon specific manipulations incellular metabolism that alter the redox ratio of NADH:NAD+ in CVSM. We will quantify changes inNADH/NAD+ redox in CVSM using genetically-encoded fluorescent biosensors and MALDI-MS imaging anddetermine the role of NAD(H) turnover by Kv catalysis in regulation of coronary vasodilation andenhancement of MBF. In Aim 3 we will clarify the role of Kv in cardiovascular adaptation to exerciseconditioning. To do this we will subject WT and genetically-modified animals to a forced treadmill runningexercise protocol before measuring adaptations in MBF coronary vasodilatory capacity and Kv activation andinactivation properties. This aim will also address the overall dependence of physiological myocardialadaptations and enhancement of exercise capacity on coronary Kv-dependent changes in MBF.

project_terms:
Address;Affect;Affinity;Animals;Binding;Biochemistry;Biosensor;Blood;Blood Vessels;Blood flow;Caliber;Cardiac;Cardiovascular system;Catalysis;Cells;Complex;Contrast Echocardiography;Coronary;Coronary Arteriosclerosis;Coronary Vessels;Coronary artery;Coronary heart disease;Couples;Coupling;Cues;Data;Dependence;Development;Electrophysiology (science);Exercise;Family;Genetically Engineered Mouse;Genetically Modified Animals;Goals;Heart;Heart Contractilities;Heart Diseases;Heart Rate;Hyperemia;Image;Impairment;In Vitro;Ischemia;Link;Measurement;Measures;Mediating;Mediator of activation protein;Membrane Potentials;Metabolic;Metabolism;Molecular;Molecular Biology;Monitor;Myocardial;Myocardial Ischemia;Myocardial perfusion;Myocardium;Myography;NADH;Norepinephrine;Oxidation-Reduction;Oxides;Oxidoreductase;Oxygen;Patients;Physiological;Play;Process;Property;Proteins;Protocols documentation;Pump;Recurrence;Regulation;Resistance;Rest;Role;Running;Signal Transduction;Smooth Muscle;Smooth Muscle Myocytes;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Stress;Structural Protein;Testing;Transgenic Animals;Treatment Efficacy;Vascular Smooth Muscle;Vasodilation;Voltage-Gated Potassium Channel;Work;Workload;arteriole;base;comorbidity;conditioning;coronary artery occlusion;exercise capacity;exercise regimen;exercise training;heart function;heart metabolism;hypoperfusion;in vivo;insight;member;novel;novel imaging technique;novel therapeutics;patch clamp;prevent;pyridine nucleotide;reconstitution;response;sedentary;tool;treadmill;voltage

public_health_relevance:
PROJECT NARRATIVERecent evidence indicates that defective coupling between cardiac metabolic demand and coronary vascularfunction contributes to myocardial ischemia in patients with heart disease. We will establish a novel paradigmof myocardial blood flow regulation by elucidating the molecular components that establish the connectionbetween cellular metabolism and vascular smooth muscle excitability. Thus insights generated during thisproject could reveal new targets for the development of more effective therapeutic strategies to prevent orreverse ischemia-related cardiac disorders.


application_id: 9971454
project_number: 5R01AI139671-02
administering_ic: NIAID
award_notice_date: 2020-07-01
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AI
serial_number: 139671
program_official: HILTKE, THOMAS J
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: 2020-07-01
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;Epithelium;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


application_id: 9971187
project_number: 2R01AA017226-12
project_title: Alcohol and Breast Cancer
administering_ic: NIAAA
award_notice_date: 2020-05-15
opportunity_number: PA-19-056
application_type: 2
activity_code: R01
ic: AA
serial_number: 017226
program_official: MURRAY, GARY
project_start_date: 2020-05-15
project_end_date: 2020-07-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
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:
Epidemiological and clinical studies indicate that alcohol abuse promotes the development of breastcancer. There are two features of alcohol-induced tumor promotion: 1) alcohol consumption increases the riskof breast cancer; 2) alcohol promotes cancer progression and is associated with more aggressive forms ofbreast cancer. Therefore alcohol exposure could affect both phases of mammary tumor development namelytumorigenesis (cell transformation and onset of tumor) and cancer aggression (tumor growth metastasis anddrug resistance/recurrence). Adolescent alcohol drinking is a serious problem worldwide. The drinking age isgetting younger while the amount of alcohol uptake per occasion has increased. Adolescentalcohol consumption is a risk factor for accidents injuries mental illnesses or some chronic diseases andpathologies as well as for the appearance of addictions including alcoholism. Although the harmful effect ofadolescent alcohol exposure on the brain structures and behaviors such as cognitive deficits and addictionhas been well studied its effect on tumor risk has never explored. The molecular mechanisms underlyingalcohol tumor promotion however remain unclear. The adolescent is a critical period of mammary glanddevelopment. Our study indicated that adolescent mice were more sensitive to alcohol tumor promoting effectthan adult mice. Our findings suggest that alcohol-induced tumorigenesis and progression/aggressiveness mayoperate by different mechanisms. The p21 Activated Kinases (PAKs) are a family of serine threonine kinases;PAK1 and PAK4 are particularly implicated in the carcinogenesis of mammary tumor. There are four membersof the mammalian p38 mitogen-activated protein kinase (MAPK) family namely p38 p38 p38 and p38.Although some of their physiological functions may overlap the role of these MAPKs is quite different.p38MAPK has been suggested to involve in the progression/aggressiveness of breast cancer. The centralhypothesis for this proposal is that alcohol-promoted mammary tumorigenesis and aggressiveness is mediatedby different mechanisms: alcohol-induced tumorigenesis is mainly mediated by PAK1/PDK4 andestrogen/progestrone signaling pathway in the adolescents while alcohol-induced aggressiveness mainly ismediated by p38MAPK signaling pathway. We also hypothesize that the enhanced sensitivity of adolescentto alcohol is due to that the signaling pathways regulating the development of mammary glands are moresensitive to alcohol exposure. This proposal will test the hypothesis using both in vitro and in vivo approaches.This proposal will for the first time investigate the impact of adolescent alcohol exposure on the development ofmammary glands and tumorigenesis/progression. It will not only elucidate the cellular and molecularmechanisms underlying alcohol-mediated tumor promotion but also help to develop therapeutic strategies fortreating alcohol promotion of breast cancer.

project_terms:
Accidents;Adolescence;Adolescent;Adolescent and Young Adult;Adult;Affect;Age;Aggressive behavior;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcoholism;Alcohols;Animal Model;Appearance;Behavior;Behavior Disorders;Brain;Breast Cancer Model;Breast Cancer Risk Factor;Breast Cancer cell line;Breast Epithelial Cells;Chronic;Chronic Disease;Clinical Research;Cognitive deficits;Development;Diagnosis;Disease;Drug resistance;Estrogens;Family;Female;Funding;In Vitro;Individual;Injury;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mammary gland;Mediating;Mental disorders;Mitogen-Activated Protein Kinases;Modeling;Molecular;Mouse Mammary Tumor Virus;Mus;Neoplasm Metastasis;Pathology;Pathway interactions;Phase;Physiological;Prevalence;Process;Protein-Serine-Threonine Kinases;Recurrence;Risk;Risk Factors;Role;Signal Pathway;Structure;Testing;Therapeutic;Time;Transgenic Mice;Treatment outcome;Tumor Promotion;United States;Vulnerable Populations;Woman;addiction;adolescent alcohol effect;adolescent alcohol exposure;aged;alcohol abuse therapy;alcohol effect;alcohol exposure;alcohol risk;binge drinking;brain behavior;breast cancer progression;cancer risk;cell transformation;critical period;drinking;epidemiology study;in vitro Model;in vivo;malignant breast neoplasm;mammary gland development;member;neoplastic cell;novel;p21 activated kinase;p38 Mitogen Activated Protein Kinase;tumor;tumor growth;tumor progression;tumorigenesis;underage drinking;uptake;young adult

public_health_relevance:
Alcohol consumption is associated with increased risk and aggressiveness of breast cancersuggesting that alcohol may enhance tumorigenesis and progression of breast cancer. Wehypothesize that alcohol-induced tumorigenesis and aggressiveness are mediated by differentmechanisms. This proposal will elucidate the mechanisms of alcohol-induced tumor promotion.


application_id: 9970649
project_number: 1R01NS112693-01A1
project_title: Mitochondrial Uncoupling Prodrug as a Translational Therapy for TBI
administering_ic: NINDS
award_notice_date: 2020-03-10
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: NS
serial_number: 112693
suffix: A1
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2020-03-15
project_end_date: 2025-01-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: KILBAUGH, TODD JUSTEN
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:
24-Dinitrophenol;Acute;Address;Adult;Aftercare;Aging;Anxiety;Axon;Behavior;Bioenergetics;Biological Assay;Biological Markers;Biosensor;Blinded;Blood Platelets;Brain;Brain Contusions;Brain Injuries;Chronic;Clinical;Clinical Pharmacology;Cognition;Cognitive;Cognitive deficits;Contusions;Data;Dinitrophenols;Dose;Drug Kinetics;FDA approved;Family suidae;Female;Goals;Healthcare;Homeostasis;Huntington Disease;Impaired cognition;Impairment;Individual;Injury;Inner mitochondrial membrane;Institution;Intervention;Link;Measures;Mediating;Membrane Potentials;Mitochondria;Mitochondrial Matrix;Morphology;Motor Activity;Movement;Mus;Neurons;Outcome;Oxidative Stress;Pediatric Hospitals;Pharmacodynamics;Pharmacological Treatment;Pharmacology;Philadelphia;Physiology;Pre-Clinical Model;Prodrugs;Production;Property;Protons;Publishing;Randomized;Reactive Oxygen Species;Recovery;Rodent;Scanning;Spinal cord injury;Stroke;Synapses;TBI treatment;Techniques;Testing;Therapeutic;Therapeutic Effect;Therapeutic Intervention;Time;Tissues;Translating;Translational trial;Translations;Traumatic Brain Injury;Traumatic Brain Injury recovery;Treatment Efficacy;United States;Work;behavior measurement;behavioral outcome;biosignature;clinically relevant;cognitive testing;cohort;design;dosage;experimental study;improved;in vivo;innovation;male;mitochondrial dysfunction;mitochondrial membrane;mouse model;neurochemistry;neuroimaging;neurological recovery;neuropathology;neuroprotection;neurotropic;novel;novel marker;novel strategies;oxidative damage;pre-clinical;preclinical efficacy;primary endpoint;repaired;residence;response;restoration;severe injury;sex;therapeutic evaluation


application_id: 9970503
project_number: 5R00ES026653-05
project_title: Mechanisms of mismatch repair mediated cell death after alkylating agent exposure
administering_ic: NIEHS
award_notice_date: 2020-08-11
opportunity_number: PA-15-083
application_type: 5
activity_code: R00
ic: ES
serial_number: 026653
program_official: SHAUGHNESSY, DANIEL
project_start_date: 2018-09-01
project_end_date: 2022-07-31
study_section: NSS
contact_pi_person_id: 9458652
contact_pi: GOELLNER, EVA MARIE
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant)       Dr. Eva Goellner received her bachelor's degree in Chemical Engineering and Biomedical Engineering from Carnegie Mellon University in 2006. She did her Ph.D. research at the University of Pittsburgh School of Medicine in the Laboratory of Dr. Robert Sobol. Her work primarily focused on the mechanisms behind the toxicity of repair intermediates that are generated when the DNA base excision repair (BER) pathway cannot complete repair. Her work helped elucidate the interaction of BER repair intermediates with cellular metabolism. Her graduate work resulted in a first author manuscript in Cancer Research two co-first author manuscripts a first author review and several co-author works and provided a strong background in cellular and molecular biology mammalian cell culture pharmacology and measurements of cellular metabolism. Dr. Goellner joined the laboratory of Dr. Richard Kolodner in October of 2011 working on a separate DNA repair pathway DNA mismatch repair (MMR) that repairs mispairs formed during normal replication. Mismatch repair requires an excision step to remove the DNA up to and including the mispair however deletion of the only known exonuclease involved Exo1 does not have the strong mutator phenotype expected of a required MMR component. This lead to the hypothesis that Exo1-independent and Exo1-dependent subpathways exist.  Dr. Goellner received an NIH NRSA Ruth L. Kirschstein F32 postdoctoral fellowship to perform a screen for mutations in the loading clamp PCNA that specifically disrupted Exo1-independent MMR. Using Saccharomyces cerevisiae Dr. Goellner identified a number of the desired mutations and through the study of them provided a model of how Exo1-independent MMR is carried out. This work was published in a first author manuscript in Molecular Cell a first author review and a co-author paper currently under revision. Her postdoctoral work provided her with a new model system and technical expertise in yeast genetic screens and biochemistry. Dr. Goellner's postdoctoral work and the mentored portion of this award will be carried at the Ludwig Institute for Cancer Research at the University of California School of Medicine Campus. The Ludwig Institute is a diverse group of researchers in nine research laboratories spanning topics of genetics genome integrity proteomics structural biology chromosome biology cell biology and cell signaling. The San Diego branch is part of a worldwide community of Ludwig Institute Centers and is characterized by its excellence in research. These nine laboratories work together to provide a highly collaborative environment in which almost any biological problem can be answered through an in-house collaboration and it provides a high quality research environment with each laboratory regularly publishing in the highest impact journals. The Ludwig Institute has an excellent track record in producing postdoctoral fellows that go on to tenure track positions at top tier universities and is stronglydevoted to the training and success of its postdoctoral fellows. Additionally as part of the Ludwig Institute Dr. Goellner has access to a number of shared UCSD seminar series resources and Core Facilities as well as the opportunity to interact with the large number of research institutes in San Diego. The K99/R00 pathway to independence proposal focuses on answering long-standing questions into the mechanisms of MMR-dependent cell death after alkylating agent exposure. By using separation-of-function mutations in multiple MMR genes she will be able to systematically evaluate this process at a level of mechanistic detail not previously available. Dr. Goellner will combine her unique background in human cell biology molecular pharmacology Saccharomyces cerevisiae genetics and biochemistry to approach this question with a wide variety of techniques and multiple model systems. During the K99 mentored portion of the award Dr. Goellner will identify mutations that specifically disrupt the Exo1-dependent pathway of MMR and will investigate their genetic and biochemical consequences on repair of replication induced mispairs. This will also generate additional important mutations to use in the evaluation of MMR sub-pathways in the response to alkylating agent sensitivity. It will also provide training in new techniques such as biophysical interaction assays and super resolution imaging. During the R00 independent portion a collection of separation of function mutations will be used to study which MMR protein functions are required to induce cell death after DNA alkylation damage. This proposal will also test if downstream repair processing and excision are required for this response and if so what roles the Exo1- independent and Exo1-dependent MMR sub-pathways play. This work will be translated into human cell culture in order to better comprehend the human health consequences of mutations in MMR genes and how they interact with environmental agents. This will provide training in recent advances in genome editing such as CRISPR/Cas9 techniques. This pathway to independence award will provide additional training not only in critical techniques but also in theskills required to be a successful independent researcher and achieve her goal of a tenure track position. This work is a clear departure from Dr. Kolodner or Dr. Sobol's areas of research and will provide Dr. Goellner a unique research program based on her particular interests and training.

project_terms:
ATP phosphohydrolase;ATR gene;Alkylating Agents;Alkylation;Apoptosis;Area;Award;Bachelor's Degree;Base Excision Repairs;Binding;Binding Proteins;Biochemical;Biochemistry;Biological;Biological Assay;Biological Models;Biology;Biomedical Engineering;Biophysics;CRISPR/Cas technology;California;Cell Culture Techniques;Cell Cycle;Cell Cycle Arrest;Cell Death;Cell Line;Cell Survival;Cell model;Cells;Cellular Assay;Cellular Metabolic Process;Cellular biology;Cessation of life;Chemical Engineering;Chromosomes;Closure by clamp;Collaborations;Collection;Communities;Complex;Core Facility;DNA;DNA Alkylation;DNA Damage;DNA Repair Pathway;DNA lesion;Data;Dependence;Development;Doctor of Philosophy;EXO1 gene;Eating;Engineering;Environment;Evaluation;Excision;Exonuclease;Exposure to;Fellowship;Food;Futile Cycling;G2/M Arrest;Genetic;Genetic Screening;Genome;Goals;Health;Human;Image;In Vitro;Industrialization;Institutes;Journals;Kinetics;Laboratories;Laboratory Research;Lead;Libraries;MGMT gene;Malignant Neoplasms;Mammalian Cell;Manuscripts;Measurement;Measures;Mediating;Mentors;Metabolism;Methyltransferase;Mismatch Repair;Modeling;Molecular;Molecular Conformation;Molecular and Cellular Biology;Mutation;National Research Service Awards;Nitroso Compounds;Nuclear Extract;Paper;Pathway interactions;Pharmacology;Phase;Phenotype;Phosphotransferases;Plasmids;Play;Positioning Attribute;Postdoctoral Fellow;Process;Proteins;Proteomics;Publishing;Reaction;Reporter;Research;Research Institute;Research Personnel;Resolution;Resources;Role;S-Adenosylmethionine;Saccharomyces cerevisiae;Series;Signal Transduction;Structure;TEL1 Gene;Technical Expertise;Techniques;Technology;Testing;Thymidine;Toxic effect;Training;Translating;United States National Institutes of Health;Universities;Work;Yeasts;anticancer research;base;collaborative environment;endonuclease;environmental agent;environmental tobacco smoke;exposed human population;gene repair;genome editing;genome integrity;genotoxicity;insight;interest;medical schools;mutant;mutation screening;programs;protein function;public health relevance;reconstitution;recruit;repaired;response;skills;structural biology;success;tenure track;tool;yeast genetics

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Humans are exposed to alkylating agents through second hand smoke the food we eat and exposure to industrial processes. Alkylating agents can damage our DNA resulting in either toxicity or the accumulation of mutations in our genome that can eventually lead to cancer development. However the cell has a number of DNA repair pathways to remove this damage and this study will focus on how one particular DNA repair pathway mismatch repair recognizes DNA damaged by alkylating agents and signals for a cell death response.


application_id: 9970462
project_number: 5K01DA043652-03
project_title: Neural Mechanisms of Cannabinoid-Impaired Decision-Making in Emerging Adults
administering_ic: NIDA
award_notice_date: 2020-06-12
opportunity_number: PA-16-190
application_type: 5
activity_code: K01
ic: DA
serial_number: 043652
program_official: LIN, YU
project_start_date: 2018-07-15
project_end_date: 2023-06-30
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 10239541
contact_pi: WESLEY, MICHAEL J
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT ABSTRACT This mentored career development award (K01) will enable Dr. Michael Wesley to achieve his long-termgoal of becoming an independent investigator with a clinical neuroscience research program examiningcannabis use disorder (CUD) in emerging adults which is a current NIDA funding priority. Dr. Wesley is a newAssistant Professor in the University of Kentucky (UK) College of Medicine. The activities proposed in thisaward build on Dr. Wesleys background expertise in neuroimaging and drug abuse research and will allow himto accomplish the following short-term objectives: Become an expert in (1) clinical pharmacology and (2)non-invasive brain stimulation research in an emerging adult population with CUD and enhance/develop his(3) knowledge of the responsible conduct of research (4) skills for scientific communication and grant writingand (5) ability to manage an independent research program. UK has numerous faculty and projects focused on drug abuse research and is an ideal environment forDr. Wesley to complete this award. Dr. Wesley has assembled a stellar mentoring team consisting of Dr. JoshLile (Mentor) who has a successful NIH-funded clinical pharmacology research program at UK and Dr. MarkGeorge (Co-Mentor) who pioneered the use of non-invasive brain stimulation for treating depression. Inaddition Dr. Lumy Sawaki (Internal Preceptor) and Dr. Lon Hays (Study Physician) will provide local safetyoversight and medical supervision and Dr. Terry Lohrenz (External Preceptor) will provide guidance withadvanced statistical analysis of neuroimaging data. Dr. Wesley will also engage in a series of formal classeslab exchanges and research seminars/meetings to assist him in accomplishing the objectives of this award. The proposed research project is based on the premise that cannabis impairs decision-making processesand these impairing effects contribute to an increased risk of developing CUD in emerging adults. Thisresearch will combine the acute administration of 9-tetrahydrocannabinol (THC) the main psychoactiveingredient in cannabis with high-definition transcranial direct current stimulation (HD-tDCS) and neuroimagingusing rigorous methods to examine the role of prefrontal cortex regions of interest in cannabis-impaireddecision-making in emerging adults. Aim 1 will test the hypotheses that raising intrinsic PFC activity (Exp. 1)will attenuate whereas lowering activity (Exp.2) will enhance the impairing effects of THC on measures ofdecision-making and associated neurocognitive processes in emerging adults. Aim 2 will test the hypothesisthat brain activity and connectivity during baseline task performance is associated with the subsequentresponse to THC and HD-tDCS. This highly innovative project will improve our understanding of themechanisms involved in cannabis-impaired decision-making which will inform CUD management and addressa growing public health concern.

project_terms:
Acute;Address;Anodes;Attenuated;Award;Behavior;Behavioral Mechanisms;Brain;Cannabinoids;Cannabis;Cathodes;Chemicals;Clinical;Clinical Pharmacology;Communication;Data;Decision Making;Development;Disease Management;Dorsal;Drug Use Disorder;Drug abuse;Drug usage;Environment;Faculty;Functional Magnetic Resonance Imaging;Funding;Genetic;Goals;Grant;Impairment;Individual;Individual Differences;Intervention;Intoxication;K-Series Research Career Programs;Kentucky;Knowledge;Lateral;Lesion;Link;Maps;Measures;Medial;Medical;Medicine;Membrane Potentials;Mental Depression;Mentors;Methodology;Methods;National Institute of Drug Abuse;Nature;Neurocognitive;Neurons;Neurosciences Research;Neurotransmitters;Perception;Pharmaceutical Preparations;Physicians;Physiological;Population;Predisposition;Prefrontal Cortex;Process;Public Health;Research;Research Personnel;Research Project Grants;Research Training;Rest;Risk;Role;Safety;Series;Short-Term Memory;Site;Statistical Data Interpretation;Substance abuse problem;Supervision;Task Performances;Techniques;Testing;Tetrahydrocannabinol;Tissues;Training;United States National Institutes of Health;Universities;Writing;base;career development;college;disorder prevention;emerging adult;emerging adulthood;endogenous cannabinoid system;experimental study;frontal lobe;improved;individual response;innovation;interest;marijuana use;marijuana use disorder;marijuana user;meetings;neuroimaging;neuromechanism;preclinical study;professor;programs;relating to nervous system;response;responsible research conduct;skills;social;success

public_health_relevance:
PROJECT NARRATIVECannabis intoxication impairs decision-making processes which may confer increased risk of developingcannabis use disorder (CUD) in emerging adults. The proposed research will combine clinical pharmacologybrain stimulation and neuroimaging to establish the neural mechanisms contributing to cannabinoid-impaireddecision-making in emerging adults with CUD. Results from this project will inform CUD prevention/treatmentefforts and address a growing public health concern.


application_id: 9970160
project_number: 5R01AA026255-03
project_title: A Novel Drug Combination for Alcohol-Use Disorders: A Human Laboratory Study
administering_ic: NIAAA
award_notice_date: 2020-07-21
opportunity_number: PA-15-256
application_type: 5
activity_code: R01
ic: AA
serial_number: 026255
program_official: FALK, DANIEL EVAN
project_start_date: 2018-07-01
project_end_date: 2023-06-30
study_section: Clinical, Treatment and Health Services Research Study Section[AA-3]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT/SUMMARY Alcohol-use disorder (AUD) is an unrelenting public-health concern. AUD is characterized by perturbationsof central monoamine (i.e. dopamine [DA] serotonin [5HT] and norepinephrine [NE]) systems making them alogical target for medications development. Individual monoamine-uptake inhibitors were moderately effectivein a majority of the trials in which they were tested for managing AUD. Continuing to target monoamine-uptakeinhibition for AUD is warranted but novel strategies are needed to identify a highly efficaciouspharmacotherapy. We propose to demonstrate the initial efficacy of an innovative pharmacological strategy formanaging AUD: Triple Monoamine-Uptake Inhibition. Triple monoamine-uptake inhibitors are underdevelopment but are not yet available commercially for human use. Combining available medicationshowever makes it possible to achieve triple monoamine-uptake inhibition. Duloxetine (DUL) anantidepressant has high affinity for the 5HT (ki = 0.8 nM) and NE (ki = 7.5 nM) transporters but lower affinityfor the DA transporter (ki = 240 nM). Methylphenidate (MTH) has high affinity for the DA transporter (ki = 34nM) but lower affinity for the 5HT (ki = >10000 nM) and NE (ki = 339 nM) transporters. We will combine DULand MTH to functionally produce a triple monoamine-uptake inhibitor. A mixed-model study will be conductedin which separate cohorts of non-treatment-seeking AUD participants will be randomized to differentmaintenance doses of delayed-release DUL (i.e. DUL dose is a between-subject factor). Participants (N=16)in each DUL cohort will be maintained concurrently on increasing doses of long-acting MTH (i.e. MTH dose isa within-subject factor). Alcohol (ALC) self-administration will be determined after participants in each DULcohort are maintained for 6 days on each MTH dose. A reverse-engineered ALC self-administration (ALC SA)procedure with good predictive validity for clinical efficacy will be used to demonstrate the initial efficacy ofDUL-MTH combinations. ALC craving will also be assessed. We hypothesize DUL-MTH combinations willproduce an additive or supra-additive reduction in ALC SA relative to the constituent drugs alone. Innovationsinclude: 1) testing a novel pharmacological strategy triple monoamine-uptake inhibition for AUD; 2) testing acombination of marketed drugs as opposed to waiting for compounds under development to be available fortesting in humans thereby impacting clinical research and practice more quickly; 3) the use of once dailydosing formulations of the constituent compounds which will improve compliance when advanced to clinicaltrials or practice; 4) the use of a sophisticated ALC SA procedure; 5) testing multiple doses of DUL and MTHalone and in combination to identify the most effective safe and tolerable dose combination which will enhancethe probability of success when advanced to a clinical trial or practice; and 6) providing the impetus for theconduct of a Phase II clinical trial to further demonstrate the efficacy of DUL-MTH combinations for AUD.

project_terms:
Affinity;Alcohol consumption;Alcohols;American;Anhedonia;Animals;Antidepressive Agents;Attention deficit hyperactivity disorder;Attenuated;Blood alcohol level measurement;Clinical;Clinical Research;Clinical Trials;Development;Dopamine;Dose;Ecology;Economic Burden;Engineering;Formulation;Goals;Human;Individual;Laboratory Study;Maintenance;Measures;Mus;National Institute on Alcohol Abuse and Alcoholism;Norepinephrine;Outcome Measure;Participant;Patient Self-Report;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Phase II Clinical Trials;Physiological;Probability;Procedures;Public Health;Randomized;Research;Research Design;Ritalin;Safety;Self Administration;Serotonin;Study models;System;Testing;alcohol abuse therapy;alcohol craving;alcohol response;alcohol seeking behavior;alcohol use disorder;clinical efficacy;clinical practice;cohort;craving;dopamine transporter;double-blind placebo controlled trial;drug market;duloxetine;improved;inhibitor/antagonist;innovation;monoamine;noradrenaline transporter;norepinephrine system;novel;novel drug combination;novel strategies;preclinical study;secondary outcome;serotonin transporter;success;uptake

public_health_relevance:
PROJECT NARRATIVEThe research proposed in this application will determine the initial efficacy safety and tolerability of a noveldrug combination duloxetine and methylphenidate as a pharmacotherapy for alcohol-use disorder (AUD). Arigorous clinical human laboratory study will be conducted. The proposed study is innovative and importantbecause it will provide the impetus for the conduct of double blind placebo controlled trials to furtherdemonstrate the efficacy of duloxetine-methylphenidate combinations for AUD.


application_id: 9969878
project_number: 2R01HD080205-06
administering_ic: NICHD
award_notice_date: 2020-08-04
opportunity_number: PA-18-480
application_type: 2
activity_code: R01
ic: HD
serial_number: 080205
program_official: NITKIN, RALPH M
project_start_date: 2014-09-23
project_end_date: 2025-07-31
study_section: Special Emphasis Panel[ZRG1 DKUS-B (90)]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
other_pis: HARKEMA, SUSAN J
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-08-05
project_terms:
Address;Anodes;Atrial Natriuretic Factor;Attenuated;Autonomic Dysfunction;Autonomic Dysreflexia;Biological Markers;Bladder;Blood Pressure;Cardiovascular Physiology;Cardiovascular system;Caring;Catheterization;Cathodes;Cervical;Chest;Chills;Data;Electrodes;Event;Feedback;Frequencies;Goals;Guidelines;Headache;Heart Rate;Home environment;Homeostasis;Hormones;Human;Hypertension;Hypotension;Individual;International;Intestines;Laboratories;Lesion;Location;Maintenance;Manometry;Measures;Monitor;Norepinephrine;Outcome;Participant;Persons;Physiological;Piloerection;Population;Quality of life;Questionnaires;Recovery;Rectum;Reflex action;Renin;Reporting;Research;Severities;Sex Functioning;Signal Transduction;Societies;Spinal Cord;Spinal cord injury;Symptoms;System;Tension Headache;Therapeutic;Time;Training;Urodynamics;Vasopressins;Visceral;abdominal pressure;base;blood pressure regulation;improved;indexing;mobile application;multidisciplinary;pressure;prevent;programs;psychologic;rectal;response;time interval;urinary;vasoconstriction;voltage


application_id: 9969187
project_number: 5T32ES011564-15
project_title: UofL Environmental Health Sciences Training Program
project_terms: Environmental Health;Training Programs
administering_ic: NIEHS
award_notice_date: 2020-06-01
opportunity_number: PA-14-015
application_type: 5
activity_code: T32
ic: ES
serial_number: 011564
program_official: SHREFFLER, CAROL A
project_start_date: 2002-07-01
project_end_date: 2021-07-13
study_section: Environmental Health Sciences Review Committee[EHS(TK)]
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID W
other_pis: WISE, JOHN PIERCE
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant)      The investigators have made strategic changes in their environmental health sciences training program in response to the announced restructuring and redirection of NIEHS training programs. Participating Centers Institutes and Schools and the members of the training faculty provide critical resources for cutting edge basic science clinical research computational sciences and public health. Environmental health science partnerships have resulted in a very successful NIEHS training program in environmental health sciences.  The renewal application incorporates and integrates several Schools Centers and Institutes. The investigators propose a substantially improved pre-doctoral and postdoctoral training program that serves as an umbrella for interdisciplinary and integrated approaches to environmental health sciences. The training program will support six pre-doctoral and three postdoctoral trainees. Initial student recruitment and funding for pre-doctoral trainees is provided by the University of Louisville Integrated Programs in the Biomedical Sciences recruitment gateway.  As in the first cycle pre-doctoral trainees will not be recruited directly into the environmental health sciences training program. All faculty mentors are asked to nominate trainees who have completed an approved dissertation proposal with a defined focus in environmental health sciences research. Faculty mentors will be asked to nominate either existing postdoctoral fellows (for example those already matriculated into the Clinical Chemistry and Toxicology Translational Sciences Program) or from trainees to be recruited. Teams of mentors (basic and clinical scientists or basic and population-based scientists) will be particularly encouraged to emphasize the importance of multidisciplinary training and translation of basic science findings to the patient and/or community. The training program facilitates multidisciplinary approaches for effective intervention and interfaces exceptionally well with the NIH Roadmap as well as with the strategic plans of NIEHS and the University of Louisville.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The environmental health problems faced by the nation are multi-factorial in nature and therefore require multi-disciplinary approaches for effective intervention. The training program emphasizes the importance of multidisciplinary training and translation of basic science findings to benefit the patient and/or community. This multi-disciplinary translational program interfaces with the NIH Roadmap and the NIEHS strategic plan.


application_id: 9968814
project_number: 3R01HL107326-08S1
project_title: Sex Differences in Angiotensin-Induced Vascular Diseases
administering_ic: NHLBI
award_notice_date: 2019-09-05
opportunity_number: PA-13-302
application_type: 3
activity_code: R01
ic: HL
serial_number: 107326
suffix: S1
program_official: VARAGIC, JASMINA
project_start_date: 2012-03-21
project_end_date: 2021-05-31
study_section: Special Emphasis Panel[ZRG1-VH-N(02)]
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: 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:
Abdominal aortic aneurysms (AAAs) exhibit pronounced sexual dimorphism. Similar to humans wedemonstrated previously that testosterone is a primary contributor to a 4-fold higher incidence of angiotensin II(AngII)-induced AAAs in male compared to female mice. In addition to sex hormones sex chromosomes havebeen suggested to contribute to sexual dimorphism of cardiovascular diseases. Preliminary data demonstratethat changing the sex chromosome complement from XX to XY in female mice results in an AAA incidence thatis similar to males. As testosterone promotes AngII-induced AAAs in XY males we administered testosteroneto neonatal (1 dose) and adult XY females. Testosterone caused aneurysm rupture in 73% of adult XYfemales. These results demonstrate that sex chromosome complement has a striking impact on AAA severityand that these effects are augmented by testosterone. Gene arrays on smooth muscle cells from XX versusXY females incubated with AngII or testosterone identified neprilysin and heme oxygenase 1 (HO1) as genetargets that may contribute in a sex-specific manner to higher AAA incidences severity and progression inmales compared to females. The central hypothesis of this proposal is that an interplay between sexhormones and chromosomes promotes the incidence and severity of AAAs. Moreover we hypothesize that aPrecision Medicine approach to therapeutically target specific pathways influenced by sex hormoneschromosomes or AngII will provide sex-specific efficacy against AAA formation and progression. Aim 1 willtest the hypothesis that an XY sex chromosome complement increases susceptibility to AngII-induced AAAsdue to the presence of genes on the Y chromosome. We will use a novel mouse model (XY*) that when bredto XX females enables delineation of whether XX XO XXY or XY sex chromosome complement influencesthe development and/or progression of AngII-induced AAAs. Aim 2 will test the hypothesis that sex-specifictherapeutic approaches targeting neprilysin inhibition in males versus HO1 stimulation in females will provideefficacy against the formation and/or progression of AngII-induced AAAs. These studies will increase basicknowledge of sex chromosome influences on the vasculature identify sex-specific therapies that may havetherapeutic applicability against AAAs and increase cardiovascular knowledge for the use of sex hormones inthe growing trans-gender population.

project_terms:
Abdomen;Abdominal Aortic Aneurysm;Adult;Angiotensin II;Angiotensins;Aorta;Awareness;Cardiovascular Diseases;Cardiovascular system;Characteristics;Chromosomes;Chronic;Congenital chromosomal disease;DNA;Data;Development;Dissection;Dose;Event;Exhibits;Female;Gender;Gender Identity;Gene Expression;Gene Targeting;Genes;Genotype;Gonadal Steroid Hormones;Human;Incidence;Incubated;Individual;Knowledge;Life;Link;Mus;Neonatal;Neprilysin;Pathway interactions;Pattern;Pharmacotherapy;Ploidies;Population;Predisposition;Regulation;Risk;Role;Ruptured Aneurysm;Severities;Sex Chromosomes;Sex Differences;Smooth Muscle Myocytes;Testing;Testosterone;Therapeutic;Turner's Syndrome;Vascular Diseases;X Chromosome;X Inactivation;XY females;Y Chromosome;abdominal aorta;chromosome X loss;effective therapy;follow-up;heme oxygenase-1;high risk;male;mortality risk;mouse model;novel;precision medicine;sex;sexual dimorphism;therapeutic target;transgender

public_health_relevance:
The proposed studies will define the role of sex chromosomes on the development of abdominal aorticaneurysms (AAAs). Our approach is to identify interactions between one's sex hormones (e.g. testosterone)and sex chromosomes (XX versus XY) on genes expressed in the aorta that may contribute to AAAdevelopment and progression. We also propose to tailor drug therapies using this information to be moreeffective in males versus females to treat AAAs and other cardiovascular diseases.


application_id: 9968514
project_number: 3R01HL130086-03S1
project_title: Calpains and Abdominal Aortic Aneurysms
administering_ic: NHLBI
award_notice_date: 2019-08-28
opportunity_number: PA-13-302
application_type: 3
activity_code: R01
ic: HL
serial_number: 130086
suffix: S1
program_official: REID, DIANE M
project_start_date: 2017-08-10
project_end_date: 2021-07-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 10792635
contact_pi: SUBRAMANIAN, VENKATESWARAN
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:
ABSTRACT:Abdominal aortic aneurysm (AAA) is a permanent dilation of the abdominal aorta with over 80% mortality afterrupture. The current therapy is restricted to surgical repair highlighting the need to explore mechanic insightsinto the development of effective non-surgical therapeutics. In AAA patients structural integrity of the aorticwall is disrupted due to dissociation of smooth muscle cell (SMC) contractile filaments from extracellular matrixby proteases. This association is mediated by cytoskeletal linker proteins. However the mechanismunderlying loss of vessel wall structural integrity in AAA formation is not understood. Recently usingAngiotensin II (AngII)-induced animal model of AAA we found a profound increase in protein and activity ofaortic calpain a calcium dependent cysteine protease in aneurysmal tissue. In addition calpain inhibitionsignificantly attenuated AngII-induced AAA formation. Calpains are the only known proteases targeting anarray of cytoskeletal proteins that maintain structural integrity of the aorta including filamin. Using calpain-1 or-2 the two major ubiquitous isoform-specific deficient mice we determined that genetic deficiency of calpain-2but not calpain-1 completely blunted AngII-induced AAA formation. Calpain-2 deficiency attenuated AngII-induced fragmentation of cytoskeletal proteins filamin A and talin. Immunostaining of human and mouse AAArevealed expression of calpain-2 protein by infiltrated macrophages and aortic adventitial fibroblasts (AoAFs).Macrophage specific calpain-2 deficiency in mice had no influence on AngII-induced AAA formation whichsuggest a critical role for vessel wall mainly AoAFs derived-calpain-2. In cultured AoAFs AngII promotes ASK-1/NF-kB mediated inflammatory cytokine induction via activation of calpain-2. Further calpain-2 silencingsuppressed (myo)fibroblast differentiation and migration via TGF- / Rho kinase signaling. Based on thedescribed background we will test the hypothesis that calpain-2 activation promotes AngII-induced AAAs byaccelerating adventitial fibroblast-derived NF-kB/ASK-1 mediated adventitial inflammation and(myo)fibroblasts migration to aortic media which in turn causes medial destruction by upregulating cytoskeletalfilament fragmentation in SMCs. To test this hypothesis the following aims are proposed: Aim 1: Determine thecontribution of fibroblasts derived-calpain-2 in AngII-induced AAA. A. Does calpain-2 deficiency in fibroblastsattenuate AngII-induced AAA formation? B. Does calpain-2 regulate TGF-/Rho A in promoting fibroblastsdifferentiation via LTBP3/RhoGDI1? C. Does calpain-2 depletion in AoAFs attenuate AngII-induced cytoskeletalprotein fragmentation in aortic SMCs in vitro? Aim 2: Define the mechanism by which calpain-2 promotesAngII-induced adventitial inflammation? A. Does calpain-2 contribute to ASK-1/ NF-kB activation and correlatewith adventitial inflammation during AAA development? B. Does calpain-2 regulate AngII-induced ASK-1/NF-kBactivation via TRX/IkB in AoAFs? C. Does cytoskeletal protein fragmentation in human AAA tissue associatewith calpain? Aim 3: Determine the effect of calpain-2 deficiency on progression of established AAAs.

project_terms:
Abdominal Aortic Aneurysm;Angiotensin II;Animal Model;Aorta;Aortic Rupture;Attenuated;Calcium;Calpain;Caspase;Cessation of life;Chronic;Cleaved cell;Clinical;Cytoskeletal Filaments;Cytoskeletal Proteins;Data;Development;Disease;Dissociation;Exhibits;Extracellular Matrix;Fibroblasts;Filament;Genetic;Human;In Vitro;Inflammation;Inflammatory;LTBP2 gene;Mechanics;Medial;Mediating;Membrane;Morbidity - disease rate;Mus;Myofibrils;NF-kappa B;Operative Surgical Procedures;Patients;Peptide Hydrolases;Pharmacology;Phenotype;Play;Population;Process;Protein Isoforms;Proteins;Proteolysis;Rho-associated kinase;Role;Rupture;Signal Transduction;Smooth Muscle Myocytes;Structure;Substrate Specificity;TXN gene;Talin;Testing;Therapeutic;Tissues;Transforming Growth Factor beta;Vascular remodeling;abdominal aorta;base;cytokine;filamin;inhibitor/antagonist;insight;latent TGF-beta binding protein;macrophage;migration;mortality;mouse model;new therapeutic target;novel;prevent;repaired;rho;rhoB p20 GDI;vascular inflammation

public_health_relevance:
Project NarrativeAbdominal Aortic Aneurysm (AAA) is a permanent dilation of the abdominal aorta. AAAs are the 13th leadingcause of morbidity and mortality in the US population due to aortic rupture (>80%) resulting in an estimated12000 deaths per year. The purpose of this application is to elucidate the mechanisms responsible for AAAand thereby identify new therapeutic targets to treat and prevent the devastating AAA disease.


application_id: 9968378
project_number: 5P30GM127607-03
project_title: Pilot Projects Program
administering_ic: NIGMS
award_notice_date: 2020-07-02
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
study_section: ZGM1-RCB-3
subproject_number: 5795
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
project_abstract:
ABSTRACTPILOT PROJECT PROGRAM. The overarching mission of the University of Louisville Diabetes and ObesityCenter is to enhance and enrich research into the mechanisms underlying cardiometabolic health and disease.In line with this mission the Pilot Project Program of Phase III of the COBRE will provide financial technical andintellectual support to pilot projects in the areas of diabetes obesity and cardiovascular biology. Applicants forthe Program will derive primarily from junior faculty within academic departments at the University of Louisvillewho have an interest in developing research programs in cardiometabolic disease. Additionally meritoriousprojects submitted by mid-career and senior investigators proposing to change fields or direct their futureresearch toward cardiovascular or metabolic disease will be considered for funding. Pilot project grantapplications will be solicited annually and awarded for a period of not more than two years based on the reviewand recommendations of internal grant evaluators and the External Advisory Committee. In addition we willprovide each awardee with a strong mentorship team to chaperone the development of their projects to the levelrequired for federal funding and to provide career guidance. The specific objectives of the program are to: (1)support innovative cardiometabolic research; (2) provide scientific and professional mentorship to awardrecipients; (3) strengthen the competitiveness of the Diabetes and Obesity Center; and (4) monitor efficiencyand effectiveness of the pilot program. We will encourage projects that have a high probability of both integratingwith and advancing the knowledge and capabilities of the current Center. This approach will help ensure thatwe increase the mass of investigators in the Center as well as augment our ability to conduct basic andtranslational research.

project_terms:
Address;Advisory Committees;Affect;Applications Grants;Area;Award;Basic Science;Biology;Cardiovascular Diseases;Cardiovascular system;Cell physiology;Centers of Research Excellence;Complex;Custom;Data;Development;Diabetes Mellitus;Disease;Effectiveness;Ensure;Environment;Environmental Pollution;Etiology;Extramural Activities;Faculty;Fostering;Funding;Genetic;Goals;Grant;Growth;Health;Institution;Insulin Resistance;Investments;Knowledge;Life Style;Manuscripts;Mentors;Mentorship;Metabolic;Metabolic Diseases;Methodology;Mission;Molecular Chaperones;Monitor;Obesity;Phase;Pilot Projects;Probability;Publishing;Recommendation;Regulation;Research;Research Personnel;Research Project Grants;Resources;Role;Social status;Time;Translational Research;United States National Institutes of Health;Universities;Vocational Guidance;base;cardiometabolism;cardiovascular health;career;career development;innovation;interest;mid-career faculty;novel;novel therapeutics;progenitor;programs;recruit;senior faculty;stem cells;success;synergism


application_id: 9968377
project_number: 5P30GM127607-03
project_title: Imaging and Physiology Core
administering_ic: NIGMS
award_notice_date: 2020-07-02
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
study_section: ZGM1-RCB-3
subproject_number: 5794
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
project_abstract:
The Imaging and Physiology Core (Core E) will nurture the Centers continued growth and hasten projectdevelopment by promoting scientific excellence in investigations of cardiometabolic diseases. Core E willanticipate the needs of the Centers investigatorsparticularly junior investigators whose collective needschangeby maintaining uninterrupted communication with Center members regarding their projects directions.Core E will provide access to state-of-the-art instrumentation and deliver expert instruction related to non-invasive imaging murine surgical models and advanced microscopy. The Core will promote education on thetheory and technical appreciation of relevant approaches instrumentation and techniques. The Core willcollaborate with Center members particularly junior investigators to develop new tailored procedures to answertheir experimental questions. The Director will provide guidance not only for the techniques provided by Core Ebut also mentorship to the junior faculty members in the Center. In addition to meeting the needs of the Centersprojects the Core has established a viable plan to transition to financial independence during Phase III ofCOBRE support. These collective aspirational goals will be accomplished through the following Aims: i) SupportCenter projects through excellence in imaging and physiology; ii) Become a self-sustaining feature of the Centerby cultivating the Cores financial independence; iii) Develop new protocols and techniques for future imagingand physiology needs of the Center; iv) Educate and train investigators on the theory application and analysesrelated to imaging and physiology. Support during Phases I and II of COBRE the University the Center andfaculty members have contributed significantly to the extensive instrumentation in Core E. Such investmentsreflect the important role of Core E in the progress of the Center. The Director will continue developing newprotocols acquiring the latest instrumentation and initiating collaborations with additional investigatorsthroughout the campus community. The Core will make every effort to meet the imaging and physiology needsof all of the Center members while leveraging complementary resources on campus. This Core will maintain itscurrent excellent level of service and actively seek to improve its infrastructure while provide the Center memberswith state-of-the-art instrumentation. Such progress will continue with the long-term goal of establishing a self-sustaining Core. As Core E moves into Phase III the Core will formally engage its business model to bring itsplan for self-sufficiency to fruition. Core E will work closely with Core A to maintain its financial goals to ensureits effectiveness and to enhance its efficiency. Furthermore this Core will be pivotal in bringing this Center tonational prominence in cardiometabolic research. The results of such efforts have been and will continue to beevident in the Centers COBRE graduates numerous publications and growth in NIH funding of Core-supportedCenter members. Core E will remain a bedrock of technological development scientific innovation and relevanttraining for the Center as it tackles the greatest threats to health: diabetes and cardiovascular disease.

project_terms:
Address;Affect;Area;Attention;Businesses;Cardiovascular Diseases;Cardiovascular Physiology;Cells;Centers of Research Excellence;Charge;Collaborations;Communication;Communities;Complications of Diabetes Mellitus;Counseling;Data Analyses;Development;Diabetes Mellitus;Disease;Disease model;Echocardiography;Education;Effectiveness;Ensure;Extramural Activities;Faculty;Felis catus;Fruit;Funding;Future;Goals;Grant;Growth;Health;Human Resources;Image;Individual;Infrastructure;Instruction;Investigation;Investments;Mentors;Mentorship;Microscopy;Mission;Modeling;Monitor;Mus;Obesity;Operative Surgical Procedures;Phase;Physiology;Policies;Procedures;Protocols documentation;Publications;Research;Research Design;Research Personnel;Resources;Role;Services;Surgical Models;Techniques;Tissue imaging;Training;Training and Education;United States National Institutes of Health;Universities;Work;cardiometabolism;confocal imaging;consumer product;flexibility;fluorescence imaging;heart function;imaging approach;imaging modality;improved;in vivo imaging;innovation;instrumentation;investigator training;meetings;member;non-invasive imaging;protocol development;sound;success;technological innovation;theories


application_id: 9968376
project_number: 5P30GM127607-03
project_title: Animal Models and Phenotyping Core
administering_ic: NIGMS
award_notice_date: 2020-07-02
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
study_section: ZGM1-RCB-3
subproject_number: 5793
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
project_abstract:
The function of the Animal Core of the University of Louisvilles Diabetes and Obesity Center (DOC) is toprovide members of the DOC with the resources facilities and knowhow needed for the developmentinterrogation and phenotyping of animal models for diabetes and obesity research using state-of-the-arttechniques procedures and protocols relevant to the evaluation of metabolism and assessment of adiposityinsulin resistance and the cardiovascular complications of diabetes. By successive accumulation of expertiseresources and experience the Core has become an integral component of the Center and an indispensableresource for diabetes and obesity research comparable with research cores at leading institutions around thecountry. Developing on this trajectory of success the Core will continue to provide unique and unduplicatedservices to UofL investigators and continue to grow by progressively acquiring and accumulating newcapabilities resources and expertise.

project_terms:
Animal Model;Animals;Capital;Cardiovascular system;Centers of Research Excellence;Complex;Complications of Diabetes Mellitus;Consultations;Consumption;Continuing Education;Core Facility;Country;Detection;Development;Diabetes Mellitus;Disease;Educational workshop;Equipment;Evaluation;Fees;Funding;Future;Grant;Human Resources;Infrastructure;Institution;Instruction;Insulin Resistance;Investments;Learning;Marshal;Metabolic;Metabolism;Methods;Modeling;Molecular;National Heart Lung and Blood Institute;National Institute of Environmental Health Sciences;Obesity;Phase;Phenotype;Procedures;Protocols documentation;Research;Research Personnel;Resource Sharing;Resources;Series;Services;Standardization;Structure;Study models;Superfund;Techniques;Technology;Time;Training;Training Activity;Universities;animal imaging;base;cardiometabolism;career;career development;expectation;experience;instrument;investigator training;lectures;member;metabolomics;pre-clinical;programs;success;user-friendly


application_id: 9968373
project_number: 5P30GM127607-03
project_title: Pathology and Bio-analytics Core
administering_ic: NIGMS
award_notice_date: 2020-07-02
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
study_section: ZGM1-RCB-3
subproject_number: 5792
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
project_abstract:
Overarching goal of the Center is to understand the mechanisms of pathophysiology of diabetesand obesity and their cardiovascular complications. The Bioanalytics Core is an integral part ofthe Center and will play a key role in the evolution of COBRE in Phase III. The Core will renderservices for rigorous and comprehensive bioanalytical analysis of diabetic specimens. It willprovide intellectual input with experimental design and state-of-the-art technical expertise toaddress the needs of Center investigators. The Core consists of a group of outstanding scientistswith expertise in chromatography mass spectrometry clinical chemistry cardiovascularphysiology and diabetes. Director of the Core Dr. Sanjay Srivastava has more than twenty fiveyears of research experience in analytical biochemistry and pathology vascular inflammationatherosclerosis and diabetes. He will oversee all the Core operations and will work closely withCenter investigators and COBRE-supported pilot project leaders to fulfill their analyticalbiochemistry needs. Dr. Lorkiewicz technical director of the Core has extensive experience instable isotope labeling and mass spectrometric analyses of small molecular weight compounds.He will assist the Center investigators with their metabolomics mercapturomics and otherchromatography/mass spectrometry analyses. Drs. Srivastava and Lorkiewicz will provide handson training to junior investigators for bioanalytical assays. The training acquired at the Core willfacilitate them to grow as scientists and expand their repertoire of technical skills. The Core isequipped with state-of-the-art clinical chemistry and analytical biochemistry equipment and islocated in the Delia Baxter Building. In addition to address the current requirements of the COBREprojects the Core will continue to expand its knowledgebase and technical expertise to satisfythe future needs of the Center. Long term goal of the Core is to become a fiscally independententity capable of providing cutting-edge pathology and bio-analytical services to researchersinterested in diabetes and cardiovascular pathophysiology. Continued excellence in pathologicalanalyses will foster collaborations which will not only help the Core financially but will alsoadvance the field in combatting diabetic complications.

project_terms:
Acetylcysteine;Address;Alkaloids;Analytical Biochemistry;Applications Grants;Area;Atherosclerosis;Benzene;Biological Assay;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Centers of Research Excellence;Charge;Chemicals;Chromatography;Clinical Chemistry;Collaborations;Communities;Complete Blood Count;Complications of Diabetes Mellitus;Continuing Education;Data Analyses;Detection;Diabetes Mellitus;Directed Molecular Evolution;Educational workshop;Ensure;Equipment;Evolution;Experimental Designs;Extramural Activities;Faculty;Fee-for-Service Plans;Fostering;Functional disorder;Funding;Future;Glucose;Goals;Grant;Hepatic;Human Resources;Infrastructure;Kidney;Lipids;Maintenance;Malondialdehyde;Mass Chromatography;Mass Fragmentography;Mass Spectrum Analysis;Measures;Metabolic;Methods;Molecular Weight;Neurotransmitters;Obesity;Participant;Pathologic;Pathology;Pathway Analysis;Phase;Pilot Projects;Plasma;Play;Procedures;Program Research Project Grants;Protocols documentation;Research;Research Personnel;Resolution;Resources;Role;Science;Scientist;Services;Specimen;Stable Isotope Labeling;Structure;Superfund;Technical Expertise;Techniques;Tobacco;Training;United States National Institutes of Health;Universities;Volatile Fatty Acids;Work;Xenobiotic Metabolism;combat;cost;design;diabetic;experience;experimental study;instrument;interest;investigator training;knowledge base;mass spectrometer;member;metabolomics;monoamine;muconic acid;non-diabetic;novel;operation;oxidation;ranpirnase;research facility;stable isotope;symposium;toxicant;urinary;vascular inflammation;volatile organic compound;webinar


application_id: 9968372
project_number: 5P30GM127607-03
project_title: Flow Cytometry Core
administering_ic: NIGMS
award_notice_date: 2020-07-02
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
study_section: ZGM1-RCB-3
subproject_number: 5791
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
project_abstract:
ABSTRACTThe Flow Cytometry Core (Core B) has four major goals. Its primary function is to provide state of the artequipment and expertise for flow cytometric analysis of cellular antigen expression function metabolism andsignaling thereby supporting cardiovascular research in diabetes and obesity at the University of Louisville. CoreB personnel are highly-experienced investigators who have worked for several years on flow cytometry usingvarious tissues and cells from multiple species and have extensive expertise in rare event analysis. Thecomplementary nature of their backgrounds and areas of expertise coupled with their collegial nature providesa strong foundation for productive synergy within this Core and its productive interactions with other investigatorsin the DOC at the UofL and with collaborative interactions with other Institutes. Secondly the Core is committedto an educational goal. Not only will all users be trained on the operation of instruments it is the intent that theseusers completely understand cytometric theory application and data analysis. Through hands-on training andeducational presentations it is hoped that all current and future users will be able to competently incorporateflow cytometry as an analytical tool. Third the Core is committed to developing its scope and operation to supportmultidimensional flow cytometry needs in the future. It will continue to upgrade its equipment and analyticalrepertoire. Finally this Core has the ultimate goal of developing into a self-supporting and large-scale flowcytometry operation that will cater not only to the specific needs of the Center but to other University andextramural investigators interested in diabetes and obesity research. A fully developed Flow Cytometry Corewill be a significant asset in developing future multi-investigator projects and for helping researchers conductmultifaceted basic and clinical investigations aimed at the amelioration of health hazards caused by diabetesand obesity.

project_terms:
Address;Adipocytes;Adopted;Antigens;Apoptotic;Area;Award;Biological Assay;Blood Cell Count;Blood Platelets;Cardiovascular system;Cell Therapy;Cells;Centers of Research Excellence;Chemicals;Clinical Research;Color;Communities;Continuing Education;Coupled;Data;Data Analyses;Detection;Diabetes Mellitus;Dyes;Epidemic;Equipment;Event;Extramural Activities;Fee-for-Service Plans;Fees;Felis catus;Flow Cytometry;Foundations;Funding;Future;Generations;Goals;Grant;Health Hazards;Human Resources;Immune;Individual;Institutes;Institution;Metabolism;Monitor;Nature;Obesity;Patients;Phase;Population Analysis;Procedures;Protocols documentation;Reagent;Research;Research Activity;Research Personnel;Research Project Grants;Resources;Sampling;Services;Signal Transduction;Structure;Techniques;Tissues;Training;Universities;Work;analytical tool;base;career development;cell determination;clinical investigation;diabetic;event cycle;experience;experimental study;innovation;instrument;interest;investigator training;macrophage;meetings;member;mitochondrial membrane;monocyte;novel;operation;peripheral blood;programs;rapid detection;stem cell population;synergism;theories;tissue stem cells


application_id: 9968368
project_number: 5P30GM127607-03
project_title: Center for Excellence in Diabetes and Obesity Research
administering_ic: NIGMS
award_notice_date: 2020-07-02
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
program_official: ZHOU, YANG
project_start_date: 2018-07-01
project_end_date: 2023-06-30
study_section: ZGM1-RCB-3(C3)
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Animal Model;Animals;Area;Arts;Award;Basic Science;Biomedical Research;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Centers of Research Excellence;Clinical;Complement;Core Facility;Country;Data;Development;Diabetes Mellitus;Discipline;Disease;Endocrine;Ensure;Environment;Environmental Exposure;Epidemic;Event;Excess Mortality;Faculty;Flow Cytometry;Fostering;Foundations;Funding;Goals;Grant;Growth;Health;Human;Image;Individual;Inflammation;Infrastructure;Institution;Insulin Resistance;Interdisciplinary Study;Investigation;Laboratories;Lead;Learning;Medicine;Mentors;Mentorship;Metabolic;Metabolism;Molecular;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathology;Phase;Phenotype;Physiology;Pilot Projects;Postdoctoral Fellow;Public Health Schools;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Research Training;Resources;Risk Factors;Science;Seeds;Services;Solid;Stroke;Therapeutic;Training;Translational Research;United States National Institutes of Health;Universities;Vascular Diseases;Work;base;cardiometabolism;cardiovascular disorder risk;career;career development;clinical investigation;diabetic;graduate student;innovation;interdisciplinary approach;interest;member;multidisciplinary;novel;prevent;programs;recruit;stem cell biology;sudden cardiac death


application_id: 9967350
project_number: 1R01HL147921-01A1
administering_ic: NHLBI
award_notice_date: 2020-04-22
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: HL
serial_number: 147921
suffix: A1
program_official: TJURMINA, OLGA A
project_start_date: 2020-04-22
project_end_date: 2025-03-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 15587997
contact_pi: MOHAMED, TAMER M A
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Address;Adenoviruses;Adult;Adverse effects;Area;Blood;CDC2 gene;CDK4 gene;Calcium;Cardiac;Cardiac Myocytes;Cell Cycle;Cell Proliferation;Cell division;Cells;Clinical Trials;Contracts;Cyclin D1;Cytokinesis;Data;Daughter;Disease;Electrophysiology (science);Event;Family suidae;Generations;Genetic Transcription;Heart;Heart failure;Hip region structure;Human;In Situ;In Vitro;Infarction;Ischemia;Kidney;Liver;Mediating;Methods;Mitotic;Modeling;Mosaicism;Mus;Muscle Cells;Myocardial Infarction;Natural regeneration;Neurons;Oncogenic;Organ;Pancreas;Parents;Proliferation Marker;Property;Rattus;Recording of previous events;Reperfusion Therapy;Reporter;Rest;Rodent;Safety;Slice;Specificity;Subfamily lentivirinae;System;Technology;Testing;Therapeutic;Time;Tissues;Transgenic Organisms;Treatment Failure;Troponin T;cell type;clinical application;cyclin B1;dosage;efficacy testing;first-in-human;gene therapy;healing;heart function;human old age (65+);improved;in vivo;mouse model;multicatalytic endopeptidase complex;novel;novel strategies;overexpression;preclinical efficacy;promoter;protein degradation;safety study;tool;transcriptome sequencing;tumorigenic


application_id: 9965694
project_number: 5R01AA024102-05
project_title: The role of dietary unsaturated fat and inflammasome in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2020-06-29
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AA
serial_number: 024102
program_official: RADAEVA, SVETLANA
project_start_date: 2016-07-15
project_end_date: 2022-06-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA A.
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:
DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the world. It affects millions of patients worldwide each year. Althoughsubstantial progress has been made in ALD pathogenesis the specific mechanisms responsible for ALD development and progression remain poorly understood. Importantly there is no FDA approved therapy for any stage of ALD. Recent studies from our laboratory and others have demonstrated that dietary unsaturated fat rich in linoleic acid (LA) exacerbated alcohol- mediated intestinal permeability and liver injury as compared with dietary saturated fat in an experimental animal model of ALD. In addition our preliminary data show elevated levels of circulating oxidized LA metabolites (OXLAMs) specifically 9- and 13-hydroxy-octadecadienoic acids (9- and 13-HODEs) concomitant with the up-regulation of hepatic 12/15 lipoxygenase (12/15-LO) the key enzyme involved in the oxidation of LA. These findings provide initial evidence that OXLAMs which are natural ligands to the transient receptor potential vanilloid 1 (TRPV1 subfamily V member 1) contribute to the pathogenesis of ALD. TRPV1 is a ligand-gated non-selective cation channel with high permeability for Ca2+. A number of recent studies have shown a critical role for intracellular Ca2+ in inflammasome activation. NLRP3 Inflammasome activation with release of highly pro-inflammatory cytokines interleukin-1 (IL-1) and interleukin-18 (IL-18) is an important pro-inflammatory response in ALD. However the molecular mechanisms contributing to the inflammasome priming and activation in ALD are not fully identified.  Our central hypothesis is that dietary unsaturated fat (linoleic acid enriched) exacerbates alcohol-mediated liver inflammation and injury via oxidized linoleic acid metabolites that facilitate hepatic inflammasome activation. We propose that the OXLAM/TRPV1/Ca2+ signaling pathway is an upstream mechanism of inflammasome activation. To address our hypothesis we propose the following specific aims. Aim 1. Determine the role of oxidized linoleic acid metabolites (OXLAMs) and the 12/15-LO-mediated pathway of linoleic acid oxidation in the development and/or progression of ALD.  Aim 2. Assess whether hepatic inflammasome activation is mediated by an OXLAM-TRPV1-Ca2+ pathway in an animal model of ALD.  Aim 3. Determine the potential role of 12/15-LO TRPV1 and OXLAMs in inflammasome activation in human Alcoholic Hepatitis. The proposal will provide a better understanding of alcohol-diet interactions and molecular mechanisms contributing to the pathogenesis of alcohol-induced liver inflammation and injury. The study will lead to identification of new therapeutic targets and potential dietary interventions for treating ALD andprovide a dietary mechanism to explain why only some heavy drinkers develop clinically important ALD.  A combination of in vitro in-vivo animal (gain and loss of function) and human studies will be employed.

project_terms:
Address;Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Animals;Arachidonate 15-Lipoxygenase;Attenuated;Cations;Clinical;Data;Development;Diet;Dietary Fats;Dietary Intervention;Enzymes;Ethanol;Experimental Animal Model;FDA approved;Fatty Acids;Genetic;Hepatic;Hepatocyte;Human;In Vitro;Inflammasome;Inflammatory;Inflammatory Response;Interleukin-1 beta;Interleukin-18;Intestinal permeability;Knock-in;Knockout Mice;Kupffer Cells;Laboratories;Ligands;Linoleic Acids;Mediating;Molecular;Morbidity - disease rate;Mus;Oxides;Pathogenesis;Pathway interactions;Patients;Permeability;Research;Role;Sampling;Severities;Signal Pathway;TRPV1 gene;Testing;Transgenic Organisms;United States National Institutes of Health;Unsaturated Fats;Up-Regulation;Vanilloid;Whole Blood;cytokine;in vivo;liver inflammation;liver injury;loss of function;macrophage;member;monocyte;mortality;new therapeutic target;octadecadienoic acid;overexpression;oxidation;peripheral blood;public health relevance;receptor;saturated fat;translational study

public_health_relevance:
PUBLIC HEALTH RELEVANCE: My RO1 application investigates the role of dietary fat in the development of alcoholic liver disease. Specifically the project directly examines how dietary linoleic fatty acid and its oxidized products promote alcohol-mediated liver injury.


application_id: 9964410
project_number: 7R01DA041513-04
project_title: Neural microcircuit selection by astrocyte signaling following cocaine exposure
administering_ic: NIDA
award_notice_date: 2019-11-21
opportunity_number: PA-18-590
application_type: 7
activity_code: R01
ic: DA
serial_number: 041513
program_official: SORENSEN, ROGER
project_start_date: 2017-02-01
project_end_date: 2021-11-30
study_section: Molecular Neuropharmacology and Signaling Study Section[MNPS]
contact_pi_person_id: 10632329
contact_pi: ORTINSKI, PAVEL IVANOVICH
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/AbstractA significant obstacle to developing effective drug addiction therapies is that drug-induced neuronal plasticitymay be restricted to discrete neuronal populations within brain reward areas. The processes driving selectionof specific cells from a larger pool of available neurons are not clear. Our long-term goal is to identify themechanisms that assemble medium spiny neuron (MSN) microcircuits underlying behavioral expression ofcocaine seeking and taking. In this application our objective is to identify cocaine-related neuronal adaptationsthat depend on astrocytic signaling. We propose a hypothesis that astrocytic signals recruit discretesubpopulations of MSNs within the nucleus accumbens (NAc) shell to facilitate neuronal and behavioralplasticity associated with cocaine self-administration in the rat. This hypothesis is supported by our preliminaryand published data and studies from other groups. The rationale for pursuing this hypothesis is that despite agrowing recognition that astrocytes actively modulate neuronal activity little is known about the role ofastrocytes in coordination of local circuits and even less about regulation of local circuits by cocaine. On thebasis of substantial preliminary data we will test our central hypothesis in three specific aims: 1) Characterizethe impact of astrocyte signaling on cocaine-induced NMDA receptor (NMDAR) plasticity in MSN microcircuits.2) Characterize the impact of astrocyte signaling on cocaine-induced AMPA receptor (AMPAR) plasticity insynchronously active MSNs. 3) Identify the consequences of astrocyte-synchronized neuronal activity oncocaine seeking and taking. In the first aim we will use a unique characteristic of neuronal response toastrocyte-derived signals slow inward currents (SICs) to test the hypothesis that cocaine-induced plasticity ofextrasynaptic NMDARs previously linked to cocaine exposure is restricted to NAc shell MSNs displaying SICevents. The second aim is built on classical knowledge linking NMDAR-mediated signaling to plasticity ofsynaptic AMPARs and current evidence indicating that NMDAR-mediated SICs co-occur in neuronalsubpopulations. In this aim we will determine whether cocaine-induced plasticity of synaptic AMPAR signalingis restricted to subpopulations of NAc shell MSNs synchronized by astrocyte-derived signals. In the third aimwe will test the hypothesis that facilitation and inhibition of astrocyte-driven neuronal synchronization willrespectively facilitate and inhibit cocaine-seeking behaviors. The approach is significant because it improvesour ability to identify cell populations responsible for specific behavioral responses. This ability is critical fortargeted therapeutic approaches. Our approach is innovative because: it considers a novel hypothesis ofastroglia as active participants in selection of cocaine-relevant neuronal microcircuits it facilitates developmentof novel viral tools to identify such microcircuits and it seeks to identify novel mechanisms of cocaine-inducedneuroglial plasticity. Completion of these studies will expand understanding of the relationship between glialsignaling individual neuron excitability local network function and behavioral outcomes in the context ofcocaine addiction.

project_terms:
AMPA Receptors;Acute;Addictive Behavior;Affect;Animals;Area;Astrocytes;Automobile Driving;Behavior;Behavioral;Brain;Cells;Characteristics;Cocaine;Cocaine Abuse;Cocaine Dependence;Code;Coupling;Data;Development;Dopamine;Dose;Eating;Electrophysiology (science);Event;Exposure to;Future;Glutamates;Goals;Image;Individual;Knowledge;Link;Maintenance;Mediating;N-Methyl-D-Aspartate Receptors;Neuronal Plasticity;Neurons;Nucleus Accumbens;Participant;Pharmaceutical Preparations;Play;Population;Process;Public Health;Publishing;Rattus;Regulation;Rewards;Role;Self Administration;Signal Transduction;Slice;Sucrose;Synaptic plasticity;System;Testing;Therapeutic;Training;Viral;addiction;base;behavioral outcome;behavioral plasticity;behavioral response;brain cell;cell type;cocaine exposure;design;designer receptors exclusively activated by designer drugs;drug addiction therapy;effective therapy;experience;experimental study;improved;innovation;neurotransmission;novel;quantum;receptor-mediated signaling;recruit;relating to nervous system;response;sex;targeted treatment;theories;tool

public_health_relevance:
Project NarrativeCocaine abuse a major public health problem remains without an effective treatment partly because neuronalbrain cells responsible for addictive behavior and those responsible for pursuit of natural rewards (e.g. eatingor sex) are intermingled. This application proposes that activity of astrocytes another major type of brain celldrives changes within a sub-population of neurons specifically associated with cocaine experience.Identification of discrete neurons that drive cocaine-directed behavior will facilitate development of targetedaddiction therapeutics. Successful completion of the proposed studies will expand fundamental understandingof astrocyte-neuron interactions.


application_id: 9964022
project_number: 1R15GM132818-01A1
project_title: Characterization of SAM gene mutation impacts on cellular processes and genome instability
administering_ic: NIGMS
award_notice_date: 2020-02-14
opportunity_number: PAR-18-714
application_type: 1
activity_code: R15
ic: GM
serial_number: 132818
suffix: A1
program_official: CZAPLINSKI, KEVIN
project_start_date: 2020-03-01
project_end_date: 2024-02-29
study_section: Molecular Genetics A Study Section[MGA]
contact_pi_person_id: 11294477
contact_pi: STROME, ERIN D
other_pis: Not Applicable
congressional_district: 04
department: BIOLOGY
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
project_abstract:
AbstractVariance in age of onset type of cancer developed and outcome occur in populations of women whocarry the same BRCA1 mutations. One explanation for these different cancer risks relates to the potentialfor other genetic loci termed modifier genes to influence cancer risk. Commonly used methodologies todiscover modifier genes rely either on prior knowledge of gene function or are discovered throughgenome-wide association studies which are capable of determining loci of interest but not specificgenes. These methodologies have therefore resulted in limited discovery of secondary genetic lociimpacting cancer incidence. Identification of modifier loci has the potential to save lives and thehealthcare system money aiding in development of diagnostic tests for preemptive treatment as withBRCA1 testing and identifying mechanistic cause as a starting point for therapeutic treatments. In paststudies we identified heterozygous mutations that altered genome stability rates using diploid strains ofSaccharomyces cerevisiae lacking rad9 to model BRCA1 deficient cells. We observed altered genomeinstability in a strain missing one of the S-AdenosylMethionine (AdoMet) synthetase genes (SAM) indicatingthe human homolog could be a potential cancer susceptibility gene. Sam1 and its paralog Sam2 play rolesin the methyl cycle catalyzing the biosynthesis of AdoMet. Despite Sam1 and Sam2 having high levels ofhomology and findings that both proteins localize to the cytoplasm differences in abundance regulation ofexpression and post-translational modifications have been found which speak to the differential regulationand use of these proteins by the cell. In humans three genes MAT1A MAT2A and MAT2B encodesubunits of the homologous AdoMet synthetases. These genes and their product AdoMet have beenimplicated in multiple cancer types but the mechanism of action is not well understood because bothincreases and decreases in expression are associated with cancers. Our group has conducted studies ofSAM gene dosage and determined the impacts of changes in AdoMet synthetase genes on genome stability.SAM1 and SAM2 clearly operate by two distinct mechanisms to impart different impacts on genome stability.Additional experiments conducted in rad9-deficient backgrounds add additional information to our model ofthese different mechanisms. This proposal builds on our current findings towards a more completemechanistic understanding of regulation of AdoMet and a detailed characterization of the impacts ofmutations; including effects on the methyl cycle and different types of genome instability. Our overarchinggoal is to understand the differences in the roles of the SAM1 and SAM2 genes and how both increases anddecreases in expression of the homologous genes in humans might lead to cancer. This proposal meets thestated objectives of the R15 AREA program by involving undergraduate students in hypothesis drivenresearch and strengthening the research environment at NKU.

project_terms:
Age of Onset;Anabolism;Apoptosis;BRCA1 Mutation;BRCA1 gene;BRCA2 gene;Cancer-Predisposing Gene;Cell physiology;Cells;Cysteine;Cytoplasm;Development;Diagnostic tests;Diploidy;Environment;Event;Gene Conversion;Gene Dosage;Gene Expression;Gene Mutation;Genes;Genetic;Genetic Markers;Genetic Nondisjunction;Genetic Polymorphism;Genetic Recombination;Genetic Transcription;Genome Stability;Genomic Instability;Glutathione;Goals;Growth;Healthcare Systems;High-Risk Cancer;Homologous Gene;Human;Incidence;Institution;Investigation;Kentucky;Knowledge;Lead;Ligase;Link;Lipids;Malignant Neoplasms;Measures;Metabolic Pathway;Methodology;Methylation;Microarray Analysis;Modeling;Modernization;Molecular;Mutation;Other Genetics;Outcome;Pathway interactions;Phenotype;Play;Point Mutation;Polyamines;Population;Post-Translational Protein Processing;Process;Production;Protein Methylation;Proteins;Public Health;RAD9A gene;RNA;Reaction;Reactive Oxygen Species;Regulation;Reporting;Research;Risk;Role;Saccharomyces cerevisiae;Techniques;Testing;Therapeutic;Training;Translations;Universities;Woman;cancer genetics;cancer risk;cancer type;cell growth regulation;differential expression;epigenetic regulation;experimental study;gene function;genome wide association study;genomic locus;insight;interest;methionine adenosyltransferase;methyl group;multidisciplinary;mutant;overexpression;paralogous gene;programs;reconstruction;repaired;small molecule;stem;transcriptome sequencing;transmethylation;undergraduate student

public_health_relevance:
Project NarrativeThe objective of the proposed research is relevant to public health because S-adenosylmethionine (AdoMet)synthetase genes and AdoMet have been implicated in multiple cancer types but the mechanism of action isnot well understood because both increases and decreases in expression are associated with cancers. Ourgroup has conducted studies on the AdoMet synthetase genes SAM1 and SAM2 in S. cerevisiae anddetermined the impacts of changes in these homologous genes on genome stability. In addition to advancingthe field towards a more complete mechanistic understanding of regulation of AdoMet and a detailedcharacterization of the impacts of mutations; including effects on the methyl cycle and different types ofgenome instability this multi-disciplinary project meets the stated objectives of the AREA program by offeringundergraduate students hands-on training in classical genetics and modern molecular techniques andstrengthens the research environment at Northern Kentucky University.


application_id: 9963254
project_number: 5T32ES007266-30
project_title: Training Grant in Molecular Mechanisms of Toxicity
project_terms: Grant;Molecular;Toxic effect;Training
administering_ic: NIEHS
award_notice_date: 2020-05-26
opportunity_number: PA-14-015
application_type: 5
activity_code: T32
ic: ES
serial_number: 007266
program_official: SHREFFLER, CAROL A
project_start_date: 1990-07-01
project_end_date: 2022-02-28
study_section: Environmental Health Sciences Review Committee[EHS(TK)]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: MELLON, ISABEL W
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant)      The objectives of the Molecular Mechanisms of Toxicity Training Program are to provide pre-doctoral trainees with a fundamental education in the mechanisms by which environmental exposures induce human disease integrated with the basic cellular processes upon which environmental agents impact and cause disease. The training program is based on an understanding of biochemistry physiology and molecular/cell biology toxicology courses in mechanisms by which environmental agents induce toxicity together with the cellular and molecular processes by which the body defends itself against environmental insult. This didactic training is intimately coupled with in-depth laboratory research training. The goal is to prepare the next generation of scientists to address the ever-present environmental challenges to human health by the prevention of disease either by nutritional or life-style intervention where possible or by otherwise exploiting human defense systems. The Training Program is based in the Department of Toxicology and Cancer Biology (DTCB) a basic science department in the College of Medicine that grants the Ph.D. in toxicology and provides an administrative and teaching nucleus of 18 Core Faculty. Joint Faculty from the Colleges of Medicine Pharmacy and Agriculture enrich the diversity of training opportunities; 26 of these Core and Joint Faculty with strong research programs make up the Training Grant Faculty. This application requests support for 4 pre-doctoral trainees and is focused on three disease areas that have an environmental basis: Cancer Cardiovascular Disease and Neurotoxicity/Neurodegenerative Disease. Oxidative stress DNA damage/repair and metabolomics are mechanistic themes that underlie many of the research programs and provide highly collaborative and multidisciplinary approaches to problems thereby providing a rich research training environment. The pre-doctoral training program requires a Biomedical Base (18 credits including Ethics in Scientific Research) a Toxicology Base (12-14 credits) and an Elective identified by the student's Advisory Committee (3 credits). Pre-doctoral trainees will be supported for a maximum of three years e.g. years 2-4 of doctoral training. Current enrollment in the Toxicology Ph.D. program is 25 including three Underrepresented Minority students. Recent minority graduates have been primarily recruited from the University of Puerto Rico and have been supported by T35 and R25 NIEHS mechanisms that support summer research experiences in Toxicology; this longstanding tradition of a diverse student body continues to attract new minority students to the training program. The University continues to provide strong support for the DTCB in the form of student fellowships supplementation to this Training Grant and new faculty lines space and equipment so that the program has grown vigorously over the last five years and is anticipated to continue to do so.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This application will train young scientists to understand the underlying biology that defines basic mechanisms by which humans respond to environmental stressors that lead to human disease. Human diseases addressed in this application include cancer cardiovascular disease and neurotoxicity that can lead to neurodegenerative disease. The long term goal is to identify methods of prevention of disease including nutritional and life-style interventions and utilization of the body's natural defense systems against environmental stressors.


application_id: 9962713
project_number: 272201400004I-0-759301900131-1
project_title: DMID CLINICAL CENTRAL LABORATORY SERVICES
administering_ic: NIAID
project_start_date: 2014-05-13
project_end_date: 2021-05-12
contact_pi_person_id: 15975150
contact_pi: KIRKBY, MATTHEW
other_pis: Not Applicable
department: Unavailable
primary_duns: 184227809
primary_uei: YPNJBDKDGJV7
duns_number: 184227809
uei: YPNJBDKDGJV7
fips: US
organization_id: -418027
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: Unavailable
organization_zip: 410769167
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
To support clinical laboratory services in support of research studies and trials of infectious disease countermeasures supported by NIAID.

project_terms:
Clinical;Clinical Research;Communicable Diseases;Laboratories;National Institute of Allergy and Infectious Disease;Research Support;Services;research study


application_id: 9962483
project_number: 5R01HL142969-03
project_title: The role of soluble prorenin receptor in hypertension associated with obesity
administering_ic: NHLBI
award_notice_date: 2020-06-18
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: 2022-06-30
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 10353515
contact_pi: YIANNIKOURIS, FREDERIQUE
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;Genes;Goals;HepG2;Hepatic;High Fat Diet;Homeostasis;Human;Hypertension;In Vitro;Incubated;Infusion procedures;Kidney;Knockout Mice;Liquid substance;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: 9962329
project_number: 5P30CA177558-08
project_title: Protocol Review and Monitoring System
administering_ic: NCI
award_notice_date: 2020-06-29
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5640
contact_pi_person_id: 1926108
contact_pi: ANTHONY, LOWELL B.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
project_abstract:
PROJECT SUMMARY/ABSTRACT The Markey Cancer Center's (MCC) clinical research mission is to conduct the highest quality research intothe causes and treatment of cancer. In accordance with the CCSG guidelines for National Cancer Institute-designated Cancer Centers MCC has established appropriate mechanisms for assuring rigorous scientificscrutiny and oversight of cancer-relevant clinical trials through the Protocol Review and Monitoring System(PRMS). The MCC Protocol Review and Monitoring Committee (PRMC) is responsible for independent peerreview of scientific merit feasibility and prioritization of new protocols and monitoring all trials for scientificprogress and accrual (including termination of studies not meeting MCC scientific goals). Protocols are submitted to the PRMC following review by disease groups called Clinical Care andResearch Teams (CCARTs) for fit with the portfolio and endorsement by investigators and review by theFeasibility Review Committee (FRC) for operational feasibility. The goal of prior review and input by theCCARTs and FRC is to enrich the scientific quality and prioritization of protocols submitted to the PRMC. ThePRMC ensures that all interventional cancer research studies involving human subjects conducted under theauspices of the MCC: 1) serve and support the mission of MCC including prioritization of research trialsrelevant to catchment area needs; 2) have high scientific merit; 3) are statistically sound and appropriatelydesigned; 4) are feasible for timely completion based on the available patient population and in the context ofthe current trial portfolio; 5) are prioritized based on MCC criteria and in light of actively accruing trials; and 6)are inclusive of underserved populations (e.g. women minorities children). After activation protocols aremonitored by the PRMC for ongoing scientific progress and accrual per MCC policy. The PRMC has ultimateauthority to suspend or close protocols for low accrual or significant change in scientific merit and theresponsibility for continuous monitoring of its efficiency and quality in the timely review of trials. During this funding period the PRMS has undergone significant improvement in procedures and policyupdates. Specifically the PRMS enhanced scientific rigor of its review process by increasing senior reviewersstandardizing review criteria and scoring and adopting more stringent accrual monitoring practices The PRMShas a new Chair and Co-chair free from conflicts of interest with the other clinical research bodies and thePRMC members now comprises mainly senior faculty and a greater diversity of scientific disciplines. From2013 to 2016 the PRMC reviewed and/or prioritized 284 new protocols of which 264 (93%) were approvedand 20 (7%) were disapproved; and reviewed 279 active protocols for scientific progress closing 37 protocolsdue to low accrual or a change in scientific merit. As the MCC grows the PRMS will continue rigorous scientificreview of protocols appropriate prioritization adherence to MCC's mission and inclusion of trials with ascientific focus relevant to the catchment area of Kentucky.

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


application_id: 9962327
project_number: 5P30CA177558-08
project_title: Clinical Protocol and Data Management
administering_ic: NCI
award_notice_date: 2020-06-29
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
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
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
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;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;named group;operation;osteosarcoma;patient safety;precision medicine;protocol development;quality assurance;response;support tools;working group


application_id: 9962326
project_number: 5P30CA177558-08
project_title: Leadership Planning and Evaluation
administering_ic: NCI
award_notice_date: 2020-06-29
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5638
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
project_abstract:
PROJECT SUMMARY/ABSTRACT B. Mark Evers MD serves as Director for the Markey Cancer Center (MCC). Dr. Evers is assisted bynationally recognized leaders in cancer research clinical care prevention and education including: SusanneM. Arnold MD (Associate Director for Clinical Translation); Kathleen OConnor PhD (Associate Director forCancer Education and Mentoring); Daret St. Clair PhD (Associate Director for Basic Research); ThomasTucker PhD MPH (Associate Director for Cancer Prevention and Control); Heidi Weiss PhD (AssociateDirector for Shared Resources); and David M. Gosky MA MBA (Associate Director for Administration). Thishighly experienced Senior Leadership team has worked together since 2009 to ensure consistency in theshared vision and goals of the MCC; foster synergistic and highly collaborative interactions among the basictranslational and clinical components of the MCC; effectively leverage all available resources at the Universityof Kentucky state and national levels; engage in clinical trials community outreach education and mentoring;and oversee all activities of the MCC. Continual planning and evaluation are key to the development andsustained excellence of the MCC and helps ensure its strong scientific trajectory. Planning and evaluationactivities are accomplished through the External and Internal Advisory Boards the Directors Council andcommittees that provide the Director and Senior Leadership ongoing guidance and support. The MCC ExternalAdvisory Board is the primary external mechanism that provides review and advice on the MCCs progress inbasic translational and community research as well as oversight on MCCs leadership and strategic direction.Internal planning and evaluation mechanisms include: the advice and support of MCCs Senior Leaders whoformally comprise the Directors Council; MCC Research Program Leaders and Shared Resource Facility(SRF) Directors; an Education and Mentoring Committee; and an Internal Advisory Board comprised of deanscenter directors and department chairs at the university. Dr. Evers and the Senior Leadership established thefirst strategic plan for the MCC in 2009 which served as an initial road map to guide the development ofscientific research programs the reorganization of SRFs required to facilitate and achieve the scientific goalsand strategic recruitments of basic and translational scientists who synergized and further strengthened theongoing research efforts. In 2012 to reflect the tremendous progress that occurred since Dr. Everss arrival anupdated plan redefined the strategic goals for the next 5 years based on the strong foundations that were inplace. In 2017 through an extensive review and vetting process Senior Leadership developed a new strategicplan around pillars of excellence in basic research cancer prevention and control clinical translationeducation and mentoring and community engagement and outreach. Strong foundations of institutionalsupport philanthropy SRFs strategic relations administration and planning and evaluation support the 2017-2022 Strategic Plan.

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


application_id: 9962325
project_number: 5P30CA177558-08
project_title: Developmental Funds
administering_ic: NCI
award_notice_date: 2020-06-29
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
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
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
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 participatory 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: 9962324
project_number: 5P30CA177558-08
project_title: Community Outreach and Engagement
administering_ic: NCI
award_notice_date: 2020-06-29
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5636
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
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
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;Education;Environmental Exposure;Faculty;Family;Fostering;Funding;Funding Mechanisms;General Population;Goals;Grant;Health;Health Communication;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;combat;community based participatory research;community center;evidence base;genetic linkage analysis;health assessment;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


application_id: 9962322
project_number: 5P30CA177558-08
project_title: Genomic Instability Epigenetics and Metabolism Research Program
administering_ic: NCI
award_notice_date: 2020-06-29
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5635
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
project_abstract:
PROJECT SUMMARY/ABSTRACT The Genomic Instability Epigenetics and Metabolism (GEM) Research Program represents a restructuringand programmatic expansion of the former Redox Injury and Repair (RR) Research Program to reflectburgeoning research strengths of participating members with expertise in highly complementary researchthrusts. GEM research efforts are central to the overall Markey Cancer Center (MCC) mission to decrease theburden of cancer in Kentucky surrounding communities and the nation. GEM investigators determine geneticepigenetic and metabolic mechanisms that promote cancer development fuel tumor progression andcontribute to therapeutic resistance. The overall goal of this program is to gain a comprehensive understandingof the basic mechanisms of these processes to facilitate development of novel and rational approaches forcancer prevention and therapy. To achieve this goal GEM has established 3 inter-related themes: 1) researchinto genomic instability and DNA repair will identify how innate DNA repair pathways interact withenvironmental mutagens to impact carcinogenesis; 2) research on epigenetic mechanisms of malignancy willdelineate how alterations in the epigenome and gene transcription influence carcinogenesis; and 3) researchon cancer metabolic reprogramming will decipher the role of metabolic processes that contribute to cancerdevelopment with a focus on mitochondrial function and redox-mediated dysregulations. The themes areconceptually linked and feature robust faculty collaboration. GEM program members are pioneers and expertsin redox biology DNA repair epigenetic regulation and cancer metabolism. The program consists of 18members from 6 departments in the Colleges of Medicine and Arts and Sciences. The program's cancer-related funding is over $4.9M total annual funding ($3.3M direct costs of which 33% is from the NationalCancer Institute). GEM program members have actively used MCC Shared Resource Facilities since initialCancer Center Support Grant funding in 2013. Members have published 164 manuscripts (2013 to 2017) ofwhich 72 (44%) are inter-programmatic 36 (22%) are intra-programmatic and 99 (60%) are inter-institutional.The program is co-led by 2 researchers with complementary scientific and leadership expertise. Dr. JohnD'Orazio (a physician scientist focusing on DNA repair) and Dr. Peter Zhou (a specialist in epigenetic andmetabolic reprogramming of epithelial-mesenchymal transmission) bring together expertise in geneticinstability and cancer (D'Orazio Theme 1) epigenetic regulation and metabolism (Zhou Themes 2 and 3). Inaddition to their scientific leadership roles each offers significant strengths in clinical translation junior facultymentoring communications among MCC programs and expertise on populations within the MCC catchmentarea.

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


application_id: 9962321
project_number: 5P30CA177558-08
project_title: Drug Discovery Delivery and Translational Therapeutics Research Program
administering_ic: NCI
award_notice_date: 2020-06-29
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
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
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
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;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: 9962319
project_number: 5P30CA177558-08
project_title: Cancer Prevention and Control Research Program
administering_ic: NCI
award_notice_date: 2020-06-29
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5633
contact_pi_person_id: 10885868
contact_pi: STAPLETON, JEROD L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
project_abstract:
PROJECT SUMMARY/ABSTRACT  Markey Cancer Center's (MCC) Cancer Prevention and Control (CP) Research Program unites highly complementary strengths in the areas of population-based research and community-based cancer control research with the overarching goal of reducing cancer disparities in Kentucky with an emphasis on the state's Appalachian and rural populations. Kentucky has the highest overall cancer incidence and mortality rates among all 50 United States. Alarmingly the cancer incidence and mortality rates in Appalachian Kentucky are far higher than the rates for the non-Appalachian area of the state. These elevated rates are driven by a variety of underlying factors including low socioeconomic status low educational attainment high risk behaviors cultural barriers and environmental exposures. Strengths of the CP program include studies focused on uncovering the role environmental exposures play in Kentucky's high cancer incidence rates testing intervention programs that address unique cultural barriers and smoking cessation policy development initiatives. CP program members are also national leaders in developing population-based methods and measures that facilitate inter-programmatic cancer research. The CP program combines these strengths to address 3 thematic areas: identification of social cultural behavioral genetic and environmental factors that contribute to the elevated cancer incidence and mortality rates (Theme 1); design testing implementation and evaluation of intervention strategies that address identified risk factors (barriers) and reduce the cancer burden (Theme 2); and development of population-based methods and measures that facilitate inter-programmatic cancer research directed at more precisely identifying the distribution of treatment patterns and biomarkers in the population (Theme 3). Most recently the CP program recruited 2 National Cancer Institute-funded cancer molecular epidemiologists to build on its unique research resources. The current 28-member CP team draws from 5 colleges and 12 departments at the University of Kentucky thus promoting active interdisciplinary translational research. CP productivity is reflected by total annual external cancer-related funding of over $9.7M ($6.7M annual direct costs) and 245 total publications in the current funding period 30 (12%) of which are inter-programmatic 83 (34%) intra-programmatic and 162 (66%) inter-institutional. CP research encompasses all segments of the cancer control continuum: prevention early detection treatment and survivorship. CP studies address a number of cancer sites including those that disproportionately contribute to Kentucky's high cancer burden (i.e. lung colon breast and cervical cancers). Thus the CP program is integral to achieving the overall MCC mission to reduce cancer morbidity and mortality in the Commonwealth.

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


application_id: 9962318
project_number: 5P30CA177558-08
project_title: Cancer Cell Biology and Signaling Research Program
administering_ic: NCI
award_notice_date: 2020-06-29
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
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
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
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;Epithelium;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: 9962311
project_number: 5P30CA177558-08
project_title: Biospecimen Procurement and Translational Pathology Shared Resource Facility
administering_ic: NCI
award_notice_date: 2020-06-29
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5627
contact_pi_person_id: 8368087
contact_pi: JENNINGS, DARRELL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
project_abstract:
PROJECT SUMMARY/ABSTRACT The Biospecimen Procurement and Translational Pathology Shared Resource Facility (BPTP SRF) is aMarkey Cancer Center (MCC)-managed resource. It facilitates the use of well-annotated human and animalspecimens and provides a wide range of translational pathology technical services in support of MCC clinicaltranslational population-based and basic science research. Over the award period the BPTP SRF hasincreased annual biospecimen dispensation from 1738 in FY12 to 4446 in FY17 (156% increase) increasedthe total number of MCC users by 23% (48 in FY17 up from 39 in FY12) including 38 peer-reviewed fundedMCC 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 incancer metabolism; the development of novel model systems (e.g. Warburg tissue slices for metabolicanalysis patient-derived xenograft organoids); review of all clinical trials including investigator-initiated trialsto identify specimen collection needs and develop collection protocols; fresh tissue collections and rapid bloodprocessing for clinical trials resulting in support for 40 clinical trials over the funding period. The addition of aresearch histology laboratory operated per clinical guidelines allows for an increased capacity for technicalservices such as histology immunohistochemistry molecular pathology laser capture microscopy andDNA/RNA extraction. BPTP SRF has increased its consent capacity through the cross training of all BPTPSRF staff as well as by using a universal opt-in consent for repository collections. BPTP SRF's name changereflects its increased focus on translational pathology facilitated by the support of faculty in the University ofKentucky (UK) Department of Pathology who assist BPTP SRF staff in the development and interpretation ofnovel assays on-site evaluation of specimen content and quality for fresh tissue dispense and identification ofretrospective study and tissue microarray cohorts from surgical archive specimens dating back to 1995. Thispartnership strengthened by BPTP's leadershipC. Darrell Jennings MD chair of the Department ofPathology and Laboratory Medicine with Associate Director Qiuying Shi MD Assistant Professor inPathologyensures MCC investigators have a clear path to the specimen resources and pathologic servicesessential to their work. The BPTP SRF has streamlined operations by transitioning to the OnCore databaseand adding a manager to oversee daily operations leveraging existing resources within the MCC including theClinical Research Office the Surveillance Epidemiology and End Results Kentucky Cancer Registry andCancer Research Informatics and Biostatistics and Bioinformatics SRFs as well as non-MCC entities such asthe Department of Pathology and Laboratory Medicine UK Office of Research Integrity and the Center forClinical and Translational Science.

project_terms:
Ambulatory Care Facilities;Animals;Appalachian Region;Archives;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;Xenograft procedure;anticancer research;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 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: 9962310
project_number: 5P30CA177558-08
project_title: Career Enhancement
administering_ic: NCI
award_notice_date: 2020-06-29
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5626
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
project_abstract:
PROJECT SUMMARY/ABSTRACTInnovation and progress in cancer research require dedication to the career development of the nextgeneration of cancer researchers. Accordingly the University of Kentuckys Markey Cancer Center (MCC)with a robust annual institutional investment of $450000 and the dedication of its members established acomprehensive Oncology Career Enhancement Program. Over the past funding cycle this program hasprovided enriching experiences for nearly 570 K-12 and undergraduate students; extensive research trainingfor 50 high school students 223 undergraduates and 544 graduate/postdoctoral researchers; and mentorshipto 46 junior faculty. Notably key education activities address the academic challenges of rural AppalachianKentucky and underrepresented minorities through the support from 4 grants that include Continuing Umbrellaof Research Experiences and Geographic Management of Health Disparities Program National CancerInstitute supplements. Academic and professional development of all trainees through intensive mentoredresearch engagement and/or formal research training at the undergraduate graduate and postdoctoral levelscomplement elementary and high school education strategies. Formal curricula in cancer biology have beenestablished at the undergraduate masters and pre-doctoral levels that provide the academic context for thistraining. Furthermore 4 T32 training programs support cancer career development for trainees including 2funded by the National Cancer Institute 1 of which is uniquely devoted to surgeon-scientists. Overall MCCtraining and career development extramural support has risen by 52% since 2012 to 26 grants totaling $2.3M(direct costs) in 2017. Early-career faculty benefit from team-based mentoring through formal mentoringcommittees a Grant Writing Study Hall the Clinical Trials Boot Camp and synergistic mentorship throughvarious institutional efforts. This mentorship has resulted in 95 awarded grants (50 extramural 45 intramural)and the development of 11 clinician scientists who went on to lead 31 clinical trials. A rich set of seminarsymposia meetings and other career enhancement activities facilitate successful career development for allindividuals engaged in cancer research and clinical practice. All current and proposed career enhancementactivities leverage the robust research strengths within the MCCs 4 Research Programs to provide immersivetraining across the pipeline and to ensure that faculty within these programs successfully develop asindependent scientists. The MCCs collective efforts also draw on strong institutional training resources toachieve 2 overarching goals of this program: to guide cohesive growth and coordinate transdisciplinaryeducation and mentoring endeavors across the MCC; and to integrate with other efforts campus wide. ThroughCCSG support this comprehensive program will continue to evolve innovative curricula and strategically linkedinitiatives that prepare trainees and early-career faculty for modern cancer career opportunities. Furthermorethese efforts will drive research innovation that will improve the lives of all Kentuckians.

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


application_id: 9962309
project_number: 5P30CA177558-08
project_title: Administration
administering_ic: NCI
award_notice_date: 2020-06-29
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5625
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-01
budget_end_date: 2021-06-30
project_abstract:
PROJECT SUMMARY/ABSTRACT  Markey Cancer Center (MCC) Administration provides efficient and effective administrative support to MCC's Director Senior Leadership Research Program Leaders Shared Resource Facility (SRF) Directors and MCC members. The role of MCC Administration is to operationalize MCC's most critical research functions by fulfilling the following Specific Aims: 1) to accelerate the remarkable evolution of the MCC by leveraging resources and expanding MCC's infrastructure; 2) to promote the strategic planning and evaluation efforts of the MCC; and 3) to support the comprehensive basic science clinical and cancer prevention activities of the MCC by fostering transdisciplinary and translational science. The MCC is a matrix cancer center with administrative staff providing support to 119 MCC members from 28 departments in 8 University of Kentucky colleges with 28 faculty recruited in the last 4 years. MCC Administration leverages the expertise of its team members while operating in an innovative and efficient manner. New initiatives supported since the last grant cycle include: 1) implementing iLab Solutions (Agilent Technologies) across SRFs; 2) deploying $4.2M for new seed grant opportunities; 3) developing the Markey Women Strong program in collaboration with the Markey Cancer Foundation to provide two $50000 awards annually to female researchers in the MCC; 4) supporting a 38% increase of direct cancer-related research funding from $19.9M to $27.4M (corresponding 36% increase of total cancer-related research funding from $28.4M to $38.7M) between 2012-2017; 5) facilitating 7 successful CCSG supplement applications; 6) initiating development of 2 SRFs (Oncogenomics and Behavior and Community-Based Research); 7) providing full support for a Center of Biological Research Excellence application and funded award; 8) establishing the Department of Toxicology and Cancer Biology and the Center for Environmental and Systems Biochemistry to support research and educational efforts; 9) increasing the number of MCC Network sites from 8 in 2013 to 24 in 2017; 10) creating the MCC Research Network; 11) promoting communication throughout the MCC and catchment area with a new website and additional social media platforms; 12) fostering growth of the Clinical Research Office and creating the Clinical Research Enrollment and Development of Investigational Trials program to recognize faculty for clinical research efforts; 13) overseeing the expansion of space including a dedicated Precision Medicine Center (PMC) a new inpatient floor with 63 additional beds and dedicated administrative space for the MCC Affiliate and Research networks; 14) planning utilization of 2 MCC research floors (50329 sq. ft.) in the new Research Building 2 scheduled to open in 2018; 15) creating the MCC Community Outreach Program and establishing the annual Expressions of Courage event for cancer survivors; and 16) facilitating development and implementation of the 2017-2022 Strategic Plan.

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


application_id: 9962062
project_number: 1UH3NS116238-01
administering_ic: NINDS
award_notice_date: 2020-09-09
opportunity_number: RFA-NS-18-023
application_type: 1
activity_code: UH3
ic: NS
serial_number: 116238
program_official: GROSS, BROOKS ANDREW
project_start_date: 2020-09-15
project_end_date: 2026-06-30
study_section: Special Emphasis Panel[ZNS1 SRB-C (03)]
contact_pi_person_id: 11410337
contact_pi: ANGELI, CLAUDIA
other_pis: BOAKYE, MAXWELL
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
budget_start_date: 2020-09-15
project_title:
Inter-System Closed-Loop Control of Locomotor and Bladder Function in Individuals with Acute Spinal Cord Injury

project_abstract:
SUMMARY ABSTRACTMore than 1.2 million people in the United States have a spinal cord injury (SCI) and each year there are 10000new cases. In the last few years we have shown that neuromodulation using epidural stimulation of thelumbosacral spinal cord can activate latent neural circuits and restore voluntary movement standing andstepping in individuals with chronic SCI. One participant in this study also reported gains in bladder functionfollowing training with spinal cord epidural stimulation. However there are persistent gaps that need to be filledin order to advance the field of neuromodulation forward. Technological advances to upgrade the stimulatorsprogramming and wireless communication platforms are critically needed in order to integrate multiple trainingparadigms across multiple systems (i.e. motor and autonomic) as well as take advantage of wireless monitoringtechnology that could improve the patient experience. For this study first we will acquire data necessary for theimplementation of learning algorithms and closed-loop systems with the implanted neurostimulator. Second 8additional individuals will be randomized into training interventions for locomotion and bladder. The purpose ofthis phase is to implement the closed-loop controls and learning algorithms developed with data from phase 1.This two phase design will allow us to acquire necessary data for the development of technical tools with a groupof 8 individuals and test the closed-loop controls with a second group of individuals that have not received priorto training. This trial will upgrade technology for epidural stimulation and make it specific for use by individualswith spinal cord injury.

project_terms:
Activities of Daily Living;Acute;Address;Autonomic Dysreflexia;Autonomic nervous system;Awareness;Bladder;Blood Pressure;Blood Pressure Monitors;Cardiovascular system;Catheterization;Chronic;Chronic Phase;Clinical Trials;Communication;Communities;Data;Development;Devices;Diastolic blood pressure;Educational Intervention;Evaluation;Feedback;Heart Rate;Home environment;Impairment;Implant;Incidence;Individual;Injury;Intestines;Laboratories;Locomotion;Locomotor training;Manuals;Measures;Monitor;Motor;Movement;Participant;Patients;Phase;Physiological;Positioning Attribute;Publishing;Quality of life;Rain;Randomized;Recovery;Regulation;Reporting;Series;Spinal Cord;Spinal cord injury;Symptoms;System;Systolic Pressure;Technology;Testing;Time;Training;Training Programs;United States;Walking;Wireless Technology;base;blood pressure regulation;design;experience;flexibility;improved;intimate behavior;learning algorithm;locomotor control;locomotor tasks;motor function recovery;neural circuit;neuroregulation;normotensive;prediction algorithm;prevent;sensor;sensory system;therapeutic evaluation;tool;treadmill;treatment effect;wireless communication

public_health_relevance:
PROJECT NARRATIVEWe propose a small scale pilot clinical trial to evaluate technology specific improvements for the use of spinalcord epidural stimulation to function in individuals with spinal cord injury. We will develop technology that willinteract with currently available stimulators to facilitate the implementation and integration of training programsfor the recovery of locomotion and bladder function in individuals with acute spinal cord injury and promote safelong-term use of the technology in the home and community. This study will start addressing some technologygaps by developing a flexible communication platform specific for spinal cord injury.


application_id: 9961508
project_number: 5R21CA231911-02
project_title: STAN-CT: Standardization and Normalization of CT images for Lung Cancer Patients
administering_ic: NCI
award_notice_date: 2020-06-17
opportunity_number: PAR-15-334
application_type: 5
activity_code: R21
ic: CA
serial_number: 231911
program_official: KIM, BOKLYE
project_start_date: 2019-07-01
project_end_date: 2022-06-30
study_section: ZCA1-TCRB-D(M1)
contact_pi_person_id: 10950301
contact_pi: CHEN, JIN
other_pis: FEI, BAOWEI ;ZHANG, GUO-QIANG
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/AbstractLung cancer is the leading cause of cancer death and one of the most common cancers among both men andwomen in the United States. Recent advances in high-resolution imaging set the stage for radiomics tobecome an active emerging field in cancer research. However the promise of radiomics is limited by a lack ofimage standardization tools because computed tomography (CT) images are often acquired using scannersfrom different vendors with customized acquisition parameters posing a fundamental challenge to radiomicstudies across sites. To overcome this challenge especially for large-scale multi-site radiomic studiesadvanced algorithms are required to integrate standardize and normalize CT images from multiple sources.We propose to develop STAN-CT a deep learning software package that can automatically standardize andnormalize a large volume of diagnostic images to facilitate cross-site large-scale image feature extraction forlung cancer characterization and stratification. By precisely mitigating the differences in advanced radiomicfeatures of CT images STAN-CT will overcome research silos and promote medical image resource sharingultimately improving the diagnosis and treatment of lung cancer. Our goal will be achieved through two Aims.In Aim 1 we will develop a working prototype to standardize CT images. First we will collect raw image datafrom lung cancer patients and reconstruct CT images using multiple image reconstruction parameters and wewill scan a multipurpose chest phantom along with five different nodule inserts. Then we will develop and trainSTAN-CT for CT image standardization. An alternative training architecture will be developed to achieve theimproved model training stability. In Aim 2. We will deploy and test STAN-CT for image standardization locallyand across three medical centers. First we will make the STAN-CT software package available to the public byproviding a menu-driven web-interface so that that users can conveniently convert medical images that weretaken using non-standard protocols to one or multiple standards that they specify. Second we will deploySTAN-CT at the University of Kentucky for local performance validation. We will test the functionality reliabilityand performance of STAN-CT using both patient chest CT image data collected at large-scale and thephantom image data both independent to training. Third we will deploy and test STAN-CT at the University ofKentucky as well as the University of Texas Southwestern Medical Center and Emory University for cross-center performance validation. We will use the same multipurpose chest phantom and both standard and non-standard protocols to validate STAN-CT at the three centers. We will test the generalizability of STAN-CTusing clinical CT images of human patients and will determine whether a model trained using the data fromone medical center are applicable for images collected at another place. Finally we will distribute the softwarepackage of STAN-CT for public use. STAN-CT will enable a wide range of radiomic researches to identifydiagnostic image features that strongly associated with lung cancer prognosis.

project_terms:
Algorithms;Anatomic Models;Anatomy;Architecture;Cancer Etiology;Cancer Patient;Cancer Prognosis;Cessation of life;Characteristics;Chest;Clinical;Communities;Computed Tomography Scanners;Computer software;Custom;Data;Diagnosis;Diagnostic Imaging;Disease Management;Evolution;Faculty;Goals;Human;Image;Imaging Phantoms;Imaging technology;Kentucky;Life;Malignant Neoplasms;Malignant neoplasm of lung;Medical Imaging;Medical center;Modeling;Multi-Institutional Clinical Trial;Names;Nodule;Non-Small-Cell Lung Carcinoma;Outcome;Patients;Performance;Phase;Phenotype;Protocols documentation;Quality Control;Radiology Specialty;Research;Resource Sharing;Scanning;Site;Source;Specific qualifier value;Standardization;Stratification;Survival Rate;System;Testing;Texas;Tissues;Training;United States;Universities;Validation;Vendor;Woman;X-Ray Computed Tomography;anticancer research;base;cancer diagnosis;cancer imaging;cancer therapy;chest computed tomography;computational platform;data to knowledge;deep learning;feature extraction;high resolution imaging;human imaging;image reconstruction;imaging modality;improved;lung imaging;member;men;outcome forecast;prototype;quantitative imaging;radiomics;response;spatial temporal variation;tool;trait;tumor;web interface

public_health_relevance:
Project NarrativeComputed tomography (CT) is one of the most popular diagnostic image modalities routinely used forassessing anatomical tissue characteristics for disease management. However CT images are often acquiredusing scanners from different vendors with different imaging standards posing a fundamental challenge toradiomic studies across sites. The goal of the Standardization and Normalization of CT images for lung cancerpatients (STAN-CT) project is to develop a deep learning software package that can automatically standardizeand normalize a large volume of chest CT images to facilitate cross-site large-scale image feature extractionfor lung cancer characterization and stratification.


application_id: 9960605
project_number: 5R01NR016824-05
project_title: Rural Intervention for Caregivers' Heart Health (RICHH)
administering_ic: NINR
award_notice_date: 2020-06-11
opportunity_number: RFA-NR-16-003
application_type: 5
activity_code: R01
ic: NR
serial_number: 016824
program_official: HUSS, KAREN
project_start_date: 2016-09-26
project_end_date: 2022-06-30
study_section: ZNR1-REV-M(25)
contact_pi_person_id: 1906318
contact_pi: MOSER, DEBRA KAY
other_pis: CHUNG, MISOOK LEE
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 NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT In the patient-family caregiver dyad emphasis traditionally has been on the patient or on helping thecaregiver take care of the patient. This approach ignores the health of the caregiver. Family caregivers ofpatients with chronic disease are at uniquely high risk for development of cardiovascular disease (CVD).Because of the environment they share with the patient lack of time for personal care due to caregivingdemands and persistent psychological distress caregivers of patients with chronic illness have substantiallyhigher risk for CVD than non-caregivers. To reduce this risk cardiovascular health interventions aimed at (1)CVD risk reduction (2) improving adherence to self-management of CVD risk reducing behaviors and (3)preventing and managing depressive symptoms are required. Rural caregivers are particularly at risk for poorhealth. Most rural areas are characterized by marked health disparities including elevated CVD risk persistentpoverty and lack of social and healthcare resources. As such innovative intervention programs are needed toimprove cardiovascular health among rural caregivers while overcoming personal and environmental barriersto achieving this goal. The Rural Intervention for Caregivers Heart Health (RICHH) program proposed in this study willaddress the important components of CVD risk reduction for rural caregivers of patients with chronic illness most notably improved self-management of CVD risk reduction efforts including prevention and managementof depressive symptoms. We propose an innovative delivery modality designed to overcome environmentalbarriers in socioeconomically austere rural areas. The purpose of the proposed 2-group (RICHH vs control)randomized clinical trial is to examine short- and long-term effects of the RICHH intervention on CVD risk (i.e.lipid profile body mass index and blood pressure) self-care behaviors (i.e. diet quality physical activity levelself-reported adherence to health behaviors) and depressive symptoms compared to usual care control inrural caregivers of persons with chronic disease. A total of 280 caregivers of patients with chronic illness will beenrolled. Rural caregivers will be randomly assigned to either the RICHH intervention group or a usual carecontrol group. We will stratify caregivers by gender in order to examine the moderating effect of gender onintervention outcomes given the many differences between male and female caregivers. The RICHHintervention (6 interactive modules) will be delivered for 12 weekly sessions (30- to 45 minutes per session). Inorder to enhance maintenance of behaviors we will also deliver 8 biweekly (every other week) boostersessions (20-30 minutes per sessions) for 2 months and then 6 monthly sessions. All sessions are deliveredindividually using a video-conferencing program on a multimedia digital device (i.e. mini iPad). Data onoutcomes will be collected at baseline 4 months and 12 months.

project_terms:
Address;Adherence;Adult;American;Behavior;Blood Pressure;Body mass index;Cardiac health;Cardiovascular Diseases;Caregivers;Caring;Cessation of life;Chronic Disease;Chronically Ill;Communication;Computer software;Data;Development;Devices;Diagnostic;Diet;Distress;Economically Deprived Population;Enrollment;Environment;Epidemic;Family;Family Caregiver;Family member;Female;Fibrinogen;Gender;Goals;Health;Health Personnel;Health Policy;Health Promotion;Health Resources;Health behavior;Healthcare;Heart Diseases;High Prevalence;Individual;Intervention;Kentucky;Light;Lipids;Long-Term Effects;Maintenance;Major Depressive Disorder;Mental Depression;Mental Health;Methods;Modality;Multimedia;Outcome;Patient Care;Patient Self-Report;Patients;Personal Satisfaction;Persons;Physical activity;Policy Maker;Population;Poverty;Prevention;Psyche structure;Quality of life;Randomized;Randomized Clinical Trials;Randomized Controlled Trials;Reporting;Research;Resources;Risk;Risk Factors;Risk Reduction;Rural;Rural Health;Self Care;Self Management;Skilled Nursing Facilities;Symptoms;Tablets;Technology;Testing;Time;United States Health Resources and Services Administration;Videoconferencing;Work;associated symptom;cardiogenesis;cardiovascular disorder risk;cardiovascular health;cardiovascular risk factor;caregiver interventions;caregiving;clinically significant;depressive symptoms;design;digital;efficacy testing;evidence base;group intervention;health care availability;health disparity;high risk;improved;informal caregiver;innovation;intervention effect;intervention program;male;mortality;physical conditioning;physically handicapped;prevent;primary caregiver;primary outcome;programs;psychological distress;rural America;rural area;rural dwellers;rural environment;rural setting;self-management program;social;socioeconomics;treatment as usual;usual care arm

public_health_relevance:
PROJECT NARRATIVE Rural caregivers of individuals with chronic illness are at uniquely high risk for development of heartdisease. We propose to test the Rural Intervention for Caregivers Heart Health program an innovative self-management program designed to lower heart disease and depression risk and overcome environmental andpersonal barriers to self-management. This innovative intervention program will improve physical andpsychological health for rural caregivers of chronically ill patients in rural Kentucky.


application_id: 9960518
project_number: 5R01DA047690-03
project_title: Accelerated Development of Lofexidine for Neonatal Opioid Withdrawal Syndrome
administering_ic: NIDA
award_notice_date: 2020-06-17
opportunity_number: PAR-18-218
application_type: 5
activity_code: R01
ic: DA
serial_number: 047690
program_official: KLINE, RICHARD
project_start_date: 2018-09-30
project_end_date: 2021-06-30
study_section: ZDA1-IXN-O(06)S
contact_pi_person_id: 15430214
contact_pi: GULLO, KRISTEN LEANN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 087875626
primary_uei: NKGSYBV5UGN1
duns_number: 087875626
uei: NKGSYBV5UGN1
fips: US
organization_id: 10003722
organization_name: US WORLDMEDS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40241
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY:Over the past decade rates of opioid use among the general population has continued to rise in the UnitedStates. This astounding increase in opioid use has resulted in the government declaring a public healthemergency in 2017. Compounding the problem a concurrent rise in opioid use among pregnant females hasresulted in a massive increase in infants born suffering from opioid withdrawal termed Neonatal OpioidWithdrawal Syndrome (NOWS). The NOWS epidemic has led to significant increases in healthcare costs andburden on the healthcare system due to increased length of hospital stay and level of required care. A normalinfant averages 2.1 days of hospital care post-birth costing $3500 whereas an infant born with NOWS averages16.9 days of inpatient care costing $66700. Currently there are no FDA-approved medications available fortreatment of NOWS. US WorldMeds (USWM) has developed lofexidine in collaboration with NIDA for thetreatment of opioid withdrawal in adults and anticipates possible Food and Drug Administration (FDA) approvalfor this use in May 2018. USWM now proposes to extend this successful co-development program throughinvestigation of the safety and efficacy of lofexidine in NOWS. This application proposes a strategic alliancebetween USWM and the National Institute on Drug Abuse (NIDA) to complete development and registrationprerequisites prior to initiation of clinical assessment of lofexidine in the neonatal patient population.The FDA has requested that USWM develop and establish safety information on lofexidine for neonate patientuse. Initial requirements for registration of lofexidine for pediatric use are clearly defined and agreed upon withthe FDA and include a total of five nonclinical studies in animals seven clinical studies and commitment todeveloping a pediatric specific formulation. The overall goal of this project is to develop a strategic alliance withNIDA and leverage this partnership to accelerate the development of the pediatric lofexidine program withspecific emphasis on the activities relevant for NOWS development. The research strategy in this proposalspecifically targets the FDA requested development of lofexidine for NOWS treatment and will be supported by:1) the development scale up and clinical trial material production of a neonatal-appropriate lofexidineformulation (Specific Aims 1 and 5) 2) completion of pivotal nonclinical studies to establish safety margins innonclinical juvenile rodent models considered appropriate to assess safety related to early brain developmentand general toxicity (Specific Aims 2 3 and 4) and 3) completion of a comparative bioavailability study withadult and pediatric formulations in normal healthy adult volunteers (Specific Aim 6).

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

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


