# projects

application_id: 10012229
project_number: 1K01MH119942-01A1
project_title: Examining HIV-related Stigma and HIV Testing Among Formerly Incarcerated African American Youth
administering_ic: NIMH
award_notice_date: 2020-04-09
opportunity_number: PA-19-126
application_type: 1
activity_code: K01
ic: MH
serial_number: 119942
suffix: A1
program_official: GREENWOOD, GREGORY LOUIS
project_start_date: 2020-05-01
project_end_date: 2024-04-30
study_section: Population and Public Health Approaches to HIV/AIDS Study Section[PPAH]
contact_pi_person_id: 12373928
contact_pi: KERR, JELANI
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
AIDS prevention;Address;Affect;African American;Age;Alcohol or Other Drugs use;Behavior;Behavior Therapy;Behavioral;Belief;Caring;Characteristics;Communities;Criminal Justice;Data;Data Collection;Demographic Factors;Development;Diagnosis;Drug usage;Early Diagnosis;Environment;Equation;Exhibits;Fostering;Fright;Gender;Gender Identity;General Population;Goals;HIV;HIV Infections;HIV Seronegativity;HIV diagnosis;HIV risk;Health;Health behavior;Homophobia;Human immunodeficiency virus test;Imprisonment;Individual;Intervention;K-Series Research Career Programs;Kentucky;Knowledge;Longitudinal Surveys;Mediating;Mediator of activation protein;Methods;Modeling;Morbidity - disease rate;Neighborhoods;Participant;Pathway interactions;Persons;Population;Poverty;Predisposition;Prevention;Prevention strategy;Preventive;Psychosocial Factor;Public Health;Recording of previous events;Research;Research Personnel;Research Project Grants;Risk;Risk Behaviors;Science;Sex Behavior;Sex Orientation;Statistical Methods;Stereotyping;Stigmatization;Structure;Subgroup;Survival Analysis;System;Testing;Time;Translational Research;Unemployment;United States;Vulnerable Populations;Work;Youth;aged;base;behavior test;care systems;career development;condoms;experience;health disparity;illicit drug use;improved;male;mortality;pre-exposure prophylaxis;prediction algorithm;prevent;prevention service;psychologic;public health priorities;racial and ethnic disparities;racial disparity;response;sexual risk behavior;skills;social stigma;therapy development;treatment disparity;uptake


application_id: 10011836
project_number: 5R01MH119119-02
project_title: Estrogen Effects on ADHD and Cognition
administering_ic: NIMH
award_notice_date: 2020-08-24
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: MH
serial_number: 119119
program_official: PACHECO, JENNIFER LYNN
project_start_date: 2019-09-10
project_end_date: 2023-08-31
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 8204810
contact_pi: MARTEL, MICHELLE M
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:
Females with Attention-Deficit/Hyperactivity Disorder (ADHD) remain dramatically understudied even thoughthey exhibit increased impairment beginning around puberty. Estrogen rises rapidly at puberty and exertsimportant effects on dopamine and cognition in both humans and animals. Both animal and human worksuggest that cognition and ADHD symptoms may be sensitive to hormonal effects particularly in highlyimpulsive females. Yet the effect of estrogen on ADHD symptoms in young adult women remains virtuallyunstudied. Our pilot data in 33 naturally-cycling young women suggest that among women with greater ADHDsymptoms within-person declines in estrogen particularly in the context of rising levels of progesterone justpost-ovulation are associated with clinically significant increases in ADHD symptoms. Yet no publishedempirical work has directly examined the role of circulating estrogen in relation to ADHD symptoms andcognitive mechanisms in women with ADHD. The current study would pioneer a new stage of work by beingthe first to utilize a rigorous quasi-experimental design that involves intensive longitudinal measurement acrossthe menstrual cycle in order to examine within-person estrogen effects on ADHD and cognitive mechanisms inyoung women with ADHD. A sample of 120 young women ages 18 to 25 with inattention overactivity orimpulsivity problems will be recruited from the university health center and local ADHD clinic psychologydepartment and through social media. Participants will be comprehensively assessed for ADHD and exclusioncriteria (e.g. use of hormone-based medication or hormonal conditions). Female participants will completewell-established assessment measures of ADHD and other psychopathological symptoms and diagnoses andcognition and provide saliva samples of hormones in the laboratory during a baseline laboratory visit within thefirst few days of the start of their menstrual cycle (i.e. during the mid-follicular phase characterized by stablelow estrogen). Then they will provide daily saliva samples for hormone assay each morning and completeshort daily assessments of ADHD and cognition every evening for up to 2 full menstrual cycles. They will alsocomplete laboratory cognitive testing of inhibition and working memory targeted to key cycle phasescharacterized by declining estrogen (post-ovulatory perimenstrual) and a cycle phase characterized by stablehigh estrogen levels (midluteal) based on menses onset and ovulation test results. Multi-level modeling willevaluate the clinical significance of within-person estrogen associations with ADHD and cognition withconsideration of progesterone as an interactive factor. Effects of comorbid disorders and affect will also beexplored. Study results have the potential to shift our understanding of ADHD in women by consideration ofdynamic hormone influences. In addition results will change clinical practice by indicating the need to accountfor cycle phase in ADHD evaluations in women as well as suggest personalized approaches to treatmenttargeted to cycle phase or hormone levels.

project_terms:
Adolescence;Adult;Affect;Age;Animals;Attention;Attention deficit hyperactivity disorder;Back;Basic Science;Biological;Biological Assay;Childhood;Clinic;Clinical;Cognition;Cognitive;Communities;Data;Deltastab;Diagnosis;Disease;Dopamine;Estradiol;Estrogens;Evaluation;Exclusion Criteria;Exhibits;Experimental Designs;Feasibility Studies;Female;Goals;Gonadal Steroid Hormones;Health;Hormonal;Hormone use;Hormones;Human;Impairment;Impulsivity;Laboratories;Link;Longitudinal Studies;Measurement;Measures;Menstrual cycle;Menstruation;Neurocognitive;Ovarian hormone;Ovulation;Participant;Persons;Pharmaceutical Preparations;Phase;Prevalence;Progesterone;Psychology;Puberty;Publishing;Rattus;Research Design;Risk;Risk Factors;Role;Saliva;Sampling;Short-Term Memory;Symptoms;Test Result;Testing;Thinking;Translating;Universities;Visit;Withdrawal;Woman;Work;animal data;base;clinical practice;clinical predictors;clinically significant;cognitive function;cognitive performance;cognitive testing;comorbidity;design;falls;hypothalamic pituitary gonadal axis;improved;inattention;innovation;male;multilevel analysis;perimenstrual;personalized approach;proliferative phase Menstrual cycle;recruit;response;sex;social media;treatment response;virtual;young adult;young woman

public_health_relevance:
The current project will evaluate how changes in hormones across the menstrual cycle influence Attention-Deficit/Hyperactivity Disorder (ADHD) and thinking in young adult women. Results will change the way ADHDis understood by suggesting hormonal influences on ADHD symptom expression in women changing clinicalpractice by requiring consideration of sex pubertal status menstrual cycle phase or even hormone profiles in assessment and treatment of ADHD in women.


application_id: 10010033
project_number: 1R43HL152894-01
project_title: Development of a Partial Occlusion Device to Aid in Coring and Anastomsis of the Aorta
administering_ic: NHLBI
award_notice_date: 2020-08-21
opportunity_number: PA-19-272
application_type: 1
activity_code: R43
ic: HL
serial_number: 152894
program_official: LEE, ALBERT
project_start_date: 2020-08-21
project_end_date: 2022-08-20
study_section: Special Emphasis Panel[ZRG1 SBIB-Y (12)]
contact_pi_person_id: 11183980
contact_pi: TOMPKINS, LANDON HEATH
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 838779366
primary_uei: FM8XH18NYPC7
duns_number: 838779366
uei: FM8XH18NYPC7
fips: US
organization_id: 10038616
organization_name: MYOCARDIAL ASSIST SYSTEMS AND TECHNOLOGY
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021208
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Heart failure (HF) accounts for 1 in 4 deaths in the US each year making it the leading cause of death with aHF patient population of over 6.5 million people. Due to a scarcity of donor hearts left ventricular assistdevices (LVADs) have gained clinical acceptance as an alternative treatment option to heart transplantationdue to their durability and long-term viability. Improved survival and reduced mortality have been associatedwith less invasive and off-pump approaches. Current clinically-approved LVADs require aortic partial clampingto facilitate outflow graft anastomosis and may also require cross-clamping of the aorta and cardiopulmonarybypass (CPB) during LVAD implantation. To improve clinical outcomes MAST LLC (Louisville KY) isdeveloping a two-balloon partial occlusion device (CardiAction) designed to provide a safe reliable andeffective hemostatic field that allows for the anastomosis of an LVAD outflow graft without the need for externalclamping. The CardiAction system internally occludes the ascending aorta (clamping) creating a hemostaticpocket for which an anastomosis can be placed while still allowing vessel perfusion (up to 5 L/min flow < 5mmHg) without vessel tissue damage. CardiAction is a catheter-based system comprised of a balloon-stentstructure multi-lumen conduit and a delivery sheath. The balloon-stent structure which consists of twopolyurethane toroidal balloons positioned on the ends of a woven-polyester covered self-expanding andcollapsible stent will provide aortic occlusion enabling the perfusion through the device lumen. The balloonsare inflated until sufficient vessel wall contact is achieved creating a static environment between the balloons.The multi-lumen conduit and delivery sheath will assist in device placement deployment and retraction. Theproposed tool will be a less invasive 18Fr sheath catheter-based solution. The stent cover provides a centrallumen for perfusion eliminating risks associated with complete vessel occlusion. The inflated balloons provideintravascular occlusion that maintains the natural vascular structure thereby creating a static environment thatwill provide the surgeon with a leak-free area to operate on the vessel while also reducing the potential fortissue damage. In this SBIR phase I proposal we will demonstrate feasibility of the CardiAction system andthen plan to submit a phase II proposal to complete engineering development to achieve a design freeze of theCardiAction system and complete pre-clinical testing to demonstrate efficacy safety and reliability. The phaseII experimental data will be used to support an Investigational Device Exemption (IDE) application to the Foodand Drug Administration (FDA) for clinical trials.

project_terms:
Anastomosis - action;Animal Model;Aorta;Area;Balloon Occlusion;Blood Vessels;Cadaver;Caliber;Cardiopulmonary Bypass;Cardiovascular system;Catheters;Cause of Death;Cessation of life;Clinical;Clinical Trials;Closure by clamp;Coupled;Custom;Data;Development;Device Designs;Devices;Dissection;Distal;Drops;Embolism;Engineering;Environment;Family suidae;Freezing;Goals;Heart;Heart Transplantation;Heart failure;Hemostatic Agents;Hemostatic function;Human;Implant;Implantation procedure;Incidence;Institutes;Investigation;Length of Stay;Liquid substance;Mechanics;Modeling;Monitor;Operative Surgical Procedures;Outcome;Patient-Focused Outcomes;Patients;Perfusion;Phase;Polyesters;Polyurethanes;Positioning Attribute;Preclinical Testing;Procedures;Pump;Quality of life;Recovery;Research Personnel;Risk;Safety;Silicones;Small Business Innovation Research Grant;Stents;Sternotomy;Structure;Study models;Surgeon;System;Techniques;Technology;Testing;Thoracotomy;Tissues;Translating;United States Food and Drug Administration;United States National Institutes of Health;Universities;Visualization;Work;alternative treatment;arm;ascending aorta;axillary artery;base;blood perfusion;calcification;clinical practice;clinically relevant;design;good laboratory practice;implantable device;implantation;improved;in vitro testing;innovation;left ventricular assist device;minimally invasive;mortality;novel;patient population;phase 2 study;pressure;prototype;seal;tool;verification and validation

public_health_relevance:
Investigators at MAST LLC (Louisville KY) and the University of Louisville (Louisville KY) are developing aballoon partial occlusion device CardiAction to facilitate minimally-invasive surgery for implant of mechanicalcirculatory support (MCS) device outflow grafts. The CardiAction system will enable surgeons to connect theMCS device outflow graft to the aorta without the need for external partial clamping of the aorta or CPBsupport which should result in shorter procedures with improved patient outcomes and better quality of life.


application_id: 10009252
project_number: 5U01AA022618-05
project_title: Role of Gut Microbiome and DHA Deficiency in Alcohol Induced Neuroinflammation
administering_ic: NIAAA
award_notice_date: 2020-08-24
opportunity_number: PAR-13-133
application_type: 5
activity_code: U01
ic: AA
serial_number: 022618
program_official: WANG, JOE
project_start_date: 2016-08-15
project_end_date: 2024-07-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Long-term excessive use of alcohol is capable of damaging nearly every organ and system in the body. The adverse effects of chronic alcohol consumption on the brain include not only psychiatric disorders but also severe alcohol-related neuroinflammation and brain damage. Work done by us and others has shown that chronic alcohol exposure causes intestinal oxidative stress epithelial barrier disruption enhancement of gut leakiness and consequent systemic endotoxemia and inflammation. Our recent work has begun to identify specific alcohol-induced alterations in enteric microbiota (dysbiosis) and shows that chronic alcohol consumption leads to a significant expansion of pathogenic gram-negative bacteria that may lead to the development of systemic endotoxemia. Moreover our earlier work has shown that chronic alcohol exposure increases the expression and activity of phosphodiesterase-4 (PDE4) decreases cellular cAMP and primes monocytes/macrophages leading to exaggerated expression of endotoxin-inducible inflammatory cytokines such as TNFa. Additionally alcohol exposure leads to a deficiency in brain docosahexanoeic acid (DHA) which likely contributes to the development/augmentation of cerebral inflammation and neurodegenerative pathologies. We hypothesize that alcohol-mediated enteric dysbiosis systemic endotoxemia and elevated inflammatory responses induce/exacerbate alcohol-associated neuropathologies via TLR4- and PDE4-mediated signaling DHA deficiency microglial activation neuroinflammation and injury. The proposed study is an intramural-extramural collaborative effort that combines the relevant expertise to investigate the complex interactive mechanisms involving intestinal dysbiosis systemic endotoxemia and inflammatory responses (UofL) and cerebral DHA deficiency in alcohol-induced neuropathologies (NIAAA). Moreover a translational aspect will examine the therapeutic potential of specific mechanism-based strategies in mitigating alcohol-induced injury. The Specific aims of the application are: Aim 1: Determine alcohol mediated changes in the gut bacterial composition and intestinal permeability and correlate these changes to the development of peripheral endotoxemia and brain inflammation. Aim 2: Examine the role of PDE4 in alcohol-induced brain inflammatory signaling associated with DHA deficiency and injury. Aim 3: Evaluate the therapeutic efficacy of three intervention strategies targeting (i) enteric dysbiosis (ii) PDE4 activity and (iii) DHA deficiency in attenuating alcohol mediated brain inflammation and injury.

project_terms:
16S ribosomal RNA sequencing;Acids;Adverse effects;Alcohol abuse;Alcohol consumption;Alcohol-Induced Disorders;Alcohols;Animals;Anti-Inflammatory Agents;Astrocytes;Attenuated;Bacteria;Brain;Brain Injuries;Cells;Cerebrum;Chronic;Complex;Cyclic AMP;Data;Development;Diet;Encephalitis;Endotoxemia;Endotoxins;Epithelial;Epithelium;Ethanol;Extramural Activities;Feedback;Functional disorder;Gene Expression;Gram-Negative Bacteria;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Intervention;Intestinal permeability;Intestines;Knockout Mice;Lactobacillus;Lactobacillus casei rhamnosus;Lead;Leaky Gut;Link;Mediating;Membrane;Mental disorders;Microglia;Mus;National Institute on Alcohol Abuse and Alcoholism;Nerve Degeneration;Omega-3 Fatty Acids;Oxidative Stress;PDE4B;Pathogenicity;Pathology;Peripheral;Permeability;Play;Populations at Risk;Preventive;Probiotics;Process;Production;Proteins;Proteobacteria;Role;Rolipram;Signal Transduction;Supplementation;TLR4 gene;TNF gene;Therapeutic;Tight Junctions;Treatment Efficacy;Universities;Work;alcohol effect;alcohol exposure;bacterial community;base;body system;brain cell;chronic alcohol ingestion;cytokine;dysbiosis;enteric dysbiosis;feeding;gut microbiome;gut microbiota;immune activation;inhibitor/antagonist;intestinal barrier;macrophage;metagenomic sequencing;monocyte;neuroinflammation;neuropathology;next generation sequencing;phosphodiesterase IV;prevent;probiotic supplementation;public health relevance;sequencing platform;translational study

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Recent work indicates that the brain is an important target for alcohol-induced damage and is often associated with gut-generated signals. Findings from this project could provide important mechanisms by which alcohol-induced pathology in the gut influences the brain inflammatory responses often observed in alcohol abuse. Moreover the findings from this study would be significant in the development of successful preventive and therapeutic strategies in most-at-risk populations.


application_id: 10009211
project_number: 1R43CA250750-01
project_title: Robust Visualization in CT Colonography
administering_ic: NCI
award_notice_date: 2020-04-14
opportunity_number: PA-19-272
application_type: 1
activity_code: R43
ic: CA
serial_number: 250750
program_official: FRANCA-KOH, JONATHAN C
project_start_date: 2020-04-15
project_end_date: 2021-09-30
study_section: Special Emphasis Panel[ZRG1 SBIB-T (10)]
contact_pi_person_id: 1871123
contact_pi: FARAG, ALY A
other_pis: Not Applicable
congressional_district: 02
department: Unavailable
primary_duns: 828955026
primary_uei: JU9YMZGJMNS5
duns_number: 828955026
uei: JU9YMZGJMNS5
fips: US
organization_id: 10027536
organization_name: KENTUCKY IMAGING TECHNOLOGIES, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402456516
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Computed-Tomography Colonoscopy (CTC) refers to visualization of the colon surface (lumen) by radiologistsfollowing an abdominal CT scan of prepped patients. Removal of colonic polyps is performed by a minimally-invasive procedure known as Optical Colonoscopy (OC). Through a sequence of image analysis steps a three-dimensional (3D) representation of the colon can be constructed which is then visualized by radiologists usinga virtual camera in order to examine the colon surface for abnormalities and polyps. A proper synchronizationbetween CTC for early detection of polyps and OC for their removal is the most effective and economicalapproach to prevent colon cancer which has over 95% rate of recovery with early detection. With improvedefficacy and safety of the procedure debate regarding the acceptance of CTC as a clinical and reimbursableprocedure for early detection of colon cancer has evolved in its favor. However the limitations of current CTCvisualization methods in terms of distortions and large false positive rates coupled with the fact that only a verysmall segment of the population undergoes OC or CT screening means that only about 4 out of 10 colorectalcancers are found at an early stage. Reduction of false positive and proper synchronization of the CTC-OC cyclehold promise for combating colorectal cancer.This Phase 1 project introduces a novel CTC visualization which is entirely model-based enabling quantifyingthe performance with respect to the topology of the colon and the types and size of colonic polyps. The approachuses a virtual camera rig arranged in a specific pattern within the colons inner surface (lumen) and will bedenoted by Fly-In and would be abbreviated by FI. This rig provides visualizes the lumen and presents it as asheet (filet) without distortion. This arrangement of virtual cameras is adaptable to topological variations in the3D tubular shape (e.g. constrictions and expansions bends and deformations) and the textural content of thelumen. Thus FI transforms the 3D tubular object into a sheet/filet without distortions.Specific Aims: This Phase 1 will have three main Specific Aims: 1) Implementation of the FI method. Atheoretical framework for the image formation in FI will be established to relate the lumen details to the numberof the virtual cameras in the rig to be used; focus would be on detecting and classification of all polyps above 5mm in size. 2) Developing an automatic polyp methods for the method using curvature and planar texturemeasures as well in order to detect various type of polyps. 3) Evaluate the FI method on synthetic andretrospective scans of up to 50 CTC patients and comparing its performance against traditional CTC methodssuch as Fly-Through (FT) and Fly-Over (FO) and Colon Flattening (Filet approach).With successful execution of Phase 1 the investigators will move into clinical testing using a multi-center studyand will pursue NIH Phase II funding and other venues for commercialization.

project_terms:
3-Dimensional;Abdomen;Adenomatous Polyps;Adopted;Advocate;Cancer Etiology;Carbon Dioxide;Cessation of life;Classification;Clinical;Colon;Colon Carcinoma;Colonic Polyps;Colonoscopy;Colorectal Cancer;Computed Tomographic Colonography;Computers;Coupled;Detection;Devices;Diagnosis;Disease;Dose;Early Diagnosis;Early treatment;Economic Development;Economics;Excision;Feces;Funding;Gastroenterologist;Growth;Health Care Costs;Hemorrhage;Hospitals;Image;Image Analysis;Imaging technology;Individual;Ingestion;Kentucky;Liquid substance;Malignant Neoplasms;Measures;Medial;Methods;Modeling;Modernization;Multicenter Studies;Optics;Oral;Patients;Pattern;Performance;Phase;Polyps;Population;Procedures;Radiology Specialty;Recovery;Research Personnel;Residual state;Risk;Scanning;Sedation procedure;Sensitivity and Specificity;Shapes;Stress;Surface;System;Technology;Telemedicine;Testing;Texture;Tubular formation;United States;United States National Institutes of Health;Variant;Visualization;Woman;X-Ray Computed Tomography;abdominal CT;base;cancer diagnosis;colon cancer prevention;colon cancer screening;colon cancer treatment;combat;commercialization;computed tomography screening;constriction;flexibility;fly;improved;innovation;low dose computed tomography;men;minimally invasive;novel;procedure safety;radiologist;research clinical testing;screening;statistics;tool;two-dimensional;virtual

public_health_relevance:
Project NarrativeColorectal cancer (CRC) is the second leading cause of cancer death (when combining men and womenstatistics of the disease) in the United States and is the third most commonly diagnosed cancer with less than40% of the eligible population taking advantage of current screening methods. Early detection and removal ofcolonic polyps using Optical Colonoscopy is an effective approach to combat colon cancer. Computed-Tomography Colonography (CTC) conducted on prepped patients is a non-invasive approach for earlydetection of colonic polyps. With proper synchronization between Optical Colonoscopy (OC) and CTC aneconomic and robust approach for early detection and treatment of colon cancer is within reach. The proposedFly-In CTC technology aims to provide unprecedented accuracy (in terms of sensitivity and specificity) of polypdetection by the radiologists and the computer.


application_id: 10006844
project_number: 5K23MH111977-04
project_title: Enhancement of extinction learning using transcranial direct current stimunation
administering_ic: NIMH
award_notice_date: 2020-08-13
opportunity_number: PA-16-198
application_type: 5
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;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;functional MRI scan;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: 10005694
project_number: 3R01HL147343-01S1
administering_ic: NHLBI
award_notice_date: 2020-03-03
opportunity_number: PA-18-906
application_type: 3
activity_code: R01
ic: HL
serial_number: 147343
suffix: S1
program_official: POSTOW, LISA
project_start_date: 2020-03-05
project_end_date: 2022-04-30
contact_pi_person_id: 11702638
contact_pi: CARLL, ALEX PERROW
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-03-05
project_title:
The Role of E-cigarette Characteristics and Constituents in Cardiac Dysfunction--Diversity Supplement

project_abstract:
ABSTRACTE-cigarettes (e-cigs) have become increasingly popular but their acute and chronic health effects aremostly unknown. Conventional cigarette smoking increases the risk of cardiac arrhythmia by slowingventricular repolarization and inducing QT interval prolongation on the electrocardiogram (ECG). E-cigsproduce several of the harmful and potentially harmful constituents (HPHCs) found in cigarette smoke.When aerosolized the e-cig solvents propylene glycol (PG) and vegetable glycerin (VG) may similarlyaffect repolarization. Our preliminary data indicate exposure to e-cig solvent aerosols of equal-ratio PGand VG (PG:VG) prolongs QT and alters gene expression of ion channels key for repolarization in themouse heart suggesting inhalation of e-cig solvent aerosols may convert the heart into an arrhythmogenicsubstrate. However e-cigs produce HPHCs at levels that vary markedly according to devicecharacteristics operating conditions and use patterns. Thus the full spectrum of their health impactsremains unclear. This project is designed to identify specific device characteristics and e-cig constituentsassociated with cardiac toxicity. It will apply both ECG and programmed stimulus electrophysiology (EP)studies to test the hypothesis that e-cigs induce electrical disturbances in the heart and that these effectsdepend upon e-cig characteristics and constituents. The studies will 1: Determine how devicecharacteristics influence the acute electrophysiologic effects of e-cigs in mice and 2: Assess theimpacts of chronic e-cig exposure on cardiac electrophysiology and hemodynamics. Real-timecardiac physiology will be monitored through ECG telemetry during and after acute exposures to PG:VGaerosols from e-cigs of various characteristics (device type user settings nicotine levels) to delineate howthey affect both HPHC production and ECG measures of cardiac dysfunction. The device characteristicswith the greatest and slightest acute cardiac effects will then be selected for chronic exposure studies inwhich cardiac EP and hemodynamics will be comprehensively assessed through telemetryechocardiography programmed electrical stimulation of the heart molecular and histologic assaysaerosol assessments of HPHCs and analyses of biomarkers of HPHC exposures. All exposure groupswill be simultaneously compared to cigarette smoke and filtered-air exposure groups. Our research plan isresponsive to the research priorities of the FDA/CTP especially the interest area of toxicity. We expectthat our results will elucidate the relative toxicity of different e-cig devices constituents and settings andprovide novel and significant insights into how each influences the arrhythmogenic potential of e-cigaerosols. We believe the outcome of our project would provide comprehensive and rigorous data to guidepolicies on e-cig product standards and to inform regulatory authorities of the cardiac risks associated withspecific e-cig constituents and characteristics.

project_terms:
Acute;Adverse effects;Aerosols;Affect;Aldehydes;Animals;Area;Arrhythmia;Biochemical;Biochemistry;Biological Assay;Biological Markers;Blood Pressure;Cardiac;Cardiac Electrophysiologic Techniques;Cardiac health;Cardiotoxicity;Cardiovascular system;Characteristics;Chronic;Data;Devices;Echocardiography;Electric Stimulation;Electrocardiogram;Electrodes;Electronic cigarette;Electrophysiology (science);Exposure to;Failure;Female;Functional disorder;Gap Junctions;Gene Expression;Generations;Glycerol;Goals;Harm Reduction;Health;Health Policy;Heart;Heart Atrium;Histologic;Histopathology;Human;Inhalation;Ion Channel;Mainstreaming;Measures;Mission;Molecular;Monitor;Mus;Myocardial dysfunction;Nicotine;Outcome;Particulate Matter;Pattern;Periodicity;Physiology;Policies;Predisposition;Production;Propylene Glycols;Public Health;Refractory;Regimen;Research;Research Personnel;Research Priority;Risk;Role;Safety;Smoking;Solvents;Stimulus;Structure;Telemetry;Testing;Time;Tissues;Toxic effect;United States National Institutes of Health;Vegetables;Ventricular;Western Blotting;Work;aerosolized;air filter;atrioventricular node;authority;cardiovascular health;cigarette smoke;cigarette smoking;combustible cigarette;design;disability;e-cigarette aerosols;electronic cigarette use;heart function;heart rate variability;hemodynamics;insight;interest;male;novel;sex;urinary

public_health_relevance:
Project NarrativeThe proposed project is relevant to public health because it will provide new insight on the cardiac risks ofelectronic cigarette use and identify the characteristics of e-cigarette devices that pose the greatest harm toheart health. Upon this project identifying the device characteristics with the greatest cardiac effects in animalsthese observations may guide human studies and be used to set product standards to protect the public fromthe most harmful e-cigarette features. Thus the proposed research is relevant to the FDA mission to assurethe safety of FDA-regulated products and also relevant to the NIH mission to reduce illness and disability.


application_id: 10005625
project_number: 3OT2OD024898-01S3
administering_ic: OD
award_notice_date: 2019-09-17
opportunity_number: RFA-RM-15-018
application_type: 3
activity_code: OT2
ic: OD
serial_number: 024898
suffix: S3
program_official: QASHU, FELICIA M
project_start_date: 2017-09-20
project_end_date: 2020-08-31
study_section: Anatomical and Functional Mapping of the Innervation of Marjor Internal Organs[AFMI(53)]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
other_pis: HARKEMA, SUSAN J
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Functional Mapping with Lumbosacral Epidural Stimulation for Restoration of Bladder Function After Spinal Cord Injury

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

project_terms:
Address;Affect;Animal Model;Animals;Anodes;Anti-Cholinergics;Anus;Autonomic Dysreflexia;Bladder;Bladder Control;Bladder Dysfunction;Body Weight;Cardiovascular system;Caregivers;Caring;Catheterization;Catheters;Cathodes;Chronic;Clinic;Clinical;Collaborations;Country;Data;Dependence;Development;Devices;Disease;Electrodes;Engineering;Family suidae;Feasibility Studies;Female;Foundations;Frequencies;Future;Gender;Goals;Health;Healthcare Systems;Human;Impairment;Implant;Increased frequency of micturition;Individual;Injury;Intervention;Intestines;Kentucky;Knowledge;Lead;Lesion;Life;Location;Locomotor training;Long-Term Effects;Lower urinary tract;Manometry;Manuals;Maps;Measurable;Measurement;Measures;Modeling;Morbidity - disease rate;Motor;Movement;Neuronal Plasticity;Operative Surgical Procedures;Organ;Paralysed;Participant;Patients;Peripheral;Pharmaceutical Preparations;Pharmacology;Phase;Physiologic pulse;Pilot Projects;Predisposition;Publications;Quality of life;Questionnaires;Rattus;Rehabilitation therapy;Research;Residual volume;Risk;Rodent;Safety;Scientific Advances and Accomplishments;Scientist;Sensory;Severities;Sex Functioning;Societies;Source;Specific qualifier value;Sphincter;Spinal;Spinal Cord;Spinal cord injury;Stents;Techniques;Technology;Testing;Therapeutic;Time;Training;Translating;Translations;United States;Urethra;Urinalysis;Urinary tract infection;Urination;Urologic Diseases;Width;base;clinical application;clinically relevant;cohort;cost;diaries;dosage;experience;experimental study;functional electrical stimulation;functional gain;improved;innovation;life time cost;male;multidisciplinary;neural circuit;neuroregulation;novel;pressure;prevent;programs;restoration;side effect;statistics;symptom treatment;treadmill;urinary;urologic;voltage;white matter

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


application_id: 10004795
project_number: 272201400004I-0-759301900132-1
project_title: Clinical Central Laboratory Services to support a VTEU trial for an Influenza vaccine
administering_ic: NIAID
project_start_date: 2019-08-09
project_end_date: 2020-02-28
contact_pi_person_id: 16122383
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;Influenza A Virus H1N1 Subtype;Influenza A virus;Laboratories;National Institute of Allergy and Infectious Disease;Research Support;Services;influenza virus vaccine;novel;research study;vaccine trial


application_id: 10004685
project_number: 5UT2GM130174-03
project_title: Southeast Xlerator Network
administering_ic: NIGMS
award_notice_date: 2020-09-18
opportunity_number: RFA-GM-18-001
application_type: 5
activity_code: UT2
ic: GM
serial_number: 130174
program_official: ARORA, KRISHAN
project_start_date: 2018-09-01
project_end_date: 2022-08-31
study_section: Special Emphasis Panel[ZRG1-IMST-K(14)B]
contact_pi_person_id: 15333536
contact_pi: WILLMOT, JACQUELINE
other_pis: KRENTSEL, EUGENE ;MCCLURE, IAN D;SAUNDERS, ROBERT
congressional_district: 03
department: Unavailable
primary_duns: 080949252
primary_uei: JYN1A3M4LD29
duns_number: 080949252
uei: JYN1A3M4LD29
fips: US
organization_id: 10048196
organization_name: XLERATEHEALTH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402023346
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Southeast XLerator Network proposes to create a networked and easily accessible regionaltechnology transfer accelerator hub (XLerator Hub or Hub) to share best practicesdisseminate education content and offer products services facilities and other resourcesconnected through both physical and online platforms for innovators and trainees in the SoutheastIDeA states. Led by XLerateHealth LLC an SBA award-winning healthcare-focused technologyaccelerator the Hub will 1) bridge the divide between great ideas and the marketplace byleveraging and connecting existing resources and unique expertise assets across all participatingentities in the Southeast IDeA state region 2) fill the gaps that constitute barriers to efficientcommercialization among partner institutions and 3) deliver the necessary resources educationand business networks to foster and sustain a culture of entrepreneurship across the region. Thisproject will address significant disparities and lack of access to resources talent and capital inrespective local commercialization ecosystems for biomedical technologies that are pervasiveacross the Southeast IDeA state region making the rates of technology transfer andcommercialization of academic research discoveries in this region suboptimal. The Hubobjectives/ core functions are: 1. To improve knowledge and understanding by innovators about how technologies are brought to market. 2. To improve knowledge and understanding by accelerators and technology transfer offices about the unique commercialization pathways of various biomedical technologies 3. To facilitate access to technology/product development and commercialization resources required for early-stage technology advancement and later-stage product development 4. To help close the gap(s) in funding (a) between basic research discoveries and scientific proof of feasibility and (b) between exhaustion of grant funding and private capital required to generate products and revenues. 5. To commercialize new innovation in pharmaceuticals medical devices healthcare IT and electronics and other biomedical technologies through entrepreneurship licensing and partnerships with established companies and additionally commercialize the Hubs platform programs and materials through access by other regions.The impact of the Hub will be increased market-ready technologies and patents more successfulstartups and increased biomedical technology acceleration.

project_terms:
Acceleration;Address;Adopted;Advocate;Astronomy;Award;Basic Science;Biological Sciences;Biomedical Technology;Businesses;Capital;Development;Economic Development;Ecosystem;Education;Electronics;Entrepreneurship;Evaluation;Faculty;Fostering;Funding;Goals;Grant;Health Sciences;Healthcare;Incubators;Industry;Institution;Intellectual Property;Kentucky;Knowledge;Leadership;Learning;Legal patent;Licensing;Medical Device;Medical Technology;Mentors;Outcome;Pathway interactions;Pharmacologic Substance;Phase;Privatization;Process;Puerto Rico;Research;Resources;Services;Small Business Innovation Research Grant;Small Business Technology Transfer Research;Structure;Survival Rate;Talents;Techniques;Technology;Technology Transfer;Trainers Training;Training;Training Programs;Training and Education;United States National Institutes of Health;Universities;Vision;West Virginia;commercialization;design;education resources;exhaustion;experience;improved;innovation;inter-institutional;operation;product development;programs;public-private partnership;success;technology development;tool

public_health_relevance:
Project NarrativeThis project will significantly enhance commercialization knowledge increase market-ready technologies and patents create more successful startups and as a resultaccelerate biomedical technology commercialization in the Southeast IDeA region.


application_id: 10004591
project_number: 5U18FD005814-05
project_title: Implementation of the Animal Feed Regulatory Program Standards in Kentucky
administering_ic: FDA
award_notice_date: 2020-08-20
opportunity_number: RFA-FD-16-022
application_type: 5
activity_code: U18
ic: FD
serial_number: 005814
program_official: ISAKSON, ISAIAH
project_start_date: 2016-09-20
project_end_date: 2021-08-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 14105899
contact_pi: JOHNSON, DARRELL DUANE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Implementation of the Animal Feed Regulatory Program Standards in KentuckyCompetition B:Feed Program: The University of Kentucky Division of Regulatory Services seeks toenter into a cooperative agreement with the FDA to fully implement the Animal FeedRegulatory Program Standards (AFRPS). Funding is required to develop andimplement these standards develop and maintain best practices enhance food safetyand better direct regulatory efforts to reduce foodborne illness attributed to feed safetyhazards. The initial self-assessment conducted in 2014 identified both strengths andweaknesses in our program. Following our 18-month audit in January 2016 the self-assessment was adjusted and updated to reflect the audit results. Our compliancesampling program is one of the most extensive in the nation with this funding we willbetter define our sampling plans and expand our program particularly in the area ofcontaminant testing.Lab Certification: This project will seek to increase the level of confidence of the dataproduced by the feed laboratory for the feed regulatory program within the KentuckyDivision of Regulatory Services by developing and implementing a quality managementsystem quality manual and attaining accreditation to the ISO/IEC 17025:2005standard. The supplemental money from the cooperative agreement will assist withtraining personnel participation in FERN and mentoring increasing laboratory capabilityand confidence in results and achieving the ISO/IEC 17025:2005 accreditation.AFRPS  UKRS Proposal Page 1

public_health_relevance:
Project NarrativeImplementation of the Animal Feed Regulatory Program Standards in KentuckyThe University of Kentucky Division of Regulatory Services seeks to enter into acooperative agreement with FDA to fully implement the Animal Feed RegulatoryProgram Standards (AFRPS). Funding is required to develop and implement thesestandards develop and maintain best practices enhance food safety and better directregulatory efforts to reduce foodborne illness attributed to feed safety hazards.Additionally we seek funding for our laboratory that supports our animal feed programto achieve accreditation under ISO/IEC 17025:2005 standards.AFRPS  UKRS Proposal Page 1


application_id: 10004391
project_number: 2R01DE026963-03
project_title: P. gingivalis genes essential for tobacco smoke survival
administering_ic: NIDCR
award_notice_date: 2020-06-10
opportunity_number: PA-19-056
application_type: 2
activity_code: R01
ic: DE
serial_number: 026963
program_official: MCNEALY, TAMARA L
project_start_date: 2017-09-01
project_end_date: 2025-06-30
study_section: Special Emphasis Panel[ZRG1 MOSS-C (02)]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abscess;Adult;Alveolar Bone Loss;Anaerobic Bacteria;Award;Bacteria;Basic Science;Biological;Biological Assay;Biological Process;Blood Vessels;Cells;Chronic;Cigarette;Clinical;Communicable Diseases;Complex;Consumption;Data;Databases;Developed Countries;Diabetes Mellitus;Disease;Dose;Economic Burden;Environment;Epidemiology;Epithelial;Epithelial Cells;Epithelium;Essential Genes;Exhibits;Exposure to;Financial cost;Funding Mechanisms;Future;Gene Deletion;Genes;Genome;Gingiva;Growth;Health;Homologous Gene;Immune;Immune response;In Vitro;Infection;Inflammation;Libraries;Lung diseases;Modeling;Mouth Diseases;Mus;National Institute of General Medical Sciences;New Zealand;Nicotine;Oral;Oral cavity;Patients;Peptide Hydrolases;Periodontal Diseases;Periodontitis;Physiology;Population;Porphyromonas gingivalis;Predisposition;Premature Birth;Prevention;Refractory;Research;Resistance;Resources;Scandinavia;Smoke;Smoker;Smoking;Standardization;Stress;Subcutaneous abscess;System;Testing;Tissues;Tobacco;Tobacco smoke;Tobacco smoking behavior;Tooth structure;Toxin;Treatment Protocols;Variant;Vascular Diseases;Virulence;Work;base;biological adaptation to stress;cigarette smoke;cigarette smoke-induced;fitness;immune resistance;in vivo;infection rate;insight;mouse model;mutant;non-smoker;novel;novel vaccines;oral cavity epithelium;pathogen;periodontopathogen;success;therapeutic target;trait;transcriptome;transcriptome sequencing;transposon sequencing


application_id: 10003915
project_number: 5U01AA026225-04
project_title: 2/2 Alcohol associated Comorbidities and Microbiome Evaluation in HIV (ACME HIV)
administering_ic: NIAAA
award_notice_date: 2020-08-25
opportunity_number: RFA-AA-17-014
application_type: 5
activity_code: U01
ic: AA
serial_number: 026225
program_official: WANG, JOE
project_start_date: 2017-09-22
project_end_date: 2022-08-31
study_section: ZAA1-DD(14)V
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: COOK, ROBERT L
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Heavy alcohol drinking and HIV-1 infection are independently associated with the development ofabnormalities in the brain function and cognition and increasing evidence indicates that the combinatorialeffects of HIV infection and alcohol are likely to worsen these abnormalities. Significantly both HIV- 1 infectionand chronic alcohol abuse cause alterations in gut microbiome (dysbiosis) and increase intestinal permeabilityand microbial translocation (MT) which are major pathogenic factors driving local and systemic inflammation.The dysbiosis is characterized by loss of gut bacterial biodiversity a reduction in beneficial bacteria and/or anexpansion of harmful or pro-inflammatory bacteria. However there is limited understanding of (i) the interactiveeffects of heavy alcohol drinking and HIV-1 infection on gut dysbiosis and (ii) the longitudinal qualitative(microbial membership) and quantitative (relevant abundance) determinants of dysbiosis. The current proposaladdresses these gaps with an overall goal to promote the development of rational therapies targeting gutdysbiosis. Accordingly we pursue a unifying hypothesis that in HIV-infected individuals heavy alcohol usecompounds gut dysbiosis and consequent peripheral immune inflammation leading to exacerbation of neuro-inflammation and cognitive dysfunction. To test these hypotheses we will enroll 100 HIV+ participants from30-to-90-day challenge Florida SHARC study (AA020797). This is a funded prospective cohort study in whichenrolled heavy drinkers are challenged to stop drinking for 30 to 90 days assisted by contingencymanagement (CM) payments and motivational interviewing. This application Alcohol associatedComorbidities and Microbiome Evaluation in HIV (ACME HIV 2/2) leverages the existing resources of30-to-90-day challenge Florida SHARC study: participant recruitment measures of alcohol consumptionbiospecimen and biomarker collection; expertise in alcohol HIV and neuroimaging. New data include:longitudinal changes in gut dysbiosis correlative changes in peripheral inflammation and measures ofcognition and neuroinflammation. In response to RFA-AA-17-014 we will partner with the St. PETER HIVstudy (ACME HIV 1/2) to corroborate our findings in Aims 1 and 2 and to conduct combined cross-cohortanalyses. We will complete the following Specific Aims among HIV+ heavy drinkers: AIM 1: To assesslongitudinal qualitative and quantitative changes in the gut microbiome (dysbiosis) associated with very heavyalcohol consumption. AIM 2: To determine the impact of HIV infection and alcohol abuse induced gut dysbiosison intestinal permeability microbial translocation (MT) and resultant peripheral endotoxemia immuneactivation and inflammation. AIM 3: To investigate the impact of dysbiosis and peripheral inflammation ondevelopment of neuro-inflammation and cognitive function. Completion of these aims will lay groundwork for anintervention targeting alcohol-associated dysbiosis which could profoundly reduce inflammation and improvecognitive functions in HIV+ heavy drinkers.

project_terms:
16S ribosomal RNA sequencing;Address;Adverse effects;Alcohol abuse;Alcohol consumption;Alcoholic beverage heavy drinker;Alcohols;Automobile Driving;Bacteria;Bacterial Genes;Behavior assessment;Biodiversity;Biological Markers;Brain;Chronic;Clinical Research;Cognition;Cognitive;Cohort Analysis;Cohort Studies;Collection;Data;Development;Endotoxemia;Enrollment;Evaluation;Evaluation Studies;Florida;Functional disorder;Funding;Goals;HIV;HIV Infections;HIV-1;Heavy Drinking;Immune;Impaired cognition;Impairment;Individual;Infection;Inflammation;Inflammatory;Intervention;Intestinal permeability;Link;Longitudinal Studies;Measures;Neurobiology;Neurocognitive;Neurocognitive Deficit;Outcome;Participant;Pathogenesis;Pathogenicity;Pathologic;Patient Recruitments;Peripheral;Phylogeny;Prospective cohort study;Research;Resolution;Resources;Role;Sample Size;Shotguns;Structure;Taxonomy;Testing;Virulence Factors;alcohol effect;alcohol measurement;alcohol research;clinically relevant;cognitive function;cognitive performance;cognitive testing;combinatorial;comorbidity;contingency management;cooking;drinking;dysbiosis;gut microbiome;gut microbiota;gut-brain axis;immune activation;improved;metagenomic sequencing;microbial;microbial community;microbiome;microbiome alteration;microbiota;motivational enhancement therapy;neuroimaging;neuroinflammation;outcome prediction;payment;preclinical study;prospective;relating to nervous system;response;targeted treatment;whole genome

public_health_relevance:
The goal of this proposal is to investigate the effects of heavy alcohol drinking on intestinal microbiota and gutbarrier dysfunction with consequent peripheral inflammation which ultimately worsen neurocognitive functionsin HIV-1 infected individuals.


application_id: 10003240
project_number: 5R01ES029942-02
project_title: Mechanism of hexavalent chromium carcinogenesis - Role of long non-coding RNA dysregulation
administering_ic: NIEHS
award_notice_date: 2020-05-14
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: ES
serial_number: 029942
program_official: TYSON, FREDERICK L
project_start_date: 2019-09-01
project_end_date: 2021-05-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 9719630
contact_pi: YANG, CHENGFENG
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/ABSTRACTHexavalent chromium [Cr(VI)] is a common and well-recognized environmental carcinogen causing lung and othercancers however the mechanism of Cr(VI) carcinogenesis remains elusive. Previous Cr(VI) carcinogenesisstudies mostly focus on its genotoxic effects. However studies showed that Cr(VI) exposure also causes non-genotoxic effects such as epigenetic changes as evidenced by dysregulations in DNA methylation and histoneposttranslational modifications. While these observations open new directions for studying Cr(VI) carcinogenesis itremains to be determined how Cr(VI)-caused epigenetic dysregulations contribute to Cr(VI) carcinogenesis.Moreover very little is known about the role of non-coding RNAs (ncRNAs) especially the long non-coding RNAs(lncRNAs) another epigenetic mechanism regulating gene expression in Cr(VI) carcinogenesis. Recent studiesshow that lncRNAs are emerging key regulators of gene expression and play critical roles in cancer. The goal ofthis study is to investigate the mechanism of Cr(VI) carcinogenesis focusing on the role of lncRNA dysregulation.Our preliminary studies found: (i) Chronic Cr(VI) exposure increases the expression of the lncRNA ABHD11-AS1which contributes causally to Cr(VI)-induced cell transformation cancer stem cell (CSC)-like property andtumorigenesis; (ii) Chronic Cr(VI) exposure down-regulates the expression of miR-182-5p; but knockdown ofABHD11-AS1 increases the level of miR-182-5p. Moreover overexpressing miR-182-5p in Cr(VI)-transformed cellssignificantly reduces their transformed phenotypes phenocopying the effect of ABHD11-AS1 knockdown; (iii) TheRho GTPase Rac1 and Erk1/2 MAPK are highly activated in Cr(VI)-transformed cells; (iv) The expression level ofthe oncogenic Rac-GEF Tiam1 is significantly up-regulated in Cr(VI)-transformed cells; but overexpressing miR-182-5p or knockdown of ABHD11-AS1 greatly decrease Tiam1 level; (v) The expression level of PARP-1 a criticalDNA repair gene and a key regulator of gene expression is significantly up-regulated in Cr(VI)-transformed cells;(vi) The level of protein PARylation is drastically increased in Cr(VI)-transformed cells; inhibition of PARP-1 orknockdown of PARP-1 greatly decrease the levels of protein PARylation and ABHD11-AS1 and the transformedphenotype of Cr(VI)-transformed cells. Based on literature review and our novel preliminary data our centralhypothesis is: Chronic Cr(VI) exposure-upregulated lncRNA ABHD11-AS1 sponges miR-182-5p and causes itsdown-regulation which leads to increased level of the oncogenic Rac-GEF Tiam1 promoting Cr(VI)carcinogenesis. Three aims are proposed: Aim 1 will determine the mechanism by which chronic Cr(VI) exposureup-regulates ABHD11-AS1. Aim 2 will demonstrate that ABHD11-AS1 sponges miR-182-5p causing its down-regulation and promoting Cr(VI)-exposure-induced CSC-like property cell transformation and tumorigenesis. AndAim 3 will demonstrate that down-regulation of miR-182-5p increases levels of the oncogenic Rac-GEF Tiam1promoting Cr(VI)-exposure-induced CSC-like property cell transformation and tumorigenesis. Tiam1 knockoutmice will be used to demonstrate that Tiam1 plays an important role in Cr(VI)-induced lung carcinogenesis.

project_terms:
3' Untranslated Regions;Affect;Affinity Chromatography;Biological Assay;Cancer Etiology;Carcinogens;Cell Maintenance;Cells;Chromatin Remodeling Factor;Chronic;Country;DNA Methylation;DNA Repair Gene;Data;Down-Regulation;Environmental Carcinogens;Environmental Health;Epigenetic Process;Exposure to;Gene Expression;Genetic Transcription;Goals;Guanine Nucleotide Exchange Factors;Histones;KDM5B gene;Knockout Mice;Length;Luciferases;Lung;Lysine;MAP Kinase Gene;Malignant Neoplasms;Mediating;Metabolic;Metal Carcinogenesis;Mus;Neoplasm Metastasis;Nuclear;Occupational;Oncogenic;Phenotype;Play;Poly(ADP-ribose) Polymerases;Porifera;Post-Translational Protein Processing;Property;Proteins;RNA;RNA Polymerase II;Reactive Oxygen Species;Regulator Genes;Relapse;Reporter;Review Literature;Role;Series;United States;Untranslated RNA;base;cancer cell;cancer initiation;cancer stem cell;carcinogenesis;carcinogenicity;cell transformation;chromium hexavalent ion;genotoxicity;insight;knock-down;lung carcinogenesis;lung tumorigenesis;novel;overexpression;pollutant;promoter;recruit;rho GTP-Binding Proteins;stem cell differentiation;stem-like cell;therapy resistant;tumorigenesis

public_health_relevance:
PROJECT NARRATIVEHexavalent chromium [Cr(VI)] is one of the most common environmental and occupational pollutants andexposure to Cr(VI) is a major environmental health concern affecting millions of people in the United States aswell many other countries. The goal of this study is to study the mechanism of Cr(VI) exposure causing cancerfocusing on the role long non-coding RNA dysregulation.


application_id: 10002615
project_number: 1R56HL145051-01
administering_ic: NHLBI
award_notice_date: 2019-09-19
opportunity_number: PA-18-484
application_type: 1
activity_code: R56
ic: HL
serial_number: 145051
program_official: HASAN, AHMED A K
project_start_date: 2019-09-20
project_end_date: 2020-06-30
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 10451500
contact_pi: VENDITTO, VINCENT JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-09-20
project_title:
Understanding the role of anti-apolipoprotein A-I antibodies in atherosclerotic cardiovascular disease

project_abstract:
PROJECT SUMMARY/ABSTRACTThe identification of autoantigens in atherosclerotic plaques has prompted investigation of the antibody-mediatedpathogenesis of atherosclerotic cardiovascular disease (ASCVD). One target of IgG antibody induction inASCVD patients is apolipoprotein A-I (ApoA-I) the major protein of high density lipoprotein (HDL). Although anti-ApoA-I antibodies have been identified in mice and human subjects their role has not been elucidated.Continued evaluation of the detailed antibody profile of ApoA-I will improve our understanding of the immuneresponses associated with ASCVD. The overall goal of this project is to elucidate the role of anti-ApoA-Iantibodies and to characterize their molecular composition and functional impact in ASCVD. To achieve thisgoal we will characterize the molecular components of the anti-ApoA-I antibody response in mice and patientserum samples and correlate these factors with cellular interactions functional outcomes and atherosclerosisprogression. The hypothesis is that anti-ApoA-I antibodies can exhibit a pro-inflammatory or anti-inflammatoryeffect depending on the specific antibody characteristics (i.e. antigen engagement subclass epitope specificityFc receptor interaction) and these effects are exacerbated or suppressed in ASCVD patients. The rationale forthis proposed research is that understanding one component of the humoral immune response associated withASCVD will lead to a better understanding of the underlying mechanisms and improved patient outcomes. Thishypothesis will be tested through two specific aims: 1) Elucidate the molecular components and functionalimplications of antibodies targeting ApoA-I in mouse models of atherosclerosis; and 2) Delineate the associationbetween antibody profiles and ASCVD events in a large community-based prospective patient cohort. Aim 1 willemploy novel immunomodulation strategies developed in Dr. Venditto's laboratory to achieve epitope-specificmodulation of antibody responses to elucidate antibody/epitope function and role in atherosclerosis progression.In the second aim sera from patients in the Multi-Ethnic Study of Atherosclerosis (MESA) will be evaluated forantibody profiles and correlated with patient outcomes. The approach is innovative due to the utilization of invivo immunomodulation approaches that can alter the anti-ApoA-I IgG profiles and our ability to achieve epitope-specific immune suppression in mice. The proposed research is significant as the outcomes of this researchwill improve our understanding of B cell-mediated immune responses to ApoA-I to elucidate the role of antibodieson ASCVD progression. Detailed characterizations of the antigen epitope specificity antibody subclass andreceptor engagement will enhance understanding of ASCVD to guide therapeutic development and future effortsto improve risk stratification procedures in patients to decrease the burden of ASCVD in patients.

project_terms:
Anti-inflammatory;Antibodies;Antibody Response;Antibody Therapy;Antigen-Antibody Complex;Antigens;Antiinflammatory Effect;Apolipoprotein A-I;Arterial Fatty Streak;Atherosclerosis;Autoantibodies;Autoantigens;Autoimmune Diseases;B-Cell Development;B-Lymphocytes;Blood Circulation;Cardiovascular Diseases;Cardiovascular system;Characteristics;Communities;Data;Development;Disease;Disease Outcome;Disease Progression;Epitopes;Evaluation;Event;Exhibits;Fc Receptor;Formulation;Foundations;Future;Goals;High Density Lipoproteins;Homeostasis;Human;IgG1;IgG3;Immune response;Immunization;Immunoglobulin G;Immunologics;Immunosuppression;Immunosuppressive Agents;Incidence;Inflammatory;Inflammatory Response;Interleukin-10;Interleukin-12;Investigation;Laboratories;Measures;Mediating;Molecular;Multi-Ethnic Study of Atherosclerosis;Multivariate Analysis;Mus;Obesity;Outcome;Outcomes Research;Participant;Pathogenesis;Patient-Focused Outcomes;Patients;Peptide antibodies;Phenotype;Plant Roots;Procedures;Property;Prospective cohort;Proteins;Protocols documentation;Research;Risk;Risk Factors;Risk stratification;Role;Sampling;Serum;Specificity;Stratification;TLR4 gene;Testing;Therapeutic antibodies;Time;adjudicate;base;burden of illness;cardiovascular disorder risk;cardiovascular health;cell mediated immune response;clinical risk;cohort;drug development;follow-up;functional outcomes;human subject;immunoregulation;improved;in vivo;inflammatory milieu;innovation;mouse model;new technology;new therapeutic target;novel;novel strategies;programs;prospective;protocol development;receptor;therapeutic development;treatment strategy;western diet


application_id: 10001522
project_number: 5U01DK074007-15
project_title: University of Louisvilles Clinical Center in Gastroparesis Clinical Research Consortium
administering_ic: NIDDK
award_notice_date: 2020-08-13
opportunity_number: RFA-DK-16-010
application_type: 5
activity_code: U01
ic: DK
serial_number: 074007
program_official: SERRANO, JOSE
project_start_date: 2006-04-15
project_end_date: 2022-08-31
study_section: ZDK1-GRB-8(O2)S
contact_pi_person_id: 8264660
contact_pi: ABELL, THOMAS LYMAN
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:
Gastroparesis is a disorder of gastric function characterized by delay in gastric emptying frequently associatedwith chronic nausea and vomiting early satiety postprandial fullness abdominal pain and malnutrition thatmay require nutritional support. Gastroparesis has a devastating impact on quality of life and predominantlyaffects younger women. In the past 5 years the Gastroparesis Clinical Research Consortium (GpCRC) hasmade a series of important contributions (see below) to improve our understanding of this disorder andadvancing the goals of patients physicians and the NIH for management of gastroparesis. Yet much remainsto be learned about its etiology natural history treatment strategies and clinical course whichis the rationale behind our response to the Continuation of the Gastroparesis Consortium RFA-DK-10-502. Thebiggest barrier to effective therapeutic approaches to gastroparesis is our lack of knowledge about either itspathogenesis or its pathophysiology. Further the correlation between the major symptoms such as nauseavomiting pain and current methods to measure change in gastric function (electrical motor activity mealemptying times) is poor at best. Finally we do not understand the long-term outcomes of these patients andwhether outcomes differ on the basis of etiology symptom severity and degree of emptying abnormalities.Consequently our approach to these patients is erratic and treatment has been empirical and only partiallyeffective if at all in relieving the major symptoms. The mission of the GpCRC is completely aligned with therecommendations of the National Commission on Digestive Diseases;5 specifically Research Goal 2.6 relatesto gastroparesis and states: "Understand the noxious visceral signaling causing nausea and vomiting related togastric neuro-electrical and/or motor dysfunction and the bi-directional brain-gut interactions. Gastroparesisprovides an archetypal disease for investigative inquiry. Chronic vomiting a debilitating and socially isolatingdigestive symptom creates potentially life-threatening disruptions in fluid and electrolyte homeostasis andcompromises nutritional status. Chronic nausea remains a significant hidden disability. Nausea and vomitingusually occur in tandem and overlay with other Gl symptoms as well as presenting in numerous digestivediseases. More effective treatments for nausea and vomiting would improve quality of life and physicalfunctioning in a vast array of illnesses. A paucity of research exists for defining peripheral noxious signaling ofnausea and vomiting related to primary Gl motor/sensory disturbances."The Specific Aims of this proposal are to: 1. Complete the current GpCRC registry; 2. To continue the GpCRCcore lab responsible for anatomic and related studies on tissue sample of patients with Gp syndromes; 3.Continue pharmacologic studies on patients with Gp syndromes; 4. Continue device studies for patients withthe Gp syndromes; and 5. A new multicenter study based on several GpCRC ancillary studies and other pilotdata.

project_terms:
Abdominal Pain;Affect;Anatomy;Ancillary Study;Area;Chronic;Clinical;Clinical Research;Complex;Data;Databases;Devices;Digestive System Disorders;Disease;Effectiveness;Electric Stimulation;Electrolytes;Electrophysiology (science);Enteral;Etiology;Functional disorder;Gastric Emptying;Gastroparesis;Goals;Grant;Health;Homeostasis;Inflammatory;Insulin Infusion Systems;Knowledge;Life;Liquid substance;Malnutrition;Measures;Methods;Mission;Motor;Motor Activity;Multicenter Studies;Natural History;Nausea;Nausea and Vomiting;Nortriptyline;Nutritional Support;Nutritional status;Outcome;Pain;Pathogenesis;Patient-Focused Outcomes;Patients;Peripheral;Pharmacology Study;Physical Function;Physicians;Psychological Impact;Publications;Publishing;Quality of life;Recommendation;Registries;Research;Safety;Sensory;Series;Severities;Signal Transduction;Stomach;Symptoms;Syndrome;Time;Tissue Sample;Treatment Efficacy;United States National Institutes of Health;Universities;Visceral;Vomiting;Work;aprepitant;base;clinical center;disability;early satiety;effective therapy;glucose monitor;gut-brain axis;improved;motor disorder;novel strategies;recruit;response;social;treatment strategy;young woman

public_health_relevance:
This proposal aims to gather a better understanding of gastroparesis which is a devastating disorder inpredominantaly younger women. This is a continuation of the Gastroparesis Clinical Research Consortium(GpCRC). The GpCRC has made a series of important contributions to improve our understanding of thisdisorder and advancing the goals of patients physicians and the NIH for management of gastroparesis. Thisproposal continues the mission of the GpCRC to better understand and treat this disorder.


application_id: 10001467
project_number: 5R01CA230758-03
project_title: Characterize the role of EBF1 in breast cancer progression
administering_ic: NCI
award_notice_date: 2020-08-26
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 230758
program_official: SALNIKOW, KONSTANTIN
project_start_date: 2018-09-01
project_end_date: 2024-08-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 11716117
contact_pi: WU, YADI
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:
Basal-like breast cancer (BLBC) is a devastating form with limited therapeutic options. Duringtumor progression and metastasis tumor cells rewire their metabolism which results in anenhanced nutrient uptake to supply the energetic and biosynthetic pathway under the hypoxiccondition. It is important for tumor cells to activate mitochondrial selective autophagy (mitophagy)to avoid metabolic crisis and maintain the mitochondrial homeostasis. The means by which BLBCcells fine-tune mitochondrial biogenesis and mitophagy to maintain metabolic and mitochondrialhomeostasis in order to adapt the hypoxic microenvironment remain elusive. We found that EBF1is highly expressed in BLBC. Knockdown of EBF1 induced extensive mitophagy and eventualcell death. Interestingly silencing HIF1 blocked the EBF1 deficiency-induced mitophagy and celldeath in BLBC. In addition we found that HIF1 induced EBF1 expression and that EBF1interacted with HIF1 and inhibited HIF1 activity. Based on these preliminary data we speculatethat EBF1 functions as a safeguard to ensure metabolic homeostasis through a regulation ofHIF1 activity which when compromised can contribute to imbalanced mitochondria andmassive mitophagy in BLBC. Our strategy will be to first delineate the role of EBF1 in BLBC (Aim1); then determine the molecular interplay between EBF1 and HIF1 (Aim 2); and to characterizethe role of EBF1 in vivo in human samples as well as in several mouse models (Aim 3). Theknowledge gained from these studies will increase our fundamental understanding about biologicrelationship between metabolic reprogramming and mitochondrial homeostasis particular duringhypoxia. Our work also reveals a pivotal function for the EBF1 in BLBC and suggests that targetingthis pathway may offer alternative treatment strategies for this aggressive subtype of breastcancer.

project_terms:
Address;Affect;Attenuated;Autophagocytosis;B-Lymphocytes;Biogenesis;Bioinformatics;Biological;Brain;Breast Cancer Cell;Breast Cancer cell line;Cell Death;Cells;Cessation of life;Clinical;Data;Disease;EP300 gene;Early identification;Ensure;Environment;Event;Feedback;Genes;Genetic Transcription;Goals;Growth;HIF1A gene;Homeostasis;Human;Hypoxia;Hypoxia Inducible Factor;Immunocompetent;Interruption;Intrinsic factor;Knockout Mice;Knowledge;Luciferases;Lung;Malignant Neoplasms;Mammary gland;Mediating;Metabolic;Metabolism;Mitochondria;Molecular;NCI-Designated Cancer Center;Neoplasm Metastasis;Nutrient;Oxygen;Pathogenesis;Pathologist;Pathway interactions;Patients;Play;Process;Reaction;Reagent;Regulation;Research;Response Elements;Role;Sampling;Signal Transduction;Specimen;Stress;System;Talents;Testing;Therapeutic;Tumorigenicity;Work;alternative treatment;base;breast cancer progression;cancer initiation;conditional knockout;druggable target;in vivo;inhibitor/antagonist;innovation;insight;interest;knock-down;malignant breast neoplasm;mouse model;multidisciplinary;neoplastic cell;novel;outcome forecast;overexpression;prevent;programs;response;targeted treatment;transcription factor;treatment strategy;tumor;tumor growth;tumor metabolism;tumor microenvironment;tumor progression;uptake

public_health_relevance:
Despite immense interest in metabolic reprogramming related to tumor progression we still havelittle knowledge about how this process is balanced to maintain catabolic homeostasis particularlyduring conditions of stress. By defining the role of EBF1 in regulation of HIF1 activity this projectwill provide unique and new insight into how HIF1-mediated metabolic reprogramming isregulated through EBF1.


application_id: 10001327
project_number: 5R25CA221765-03
project_title: Appalachian Career Training in Oncology (ACTION) Program
administering_ic: NCI
award_notice_date: 2020-08-21
opportunity_number: PAR-17-059
application_type: 5
activity_code: R25
ic: CA
serial_number: 221765
program_official: GHOSH, SANGEETA AHUJA
project_start_date: 2018-09-18
project_end_date: 2023-08-31
study_section: ZCA1-RPRB-Z(O2)
contact_pi_person_id: 11045331
contact_pi: VANDERFORD, NATHAN LANE
other_pis: EVERS, BERNARD MARK;FRAZIER, DONALD T
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTAppalachian Kentucky has significant challenges associated with health socioeconomic and educationdisparities. This predominantly rural region not only has the highest cancer incidence and mortality rates in theUnited States it is also one of the most economically disadvantaged medically underserved and poorlyeducated regions of the country in which less than 1% of residents earn doctoral degrees. These disparities formthe basis for the need to create targeted educational and scientific workforce preparedness and health literacyintervention strategies for this population. As such the research educational and outreach strengths of theUniversity of Kentucky's Markey Cancer Center will be leveraged to develop the Appalachian Career TrainingIn ONcology (ACTION) Program as a Youth Enjoy Science education intervention. The ACTION Program willimmerse underrepresented and underserved high school and undergraduate students from AppalachianKentucky in cross-disciplinary mentored research projects cancer care observational experiences and cancereducation and career development activities as well as provide hands-on community and school outreachopportunities. The overarching goal of the program is to enhance cancer-focused biomedical workforce diversityin a high-risk rural population and to increase the community's cancer-related literacy. Expected impacts of theprogram include: 1) increasing our students' matriculation into post-secondary professional and/or graduatescience degree programs; 2) instilling in our students lifelong commitments to research education/outreach orhealth care careers focused on the cancer burden and unique challenges in Appalachian Kentucky and beyond;and 3) enhancing the Appalachian Kentucky community's understanding of cancer research and clinical carelinking these facets to the benefits of science education. The overarching goal and the program impacts will beaccomplished through four Specific Aims including: 1) developing participants' cancer research knowledge andskills through cross-disciplinary faculty-mentored research training experiences; 2) enhancing students' cancer-focused career preparation by providing didactic cancer education and career development mentoring throughfaculty-led courses workshops seminars and career coaching and mentoring; 3) conducting outreach activitiesin participant communities to increase the understanding of the research and clinical aspects of cancer and theimportance of science education among universities; primary and secondary school groups; civic organizations;health care providers; and the families and communities of our student participants; and 4) evaluating programprogress and impacts focusing on longitudinal participant data (including tracking progression of participantsthrough their academic and professional careers) and outreach activity efficacy. Ultimately the program willestablish a new paradigm for enhancing cancer-focused educational preparation among rural low-socioeconomic students and increasing citizens' understanding of cancer and the importance of scienceeducation in rural low-socioeconomic and low-education-attainment areas.

project_terms:
Academic achievement;Achievement;Address;Appalachian Region;Area;Award;Cancer Burden;Cancer Center;Cancer Research Project;Clinical;Communities;Country;County;Data;Degree Completion;Degree program;Doctor's Degree;Early Intervention;Economically Deprived Population;Education;Education and Outreach;Educational Intervention;Educational workshop;Faculty;Family;Fostering;Funding;Goals;Health;Health Personnel;Healthcare;Home environment;Incidence;Income;Intervention;Kentucky;Knowledge;Link;Literature;Localized Malignant Neoplasm;Malignant Neoplasms;Mentors;Mentorship;Participant;Population;Poverty;Preparation;Primary Schools;Readiness;Research;Research Project Grants;Research Training;Rest;Rural;Rural Population;Schools;Science;Secondary Schools;Socioeconomic Status;Students;Training;Training and Education;Underrepresented Students;Underserved Population;Underserved Students;United States;Universities;Youth;anticancer research;cancer care;cancer education;cancer health disparity;cancer site;career;career development;career preparation;clinical care;economic indicator;education research;experience;faculty mentor;health literacy;high risk;high school;higher education;literacy;matriculation;medically underserved;mortality;oncology program;outreach;peer;peer learning;peer networks;programs;rural area;science education;skills;socioeconomic disparity;socioeconomics;student training;undergraduate student

public_health_relevance:
PROJECT NARRATIVEKentucky has the highest all-site cancer incidence and mortality rates in the United States with the highest burdenof cancer localized to the Appalachian region of the state. Residents of Appalachian Kentucky also experiencehigh rates of poverty and below-average education attainment. To address these issues we will create theAppalachian Career Training In ONcology (ACTION) Program which proposes a new paradigm to foster cancer-focused education and training for students from rural low-socioeconomic and low-education-attainmentcommunities and to develop a better understanding of cancer and the benefits of cancer education within suchunderserved communities.


application_id: 10000958
project_number: 5R35GM131807-02
project_title: Hedgehog Signaling in Development and Metabolism
administering_ic: NIGMS
award_notice_date: 2020-08-07
opportunity_number: PAR-17-094
application_type: 5
activity_code: R35
ic: GM
serial_number: 131807
program_official: XU, JIANHUA
project_start_date: 2019-09-01
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1-CB-J(55)R]
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adipose tissue;Basal cell carcinoma;Biochemical;Biological;Blood Circulation;Cell membrane;Cell surface;Cholesterol;Development;Diagnostic;Drosophila genus;Drug resistance;Embryonic Development;Endocytosis;Erinaceidae;Event;Fat Body;Foundations;G-Protein-Coupled Receptors;Genes;Genetic;Genetic Transcription;Goals;Human;Insecta;Integral Membrane Protein;Investigation;Knowledge;Lipids;Lipolysis;Malignant Neoplasms;Mammals;Metabolic Control;Metabolic Diseases;Metabolism;Modeling;Mutation;Na(+)-K(+)-Exchanging ATPase;Obesity;Outcome;Pathway interactions;Pattern;Pattern Formation;Phosphorylation;Phosphotransferases;Play;Process;Protein Family;Proteins;Publishing;Regulation;Research;Role;Signal Pathway;Signal Transduction;System;Ubiquitination;cancer type;cell growth;cholesterol biosynthesis;developmental disease;hedgehog signal transduction;human disease;insight;lipid biosynthesis;lipid metabolism;medulloblastoma;novel;novel therapeutic intervention;patched protein;programs;protein activation;protein expression;public health relevance;response;smoothened signaling pathway;tool


application_id: 10000927
project_number: 5R01ES026151-06
project_title: The epigenetic mechanism of hexavalent chromium carcinogenesis
administering_ic: NIEHS
award_notice_date: 2020-08-24
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 026151
program_official: TYSON, FREDERICK L
project_start_date: 2016-09-01
project_end_date: 2021-02-28
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 9719630
contact_pi: YANG, CHENGFENG
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/ABSTRACTHexavalent chromium [Cr(VI)] is one of the most common environmental pollutants causing lung and othercancer. The mechanism of Cr(VI) carcinogenesis has not been elucidated. The long-term goal of this study is todetermine the mechanism of Cr(VI) carcinogenicity and identify targets for better treatment and prevention oflung cancer resulting from Cr(VI) exposure. Epigenetics refers to heritable changes in the pattern of geneexpression that are not caused by changes in DNA sequence but are mediated by DNA methylation histoneposttranslational modifications microRNAs and long noncoding RNAs. Cancer stem cells (CSCs) are cancercells possessing characteristics of normal stem cells. CSCs or CSC-like cells are considered as cancer initiatingcells. Genomic imprinting refers to an epigenetic mechanism by which certain genes are expressed in a parent-of-origin-specific manner restricting their expression from only one of the two parental chromosomes. Manystudies demonstrated that deregulation of epigenetics and genomic imprinting plays key roles in carcinogenesis.Accumulating evidence shows that Cr(VI) also causes epigenetic effects such as changing DNA methylation andhistone posttranslational modifications. However the mechanisms by which Cr(VI) triggers these epigeneticmodifications remain largely unknown and whether these epigenetic modifications play a causal role in Cr(VI)carcinogenesis are not clear. Our preliminary studies found: (i) Chronic Cr(VI) exposure induces CSC-likeproperty and cell malignant transformation; (ii) Chronic Cr(VI) exposure increases the levels of several HMTaseswhich play a causal role in Cr(VI)-induced CSC-like property and cell transformation; (iii) Higher levels of H3repressive methylation marks and their related HMTases are also detected in lung cancer tissues of humansexposed to chromium; (iv) Up-regulation of HMTases plays a crucial role in chronic Cr(VI) exposure-causedderegulation of Dlk1-Dio3 genomic imprinting cluster; (v) miR-494 down-regulation plays a causal role in Cr(VI)-induced cell transformation; and (vi) Oxidative stress increases the levels of HMTases. Based on literature andour preliminary data we hypothesize: (i) Cr(VI) exposure generates oxidative stress which increases the levelsof HMTases; (ii) Up-regulation of HMTases deregulates the Dlk1-Dio3 genomic imprinting cluster whichdecreases the level of miR-494; and (iii) Down-regulation of miR-494 increases the levels of its targets and keyCSC factors c-Myc and BMI1 which produce CSC-like property promoting Cr(VI)-induced cell transformation andtumorigenesis. This proposed study not only fills the knowledge gap of epigenetics and Cr(VI) carcinogenesisbut also provides novel mechanistic insights for the crucial role of oxidative stress in Cr(VI) carcinogenesis. Threeaims are proposed: Aim 1: Induction of CSC-like property by down-regulating miR-494 of Dlk1-Dio3 imprintingcluster and its role in Cr(VI)-induced cell transformation and tumorigenesis. Aim 2: Down-regulation of miR-494by chronic Cr(VI) exposure-induced HMTases through deregulating Dlk1-Dio3 genomic imprinting cluster. Aim 3:Up-regulation of HMTases by chronic Cr(VI) exposure through oxidative stress.

project_terms:
Affect;BMI1 gene;Cancer Etiology;Cells;Characteristics;Chromium;Chromosomes;Chronic;Country;Cultured Cells;DNA Methylation;DNA Modification Methylases;DNA Sequence;Data;Down-Regulation;EZH2 gene;Elements;Environmental Health;Environmental Pollutants;Epigenetic Process;Epithelial Cells;Exposure to;Gene Expression Profile;Genes;Genomic Imprinting;Goals;Heritability;Histone H3;Histones;Human;Impairment;Inherited;Knowledge;Literature;Lung;Lung Neoplasms;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Methylation;MicroRNAs;Modification;Occupational;Oxidative Stress;Parents;Play;Post-Translational Protein Processing;Promoter Regions;Property;Rattus;Reactive Oxygen Species;Regulation;Role;Stem Cell Factor;Tumor Suppressor Genes;Tumor Tissue;United States;Untranslated RNA;Up-Regulation;base;bronchial epithelium;c-myc Genes;cancer cell;cancer stem cell;carcinogenesis;carcinogenicity;cell transformation;chromium hexavalent ion;genotoxicity;histone methyltransferase;human tissue;imprint;insight;lung cancer prevention;novel;overexpression;pollutant;recruit;stem cells;stem-like cell;tumorigenesis;tumorigenic

public_health_relevance:
PROJECT NARRATIVEHexavalent chromium [Cr(VI)] is one of the most common environmental and occupational pollutants andexposure to Cr(VI) is a major environmental health concern affecting millions of people in the United States aswell many other countries. The goal of this study is to determine the epigenetic mechanism by which Cr(VI)exposure causes cancer.


application_id: 10000526
project_number: 3P42ES007380-21S5
project_title: Administrative Core - Core A
administering_ic: NIEHS
award_notice_date: 2019-09-12
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S5
program_official: HENRY, HEATHER F
study_section: ZES1-LKB-K
subproject_number: 7476
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY (Administrative Core - Hennig Ormsbee Hoover) The overarching goal of the University of Kentucky Superfund Research Center (UK-SRC) is to reduce risk from exposure to environmentally persistent chlorinated organics which are prevalent at Superfund sites using polychlorinated biphenyls (PCBs) as a model pollutant. The UK-SRC proposes to address this goal through an integrated program of biomedical and environmental science research focused on pro-inflammatory health impacts of PCBs and innovations in environmental remediation technology. Further the Center uses the combined understandings from these two complementary areas of study to explore positive lifestyle practices (e.g. nutrition-based approaches) to modulate health effects as well as environmentally benign nano-based approaches to mitigate the environmental threat. To achieve these goals the Administrative Core provides high level coordination of transdisciplinary scientific interactions across biomedical and environmental science domains associated interdisciplinary research training and multi-directional translation efforts across diverse sectors-federal government state agencies the private sector and other stakeholders at community and individual levels. To provide an optimal support environment and the requisite infrastructure to accomplish the Center's goal we propose four specific aims to: 1) implement high level planning and coordination of research activities by implementing effective leadership identifying emerging research facilitating complementary approaches and establishing processes for dissemination translation and engagement; 2) integrate diverse cross-disciplinary areas of research by promoting intra- and extra-Center communication and fostering collaboration and cooperation across projects and cores; 3) provide effective fiscal management processes and oversight of core resources; 4) facilitate high quality management processes that promote continuing research productivity effective mentoring accurate documentation/reporting and capacity to meet future challenges. The focus of the Administrative Core on the establishment and maintenance of iterative program development processes along with multidirectional internal and external relationships positions our Center to contribute not only important scientific findings but also collaborative processes stakeholder-derived information and innovative endeavors to the national Superfund Research Program.

project_terms:
Address;Advisory Committees;Area;Benign;Cardiovascular system;Chemicals;Collaborations;Communication;Communities;Discipline;Documentation;Ecology;Educational workshop;Engineering;Ensure;Environment;Environmental Health;Environmental Pollution;Event;Exercise;Exposure to;Federal Government;Fostering;Future;Goals;Health;Housing;Human Resources;Individual;Inflammatory;Information Centers;Infrastructure;Interdisciplinary Study;Kentucky;Leadership;Life Style;Maintenance;Medicine;Mentors;Mentorship;Modeling;National Institute of Environmental Health Sciences;Outcome;Output;Pharmacology;Physiological;Polychlorinated Biphenyls;Positioning Attribute;Private Sector;Process;Productivity;Program Development;Public Health;Reporting;Research;Research Activity;Research Infrastructure;Research Project Grants;Research Support;Research Training;Resources;Risk;Role;Science;Scientist;Superfund;Targeted Research;Technology;Toxic effect;Toxicology;Training;Translational Research;Translations;Universities;base;experience;health science research;innovation;meetings;nano;nutrition;pollutant;programs;remediation;superfund chemical;superfund site;training project

public_health_relevance:
PROJECT NARRATIVE (Administrative Core - Hennig Ormsbee Hoover) The Administrative Core of the University of Kentucky Superfund Research Program will continue to promote a set of approaches that apply principles of team science and rely on perspectives from different biomedical and environmental science disciplines. These approaches will address the problem of environmental contamination from a class of pollutants known as chlorinated organics. The goal will be to reduce risk from exposure to these compounds by studying their health effects and potential technical solutions in the environment.


application_id: 10000521
project_number: 3P42ES007380-21S5
project_title: Nutrition and Superfund Chemical Toxicity
administering_ic: NIEHS
award_notice_date: 2019-09-12
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S5
program_official: HENRY, HEATHER F
project_start_date: 1997-04-07
project_end_date: 2020-03-31
study_section: ZES1-LKB-K(S)
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant) Due to their relative chemical stability and ubiquity in the environment chlorinated organic contaminants such as polychlorinated biphenyls (PCBs) and trichloroethylene (TCE) pose significant health risks and enduring remediation challenges. For example extensive PCB contamination at the Paducah Gaseous Diffusion Plant the largest Superfund site in Kentucky is of major concern for its health consequences. The University of Kentucky Superfund Research Center (UK-SRC) provides a focused transdisciplinary research training and translation environment to address human health challenges associated with such exposures. Preliminary findings suggest that nutrition-based concepts and exercise can markedly influence the mechanisms of toxicity of chlorinated organics. Indeed healthful nutrition/nutritional components may provide a platform to develop primary prevention strategies for diseases associated with environmental toxic insults while also providing the basis for new risk assessment paradigms. Further novel iron-based nano-structured capture/sensing and remediation systems based on biomimetic binding domains and functionalized/responsive membrane platforms offer potential for sustainable advances in technical capability for site remediation. The UK-SRC proposes to reduce risk by: 1) developing lifestyle-related modulators of environmental disease and elucidating relevant protective mechanisms and 2) developing technologically effective and economically efficient methods for capture/sensing and remediation of PCBs. Three biomedical and two environmental science projects a Research Support Core and Administrative Research Translation Community Engagement and Training Cores collectively advance understanding of toxicant-induced mechanisms of disease introduce sustainable approaches for remediation and enhance stakeholder and community capacity to act. Biomedical projects focus on models of inflammation and associated changes in redox status and inflammatory cytokines in vascular (Project 1) fetal (Project 2) and adipose (Project 3) tissues with relevance to atherosclerosis insulin resistance/diabetes and obesity. Environmental science projects employ nanomaterials to create selective PCB-binding domains with high affinity and selectivity for PCBs (Project 4) and a functionalized polymer immobilized membrane platform to support PCB dechlorination (Project 5). All Projects focus on common PCB toxicants. Biomedical scientists with the Research Support Core also evaluate byproducts of environmental science projects for unintended effects. Use of PCBs as a model contaminant will advance understanding of inflammatory diseases associated with exposure to persistent chlorinated organic pollutants. Research results will lead to evidence-based multidirectional information/education technology transfer training policy and translational activities via UK-SRC cores. Expected outcomes include positive lifestyle interventions across the lifespan for populations at risk and advanced technical capacity to reduce public health risks.

project_terms:
Address;Adipose tissue;Affinity;Atherosclerosis;Binding;Biological;Biological Markers;Biology;Biomedical Research;Biomimetics;Blood Vessels;Chemicals;Collaborations;Communities;Coupled;Detection;Diabetes Mellitus;Diet;Diffusion;Disease;Drug Metabolic Detoxication;Ecology;Education;Environment;Environmental Health;Exercise;Exposure to;Health;Human;Immobilization;In Vitro;Inflammation;Inflammatory;Insulin Resistance;Iron;Kentucky;Lead;Learning;Life Style;Longevity;Mass Spectrum Analysis;Mediator of activation protein;Membrane;Mentorship;Methods;Modeling;Monitor;Nanostructures;National Institute of Environmental Health Sciences;Nutritional;Obesity;Outcome;Oxidation-Reduction;Oxidative Stress;Pigments;Plants;Policies;Policy Developments;Polychlorinated Biphenyls;Polymers;Population;Populations at Risk;Prevention strategy;Primary Prevention;Process;Production;Public Health;Recommendation;Research;Research Design;Research Project Grants;Research Support;Research Training;Risk;Risk Assessment;Risk Management;Role;Rotation;Scientist;Site;Statutes and Laws;Structure;Students;Superfund;System;Techniques;Technology;Technology Transfer;Tissues;Toxic effect;Toxin;Training;Translational Research;Translations;Trichloroethylene;United States Environmental Protection Agency;Universities;Work;base;biomedical scientist;chemical stability;computer infrastructure;cytokine;data management;dechlorination;development policy;evidence base;experience;fetal;global environment;improved;in vivo Model;innovative technologies;insight;lifestyle intervention;manufacturing process;nanomaterials;novel;nutrition;organic contaminant;particle;pollutant;programs;public health relevance;remediation;science education;sensor technology;superfund chemical;superfund site;technology development;tool;toxicant;translational engagement

public_health_relevance:
Public Health Relevance: The proposed research may lead to novel dietary and exercise recommendations contaminant detection and remediation technology development and policy recommendations for populations at risk to improve the health of people residing near Superfund sites. Outcomes should provide important technology tools and insights for primary stakeholders to use in improving Superfund site risk assessment and management specifically related to the class of compounds known as chlorinated organics.


application_id: 10000475
project_number: 3P42ES023716-03S2
project_title: Environmental Exposure and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2019-09-13
opportunity_number: RFA-ES-15-019
application_type: 3
activity_code: P42
ic: ES
serial_number: 023716
suffix: S2
program_official: CARLIN, DANIELLE J
project_start_date: 2017-09-01
project_end_date: 2022-03-31
study_section: ZES1-LKB-K(S)
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY (Overall)This proposal is to establish a Superfund Center at the University of Louisville. This Center will support researchon the cardiometabolic effects of volatile organic chemicals (VOCs) that are of high relevance to the SuperfundProgram. Center investigators will conduct mode-of-action research to unravel critical pathways of toxicity andto identify toxicological end-points (cardiometabolic changes) of chemicals (VOCs) found at Superfund andrelated sites. Using high throughput metabolomic and mass spectrometry approaches animal experiments andhuman population studies Center investigations will aid in the discovery and validation of novel biomarkers ofboth exposure and cardiometabolic injury that would lay the foundation for future remediation strategies. Thesestudies will employ state-of-the-art tools to develop pollutant atmospheres for animal exposure and to measureunique and sensitive biological endpoints reflective of cardiometabolic injury. In addition work supported by theCenter will lead to the development of new methods and devices for quantifying atmospheric levels of VOCs thatwill employ advanced technologies and offer precise but low-cost measurements of hazardous waste sites. Themajor objectives of the Center are to conduct state-of-the-art research on the cardiometabolic toxicity of VOCsand to determine how they affect cardiometabolic disease (CMD) prevalence and severity in exposedpopulations. These studies will be complemented by mode-of-action mechanistic studies in animals to identifythe molecular and cellular mechanisms that contribute to VOC toxicity. Center investigators will also identifyspecific conditions such as nutritional status and obesity and increase susceptibility to VOC toxicity and testtherapeutic interventions that can attenuate acute and chronic cardiometabolic effects of VOC exposures. Thefindings of these studies will contribute to both the discovery and the validation of sensitive and robust biomarkersthat could be used to assess the extent of exposure metabolism and toxicity. Center investigators will createnew technologies for detecting VOCs at low environmental levels to enable future exposure assessmentactivities. Senior Center members will educate and train junior investigators graduate students and post-doctoralFellows in the field of environmental science and promote relevant community awareness and participation toenhance mutual bidirectional understanding of exposure risk and the health effects of exposure. The findingsand discoveries of the Center will be transferred to affected communities end users in public and private sectorsand other stakeholders. For future use and analysis all samples of human and animal tissues and all datacollected during Center investigations will be stored in a computer-coded biorepository. Collectively Centeractivities will lead to rigorous evaluation and better understanding of the effects of these hazardous chemicalson obesity diabetes and cardiovascular disease.

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

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


application_id: 10000313
project_number: 3P30CA177558-07S3
project_title: University of Kentucky Markey Cancer Center - Cancer Center Support Grant
administering_ic: NCI
award_notice_date: 2019-09-13
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S3
program_official: ROBERSON, SONYA
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Achievement;Address;Appalachian Region;Area;Award;Basic Science;Behavioral Research;Bioinformatics;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Cancer Research Project;Catchment Area;Cell Separation;Cellular biology;Centers of Research Excellence;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Communities;Community Healthcare;Community Networks;Community Outreach;Community Physician;Comprehensive Cancer Center;County;Coupled;Data Sources;Development;Disease;Distress;Early Diagnosis;Ecology;Education;Education and Outreach;Environmental Risk Factor;Epigenetic Process;Faculty Recruitment;Fellowship;Flow Cytometry;Foundations;Funding;Genetic;Genomic Instability;Genomics;Health Professional;Healthcare;Immunotherapy;Incidence;Individual;Informatics;Infrastructure;Institution;Intervention;Intervention Studies;Intervention Trial;Investments;Kentucky;Malignant Neoplasms;Mediator of activation protein;Mentors;Metabolic;Metabolism;Methods;Minority;Minority Graduate Student;Mission;Molecular;Mutation;NCI Center for Cancer Research;National Cancer Institute;Natural Products;Obesity;Obesity associated cancer;Outcome;Oxidation-Reduction;Pathology;Patients;Phase;Phenotype;Population;Population Research;Population Sciences;Positioning Attribute;Prevention;Prevention therapy;Preventive;Program Development;Publications;Publishing;Quality of life;Radon;Registries;Research;Research Personnel;Resistance;Resource Sharing;Resources;Risk Factors;Role;SEER Program;Science;Scientist;Screening for cancer;Services;Signal Transduction;Site;Strategic Planning;Target Populations;Therapeutic;Training;Transcend;Translating;Translational Research;Translations;Underserved Population;Universities;anticancer research;authority;base;bench to bedside;biomedical informatics;cancer care;cancer genomics;cancer health disparity;cancer prevention;cancer research center director;cancer site;cancer survival;cancer therapy;career development;clinical development;clinical translation;cohort;college;community based participatory research;cost;drug discovery;genetic epidemiology;health assessment;health disparity;high school;higher education;improved;innovation;instrumentation;inter-institutional;medically underserved;meetings;member;metabolomics;mortality;multidisciplinary;next generation;novel anticancer drug;oncology;outreach;personalized diagnostics;personalized intervention;population health;precision medicine;precision medicine clinical trials;programs;prospective;recruit;repository;response;screening;standard of care;synergism;targeted treatment;treatment response;tumor;tumor metabolism;undergraduate student


application_id: 10000093
project_number: 5R21DE028070-02
administering_ic: NIDCR
award_notice_date: 2020-08-06
opportunity_number: PA-18-489
application_type: 5
activity_code: R21
ic: DE
serial_number: 028070
program_official: HOODBHOY, TANYA
project_start_date: 2019-09-01
project_end_date: 2022-08-31
study_section: Arthritis, Connective Tissue and Skin Study Section[ACTS]
contact_pi_person_id: 10345749
contact_pi: SEIFERT, ASHLEY WINN
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-09-01
project_title:
Characterizing T cell contribution to the injury microenvironment during tissue regeneration in African spiny mouse

project_abstract:
It remains evident that most injuries caused by surgery trauma or disease heal by fibrosis and formation ofscar tissue. Therapy to stimulate regeneration of musculoskeletal tissue in situ would alleviate much of theemotional and economic burden associated with imperfect therapies but mammalian epimorphic regenerationcontinues to be an elusive target. Multiple labs including our own have shown that immune cells are essentialfor regeneration where they orchestrate the injury response. Identifying specific immune cell subpopulationsthat regulate regeneration and how they direct resident cells to polarize the healing response are key areas ofresearch. The long-term goal of our research is to understand the mechanistic basis for mammalianmusculoskeletal regeneration in order to catalyze therapies that inhibit fibrosis and stimulate regenerationwhere it does not naturally occur. The objectives of this proposal are to characterize regulatory T (TREG) cellphenotypes associated with regenerating and scarring microenvironments functionally test the role of TREGcells for regeneration and to test how T cell paracrine factors drive local fibroblast behavior. Our centralhypothesis is that a regeneration-specific population of TREG cells are required for musculoskeletalregeneration. TREG cells represent fundamental dominant-negative immune cells that coordinate inflammation.Despite the importance of TREG cells during the inflammatory response how they contribute to regeneration inmammals remains unknown. Completing Aim 1 will enhance our understanding of whether TREG cells haveregeneration-specific phenotypes through single-cell RNAseq. Additionally it will test the functionalrequirement of these cells for musculoskeletal regeneration by generating a transgenic spiny mouse.Completing Aim 2 will illuminate how secreted T cell factors regulate fibroblast behavior and drive aregenerative phenotype by performing intra- and inter-species co-cultures of isolated T cells and primaryfibroblasts. The rationale for pursuing this work is that these results will provide the necessary foundation foran in-depth interrogation to test how specific T cell interactions and the factors they produce regulate blastemaformation in mammals.

project_terms:
Acomys;Affect;African;Animal Model;Area;Behavior;Cell Communication;Cell Cycle Progression;Cells;Cicatrix;Clinical;Coculture Techniques;Data;Development;Disease;Dominant-Negative Mutation;Ear;Economic Burden;Emotional;Enzyme-Linked Immunosorbent Assay;Extracellular Matrix;FOXP3 gene;Fibroblasts;Fibrosis;Foundations;Future;Gene Transfer Techniques;Genetic;Goals;House mice;Human;Immune;Immune response;Immunotherapy;In Situ;Inflammation;Inflammatory;Inflammatory Response;Injury;Intervention;Investigation;Laboratory mice;Lymphocyte Subtypings;Mammals;Medicine;Menstruation;Modeling;Mus;Musculoskeletal;National Institute of Dental and Craniofacial Research;Natural regeneration;Non-Insulin-Dependent Diabetes Mellitus;Operative Surgical Procedures;Outcome;Pathway interactions;Phenotype;Physiological;Physiology;Population;Pregnancy;Process;Production;Proteomics;Regenerative Medicine;Regulatory T-Lymphocyte;Research;Role;Salamander;Skeletal Muscle;T-Lymphocyte;TCF Transcription Factor;Testing;Tissues;Transgenic Organisms;Trauma;Vision;Work;Zebrafish;blastema;cell regeneration;cell type;craniofacial;diphtheria toxin receptor;external ear auricle;healing;improved;in utero;macrophage;muscle regeneration;novel therapeutic intervention;paracrine;programs;regenerative;repaired;research clinical testing;response;response to injury;single-cell RNA sequencing;time use;tissue regeneration;tissue trauma;transcriptome;wound;wound healing

public_health_relevance:
One of the goals for the NIDCR 2030 vision is to develop clinical interventions that modulate themicroenvironment of an injury to stimulate regeneration by taking advantage of the body's innate regenerativeability. In completing the proposed research we will provide a detailed characterization of what T lymphocytesubtypes an immune cell that coordinates changes in the microenvironment of a wound are unique andnecessary for mammalian regeneration. By comparing the healing process after creating a 4 mm hole in theear pinna of two mammals one that heals by fibrosis followed by formation of a scar (Mus musculus) and onethat endogenously regenerates musculoskeletal tissue (Acomys cahirinus) we will increase our understandingof what factors are necessary to stimulate tissue regeneration in situ and catalyze future therapies.


application_id: 9999611
project_number: 5R01GM121796-04
project_title: Mechanism of adrenal insufficiency as a risk factor for sepsis
administering_ic: NIGMS
award_notice_date: 2020-08-21
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: GM
serial_number: 121796
program_official: ZHAO, XIAOLI
project_start_date: 2017-09-01
project_end_date: 2022-08-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SummarySepsis is a major health issue with a mortality rate of 30%. During periods of septicstress glucocorticoid (GC) production is markedly induced in relation to an increaseddemand. However the function of this inducible GC (iGC) remains poorly understood.Importantly 25-60% of septic patients suffer relative adrenal insufficiency  insufficientiGC production in response to stress. Given the potential complications of adrenalinsufficiency GC therapy is often used for septic shock patients. However the truecontribution of adrenal insufficiency to sepsis and the efficacy of GC therapy are highlycontroversial. While a number of factors contribute to the debate the lack of a relativeadrenal insufficiency animal model has limited our capacity to address these issues.Toward a solution scavenger receptor BI (SR-BI) a well-established high densitylipoprotein (HDL) receptor was first identified in our laboratory as a critical protectivefactor in sepsis. A number of laboratories including ours recently reported that SR-BInull mice fail to produce iGC in response to ACTH stimulation establishing SR-BI nullmice as a relative adrenal insufficiency model. Using this unique model and cecalligation and puncture (CLP)-induced sepsis we demonstrated that mice with relativeadrenal insufficiency are susceptible to CLP-induced septic death and moreimportantly supplementation of GC rescued mice with relative adrenal insufficiency butsurprisingly caused more death in mice without relative adrenal insufficiency. Thesefindings provide a proof of concept that GC therapy may selectively benefits septicpatients with relative adrenal insufficiency. In this application we propose to use ournewly developed adrenal-specific SR-BI null mice as a unique relative adrenalinsufficiency animal model to elucidate the mechanism of relative adrenal insufficiencyas a risk factor for sepsis and to provide mechanistic support for the selective use of GCtherapy in a subgroup of patients with relative adrenal insufficiency. The translation ofthis preclinical study will improve the overall efficacy of sepsis therapy.

project_terms:
Address;Adrenal Cortex;Adrenal Glands;Adrenal gland hypofunction;Animal Model;Binding;Cessation of life;Corticotropin;Data;Effector Cell;Glucocorticoids;Goals;Grant;Health;High Density Lipoprotein Cholesterol;Immune;Individual;Infection;Inflammatory;Inflammatory Response;Knockout Mice;Knowledge;Laboratories;Mediating;Mitogen-Activated Protein Kinases;Modeling;Molecular;Mus;Pathogenesis;Pathway interactions;Patients;Positioning Attribute;Production;Regulation;Reporting;Risk Factors;SR-BI receptor;Sepsis;Septic Shock;Signal Transduction;Stress;Subgroup;Supplementation;TIS11 protein;Testing;Time;Toll-like receptors;Translations;Up-Regulation;base;cecal ligation puncture;clinical translation;cytokine;high density lipoprotein receptor;improved;in vivo;insight;mortality;multidisciplinary;novel;patient subsets;phosphatase-1 kinase;preclinical study;protective factors;response;septic;septic patients;uptake

public_health_relevance:
Project Narrative The goal of this application is to investigate the contribution of relative adrenalinsufficiency to sepsis. We expect that accomplishment of this study will provide novelinsights into the pathogenesis of sepsis and provide evidence to support the selectiveuse of glucocorticoid for septic patients with relative adrenal insufficiency.


application_id: 9998574
project_number: 3R01DC007176-15S1
project_title: Neurotrophin receptor regulation of adult taste bud innervation and function
administering_ic: NIDCD
award_notice_date: 2019-11-07
opportunity_number: PA-18-906
application_type: 3
activity_code: R01
ic: DC
serial_number: 007176
suffix: S1
program_official: SULLIVAN, SUSAN L
project_start_date: 2019-10-01
project_end_date: 2020-09-30
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract Taste receptor cells detect chemicals in our food and communicate this information to thenerve fibers innervating them. Our goal is to understand the structural and functionalrelationship between taste receptor cells and innervating neurons. Because taste receptor cellsundergo continuous renewal and must constantly attract and connect to nerve fibers even in theadult some mechanism exists to control this process. Since the neurotrophin BDNF controlsinitial innervation of taste buds and is present in adult taste receptor cells it may have this role.BDNF also can function as a neuromodulator regulating function so it is certainly possible thatBDNF can regulate both innervation and/or function of adult taste buds. Here we are testing thehypothesis that BDNF signaling through its receptor TrkB regulates both the structural andfunctional connections between taste receptor cells and ganglion neurons. The proposedstudies combine sparse cell genetic labeling with 3-dimensional analysis of the taste bud andelectrophysiology in mice where TrkB-signaling can be blocked using a combination ofchemical and genetic approaches to: 1) determine the identity and connectivity of BDNFexpressing taste receptor cells 2) determine the role of BDNF-TrkB-signaling in maintaining thisconnectivity and 3) determine if BDNF-TrkB signaling regulates taste function. Together theseexperiments will determine how specific taste receptor cells (BDNF-expressing) becomeinnervated by a subset of taste ganglion neurons (TrkB-expressing) during taste cell renewaland will determine if BDNF-TrkB-signaling is an important gustatory system neuromodulator ofthis pathway.

project_terms:
Adult;Agonist;Basic Science;Brain;Brain-Derived Neurotrophic Factor;Cells;Chemicals;Clinical;Disease;Electrophysiology (science);Eye;Fiber;Food;Funding;Ganglia;Genetic;Goals;Health;Individual;Label;Ligands;Mus;Nerve Fibers;Nerve Growth Factor Receptors;Nerve Regeneration;Neuromodulator;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 2;Pathway interactions;Pattern;Persons;Population;Process;Publishing;Quality of life;Random Allocation;Receptor Cell;Regulation;Research;Role;Signal Transduction;Structure;Taste Buds;Taste Disorders;Taste Perception;Testing;Therapeutic;Three-dimensional analysis;Type II Epithelial Receptor Cell;chemical genetics;experience;experimental study;genetic approach;islet;nerve supply;neurotrophic factor;parent grant;receptor;taste system

public_health_relevance:
Project Narrative. Taste disorders can have detrimental effects on a person's health andquality of life. The underlying mechanisms of these disorders are not understood but couldresult from disruption of the connections between taste buds and the neurons carrying tasteinformation to the brain. Here we are looking at the role of neurotrophins in maintaining theseconnections and evaluating the effects of potentially therapeutic neurotrophin agonists andantagonists on taste function with an eye toward basic research applicable to the larger clinicalquestion of nerve regeneration in adulthood.


application_id: 9998492
project_number: 1R01HL152714-01
administering_ic: NHLBI
award_notice_date: 2020-07-16
opportunity_number: PAR-19-274
application_type: 1
activity_code: R01
ic: HL
serial_number: 152714
program_official: CAMPO, REBECCA A
project_start_date: 2020-08-01
project_end_date: 2025-04-30
study_section: Dissemination and Implementation Research in Health Study Section[DIRH]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: SPRING, BONNIE
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-08-01
project_terms:
Accelerometer;Accountability;Address;Adult;Appalachian Region;Behavior;Behavioral;Blood Pressure;Budgets;Cardiovascular Diseases;Cellular Phone;Characteristics;Chronic;Chronic Disease;Clinical;Communities;Consumption;Data;Devices;Diabetes Mellitus;Diet;Effectiveness;Elements;Equipment and supply inventories;Evidence based intervention;Fatty acid glycerol esters;Focus Groups;Foundations;Future;Goals;Health;Hybrids;Influentials;Intake;Internet;Intervention;Interview;Lead;Leisures;Life Style;Lipids;Malignant Neoplasms;Methods;Modality;Monitor;Morbidity - disease rate;Obesity;Outcome;Participant;Physical activity;Population;Process;Public Health;Randomized;Randomized Controlled Trials;Reporting;Research Activity;Resources;Rural;Rural Appalachia;Rural Population;Shapes;Structure;Techniques;Technology;Testing;Time;Training Support;Underserved Population;Unhealthy Diet;Vulnerable Populations;active control;active lifestyle;arm;attentional control;base;behavior change;cardiovascular disorder risk;contextual factors;cost;design;effectiveness evaluation;effectiveness implementation study;effectiveness implementation trial;effectiveness research;effectiveness testing;effectiveness trial;evidence base;experience;financial incentive;fruits and vegetables;good diet;health equity;implementation research;implementation science;improved;informant;information gathering;insight;intervention cost;intervention program;iterative design;knowledge base;low socioeconomic status;mHealth;meetings;mortality;physical inactivity;prevent;primary outcome;programs;rural dwellers;rural underserved;scale up;secondary outcome;sedentary;sedentary lifestyle;smartphone Application;stress management;successful intervention;tool;tv watching;usability;virtual;waist circumference


application_id: 9997972
project_number: 5R01GM126181-04
project_title: Chronic muscle weakness in sepsis survivors
administering_ic: NIGMS
award_notice_date: 2020-08-13
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: GM
serial_number: 126181
program_official: ZHAO, XIAOLI
project_start_date: 2017-09-15
project_end_date: 2022-08-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8163817
contact_pi: SAITO, HIROSHI
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe objective of this project is to identify sub-cellular and molecular mechanisms of skeletal muscledysfunction that are responsible for chronic weakness in sepsis survivors. Using the knowledge obtained thisproject will elucidate potential therapeutic interventions targeting post-sepsis chronic muscle weakness. Over 1million sepsis survivors are now discharged from the hospital every year and a majority of these survivorsreport reduced quality of life due to considerable muscle weakness lasting for years after hospital discharge.However the lack of an appropriate animal model has been a critical barrier to identifying the changes whichpersist long after recovery from sepsis. We recently developed a new mouse model that has enabled us toevaluate long-term muscle quality and function in severe sepsis survivors. Our preliminary studies demonstratethat sepsis-surviving mice exhibit significant skeletal muscle weakness even after bacterial infection andinflammation are resolved and muscle mass is recovered giving us the unique opportunity to evaluatemolecular mechanisms of muscle weakness beyond the muscle wasting phenotype. Skeletal muscles fromthese sepsis-surviving mice also show histological abnormalities significant nitro-oxidative damage andprofound structural and functional defects in mitochondria. These preliminary results support our centralhypothesis that sepsis-induced oxidative damage causes mitochondrial dysfunction and sarcomeric proteindamage both of which remain long after sepsis recovery and these are the major contributors to the sustainedskeletal muscle weakness in sepsis survivors. Specific Aims to test the hypothesis are: (1) To determinemitochondrial damage and dysfunction in sepsis-surviving mice; (2) To investigate sarcomeric protein damageand its causal mechanisms in sepsis-surviving mice; and (3) To formulate therapeutic strategies to amelioratepost-sepsis chronic muscle weakness.

project_terms:
Acute;Animal Model;Antibiotics;Antioxidants;Atrophic;Bacterial Infections;Chronic;Defect;Development;Electron Microscopy;Exhibits;Functional disorder;Goals;Histologic;Hospitals;Incidence;Individual;Infection;Inflammation;Innate Immune Response;Kinetics;Knowledge;Life;Life Style;Liquid substance;Mitochondria;Mitochondrial Proteins;Modeling;Molecular;Multienzyme Complexes;Mus;Muscle;Muscle Proteins;Muscle Weakness;Muscular Atrophy;Mutant Strains Mice;Oxidative Stress;Oxygen Consumption;Pathology;Patients;Phase;Phenotype;Proteins;Protocols documentation;Public Health;Quality of life;Recovery;Reporting;Resuscitation;SOD2 gene;Sepsis;Skeletal Muscle;Structure;Survivors;Testing;Therapeutic;Therapeutic Intervention;Transgenic Mice;aggressive therapy;clinically relevant;effective therapy;mitochondrial dysfunction;mortality;mouse model;muscle form;novel therapeutics;oxidative damage;septic patients;skeletal muscle weakness

public_health_relevance:
PROJECT NARRATIVEThis project is relevant to public health because it will enhance our understanding of the mechanisms for post-sepsis chronic muscle weakness and allow us to elucidate a novel therapeutic strategy which would helpsepsis patients to return to a more productive and fulfilling lifestyle.


application_id: 9997469
project_number: 3R01GM107586-05S1
project_title: Light-responsive ruthenium compounds for applications in disease
administering_ic: NIGMS
award_notice_date: 2019-09-06
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: GM
serial_number: 107586
suffix: S1
program_official: FABIAN, MILES
project_start_date: 2014-08-01
project_end_date: 2021-07-31
contact_pi_person_id: 8085279
contact_pi: GLAZER, EDITH C
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryThis proposal seeks to develop a new class of light-responsive inorganic materials as chemotherapeuticagents. Cisplatin and its analogues remain the standard therapy for a variety of cancers despite theirnonspecific mechanism of action with nucleic acids resulting in general cytotoxicity and debilitating side-effects. A promising approach that will provide several key advantages is to combine the reactivity of metal-based drugs with the selectivity of photodynamic therapy (PDT) to increase the targeting of malignanttissues and reducing side-effects. We have recently shown that structural distortion can be utilized topromote photochemical reactions to create reactive ruthenium species that are strongly electrophilic andhighly photo-toxic in cell based assays. We hypothesize that distortion can be used to control light-activatedcytotoxicity for the creation of selective and potent chemotherapeutics. We propose a new class ofruthenium-based compounds that have a readily modifiable modular design to facilitate rapidly incorporationof key molecular components to efficiently develop materials exhibiting selectivity and controlled reactivity.Coordination chemistry will be used to generate a structurally diverse family of three-dimensional chiralruthenium compounds in a self-assembled manner. The structural variations in the materials will becorrelated to cytotoxic efficacy using high-throughput cell survival assays and the most promisingcompounds will be assessed for Pharmacokinetic (PK) properties Maximum Tolerated Dose (MTD) andefficacy in mouse xenograft models of lung cancer and melanoma. Mechanism of action studies will beused to define the currently unknown process of cell killing. In order to accomplish this aim a novelchemical labeling strategy is proposed to facilitate imaging of the subcellular and potentially sub-organellarlocalization of active compounds using Electron Microscopy. If successfully validated this approach couldbe extended to additional imaging applications in tissues. Alternative approaches utilize biotin-labeledruthenium materials for target pull-down with cellular targets identified through a process of gelelectrophoresis chromatography and mass spectrometry. In vitro and in cell transcription and translationassays will support these findings. Cisplatin the benchmark inorganic chemotherapeutic will be used forcomparison in all mechanism of action studies. The goal is to determine if the proposed ruthenium materialsutilize the same biological target(s) as cisplatin or may be directed to different functional targets viastructural modification. Upon completion of these studies we will have expanded our knowledge of thefundamental photochemistry of ruthenium complexes developed potent and selective cytotoxic chemicalentities identified their mechanism of action and developed a new tool for the imaging of small moleculesin biological systems.1

project_terms:
3-Dimensional;Administrative Supplement;Antineoplastic Agents;Apoptotic;Benchmarking;Biological;Biological Assay;Biotin;Cancer cell line;Cell Line;Cell Survival;Cell physiology;Cells;Cessation of life;Chemicals;Chemistry;Chromatography;Cisplatin;Complex;Confocal Microscopy;Cytology;Development;Dimensions;Disease;Drug Kinetics;Electron Microscopy;Evaluation;Exhibits;Family;Formulation;Generations;Genetic Transcription;Goals;Grant;Hypoxia;Image;Imaging Device;In Vitro;Knowledge;Label;Lead;Ligands;Light;Lysosomes;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Maximum Tolerated Dose;Metals;Methods;Mitochondria;Modeling;Modification;Molecular;Mus;Necrosis;Neutropenia;Nucleic Acids;Optics;PUVA Photochemotherapy;Pattern;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phenotype;Photochemistry;Phototoxicity;Process;Prodrugs;Property;Reaction;Reducing Agents;Reporter;Resistance profile;Resolution;Ruthenium;Ruthenium Compounds;Singlet Oxygen;Structure;System;Testing;Therapeutic;Tissues;Toxic effect;Translating;United States;Variant;Work;Xenograft Model;adduct;analog;base;biological systems;cancer cell;cancer therapy;cancer type;cell killing;cell type;cellular targeting;chemotherapeutic agent;cytotoxic;cytotoxicity;design;fluorophore;gel electrophoresis;improved;in vivo;indexing;melanoma;metal complex;novel;oxidative damage;peroxisome;preclinical trial;protein biomarkers;screening;side effect;small molecule;translation assay;tumor

public_health_relevance:
Project NarrativeCisplatin received FDA approval in 1978 for the treatment of cancer and despite producing a widerange of debilitating side-effects it is still one of the most prescribed chemotherapeutics today. Withover 500000 cancer-related deaths in the United States each year it is essential to develop newbroadly applicable therapeutic treatments for this disease. This proposal develops ruthenium materialsas selective and potent chemotherapeutic agents that reduce off target toxic effects by acting ascytotoxic species only in a spatially controlled manner when turned on by light.


application_id: 9997414
project_number: 4UH3CA233282-02
project_title: (ACCSIS) Accelerating Colorectal Cancer Screening through Implementation Science in Appalachia
administering_ic: NCI
award_notice_date: 2019-09-16
opportunity_number: RFA-CA-17-038
application_type: 4
activity_code: UH3
ic: CA
serial_number: 233282
project_start_date: 2018-09-19
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZRG1-AARR-N(52)R]
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: PASKETT, ELECTRA D.
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-09-01
project_abstract:
Accelerating Colorectal Cancer Screening through Implementation Science in AppalachiaThis multi-site project aims to increase screening and follow-up for colorectal cancer (CRC) in central Appalachiaa medically underserved region recognized as one of three distinct hotspots for CRC mortality. Specifically theAppalachian Regional Commission classifies 32 eastern Ohio (OH) counties and the 54 counties in easternKentucky (KY) as north central and central Appalachia respectively. CRC incidence and mortality rates in thearea are among the highest in the nation and neither state meets the national target of 80% of eligible residentsscreened for CRC. There have been few randomized intervention trials addressing multiple levels of influenceon CRC screening behaviors and outcomes in this region. To address this gap investigators at the University ofKentucky and The Ohio State University will build on a 12-year collaborative history strong relationships withAppalachian communities and health clinics and extensive experience with community-based cancer preventionand control intervention research to develop implement and evaluate a multilevel intervention (MLI)  adaptedfrom evidence-based interventions that include components targeting clinics and providers (in-reach) and thecommunity (outreach)  to increase CRC screening follow-up and referral-to-care among patients age 50-74 in12 counties in Appalachian KY and OH. The overall goals of this project are to contribute to the evidence-basefor a MLI that increases rates of CRC screening follow-up and referral-to-care particularly in rural medicallyunderserved populations and help showcase best practices for how MLIs can be scaled-up to reduce the burdenof CRC in the U.S. For the Planning-Exploratory Phase (UG3) in Year 1 our specific aims are to: 1) Pilot testmeasure and refine a MLI to increase rates of CRC screening follow-up and referral-to-care in Appalachian OHand Appalachian KY; and 2) Provide evidence supporting transition to the Implementation Phase (UH3) [per NCIapproval]. For the Implementation Phase (UH4) in Years 2-5 our specific aims are to: 1) Test the revised MLIin a group randomized trial delayed intervention to assess the impact of the MLI on increasing rates of CRCscreening follow-up and referral-to-care among Appalachian KY and Appalachian OH populations; and 2)Assess dissemination and sustainability of the intervention. The project will be implemented in collaboration withcommunity and clinical partners in 12 counties 6 in Ohio and 6 in Kentucky. Counties will be randomized toearly or delayed intervention after baseline data collection. The main outcome will be CRC screening as definedby US Preventive Services Task Force guidelines and measured by clinic electronic health records and county-level behavioral assessments using random digit dialed telephone surveys similar to CDCs Behavioral RiskFactor Surveillance System. Our work will be accomplished through collaboration with the ACCSIS CoordinatingCenter other ACCSIS Research Projects ACCSIS Steering Committee and Workgroups NCI and communitypartners. If effective this MLI will be disseminated to our clinical and community partners throughout Appalachia.

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

public_health_relevance:
This project will implement and evaluate community and clinical interventions designed to reduce the burden ofcolorectal cancer in Appalachian regions of Ohio and Kentucky. The first year of the project will develop andrefine the interventions to be implemented and tested in the next 4 years. Results will showcase best practicesfor how multilevel interventions can be scaled-up to reduce the burden of colorectal cancer in the U.S.


application_id: 9996143
project_number: 1R01AA028435-01
administering_ic: NIAAA
award_notice_date: 2020-07-22
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: AA
serial_number: 028435
program_official: OROSZ, ANDRAS
project_start_date: 2020-08-01
project_end_date: 2025-07-31
study_section: Special Emphasis Panel[ZRG1 IFCN-C (02)]
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-08-01
project_terms:
Address;Affect;Alcohols;CRISPR/Cas technology;CXCL12 gene;CXCR4 gene;Cells;Cephalic;Congenital Abnormality;Cranial Nerves;Craniofacial Abnormalities;Data;Defect;Distant;Edible Plants;Embryo;Ethanol;Fetal Alcohol Spectrum Disorder;Grapes;Human;In Vitro;Knowledge;Laboratories;Life;Mediating;Mental Retardation;MicroRNAs;Mission;Modeling;Molecular;National Institute on Alcohol Abuse and Alcoholism;Neural Crest Cell;Pathogenesis;Plants;Prevention;Prevention strategy;Preventive Intervention;Public Health;Regulation;Repression;Research;Role;Signal Transduction;Site;Skeleton;Testing;Therapeutic;Therapeutic Intervention;Work;Zebrafish;alcohol effect;alcohol exposure;base;craniofacial;exosome;fetal;in vivo;innovation;insight;intercellular communication;migration;nanoparticle;novel;novel strategies;novel therapeutics;prevent;public health relevance;sensory system;teratogenesis;transcriptome sequencing


application_id: 9995372
project_number: 5F31AI147417-02
administering_ic: NIAID
award_notice_date: 2020-07-01
opportunity_number: PA-18-671
application_type: 5
activity_code: F31
ic: AI
serial_number: 147417
program_official: VINCENT, LEAH REBECCA
project_start_date: 2019-08-09
project_end_date: 2022-08-08
study_section: Special Emphasis Panel[ZRG1-F13-Z(20)L]
contact_pi_person_id: 15691582
contact_pi: KEB, GABRIELLE
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-08-09
project_title:
Chlamydia trachomatis Secreted Effector Proteins: Infection Properties and Identification of Host Targets

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

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

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


application_id: 9994413
project_number: 5R01NS107548-03
administering_ic: NINDS
award_notice_date: 2020-07-29
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 107548
program_official: FOUNTAIN, JANE W
project_start_date: 2018-08-15
project_end_date: 2023-07-31
study_section: Special Emphasis Panel[ZRG1-MDCN-M(91)S]
contact_pi_person_id: 9358186
contact_pi: BAUER, BJOERN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-08-01
project_title:
A novel strategy to overcome the P-gp/BCRP drug efflux system at the blood-brain barrier to improve brain uptake of CNS therapeutics

project_abstract:
Failure of anticancer drug treatment is largely due to overexpression of the P-gp/BCRP drug efflux system atthe blood-brain barrier. New evidence suggests that glioblastoma multiforme (GBM) induces P-gp/BCRP over-expression in capillaries of the brain hemisphere that is contralateral to the tumor. Thus after surgical removalof the primary tumor remnant tumor cells that are scattered throughout the brain remain shielded from anti-cancer drugs. This poses a significant clinical problem and represents an unmet critical need to develop strat-egies to overcome P-gp/BCRP. The absence of such strategies will likely prevent improvements in GBM ther-apy. The long-term goal of the investigator is to identify molecular mechanisms that control blood-brain barrierfunction and can be targeted to improve brain uptake of anticancer drugs. The overall objective of this applica-tion is to develop an effective therapeutic strategy to overcome P-gp/BCRP-mediated anticancer drug effluxand prolong survival in mice with GBM. Based on preliminary data the central hypothesis is that GBM inducesP-gp/BCRP overexpression and that inhibiting PI3K/Akt will decrease P-gp/BCRP overexpression which willincrease brain uptake of anticancer drugs thereby reducing tumor size and prolonging GBM mouse survival.The rationale for this research is that its successful completion is expected to provide a solid evidence-basedscientific framework for translating our strategy into the clinic. Based on strong preliminary data this hypothesiswill be tested by pursuing three specific aims: 1) Determine the mechanism(s) by which GBM inducesP-gp/BCRP overexpression; 2) Identify pathways that regulate P-gp/BCRP at the human blood-brain barrier;and 3) Develop a therapeutic strategy to increase anticancer drug brain uptake in GBM mice. Under the firstaim mechanistic steps involved in GBM-induced overexpression of P-gp/BCRP will be assessed in brain capil-laries of the hemisphere contralateral to the primary tumor. The impact of blocking these steps on brain uptakeof anticancer drugs in GBM-bearing mice will be determined. Under the second aim P-gp/BCRP regulation bythe PTEN/PI3K/Akt/mTOR pathway will be determined in brain capillaries from normal individuals and fromGBM patients. Under the third aim the therapeutic benefit of combining PI3K/Akt inhibitors with anticancerdrugs to reduce P-gp/BCRP levels with the goal of improving brain uptake of anticancer drugs and prolongingsurvival will be assessed in three different GBM models. The proposed research is innovative in the appli-cant's opinion because it represents a new and substantive departure from the status quo by shifting the focusto GBM-induced overexpression of blood-brain barrier P-gp/BCRP in the contralateral hemisphere and by uti-lizing a molecular switch-based approach to overcome P-gp/BCRP-mediated drug efflux to target remnant tu-mor cells distant from the primary tumor. The proposed research is significant because it is expected that thenew knowledge may have broad translational importance in the treatment of patients with GBM and potentiallyother brain tumors as well.

project_terms:
ABCG2 gene;AKT inhibition;Antineoplastic Agents;Blood - brain barrier anatomy;Blood capillaries;Brain;Brain Neoplasms;Cells;Cerebral hemisphere;Clinic;Clinical;Contralateral;Data;Development;Distant;Drug Efflux;Excision;FRAP1 gene;Failure;Glioblastoma;Goals;Human;Individual;Ipsilateral;Knowledge;Lateral;Lead;Mediating;Mission;Modeling;Molecular;Mus;National Institute of Neurological Disorders and Stroke;Natural regeneration;Outcome;P-Glycoprotein;PTEN gene;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacotherapy;Primary Neoplasm;Public Health;Regulation;Research;Research Personnel;Signal Transduction;Solid;System;TNF gene;TNFRSF1A gene;Testing;Therapeutic;Translating;Treatment Efficacy;Treatment outcome;United States National Institutes of Health;Work;base;blood-brain barrier function;cerebral capillary;effective therapy;evidence base;expectation;improved;in vivo;inhibitor/antagonist;innovation;lapatinib;neoplastic cell;nervous system disorder;novel;novel strategies;overexpression;prevent;treatment strategy;tumor;uptake

public_health_relevance:
The proposed research is relevant to public health because it is expected to provide a novel treatment strategyto overcome blood-brain barrier drug efflux for improved delivery of therapeutics into the brain specificallyanticancer drugs. Thus the proposed research is relevant to the mission of the NIH/NINDS that pertains todeveloping fundamental knowledge that will help reduce the burden of neurological disease.


application_id: 9991932
project_number: 5UH3NS100606-05
project_title: Small vessel disease biomarkers in a longitudinally-followed "stroke-belt" cohort
administering_ic: NINDS
award_notice_date: 2020-08-18
opportunity_number: RFA-NS-16-020
application_type: 5
activity_code: UH3
ic: NS
serial_number: 100606
program_official: MCGAVERN, LINDA
project_start_date: 2016-09-30
project_end_date: 2022-02-28
study_section: ZNS1-SRB-T(19)
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: JICHA, GREGORY A
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract Vascular contributions to cognitive impairment and dementia (VCID) describes cognitive impairmentresulting from cerebrovascular disease or dysfunction. VCID is a frequent co-morbidity with Alzheimer'sdisease (AD) as well as a single dementia-causing entity. The most common vasculopathy associated withcognitive impairment is cerebral small vessel disease (SVD). It is highly likely that SVD significantly contributesto the clinical manifestation of dementia and therefore is a viable target for disease-modifying therapieswhether alone or in combination with AD-targeting therapies. One major obstacle for therapeutic developmentis the lack of biomarkers that are predictive of the presence and course of SVD-VCID. In this proposal wepresent candidate biomarkers for SV-VCID that will contribute to the consortium. We have identified MRI imaging modalities of 3D FLAIR ASL and DTI as our imaging candidatebiomarkers. We have also identified IL-12 p70 TNF PIGF and VEGFD as our candidate fluid biomarkers thatdiscriminate SVD well in the subset of our cohort that we have analyzed. In this application we have a plan fordeveloping our candidate biomarkers and validating them through the UH2 phase an individual research groupand also through the UH3 part as a member of the consortium. In addition we bring significant strengths thatwill help synergize and move the consortium as a whole forward in our collective goal of developing biomarkersthat are ready for large scale clinical trials and FDA qualification in years 6-7 of the consortium. Thesestrengths include a well characterized longitudinal cohort supported through our ADC and other NIH initiativesour long history of active participation in consortia providing the experience and infrastructure needed toensure success in this UH2/UH3 mechanism our history of data sharing resource sharing including samplesrecruitment of research participants for longitudinal studies and our foundation in basic and translationalscience.

project_terms:
3-Dimensional;ABCC9 gene;Address;Affect;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimers disease biomarker;Amyloid beta-Protein;Angiogenic Proteins;Applications Grants;Basic Science;Biological Markers;Biometry;Brain;Brain Pathology;Cerebral small vessel disease;Cerebrovascular Disorders;Cerebrum;Clinical;Clinical Trials;Cognition;Data;Dementia;Diagnosis;Diffusion;Disease;Disease Progression;Elderly;Ensure;Foundations;Genetic Polymorphism;Genotype;Goals;Image;Impaired cognition;Individual;Inflammatory;Infrastructure;Injury;Interleukin-12;Kentucky;Liquid substance;Longitudinal Studies;Longitudinal cohort;Magnetic Resonance Imaging;Measures;Microvascular Dysfunction;Monitor;Neurofilament-M;Neuropsychology;Participant;Patients;Perfusion;Phase;Plasma;Population;Process;Proteins;Public Health;Recording of previous events;Research;Research Personnel;Resource Sharing;Risk;Sampling;Severities;Spatial Distribution;Spin Labels;Stroke Belt;Subcategory;TNF gene;Therapeutic Intervention;Time;Translational Research;United States National Institutes of Health;Universities;Vascular Diseases;White Matter Hyperintensity;Work;accurate diagnosis;biomarker development;candidate marker;cerebrovascular pathology;cohort;comorbidity;data sharing networks;effective intervention;experience;imaging biomarker;imaging modality;ischemic injury;medical specialties;member;multidisciplinary;pre-clinical;predictive marker;prognostic value;recruit;response;success;targeted treatment;tau Proteins;therapeutic development;vascular cognitive impairment and dementia;vascular contributions

public_health_relevance:
Project Narrative Vascular cognitive impairment and dementia (VCID) is second only to Alzheimer's disease (AD) as aleading cause of dementia in Western populations. In addition VCID is a frequent co-morbidity with ADcomplicating the diagnosis and treatment of AD for an important proportion of patients. One major obstacle forthe advancement of VCID studies is accurate diagnosis at a preclinical state or at a time early in the diseaseprocess to allow for effective intervention. We have identified candidate biomarkers that we propose to validateas part of a consortium to establish biomarkers for VCID.


application_id: 9991215
project_number: 1F32AA027950-01A1
project_title: RvD1-FPR2 signaling ameliorates alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2020-04-07
opportunity_number: PA-19-188
application_type: 1
activity_code: F32
ic: AA
serial_number: 027950
suffix: A1
program_official: LIN, LI
project_start_date: 2020-05-01
project_end_date: 2022-11-30
study_section: Special Emphasis Panel[ZAA1 GG (32)]
contact_pi_person_id: 14169641
contact_pi: HARDESTY, JOSIAH E
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Alcoholic hepatitis (AH) is a morbid condition with poor prognosis that is primarily driven by alteredimmune cell function in response to endotoxemia but the mechanisms are not fully known orunderstood. Resolvin D1 (RvD1) is a pro-resolution lipid mediator that signals through formylpeptide receptor 2 (FPR2) in mice eliciting M2 polarization in macrophages and antibacterialfunctions in neutrophils. Plasma RvD1 levels and hepatic FPR2 expression are decreased in AHpatients suggesting this pathway is impeded in AH. Animal models suggest RvD1 treatmentameliorates alcohol induced liver injury inflammation fibrosis and endotoxemia while Fpr2-/- micedevelop exacerbated liver injury inflammation fibrosis and endotoxemia. Studies characterizingthe RvD1-FPR2 signaling pathway in alcoholic liver disease (ALD) are nonexistent but arewarranted based on preliminary data. Aim 1: This aim will determine if RvD1 acts solely throughFPR2 to elicit protection in an animal of alcoholic liver disease (ALD). Aim 2: Aim 2a will determineif the RvD1-FPR2 signaling pathway is essential for M2 polarization of Kupffer cells. Aim 2b willestablish if RvD1-FPR2 signaling is required for neutrophil-mediated defense responses againstpathogenic threats. Aim 3: AH patient and healthy control acquired neutrophils and monocyteswill be treated with or without RvD1 ex vivo followed by flow cytometry and proteomic andphosphoproteomic analysis to measure receptor activation and to characterize the signalingpathway respectively. Collectively this study will generate data that could identify RvD1 or FPR2agonists as a therapeutic approach for ALD. Due to the severity of AH and the analysis of AHpatient samples this study it is immediately impactful and informative for future treatmentstrategies. Novel biomarkers and therapeutic interventions are expected to come from theconclusion of the proposed study. Basic biology of the RvD1-FPR2 signaling pathway inneutrophils and monocytes is expected from this work as well.

project_terms:
Aftercare;Agonist;Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic steatohepatitis;Alcohols;Animal Model;Animals;Anti-Bacterial Agents;Bacteria;Biology;Cell Extracts;Cell physiology;Cells;Cessation of life;Chronic;Cirrhosis;Data;Disease model;Dopamine D1 Receptor;Endotoxemia;Ethanol;Exposure to;FPR2 gene;Fatty Liver;Fibrosis;Flow Cytometry;Future;Genes;Hepatic;Histologic;Human;Immune;Immune response;Immunology;Infection;Inflammation;Inflammatory Response;Kupffer Cells;Label;Lead;Ligands;Liver;Liver diseases;Measures;Mediating;Modeling;Morbidity - disease rate;Mus;Pathogenesis;Pathogenicity;Pathology;Pathway interactions;Patients;Phagocytes;Phagocytosis;Plasma;Play;Population;Proteomics;Receptor Activation;Receptor Cell;Regimen;Resolution;Respiratory Burst;Role;Sampling;Sampling Studies;Serum;Severities;Signal Pathway;Signal Transduction;Stimulus;Therapeutic;Tissues;Work;alcohol exposure;antimicrobial;base;chronic liver disease;cytokine;defense response;feeding;healthy volunteer;lipid mediator;liver inflammation;liver injury;macrophage;monocyte;mortality;neutrophil;novel marker;novel therapeutic intervention;outcome forecast;phosphoproteomics;prevent;response;standard care;treatment strategy

public_health_relevance:
Project Narrative: Findings from this study will demonstrate whether enhanced RvD1-FPR2signaling is a therapeutic option for alcoholic liver disease. These results will immediately impactthe treatment strategies for alcoholic hepatitis patients who have high mortality rates under thecurrent standard care. Advancements in the field of immunology and host-bacteria interactionsand the RvD1-FPR2 signaling pathway are expected from this work as well.


application_id: 9990527
project_number: 5R01AI140195-03
project_title: Innate immunity and inflammatory response of macrophages to Legionella infection
administering_ic: NIAID
award_notice_date: 2020-08-14
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AI
serial_number: 140195
program_official: ERNST, NANCY L
project_start_date: 2018-09-14
project_end_date: 2023-08-31
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryDepending on the signals in vitro macrophages can undergo transient and reversible differentiationinto two main subsets: pro-inflammatory M1 (classically activated) or anti-inflammatory M2(alternatively activated) phenotype. Upon exposure of macrophages to high levels of glucose in vitroor in diabetic patients in vivo they undergo differentiation and activation into a M1 pro-inflammatorystate which produces pro-inflammatory cytokines mediated by cellular reprogramming of metabolismthrough upregulating aerobic glycolysis. The M1 pro-inflammatory differentiation of macrophages isan import arm of the innate immune response to control bacterial infections. Our preliminary datashow that when macrophages engulf the intracellular bacterial pathogen Legionella pneumophila(Lp) they rapidly respond by differentiation into an activated M1-like pro-inflammatory phenotype.Despite this rapid macrophage pro-inflammatory activation the Legionella-containing vacuole(LCV) bypasses macrophage activation by limiting its fusion to lysosomes. We show that the earlyM1-like pro-inflammatory differentiation of human monocytes-derived macrophages (hMDMs) toLp is an innate immune response to cytosolic hyper-glucose generated through rapid degradation ofglycogen by the injected Legionella amylase (LamA) effector. We discovered that Lp has evolved alysosomal degradation bypass pathway within the pro-inflammatory hMDMs by injecting the MavEeffector which becomes localized in a micro-domain on the cytosolic side of the LCV membrane.The mavE-deficient mutant is targeted by hMDMs to the lysosomes for degradation and the mutantis totally attenuated in vitro and in vivo. We have resolved the novel three dimensional crystal structureof MavE which shows a cytosolic surface-exposed domain with an NPxY eukaryotic motif involvedin binding to phosphotyrosine-binding adaptor proteins. Our central hypothesis is: the M1-like pro-inflammatory activation of hMDMs to Lp infection is an innate immune response to the cytosolichyper-glucose elicited by LamA and the pathogen utilizes MavE to bypass the innate immunemacrophage pathway of lysosomal degradation. To test the hypothesis our specific aims are:Specific Aim I: The mechanisms of M1-like pro-inflammatory differentiation of hMDMs inresponse to the effect of LamA; and Specific Aim II: The mechanisms of evasion of the innatemacrophage function of lysosomal degradation through utilization of a lysosomes bypasspathway mediated by MavE. Upon completion of our proposed studies we will discover themechanism of the innate pro-inflammatory response of macrophages to Lp and the lysosomaldegradation bypass pathway maneuvered by the pathogen to avoid a fatal fate.

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

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


application_id: 9989830
project_number: 5K01DK114391-05
administering_ic: NIDDK
award_notice_date: 2020-07-13
opportunity_number: PAR-16-211
application_type: 5
activity_code: K01
ic: DK
serial_number: 114391
program_official: SASLOWSKY, DAVID E
project_start_date: 2017-08-01
project_end_date: 2022-05-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 12197847
contact_pi: ALAM, M. ASHFAQUL
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-08-01
project_title:
Microbially generated protons mediate interkingdom host-microbiome cross-talk and maintain intestinal homeostasis via reciprocal functions of two proton-sensing GPCRs

project_abstract:
Project Summary: Intestinal damage is observed in inflammatory bowel disease (IBD) entericinfectionsaswellasfollowingsurgicaltraumaandenvironmentalinsults.Tissuerestitutionisacomplexbutcoordinated cellular process to repair gut mucosa. We recently reported that the intestinal woundmicroenvironment specifically enriches a mucosa-associated microbial consortium which enhanced epithelialwoundhealing.Theadvancesinnextgenerationgenesequencinghaveidentifieddiversemicrobialspeciesandmetagenomesinthehost;howevertounderstandandexploitthepotentialofthemicrobiotas>8milliongenesandtheirmetabolicfunctionsapplicationofthemass-spectrometry-basedidentificationofsmallmetabolitesandfunctional characterization by the methods of cell biology are crucial. Hence this proposed study will lay afoundationformyrigoroustraininginmetabolomeandcellbiologyofgutbarrierfunction.Forthispurposeweperformedapreliminaryanalysisbymassspectrometry-basedglobalmetabolomicprofilingofintactandinjuredmucosa as well as colon of germ-free and conventional mice. We found an elevated synthesis of microbialmetaboliteswithlowpKawhichareessentialinestablishinganextracellularpHgradientinthecoloniccryptsoftheconventionalmicebutnotingermfreemice.Wealsofoundthatthecolonicepithelialcellsofconventionalmiceexpressincreasedlevelsofproton-sensingGPCRs(GPCR4andGPCR68).Basedonpreliminaryfindingstheworkinghypothesesofthisprojectare:1)theinjuredmucosaltissueanditsassociatedmicrobiotaproducemetabolitestoregulatespatiotemporalchangesintheprotonconcentrationofthecolonandtherebyregulateintestinalhomeostasisandrepair2)microbiota-producedmetabolitesmodulateprotonconcentrationwhichisperceivedbytheproton-sensingGPCRsofenterocytestoregulategutpermeability.Aim1istoconfirmtheroleofmicrobiota-producedmetabolitesinregulatingcellularproliferation&repairviaproton-sensingGPCR4andGPCR68intheGPCR4-/-andGPCR68-/-micewhosecoloniesareestablishedinouranimalfacility.Wewillalsoperform the metabolomic profiling and RNA-seq analysis of the colon of GPCR4-/- and GPCR68-/- mice.Furthermorewewilldeterminethemetabolomeoftheinjuredmucosainthegerm-freemouse.SpecificAim2willdeterminethefunctionoftheprotongradient&alsotheroleofspecificmetabolitesintheregulationofgutpermeability by tight-junction. Emory University boasts an intellectually rich research environment whoseresourceswillbeusedtocarryouttheproposedresearchaswellasthemas-spectrometrycenterlocatedacrossthetowninGeorgiaInstituteofTechnologyAtlanta.Theproposedresearchincombinationwithastructuredteam of mentor advisors and collaborators as well as the training plan that includes didactic courses andworkshopsisdesignedtofacilitatemylong-termgoalofdevelopinganindependently-fundedresearchprograminchronicgastrointestinalinflammatorydiseasessuchasIBDconsistentwiththemissionoftheNIDDK.

project_terms:
Affect;Animals;Biology;Biopsy;Cell Proliferation;Cell physiology;Cells;Cellular biology;Chronic;Colon;Complex;Development;Diabetes Mellitus;Disease;Distal;Educational workshop;Endoscopy;Enterocytes;Environment;Epithelial;Epithelial Cell Proliferation;Epithelial Cells;Epithelium;Event;Forcep;Foundations;Funding;G-Protein-Coupled Receptors;Genes;Germ-Free;Goals;Grant;Gut Mucosa;Health;Homeostasis;Immune system;In Vitro;Inflammatory;Inflammatory Bowel Diseases;Institutes;Intestinal Mucosa;Intestinal permeability;Intestines;Knowledge;Liquid substance;Liver diseases;Maintenance;Mass Spectrum Analysis;Measures;Mediating;Mediator of activation protein;Mentors;Mentorship;Metabolic;Methods;Mission;Mucous Membrane;Mus;National Institute of Diabetes and Digestive and Kidney Diseases;Natural regeneration;Obesity;Operative Surgical Procedures;Performance;Permeability;Process;Proteins;Protons;Regulation;Reporting;Research;Resources;Role;Scientist;Spectrometry;Structure;Technology;Testing;Tight Junctions;Tissues;Training;Trauma;Universities;animal facility;base;career development;cell motility;claudin 4;colonic crypt;design;differential expression;enteric infection;epithelial wound;evidence base;extracellular;gastrointestinal;gastrointestinal epithelium;gut microbiota;host microbiome;host-microbe interactions;immune activation;injured;injury and repair;intestinal homeostasis;metabolome;metabolomics;metagenome;microbial;microbial community;microbial host;microbiome;microbiota;next generation;novel;pH gradient;programs;receptor;repaired;restoration;small molecule;spatiotemporal;transcriptome sequencing;wound;wound closure;wound healing

public_health_relevance:
ProjectNarrativeImportance of extracellular proton concentration is critical in intestinal mucosa during health and disease.Howeverthereisnoevidence-basedknowledgehowextracellularpHofthemucosalmicroenvironmentregulateintestinalrepairandrestorationofhomeostasis.Leveragingthemetabolomicstudiesthisprojectisdesignedtoinvestigate two proton-sensing G-protein coupled receptors and their role in microbial metabolite-drivenextracellularpHgradientduringmucosalhomeostasisandrepair.


application_id: 9989779
project_number: 5R01AI137324-03
project_title: Immunomodulatory mechanisms of E-FABP in psoriasis pathogenesis
administering_ic: NIAID
award_notice_date: 2020-08-14
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AI
serial_number: 137324
program_official: ROTHERMEL, ANNETTE L
project_start_date: 2018-09-24
project_end_date: 2021-08-31
study_section: Arthritis, Connective Tissue and Skin Study Section[ACTS]
contact_pi_person_id: 9620088
contact_pi: LI, BING
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SummaryPsoriasis is the most prevalent and intractable immune-mediated chronic inflammatory skin disease. It is clearthat dendritic cells (DCs) and keratinocytes in the skin tissues play a central role in the pathogenesis ofpsoriasis. The objectives of this proposal are to determine the role of epidermal fatty acid binding protein (E-FABP) in promoting psoriasis pathogenesis through simultaneously targeting both DCs and keratinocytes andin linking obesity-associated psoriasis development. E-FABP first cloned in psoriatic skin tissues (also knownas psoriasis associated FABP) has been identified as a critical regulator of both metabolic and inflammatorypathways. Our preliminary studies demonstrate that E-FABP is greatly upregulated in the skin tissue frompatients with psoriasis. Intriguingly deficiency of E-FABP confers protection from imiquimod (IMQ) or IL-23-induced psoriasis-like inflammation in mouse models. While obesity is associated with increased severity ofpsoriasis and poor responses to therapy the underlying mechanisms between obesity and psoriasis areunknown. While high fat diet (HFD) increases E-FABP expression in both DCs and keratinocytes and promotesobesity-associated chronic skin inflammation in wild type mice E-FABP deficiency protects mice against HFD-induced effects. All these data suggest that E-FABP may link obesity and psoriasis via regulating metabolismand function of DCs and keratinocytes. Thus we hypothesize that E-FABP as a new link underlying theobesity-psoriasis association promotes psoriasis pathogenesis through enhancing cellular metabolism andfunction of both DCs and keratinocytes. Therefore targeting E-FABP may represent a novel strategy forpsoriasis therapy. We design three specific aims (Figure A) to address our hypotheses. Specific Aim 1 willaddress how E-FABP regulates DC metabolism and function in psoriasis. We hypothesize that E-FABP linksFA metabolism and innate immune signaling in DCs and bridges innate and adaptive immune responses forpsoriasis pathogenesis. Specific Aim 2 will determine how E-FABP promotes keratinocyte aberrantmetabolism and differentiation in psoriasis. We will design experiments to test the hypothesis that E-FABPexpression in keratinocytes mediates innate signal-induced metabolic changes that are critical for abnormalkeratinocyte differentiation. Specific Aim 3 will examine whether E-FABP links the obesity/psoriasisassociation using our unique E-FABP global and conditional knock out mouse models and samples frompsoriasis patients. In summary this proposal will demonstrate a novel mechanism by which E-FABP promotespsoriasis pathogenesis and links obesity-associated psoriasis development. Thus targeting E-FABP may offera novel strategy for treatment of psoriasis and other inflammatory skin disorders.

project_terms:
Abnormal Keratinocyte;Address;Cell physiology;Cellular Metabolic Process;Chronic;Data;Dendritic Cells;Development;High Fat Diet;Human;Imiquimod;Immune;Immune signaling;Inflammation;Inflammatory;Knockout Mice;Link;Mediating;Metabolic;Metabolism;Mitochondria;Molecular;Mus;Obese Mice;Obesity;Pathogenesis;Pathway interactions;Patients;Physiological;Play;Protein Deficiency;Psoriasis;Role;Sampling;Severities;Signal Transduction;Skin;Skin Tissue;Testing;Wild Type Mouse;adaptive immune response;chronic inflammatory skin;conditional knockout;design;experimental study;fatty acid-binding proteins;immunoregulation;innate immune function;interleukin-23;keratinocyte;keratinocyte differentiation;link protein;mouse model;novel;novel strategies;oxidation;protein expression;response;sensor;skin disorder;treatment strategy

public_health_relevance:
Project NarrativeData from this study are expected to establish E-FABP as a new player in psoriasis pathogenesis. Thisproposal will not only determine the cellular and molecular mechanisms by which E-FABP promotes psoriasispathogenesis but will also establish E-FABP as a new molecular link underlying obesity-associated psoriasisdevelopment.


application_id: 9989613
project_number: 5R01ES026657-04
project_title: Microenvironment and Arsenic Lung Tumorigenesis
administering_ic: NIEHS
award_notice_date: 2020-08-31
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 026657
program_official: HUMBLE, MICHAEL C
project_start_date: 2017-09-30
project_end_date: 2023-08-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 10212779
contact_pi: CHEN, GANG
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:
Abstract Chronic exposure of environmental arsenic promotes skin bladder liver and lung cancers. Howeverthe mechanism underlying arsenic lung carcinogenesis is unclear. Evidence from animal models and studies incancer patients indicate that the immune system monitors the host body recognizing and reacting againstnewly arising transformed/tumor cells to stop/control tumor formation. The encounter between the immunesystem and transformed/tumor cells initiates a process termed immunoediting that can bring about threeoutcomes: elimination equilibrium or escape of transformed/tumor cells from immune control. Host immunitysuppresses tumor development whereas tumor formation implies the successful escape of transformed/tumorcells from the surveillance of the immune system. Effector T cells particularly cytotoxic T (Tc) cells representa major component of cell-mediated anti-tumor immunity. One of the mechanisms modulating T cell antitumoreffector function involves the activation/inhibition receptors on a T cell membrane. Inhibition of T cell antitumorfunction through the activation of immune checkpoint pathways (e.g. PD-1/PD-L1 pathway) has been shown topromote tumor cell immune escape and tumor formation. In addition previous reports indicate that the aberrantactivation of STAT3 occurs in many human tumors and STAT3-mediated PD-L1 up-regulation impedes T cellantitumor function. Our previous in vitro study showed that the IL-6/STAT3 axis plays a critical role in arsenic-induced transformation in human bronchial epithelial cells. Using a lung tumor mouse model our newpreliminary data show that long-term arsenic exposure increased lung tumor incidence rate and multiplicity ofA/J mice. In addition arsenic exposure dose-dependently activated STAT3 increased the binding of STAT3 tothe promoter of the PD-L1 gene and up-regulated PD-L1 in mouse lungs. Flow cytometry data further indicatedthat arsenic increased PD-1+ T cell numbers and decreased CD8+/CD4+ T cell ratio in the lungs while injectionof PD-1 or PD-L1 antibodies reversed the decreased CD8+/CD4+ ratio. Since PD-1/PD-L1 up-regulation mayinhibit T cell antitumor function and promote escape of transformed cells from host immunosurveillance andeventually lead to tumor formation we hypothesize that arsenic promotes lung tumor formation throughSTAT3/PD-1/PD-L1-mediated inhibition of T cell antitumor function. Three specific aims are proposed:Aim 1: To determine if chronic arsenic exposure inhibits T cell antitumor function and the types of cells inwhich PD-1 or PD-L1 is up-regulated by arsenic in the lungs of A/J mice.Aim 2: To determine if inhibition of the PD-1/PD-L1 pathway ameliorates arsenic-promoted T cell dysfunctionand tumor formation in the lungs of A/J mice.Aim 3: To determine if activation of STAT3 is the mechanism underlying arsenic-enhanced PD-L1 up-regulation T cell dysfunction and tumor formation in the lungs of A/J mice.

project_terms:
A/J Mouse;Animal Model;Animals;Antibodies;Arsenic;Binding;CD4 Positive T Lymphocytes;CD4/CD8 ratio procedure;CD8B1 gene;Cancer Patient;Cell Count;Cell membrane;Cells;Cellular Structures;Chronic;Data;Development;Dose;Environmental Exposure;Environmental Risk Factor;Epithelial Cells;Equilibrium;Flow Cytometry;Functional disorder;Genes;Human;Immune;Immune system;Immunity;Immunologic Surveillance;In Vitro;Incidence;Injections;Interleukin-6;Investigation;Lead;Lung;Lung Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;Mediating;Modeling;Monitor;Mus;Outcome;PD-1/PD-L1;PDL1 pathway;Pathway interactions;Pharmacologic Substance;Play;Process;Receptor Inhibition;Regulation;Reporting;Role;STAT3 gene;Skin Cancer;T-Lymphocyte;T-Lymphocyte Subsets;Tumor Escape;Tumor Immunity;Tumor-infiltrating immune cells;Up-Regulation;anti-PD-L1 antibodies;anti-PD1 antibodies;bronchial epithelium;cell transformation;cell type;conditional knockout;cytotoxic;effector T cell;genetic approach;immune activation;immune checkpoint;in vivo;inhibiting antibody;inhibitor/antagonist;innovation;lung carcinogenesis;lung tumorigenesis;mouse model;neoplastic cell;novel;novel strategies;prevent;programmed cell death ligand 1;programmed cell death protein 1;promoter;tumor;tumor initiation;tumorigenesis

public_health_relevance:
This proposed study aims to investigate a mechanism for lung tumor initiation by using an arsenic-promotedlung tumor formation mouse model. We hypothesize that chronic arsenic exposure compromises hostimmune system which in turn promotes an immune escape of tumor cells from the surveillance of immunesystem. The idea has never been investigated before and will provide valuable information for thedevelopment of new approaches/strategies to prevent and treat lung cancer promoted not only by arsenicbut by other environmental factors as well.


application_id: 9989491
project_number: 1R56AG061508-01A1
project_title: The Role of Gamma Delta ()-T Cells in Age-Associated Adipose Tissue Inflammation
administering_ic: NIA
award_notice_date: 2019-08-23
opportunity_number: PA-18-484
application_type: 1
activity_code: R56
ic: AG
serial_number: 061508
suffix: A1
program_official: FULDNER, REBECCA A
project_start_date: 2019-09-01
project_end_date: 2021-08-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 10399494
contact_pi: STARR, MARLENE ELENA
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACTAging poses the greatest risk for the development of chronic conditions such as diabetes and cardiovasculardisease. Adipose tissue is a primary promoter of chronic systemic inflammation which underlies many age-related diseases; however the mechanisms responsible for driving age-related adipose tissue inflammationare not fully understood. A further limitation is that much of our current knowledge is based on studies usingmodels of obesity rather than aging. With aging adipose tissues undergo many obesity-independent changesincluding an alteration in resident immune cell populations a decline in progenitor cell function and increasedcellular senescence which may collectively promote the heightened state of chronic sterile inflammation in theaged. The goal of this project is to elucidate the role of visceral adipose tissue (VAT)-resident gamma delta()-T cells on age-dependent adipose tissue inflammation. This project is centered on our novel finding thatVAT of aged mice contains nearly 5 fold more T17 cells (IL-17 producing -T cells) than young-adult mice.Our data show that aged mice lacking -T cells have reduced systemic and VAT inflammation decreasedmarkers of cellular senescence in VAT and an improved metabolic phenotype. These novel data stronglysupport our hypothesis that accumulation of -T cells in VAT promotes preadipocyte senescence andchronic inflammation in the aged. However the manner with which these cells come to accumulate in VAT withage and the mechanisms for their action specifically in VAT are not known. Specific Aim 1 will define VAT-resident -T cells and their age-specific roles. Specific Aim 2 will delineate mechanisms leading to -T cellaccumulation in adipose tissue. Specific Aim 3 will test the hypothesis that -T cells promote cellularsenescence in adipose tissue. These studies will utilize mice which are genetically deficient in -T cells (T cellreceptor delta knockout (TCR-/-)) as well as various in vivo and in vitro techniques including surgicalmanipulations transcriptome analyses flow cytometry and primary cell culture. Collectively this project willestablish the novel concept that VAT-resident -T cells are drivers of chronic inflammation and will elucidatemechanisms underlying this process. The generated data will aid in the identification of strategies to reduce theburden of a long list of age-related disorders for which chronic inflammation is a common denominator.

project_terms:
Adipose tissue;Age;Aging;Automobile Driving;Biological Assay;Blood Circulation;CDKN2A gene;Cardiovascular Diseases;Cell Aging;Cell physiology;Cells;Characteristics;Chemotaxis;Chronic;Coculture Techniques;Conditioned Culture Media;Data;Development;Diabetes Mellitus;Disease;Event;Exhibits;Flow Cytometry;Goals;Human;Immune;In Vitro;Inflammation;Interleukin-1 beta;Interleukin-17;Interleukin-6;Knock-out;Knockout Mice;Knowledge;Label;Link;Mediating;Mediator of activation protein;Metabolic;Metabolic dysfunction;Modeling;Mus;Obesity;Operative Surgical Procedures;Peripheral;Population;Primary Cell Cultures;Process;Risk;Risk Factors;Role;Signal Transduction;Stem cells;Sterility;T-Cell Receptor;T-Lymphocyte Subsets;Techniques;Testing;Tissues;Transplantation;Visceral;Visceral fat;Wild Type Mouse;age related;aged;animal data;base;cardiometabolism;cell motility;chemokine;cytokine;delta receptors;human data;improved;in vivo;macrophage;metabolic phenotype;migration;notch protein;novel;overexpression;promoter;response;senescence;transcriptome;young adult; T cells

public_health_relevance:
PROJECT NARRATIVEAging is a major risk factor for chronic inflammation which is strongly linked to the development of age-associated disease. The proposed project will investigate the influence of adipose tissue gamma delta ()-Tcells on chronic inflammation in the aged.


application_id: 9989209
project_number: 5P01NS097197-05
project_title: Defining the therapeutic window for the treatment of Lafora Epilepsy
administering_ic: NINDS
award_notice_date: 2020-08-04
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
project_start_date: 2016-07-01
project_end_date: 2023-06-30
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8558
contact_pi_person_id: 12485842
contact_pi: GUINOVART, JOAN J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Lafora disease (LD) is an intractable fatal epilepsy with onset in teenage years. Our groups across this project discovered the genetic causes and disease mechanisms of LD. The LD genes EPM2A and EPM2B encode respectively the laforin glycogen phosphatase and the malin ubiquitin E3 ligase which regulate glycogen synthesis in particular its structure. The pathogenic pathology is the neuronal accumulation of poorly branched and insoluble glycogen termed polyglucosan into massive inclusions Lafora bodies (LB) which drive the epilepsy. Polyglucosans though malformed glycogen are glycogen nonetheless and only one enzyme generates glycogen strands namely glycogen synthase (GS).  We showed in LD mouse models that 50-100% elimination of GS activity through GS knockout experiments rescues LD. Several projects in this proposal leverage this discovery to devise a comprehensive approach towards therapy ranging from genome editing of the GS gene to small molecule inhibition of the enzyme. It is anticipated that inhibiting glycogen synthesis will prevent further LB formation and stop disease progression. Since these patients are no sicker than regular epilepsy cases early in their course stopping the disease will be tantamount to cure. But what about cases already in the throes of intractable seizures? It is not known whether LB are straight accumulations versus a net accumulation where clearance mechanisms are overwhelmed by the constant formation of new polyglucosans. If the latter is the case inhibiting further polyglucosan generation may lead to disease reversal i.e. would be effective even in advanced cases.  In Aim 1 we generate a mouse model in which the glycogen synthase 1 gene (Gys1) the muscle and brain isoform of GS is deleted at various time points of the disease course in which LBs have already formed and we analyze the progression or reversal of the phenotype histologically and by electrophysiological and behavioral experiments. In Aim 2 we generate a mouse model in which only one allele of the Gys1 gene is deleted at various time points in which LBs have already formed to check whether a 50% inhibition would be sufficient to prevent/revert the progression of this condition. These two aims will specify the window of opportunity for therapeutic intervention in LD for therapies aimed at glycogen synthesis inhibition. In Aim 3 we answer another unknown namely whether reintroducing the actual missing genes (EPM2A or EPM2B) in LD can arrest the disease or reverse it. We generate an Epm2b-/- LD mouse in which we activate Epm2b expression in different phases of the disease to determine whether this can stop disease and whether it can reverse it. The results of this project will be crucial knowledge towards future human therapy.

project_terms:
Adolescence;Alleles;Applications Grants;Behavioral;Biochemical;Birth;Brain;Child;Clinical;Complementary DNA;Deposition;Development;Disease;Disease Progression;Electrophysiology (science);Enzyme Inhibition;Enzymes;Epilepsy;Excision;Future;GYS1 gene;Gene Expression;Generations;Genes;Genetic;Glycogen;Glycogen (Starch) Synthase;Heart Abnormalities;Histologic;Human;Knock-out;Knockout Mice;Knowledge;Lafora Disease;Lead;Mus;Muscle;Nerve Degeneration;Neurons;Newly Diagnosed;Onset of illness;Pathogenesis;Pathogenicity;Pathology;Patients;Phase;Phenotype;Phosphoric Monoester Hydrolases;Physiological;Process;Protein Isoforms;Seizures;Specific qualifier value;Structure;Symptoms;Teenagers;Therapeutic;Therapeutic Intervention;Time;Tissues;Torture;disease phenotype;experimental study;genome editing;mouse model;neuronal cell body;polyglucosan;prevent;small molecule;ubiquitin-protein ligase


application_id: 9989208
project_number: 5P01NS097197-05
administering_ic: NINDS
award_notice_date: 2020-08-04
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
project_start_date: 2016-07-01
project_end_date: 2023-06-30
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8557
contact_pi_person_id: 1899198
contact_pi: HURLEY, THOMAS D.
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_title:
Suppressing glycogen storage with small molecule inhibitors as a therapeutic approach to Lafora Disease

project_abstract:
Project Summary Suppressing glycogen storage with small molecule inhibitors as a therapeutic approach to Lafora disease Lafora disease is a fatal childhood-onset progressive epilepsy caused by mutations at either the EPM2A or EPM2B genes and for which no cure is currently available. Much has been learned of the disease in the last decade that can help guide new approaches to effective therapies. A consistent feature is the accumulation of insoluble deposits called Lafora bodies in many tissues and of special significance in neurons in the brain. Lafora bodies contain polyglucosan an abnormal glycogen-like compound that is less branched and less soluble than normal glycogen. In mouse models of Lafora disease laforin-/- and malin-/- mice genetic depletion or elimination of glycogen was shown to decrease the formation of Lafora bodies and to alleviate indicators of the disease. Therefore current thinking is that the formation of Lafora bodies is causative of the disease and suppression of their formation would represent a promising approach as a therapy. In this project we propose to reduce glycogen stores in the brain by developing small molecule inhibitors of its accumulation. Aim 1: Identification and validation of small molecule glycogen synthase inhibitors. We are searching for active site and allosteric site inhibitors of glycogen synthase by high-throughput screens (HTS) using novel assays. Positives from the above screens will be validated in vitro and analyzed by the Medicinal Chemistry Core for favorable ADME their potential to cross the blood brain barrier (BBB). Aim 2. Medicinal chemistry optimization. Prioritized hits from Aim 1 will be further validated for activity through direct synthesis and a limited set of related analogs will either be purchased or synthesized to evaluate a range of sub-structures substituents and/or substitution patterns for activity by the in vitro analyses described in Aim 1. Preliminary structure-activity relationships (SAR) will inform on the potential for further pre-clinical development. Aim 3: Cell-based assay of glycogen accumulation toxicity and preliminary pharmacokinetics. We have developed two novel plate-based assays to monitor cellular glycogen levels in glycogen accumulating cell lines. The assays will be applied to evaluate and validate glycogen synthase inhibitors identified in Aim 1 and could also be developed as an alternative for HTS of compound libraries to identify novel inhibitors at the cellular level. The most promising candidates will be advanced for toxicology and pharmacokinetic analyses in mice. Aim 4: Testing inhibitors of glycogen accumulation in mouse models of Lafora disease. Compounds identified in previous Aims that show most promise will be tested in laforin-/- and malin-/- mice to assess their effects on Lafora body formation neurodegeneration and behavioral impairment associated with the disease. Any compounds making it to this stage will be candidates for further development via NINDS drug development programs of the IGNITE/BLUEPRINT initiatives such as PAR-15-071.

project_terms:
Active Sites;Age-Months;Allosteric Site;Animals;Biochemical;Biological;Biological Assay;Blood - brain barrier anatomy;Brain;Cell Line;Cells;Chemicals;Childhood;Core Facility;Data;Deposition;Development;Disease;Dose;Drug Kinetics;Enzyme Kinetics;Epilepsy;Evaluation;Genes;Genetic;Genomics;Glucose-6-Phosphate;Glycogen;Glycogen (Starch) Synthase;Histologic;Human Cell Line;Impairment;In Vitro;Investigation;Laboratories;Lafora Disease;Lead;Libraries;Long-Term Effects;Measurement;Monitor;Mus;Mutation;National Institute of Neurological Disorders and Stroke;Nerve Degeneration;Nervous System Physiology;Neurologic Symptoms;Neurons;Pathology;Pattern;Pharmaceutical Chemistry;Prevention;Program Development;Property;Protocols documentation;Radioactive;Series;Structure;Structure-Activity Relationship;Testing;Therapeutic;Thinking;Tissues;Toxic effect;Toxicology;Validation;Weaning;analog;base;behavioral impairment;blood-brain barrier penetration;cohort;drug development;effective therapy;high throughput screening;human disease;in vitro activity;inhibitor/antagonist;lead candidate;mouse model;novel;novel strategies;phosphatase inhibitor;polyglucosan;preclinical development;response;small molecule;small molecule inhibitor


application_id: 9989207
project_number: 5P01NS097197-05
project_title: Genome editing mRNA suppression and chain termintion as therapy for Lafora Epilepsy
administering_ic: NINDS
award_notice_date: 2020-08-04
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
project_start_date: 2016-07-01
project_end_date: 2023-06-30
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8556
contact_pi_person_id: 11654552
contact_pi: MINASSIAN, BERGE A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Lafora disease (LD) is a catastrophic epilepsy with onset in teenage years in otherwise normal adolescents. Its causes are known its pathogenesis in advanced understanding in major part through the research of members of this proposed program project. The disease genes EPM2A and EPM2B encode the laforin glycogen phosphatase and the malin ubiquitin E3 ligase which regulate glycogen synthesis in particular glycogen structure. Mutations of either gene lead to formation of malstructured glycogen (polyglucosan) which precipitates aggregates and accumulates into Lafora bodies (LB). These overtake neuronal somatodendritic cytoplasm and initiate a progressive soon-intractable epilepsy that aggressively escalates and leads to death after 10 years of essentially constant seizing. Our groups have shown in the LD mouse models that reducing glycogen synthesis by 50-100% through knockouts of the glycogen synthase (GS) gene or the GS activator PTG gene are safe and fully rescue murine LD. Here we propose to translate these findings from gene knockout experiments to therapeutic interventions in mouse as a step towards human therapy. In Aim 1 we target the GS and Ptg genes at the DNA level through CRISPR/Cas9 genome editing in collaboration with F Zhang co- discoverer of the CRISPR system. We deliver CRISPR/Cas9 using the AAV9 virus in collaboration with B Kaspar an AAV9 field leader. We utilize a new Cas9 enzyme recently developed in the Zhang lab with a size that for the first time allows packaging in AAV9. In Aim 2 we target the GS and Ptg genes at the mRNA level using antisense oligonucleotides with unique brain-specific chemistries. Here we already preliminarily show rescue. In Aim 3 we target glycogen itself. We utilize an innovative chain-termination approach which introduces glucose derivatives into the growing chains of polyglucosans to block extension and thus prevent their formation and prevent LB and LD. Finally in Aim 4 we utilize the ketogenic diet under which the brain utilizes ketones for energy in lieu of glucose and determine whether this can prevent LB formation. The aims of this and our other projects of this CWOW are a comprehensive intervention on the pathogenic pathway in LD. We expect that one though more likely a combination of these aims will succeed in our murine models and later translate to eliminating LD from the roster of intractable epilepsies.

project_terms:
Adolescent;Antiepileptic Agents;Antisense Oligonucleotide Therapy;Antisense Oligonucleotides;Base Pairing;Blood - brain barrier anatomy;Brain;CRISPR/Cas technology;Cessation of life;Chemistry;Child;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Cytoplasm;DNA;Dendrites;Dependovirus;Disease;Disease Progression;Enzymes;Epilepsy;GYS1 gene;Genes;Genetic;Genome;Glucose;Glycogen;Glycogen (Starch) Synthase;Homologous Gene;Hospitals;Human;Institutes;Intervention;Intractable Epilepsy;Ketones;Knock-out;Lafora Disease;Lead;Mediating;Messenger RNA;Mus;Mutation;Names;Nerve Degeneration;Neuraxis;Neurons;Oligonucleotides;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Phosphoric Monoester Hydrolases;Plasmids;Positioning Attribute;Production;Property;Protein Isoforms;Proteins;RNA;Refractory;Regulation;Research;Solubility;Staphylococcus aureus;Starch;Structure;Symptoms;System;Teenagers;Therapeutic Intervention;Time;Translating;Universities;Virus;effective therapy;experimental study;gene therapy;genome editing;hydroxyl group;innovation;ketogenic diet;knockout gene;member;mouse model;nervous system disorder;nuclease;polyglucosan;prevent;programs;receptor;small molecule;ubiquitin-protein ligase;vector


application_id: 9989205
project_number: 5P01NS097197-05
project_title: Personalized diagnosis - defining how glycogen metabolism and proteostasis impact LD
administering_ic: NINDS
award_notice_date: 2020-08-04
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
project_start_date: 2016-07-01
project_end_date: 2023-06-30
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8555
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Lafora disease (LD) is a fatal recessive neurodegenerative disorder that presents as an epileptic event in the 2nd decade of life. A hallmark of LD is the accumulation of cytoplasmic hyperphosphorylated water- insoluble glycogen-like particles called Lafora bodies (LBs). LD results from mutations in either of the genes encoding laforin a glycogen phosphatase or malin an E3 ubiquitin ligase and mutations in either gene results in development of LD. LBs cause disease from acute neurotoxicity due to the sensitivity of neurons to energy perturbations. Associated with LB formation cells display multiple markers indicating perturbations in critical cellular pathways including increased endoplasmic reticulum stress autophagy ROS production and others.  The overall focus of this Program Project Grant is to facilitate the Lafora Epilepsy Cure Initiative (LECI): which is an international collaboration devoted to the Diagnosis Treatment and Cure of LD. The goals of this project are to define the clinical biochemistry of LD mutations to provide a personalized diagnosis and establish therapeutic options. To achieve these goals we will define the molecular basis of LD utilizing structural biochemistry cellular biology and mouse models and translate our insights into mutation-specific diagnoses and novel therapeutic approaches to ameliorate LD induced epilepsy and cure LD.  We will first utilize integrated structural and functional tools to define the physical and cellular perturbations caused by LD mutations in both laforin and malin. These approaches will allow us to define the basis of neuronal-specific toxicity leading to disease. We will then develop personalized approaches to diagnosis and treat LD patients. We will define the role of neurotransmitter transporters affected in LD. Further we will determine how laforin and malin affect transporter homeostasis and how LD mouse models respond to treatment of symptoms with antiepileptic drugs. Lastly we will establish the beneficial effect of pharmacological intervention novel compounds that promote read-through of premature termination codons. Embedded in these approaches is the development of a novel bioassay will allow patient-specific diagnosis and definition of molecular sub-types of the disease key to each of the LECI Center projects. Further these results have significant broader implications since LD is one of five major progressive myoclonic epilepsies and the connection between metabolic dysfunction and epilepsy is an emerging theme.  Cumulatively these results will allow personalized therapeutic options that are developed to promote recovery of molecular and cellular function as a means of treating and curing LD.

project_terms:
Acute;Address;Affect;Antiepileptic Agents;Apoptosis;Area;Astrocytes;Autophagocytosis;Biochemical;Biochemistry;Biochemistry and Cellular Biology;Biological Assay;Brain;Cell Culture Techniques;Cell physiology;Cells;Cessation of life;Clinical;Collaborations;Cystic Fibrosis;Data;Defect;Development;Diagnosis;Disease;Disease Progression;Energy Metabolism;Epilepsy;Event;Family;Functional disorder;Genes;Glucans;Glycogen;Goals;Homeostasis;International;Intervention;Ion Channel;Knowledge;Lafora Disease;Life;Metabolic dysfunction;Modeling;Molecular;Mutation;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Neurotransmitters;Outcome;Oxidative Stress;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacology;Phosphoric Monoester Hydrolases;Production;Program Research Project Grants;Progressive Myoclonic Epilepsies;Proteins;Recovery;Research;Role;Sampling;Structural Biochemistry;Structure;Symptoms;Terminator Codon;Testing;Therapeutic;Toxic effect;Translating;Translations;Water;clinical application;design;disease-causing mutation;drug efficacy;endoplasmic reticulum stress;glycogen metabolism;in vitro Model;individualized medicine;induced pluripotent stem cell;insight;member;misfolded protein;molecular subtypes;mouse model;neuron apoptosis;neurotoxicity;new therapeutic target;novel;novel therapeutic intervention;overexpression;particle;personalized approach;personalized diagnostics;personalized therapeutic;potency testing;premature;protein degradation;protein expression;proteostasis;receptor;restoration;small molecule;symptom treatment;tool;trafficking;ubiquitin-protein ligase


application_id: 9989204
project_number: 5P01NS097197-05
project_title: Biological Core
administering_ic: NINDS
award_notice_date: 2020-08-04
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
project_start_date: 2016-07-01
project_end_date: 2023-06-30
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8554
contact_pi_person_id: 9487963
contact_pi: WORBY, CAROLYN ANN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractEpilepsy is one of the most common neurological disorders with a lifetime cumulative incidence of nearly 4%.Amongst the epilepsies Lafora Disease (LD) is the one most ready for personalized treatment. The molecularbasis of LD is known with 65-70% of LD cases due to mutations in the EPM2A gene encoding the glycogenphosphatase laforin and 25-30% of LD cases due to mutations in EPM2B the gene encoding the E3 ubiquitinligase malin. The hallmark of LD is the accumulation of starch-like polyglucosans called Lafora bodies (LBs)which present clinically as an intractable fatal epilepsy. To support the work proposed in this grant theBiological Core will generate transgenic cell culture and mouse models to both study LD mechanisms andevaluate putative therapeutics. The core will use CRISPR technilogy to genetically manipulate SY5Y (humannueronal cell line) and induced pluripotent stem cells (iPSc) to harbor a LD missense mutation and apremature stop codon in both the lafonin and malin genes (8 cell lines total). These cells will be evaluated fortheir ability to differentiate into neurons and produce LBs . These cell lines will be used in high throughput drugscreens and testing of lead compounds. The core will also generate 4 mouse models by introducing the sameLD mutations for laforin and malin used in the cell culture models. Video-EEG and behavioral studies willdocument drug effects on epilepsy and behavior of LD transgenic mice. These mouse models will be used byin Projects 1-4 to determine the efficacy of promising drugs obtained from the high throughput screens anddefine the window of opportunity for treatment. The ultimate goal of the PIs associated with this programproject grant is to combine our efforts to cure Lafora Disease.

project_terms:
Aftercare;Antisense Oligonucleotides;Ataxia;Basic Science;Behavior;Biochemical;Biological;CRISPR/Cas technology;Cell Culture Techniques;Cell Line;Cell model;Cells;Cessation of life;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Consensus;Cytoplasm;Deterioration;Development;Diagnosis;Disease;Disease Progression;Disease model;Educational workshop;Electroencephalography;Ensure;Epilepsy;Funding;Genes;Glycogen;Goals;Grant;Hormonal;Human;Impaired cognition;Incidence;Intractable Epilepsy;Knock-in Mouse;Lafora Disease;Lead;Missense Mutation;Modeling;Molecular;Mutation;Myoclonic Epilepsies;Neurologic;Neurons;Nonsense Codon;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphoric Monoester Hydrolases;Plants;Program Research Project Grants;Progressive Myoclonic Epilepsies;Reagent;Research;Research Personnel;Side;Starch;Stimulus;Structure;Techniques;Teenagers;Therapeutic;TimeLine;Transgenic Mice;Transgenic Organisms;United States National Institutes of Health;Work;behavioral study;drug testing;epileptic encephalopathies;genetic manipulation;genome editing;high throughput screening;high-throughput drug screening;induced pluripotent stem cell;innovation;meetings;member;mouse model;multidisciplinary;nervous system disorder;patient advocacy group;personalized diagnostics;personalized medicine;polyglucosan;prevent;small molecule;success;ubiquitin-protein ligase


application_id: 9989203
project_number: 5P01NS097197-05
project_title: Medicinal Chemistry Core
administering_ic: NINDS
award_notice_date: 2020-08-04
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
project_start_date: 2016-07-01
project_end_date: 2023-06-30
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8553
contact_pi_person_id: 1964895
contact_pi: WATT, DAVID STEWART
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Medicinal Chemistry CoreThe Medicinal Chemistry Core provides an integrated approach not only for the synthesis of small moleculesbut the assessment of their likely success as translational agents through feedback mechanisms involvingbiological testing and cheminformatics analyses. The Core anticipates time commitments of 25% for Project 125% for Project 2 and 50% for Project 3. Projects 1 and 2 will initially test aminoglycosides and deoxyglucoseanalogs respectively available through collaborations with other research groups. The Core will providesynthetic services related to these compounds as needed. Project 3 requires the development of glycogensynthase inhibitors through a collaborative process of screening structure analysis synthesis and testing. TheCore will perform the following Specific Aims: [1] analyze and prioritize structures from high-throughputscreening; [2] synthesize glycogen synthase inhibitors for structure-activity relationship generation; and [3]evaluate lead inhibitors in hERG activation blood-brain barrier permeation and P-glycoprotein interactionassays.

project_terms:
Affect;Affinity;Agreement;Aminoglycosides;Binding;Biological;Biological Assay;Biological Testing;Blood - brain barrier anatomy;Brain;Chemicals;Collaborations;Consultations;Cytoplasm;Dendrites;Deoxyglucose;Development;Diagnosis;Disease;Educational workshop;Enzymes;Epilepsy;Feedback;Funding;Generations;Glucose;Glycogen;Glycogen (Starch) Synthase;Grant;Human;Human Resources;Lafora Disease;Lead;Libraries;Molecular Probes;Mutation;Neurodegenerative Disorders;Neurologic Symptoms;P-Glycoprotein;Pharmaceutical Chemistry;Phase;Phosphoric Monoester Hydrolases;Process;Program Research Project Grants;Research;Research Personnel;Services;Starch;Structure;Structure-Activity Relationship;Testing;Therapeutic;Time;United States National Institutes of Health;analog;base;cheminformatics;design;glycogen metabolism;high throughput screening;inhibitor/antagonist;innovation;interdisciplinary approach;mouse model;pharmacophore;preclinical development;remediation;scaffold;screening;sex;small molecular inhibitor;small molecule;small molecule therapeutics;success;ubiquitin-protein ligase;virtual


application_id: 9989202
project_number: 5P01NS097197-05
project_title: Administrative Core
administering_ic: NINDS
award_notice_date: 2020-08-04
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
project_start_date: 2016-07-01
project_end_date: 2023-06-30
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8552
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Lafora Epilepsy Cure Initiative (LECI) Center exists to develop innovative and effectiveDiagnoses Treatments and Cures for Lafora Disease (LD). The LECI Center was initiatedduring a LD workshop held in San Diego in June 2014. The gathering of patient's familiesphysicians and scientists identified key progress that could be made when working togethertowards a cure for LD. We identified fundamental research questions and therapeutic strategiesto make this dream a reality. This Center will be a key aspect of our collaborative endeavor. The Administrative Core will be housed at the Center for Molecular Medicine within theUniversity of Kentucky College of Medicine and directed by Dr. Matthew Gentry. The LECIAdministrative Core will coordinate all of the activities of the Center. The Administrative Core isresponsible for implementing the goals of the Program overseeing the operations of thescientific and resources cores and ensuring open lines of communication within and betweenall projects as well as with NINDS. The Administrative Core will also coordinate activitiesinvolving the Executive Committee and the Advisory Board. The Administrative Core willcommunicate decisions by the Executive Committee concerning appropriate implementation ofthe LECI Charter and policies related to publications data sharing protocols and the website. This will be accomplished by: 1) Providing clear and transparent leadership; 2) Reportingcenter activities and accomplishments to all center members NINDS members of the oversightcommittees and members of the public; 3) Providing logistical support for communication withinthe project and with the community; 4) Coordinating research effort by overseeing all facets ofcollaborations both within and between the Center's four scientific projects and two scientificCores as well as with the broader scientific community to ensure the needs of the project PIsare being met.

project_terms:
Administrative Personnel;Biological;Biological Markers;Clinical;Clinical Trials;Collaborations;Committee Members;Communication;Communities;Data;Diagnosis;Disease;Dreams;Educational workshop;Electronic Mail;Ensure;Epilepsy;Event;Family Physicians;Flowcharts;Goals;Grant;Innovative Therapy;Institution;Intellectual Property;Kentucky;Knowledge;Lafora Disease;Lead;Leadership;Logistics;Medicine;Methods;Mission;Molecular Medicine;Myoclonus;National Institute of Neurological Disorders and Stroke;Neurons;Neurosciences;Newborn Infant;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phase;Policies;Property Rights;Protocols documentation;Publications;Reagent;Reporting;Research;Research Personnel;Resource Sharing;Resources;Scientist;Screening procedure;Severities;Teleconferences;Therapeutic;United States National Institutes of Health;Universities;Work;career development;college;community planning;data sharing;fundamental research;glycogen metabolism;innovation;meetings;member;operation;patient population;programs;recruit;skills;web site


application_id: 9989199
project_number: 5P01NS097197-05
project_title: Lafora Epilepsy - Basic mechanisms to therapy
administering_ic: NINDS
award_notice_date: 2020-08-04
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
program_official: LEENDERS, MIRIAM
project_start_date: 2016-07-01
project_end_date: 2023-06-30
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
contact_pi_person_id: 7353657
contact_pi: GAO, TIANYAN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Lafora Disease was originally described over 100 years ago by Dr. Gonzalo Rodriquez-Lafora as amyoclonus epilepsy with dementia. A hallmark of the disease identified by Lafora are inclusions in the brainnow known as Lafora bodies (LBs). LD is a rapidly progressing invariably fatal epilepsy. Onset is inadolescence in apparently healthy teenagers of both sexes with headaches and insidious decline in cognitivefunction. Myoclonic seizures staring spells and generalized convulsions follow and all escalate over time.Initial response to antiepileptic drugs is lost within three years and a constant myoclonus with atypical absencebegins. The young person then develops dementia often disinhibited and seizes with increased frequency.The patient becomes bedridden and death comes after a protracted decade of unceasing myoclonus in theform of a particularly massive seizure status epilepticus or aspiration pneumonitis. Identification of the genetic basis for LD by members of our group has ushered in a new era in ourunderstanding of the formation of LBs leading to LD. We have made rapid progress and have nowdemonstrated that eliminating LBs wholly cures LD in mouse models opening up the real possibility of a cure.To that end we propose the establishment of the Lafora Epilepsy Cure Initiative (LECI) Center. We haveassembled an international group of pioneers and leaders in the field. We propose to attack the disease frommultiple angles targeting the full spectrum of molecular and cellular causes of LD and believe that we areuniquely positioned to realize the dream of treating and curing LD patients. The overall focus of this Program Project Grant is to: Diagnose Treat and eventually Cure LD. Fourcomplimentary projects and three integrated core facilities form the basis of this proposal. Our projects are:Project #1: Personalized diagnosis - defining how glycogen metabolism and proteostasis impact LD.Project #2: Genome editing mRNA suppression and glycogen chain termination to inhibit glycogen storage astherapy for LD.Project #3: Suppressing glycogen storage with small molecule inhibitors as a therapeutic approach to LD.Project #4: Defining the therapeutic window for the treatment of LD. LD offers a unique window into both normal neuronal glycogen metabolism and epileptic disease when theprocess is perturbed. While this project aims at defining the basic mechanisms of LD and translating this workinto therapeutics and cures our work is likely to reveal pathogenic mechanisms common to other epilepsies.The collective effort of the LD experts will both define LD therapy options and generate abundant newcollateral data that will uncover pathways connecting the bioenergetics of the brain with the generation ofseizures and epilepsy. These insights may be particularly informative to the most daunting aspect of epilepsynamely intractability that afflicts over 30% of patients.

project_terms:
Adolescence;Antiepileptic Agents;Antisense Oligonucleotides;Bioenergetics;Biological;Biological Assay;Biological Models;Biological Products;Biology;Brain;Carbohydrates;Cessation of life;Chemistry;Child;Clinic;Clinical Research;Clinical Trials;Collaborations;Communities;Convulsions;Core Facility;Coupled;Cytoplasm;Data;Defect;Dementia;Dendrites;Development;Diagnosis;Diagnostic;Disease;Dreams;Enzymes;Epilepsy;Frequencies;Gene Expression;Generations;Genes;Genetic;Glycogen;Grant;Headache;Hormones;International;Intractable Epilepsy;Knowledge;Lafora Disease;Life;Medicine;Messenger RNA;Methods;Modality;Modeling;Molecular;Molecular Target;Mutation;Myoclonic Epilepsies;Myoclonus;National Institute of Neurological Disorders and Stroke;Neurodegenerative Disorders;Neurons;Neurosciences;Outcome;Pathogenicity;Pathology;Pathway interactions;Patients;Persons;Pharmaceutical Chemistry;Pharmacology;Phase;Phosphoric Monoester Hydrolases;Physicians;Plants;Positioning Attribute;Process;Production;Program Research Project Grants;Pulmonary Inflammation;RNA;Reagent;Refractory;Research;Research Personnel;Scientist;Seizures;Shapes;Starch;Status Epilepticus;Structural Biochemistry;Techniques;Technology;Teenagers;Testing;Therapeutic;Time;Training;Translating;United States National Institutes of Health;Vision;Work;base;brain cell;career;clinical application;cognitive function;genome editing;glycogen metabolism;induced pluripotent stem cell;innovation;insight;interdisciplinary approach;member;mouse model;novel;personalized diagnostics;proteostasis;response;sex;small molecule;small molecule inhibitor;spelling;success;sugar;therapeutic evaluation;ubiquitin-protein ligase

public_health_relevance:
Lafora disease is a catastrophic epilepsy that strikes healthy teenagers and leads to constant ever-worseningseizures until it results in death after 10 years. The collaboration in this Program Project Grant brings togetherthe clinician-scientists and researchers who discovered the causes of this disease: the shape of glycogenbecomes abnormal in this disease in fact it becomes similar to plant starch and builds up in the patients' braincells. We will utilize state of the art technologies including techniques to manipulate genes introducingbiological agents to interfere with gene expression utilization of hormones and carbohydrate-poor dies smallmolecules and sugar-mimics to down-regulate glycogen production. Our research is in a state where we see aclear track to develop effective methods to diagnose treat and ultimately cure LD. Our vision is that one day aphysician having diagnosed a child with this horrendous epilepsy would have the medicines and technologiesto stop the disease in its tracks so that the child is able to resume development and life a healthy and normallife.


application_id: 9988910
project_number: 5R01DK112136-04
project_title: Community to Clinic Navigation to Improve Diabetes Outcomes
administering_ic: NIDDK
award_notice_date: 2020-07-27
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 112136
program_official: THORNTON, PAMELA L
project_start_date: 2017-08-01
project_end_date: 2022-07-31
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
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:
ABSTRACTReducing adverse outcomes from Type 2 Diabetes Mellitus (T2DM) requires optimal self-management andappropriate clinical care.1 Combining an evidence-based intervention to improve diabetes self-managementwith individually-tailored patient navigation to improve appropriate clinical care holds great promise. Only oneknown randomized controlled trial has been tested that combines these two most essential components ofdiabetes control. That trial resulted in improvements to glycemic control blood pressure and diabetes self-management but was implemented in a clinical setting.2 We aim to enhance this work by recruiting from andlocating most research activities in community-based settings to insure involvement of the most vulnerablehardest to reach populations who may not be receiving regular health care and by leveraging CommunityHealth Workers and Patient Navigators who are essential and sustainable outreach workers in health careprofessional shortage areas.We propose testing a refined intervention Community to Clinic Navigation (CCN) shown to be promisingfeasible and acceptable in our pilot study. Given that Appalachian and rural residents maintaindisproportionately high rates of T2DM and suffer tremendous burdens from diabetic complications3 this settingprovides a perfect opportunity to test the intervention with a hard to reach population while addressing healthinequities. We will administer a 3 arm group randomized design including (1) Diabetes Self-managementProgram DSMP only; (2) tailored Patient Navigation PN only; and (3) the combined DSMP + PN: Communityto Clinic Navigation program CCN. Outcomes include biometrics (HbA1c BMI blood pressure lipids waistcircumference); diabetes self-management and clinic attendance as mediators of the primary outcomes; costeffectiveness and participant satisfaction. Persons with diabetes will be recruited through churches and othercommunity venues. Our project leverages sustainable assets available in most health disparity communities--faith organizations community centers federally qualified health clinics strong social ties and talented locallay people who can be trained to educate and navigate those diagnosed with T2DM. Our sustainedinvolvement in Appalachian Kentucky positions our team to appropriately and efficiently test this promisingprogram with strong potential for future dissemination to other traditionally underserved environments.

project_terms:
Address;Affect;American;Appalachian Region;Biometry;Blood Pressure;Church;Clinic;Clinical;Communities;Community Health Aides;Complications of Diabetes Mellitus;Data;Diabetes Mellitus;Diagnosis;Education;Environment;Epidemic;Evidence based intervention;Focus Groups;Future;Glycosylated hemoglobin A;Goals;Health;Health care facility;Healthcare;Individual;Influentials;Intervention;Interview;Kentucky;Lipids;Low income;Mediator of activation protein;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Participant;Patients;Persons;Pilot Projects;Population;Positioning Attribute;Prediabetes syndrome;Protocols documentation;Randomized;Randomized Controlled Trials;Recruitment Activity;Research;Research Activity;Rural;Rural Population;Self Management;Social support;Talents;Testing;Training;Vulnerable Populations;Work;adverse outcome;arm;base;behavioral outcome;clinical care;community center;community setting;cost effectiveness;design;diabetes control;diabetes self-management;evidence base;glycemic control;health care quality;health care service organization;health disparity;health professional shortage areas;improved;improved outcome;innovation;low socioeconomic status;meetings;member;outreach;primary outcome;programs;randomized trial;recruit;relative cost;rural dwellers;satisfaction;self-management program;social;theories;waist circumference

public_health_relevance:
PROJECT NARRATIVESince diabetes has reached epidemic proportions in the US especially among low income and rural residentswe aim to test a refine and promising program called Community to Clinic Navigation (CCN) that combinesdiabetes self-management education with tailored patient navigation to improve clinical care. To ourknowledge no one has ever combined these two approaches which is surprising because these are the mostimportant ways to manage and control diabetes. If this theory-based culturally appropriate intervention showsimprovement in physical and behavioral outcomes then CCN can easily be applied to other communities withhealth disparities.1


application_id: 9987788
project_number: 1F30EY031545-01
project_title: Ocular complications of CHARGE Syndrome: The role of Sox11
administering_ic: NEI
award_notice_date: 2020-03-09
opportunity_number: PA-19-192
application_type: 1
activity_code: F30
ic: EY
serial_number: 031545
program_official: AGARWAL, NEERAJ
project_start_date: 2020-09-01
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1 F03A-N (20)]
contact_pi_person_id: 15716225
contact_pi: KRUEGER, LAURA
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Anophthalmos;Binding Proteins;Biochemical;Biological Models;Blindness;Brain;CHARGE syndrome;CHD7 gene;Cephalic;Childhood;Choanal Atresia;Chromatin;Chromosomal Duplication;Code;Coloboma;Communication;Communication Research;Confocal Microscopy;Congenital Abnormality;Craniofacial Abnormalities;Critical Thinking;DNA Binding Domain;Data;Defect;Development;Disease;Ear;Eye;Eye Development;Eye diseases;Family;Fetal Development;Fluorescence-Activated Cell Sorting;Future;Genes;Genetic;Genetic Research;Genital system;Goals;Growth;Head;Heart Abnormalities;Human;Image;Imaging Techniques;Immunoprecipitation;Inherited;Label;Laboratories;Laboratory Study;Light;Microphthalmos;Microscopy;Modeling;Molecular Biology;Morphogenesis;Mutation;Names;Neural Crest Cell;Pathogenesis;Pathway interactions;Patients;Phenotype;Physicians;Play;Process;Proteins;Regulation;Reporter;Research;Research Ethics;Role;SOX11 gene;SOX4 gene;Scientist;Signal Pathway;Signal Transduction;Signaling Protein;Structural Congenital Anomalies;Structure;Syndrome;Testing;Training;Transcription Coactivator;Transgenic Organisms;Vision;Visual impairment;Visual system structure;Work;Zebrafish;base;bone morphogenic protein;clinical Diagnosis;clinical phenotype;developmental genetics;eye formation;helicase;improved;innovation;knock-down;malformation;member;migration;mutant;nerve stem cell;novel therapeutics;pre-doctoral;preservation;relating to nervous system;sex;skills;sry Genes;transcription factor;vision development


application_id: 9987030
project_number: 3P20GM103436-19S1
project_title: Project-002
administering_ic: NIGMS
award_notice_date: 2019-08-26
opportunity_number: PAR-18-262
application_type: 3
activity_code: P20
ic: GM
serial_number: 103436
suffix: S1
program_official: ARORA, KRISHAN
study_section: ZGM1-RCB-9(IN)
subproject_number: 8248
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Kentucky INBRE serves a statewide mission to build a sustainable infrastructure with a capacity forbiomedical and health-related research and research training. In this application the two research intensiveinstitutions the University of Louisville and the University of Kentucky will partner with our regionalcomprehensive affiliates including Eastern Kentucky University Morehead State University NorthernKentucky University and Western Kentucky University and with a number of outreach institutions tocontinue the development of a highly collaborative and successful network. The goal of our network is tobuild competitive research which will serve as the foundation for excellent training of our students in thebiomedical and health-related sciences. We plan to develop and grow our multi-disciplinary researchnetwork with an overarching theme of functional genomics. With an emphasis on sustainability we willcontinue to fund developmental research projects for our junior investigators while providing criticalmentoring as well as the requisite infrastructure support for genomics and bioinformatics Our centralizedgenomics core facility will provide access to state-of-the-art equipment for microarray and next generationsequencing technologies along with qualified technical support. Similarly we will continue to build a criticalmass of expertise and infrastructure in bioinformatics to provide data analysis services for high contentand/or high throughput data. We have built undergraduate and graduate training programs in bioinformatics.In the rapidly changing world of biomedical research these facilities and services are essential to providing apathway to independence for our next generation of investigators. We will provide junior faculty with ail of thetools necessary to become independent investigators thereby building network sustainability and at thesame time provide for high quality research training experiences for our students. In summary our strategyis designed to build a sustainable infrastructure with capacity for biomedical and health-related research aridresearch training. This strategy will aid the development of a highly skilled workforce in the Commonwealthof Kentucky.

project_terms:
Bioinformatics;Biomedical Research;Core Facility;Data;Data Analyses;Development;Equipment;Faculty;Foundations;Funding;Genomics;Goals;Health;Infrastructure;Institution;Interdisciplinary Study;Kentucky;Knowledge;Lead;Mentors;Minority-Serving Institution;Mission;Pathway interactions;Postdoctoral Fellow;Research;Research Personnel;Research Project Grants;Research Training;Science;Services;Students;Technology;Time;Training;Training Programs;Universities;base;career;community college;design;experience;functional genomics;graduate student;next generation;next generation sequencing;outreach;programs;research facility;tool;undergraduate student

public_health_relevance:
This INBRE program is designed to build infrastructure and support activities to enhance biomedicalresearch and research training in Kentucky.


application_id: 9986869
project_number: 5R01HL130086-04
project_title: Calpains and Abdominal Aortic Aneurysms
administering_ic: NHLBI
award_notice_date: 2020-07-21
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 130086
program_official: REID, DIANE M
project_start_date: 2017-08-10
project_end_date: 2022-07-31
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
arra_indicator: N
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;NF1 gene;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: 9986734
project_number: 5R01DA047952-03
administering_ic: NIDA
award_notice_date: 2021-07-23
opportunity_number: PA-18-345
application_type: 5
activity_code: R01
ic: DA
serial_number: 047952
program_official: FLOURNOY FLOYD, MINNJUAN WYNCEPHEL
project_start_date: 2018-09-30
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZRG1-AARR-K(92)S]
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-08-01
project_title:
Increasing Access to Hepatitis C Treatment in Opioid Endemic Rural Areas: the  Kentucky Viral Hepatitis Treatment (KeY Treat) Study

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

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

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


application_id: 9986713
project_number: 5R03CA235171-02
administering_ic: NCI
award_notice_date: 2020-07-22
opportunity_number: PAR-18-021
application_type: 5
activity_code: R03
ic: CA
serial_number: 235171
program_official: LEE, CECILIA H
project_start_date: 2019-08-01
project_end_date: 2022-07-31
study_section: ZCA1-TCRB-Q(M2)
contact_pi_person_id: 11642450
contact_pi: MCLOUTH, LAURIE
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: 2020-08-01
project_title:
Piloting Pathways a Hope-Enhancing Intervention to Address Activity and Role Function in Metastatic Lung Cancer Patients

project_abstract:
Project SummaryLung cancer is the second most commonly diagnosed cancer and leading cause of cancer death among menand women in the U.S. Nearly 90000 people will be diagnosed with metastatic non-small cell lung cancer(NSCLC) this year representing 40% of lung cancers. One of the more distressing consequences of metastaticNSCLC to patients is its effect on their participation in daily activities and roles. Between 40-65% of lungcancer patients report that impairment in their daily activities and roles is a top unmet supportive care need.This care gap is reflected in existing interventions which do not directly address function and are not wellintegrated into primary oncologic care. The overall goal of this research is to address this care gap byimplementing a supportive care intervention to help address activity and role function concerns in primaryoncologic care. Our research suggests that intervening on patient hope which reflects agency for pursuinggoals and identifying pathways to pursue goals may be a promising approach to address activity and rolefunction concerns in metastatic NSCLC patients. Informed by our preliminary data our multidisciplinary teamhas adapted a hope-enhancing intervention for use with metastatic NSCLC patients in primary oncologic care.The intervention called Pathways is based in Hope Theory and comprised of 5 sessions designed to helppatients identify meaningful and feasible goals to pursue and increase patient agency and pathways forpursuing goals in the presence of likely disease obstacles including lung cancer stigma. The intervention isdelivered by a nurse with training in supportive care through in-person and phone sessions. The researchproposed in this application will evaluate the feasibility of Pathways. In Aim 1 we will refine Pathways bypiloting it with 6 metastatic NSCLC patients and conducting interviews with them to evaluate its acceptabilityand gather suggestions for aspects that need to be improved. Our multidisciplinary team will review theinformation from Aim 1 and refine Pathways. Then in Aim 2 we will test the feasibility (patient accrualadherence retention patient acceptability ratings) of Pathways with 20 metastatic NSCLC patients and assesspre-post changes in hope cancer-related goal interference and outcome measures related to function anddistress. Results of this study will determine the feasibility of a nurse-delivered hope-enhancing intervention toimprove function in activities and roles in metastatic NSCLC patients and provide preliminary data to inform arandomized controlled trial of efficacy of the intervention.

project_terms:
Address;Adherence;Cancer Etiology;Cancer Patient;Caring;Cessation of life;Clinic;Data;Diagnosis;Disease;Distress;Electronic Health Record;Enrollment;Etiology;Family;Feedback;Future;Goals;Impairment;Infusion procedures;Intervention;Intervention Studies;Interview;Leisure Activities;Length;Life;Malignant Neoplasms;Malignant neoplasm of lung;Mental Depression;Motivation;Non-Small-Cell Lung Carcinoma;Nonmetastatic;Nurses;Oncology;Outcome;Outcome Measure;Palliative Care;Pathway interactions;Patient Preferences;Patients;Persons;Pilot Projects;Procedures;Protocols documentation;Randomized Controlled Trials;Reporting;Research;Research Personnel;Resources;Role;Smoking;Social Work;Stigmatization;Suggestion;Supportive care;Symptoms;Telephone;Testing;Thoracic Oncology;Training;Treatment Efficacy;Treatment Side Effects;Woman;Work;arm;base;cancer care;cancer diagnosis;cancer therapy;care delivery;clinical practice;comorbidity;design;efficacy testing;efficacy trial;evidence base;improved;improved functioning;innovation;interest;men;multidisciplinary;novel;outcome forecast;patient oriented;patient-level barriers;preference;public health relevance;social stigma;symptom treatment;theories;therapy design

public_health_relevance:
Public Health RelevanceMaintaining participation in valued daily activities and life roles is of paramount concern to the 90000 peoplewho are diagnosed with metastatic lung cancer each year in the U.S. but current clinical practice in primaryoncology does not address this significant patient concern. To address this care gap we will pilot a nurse-delivered intervention Pathways that helps patients identify and pursue meaningful goals related to dailyactivities and roles. Findings from this study will provide data on the feasibility of a patient-centeredintervention designed to overcome patient barriers and align with oncology clinic work flow.


application_id: 9985778
project_number: 5UH3DA044798-04
project_title: Kentucky Communities and Researchers Engaging to Halt the Opioid Epidemic (CARE2HOPE)
administering_ic: NIDA
award_notice_date: 2020-08-18
opportunity_number: RFA-DA-17-014
application_type: 5
activity_code: UH3
ic: DA
serial_number: 044798
program_official: CRUMP, ARIA
project_start_date: 2017-08-15
project_end_date: 2022-07-31
study_section: ZDA1-HXO-H(18)R
contact_pi_person_id: 11085214
contact_pi: YOUNG, APRIL MARIE
other_pis: COOPER, HANNAH LF
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract: The proposed project will build evidence-based community-rooted public health responses to theepidemics of non-medical prescription opioid (NMPO) and heroin injecting overdoses (ODs) and HCV and toimminent HIV outbreaks in 12 rural Appalachian Kentucky counties at the epicenter of these intertwinednational crises. 10 counties rank in the top 5% for HIV/HCV vulnerability. Rates of HCV injection drug use(IDU) and ODs are high in these counties and most are in coal country an RFA priority. Unfortunately these counties exemplify an extreme version of the implementation chasm a chasmdividing scientific knowledge from action. Evidence-based public health responses to these epidemics exist(e.g. syringe service programs [SSPs]) and are often deployed in cities. In these 12 rural counties thoughscarcities of resources and of providers conspire with drug-related stigma to constrain public health responses.The counties' public health infrastructures are weak their harm reduction infrastructures virtually non-existent. This project will bridge the implementation chasm in these 12 counties and recognizes that bridging thischasm requires more than simply importing SSPs and other evidence-based community response projects(EB-CRPs) from cities. Guided by harm reduction principles the Risk Environment Model and Community/Academic Partnerships (CAPs) in the UG3 we will: (1) Assess and enhance each county's readiness toimprove the local risk environment. (2) Examine the strengths resources needs and gaps of each county'srisk environment. We will conduct a multi-method Community Assessment of the Risk Environment thatintegrates innovative rigorous epidemiology (e.g. modeling); policy assessment; and best practices incommunity-based research (e.g. CAPs). (3) Select a package of EB-CRPs that responds to local needs andstrengths using elements of Intervention Mapping. Go/no go milestone: Each CAP will have created an EB-CRP package that (1) addresses targets common across all counties (e.g. opioid injection OD HCV HIV)and (2) is tailored to local needs resources and readiness. In the UH3 we will: (4) Tailor selected EB-CRPs toeach county's context using ADAPT-ITT. (5) Analyze the effectiveness and cost-effectiveness of each county'sEB-CRP package using an innovative stepped-wedge community randomized trial and mathematical models.We will use continuous quality improvement to enhance each EB-CRP's fidelity reach immediate effects andoutcomes. To inform interventions advanced network analyses will overlay risk networks with GHOSTphylogenetic transmission data to show where HCV has been and predict where it is going. We draw strengthfrom our collaborations. CAPs will meld residents' local knowledge with researchers' scientific expertise. Multi-PIs Young and Cooper have assembled an academic team with unsurpassed expertise in key substancetheories and methods and in multisite studies. The combination of a rigorous innovative design (e.g. step-wedge community trials) strong theories and a stellar team with community roots will ensure high impact.

project_terms:
Address;Appalachian Region;Area;Behavioral;Caring;Centers for Disease Control and Prevention (U.S.);Cities;Coal;Collaborations;Communities;Community Trial;Country;County;Disease Outbreaks;Drug user;Effectiveness;Elements;Ensure;Environment;Epidemic;Epidemiologic Methods;Epidemiology;Evidence based intervention;General Population;HIV;HIV/HCV;Harm Reduction;Health;Health Services;Hepatitis C virus;Heroin;Incidence;Infrastructure;Injecting drug user;Injections;Intervention;Kentucky;Knowledge;Laws;Letters;Methods;Modeling;Naloxone;National Institute of Drug Abuse;Needle-Exchange Programs;Outcome;Overdose;Pathway Analysis;Pharmaceutical Preparations;Phylogenetic Analysis;Plant Roots;Policies;Prescription opioid overdose;Provider;Public Health;Qualitative Research;Readiness;Research Infrastructure;Research Personnel;Resources;Risk;Risk Assessment;Rivers;Rural;Rural Appalachia;Services;Site;Substance Use Disorder;Testing;United States Substance Abuse and Mental Health Services Administration;Unsafe Sex;Work;base;combat;community based participatory research;cost effectiveness;data exchange;design;evidence base;implementation science;improved;infectious disease treatment;injection drug use;innovation;mathematical model;member;misuse of prescription only drugs;opioid epidemic;opioid injection;prescription opioid;randomized trial;response;rural counties;social stigma;theories;virtual

public_health_relevance:
Narrative: The proposed project will employ community/academic partnerships to build effective evidence-based community-grounded public health responses to combat the intertwined epidemics of heroin and non-medical prescription opioid injecting overdoses and HCV and imminent HIV outbreaks in 12 of the hardesthit rural counties in the US. Located in Central Appalachian Kentucky 10 of the 12 counties are in the top 5%for HIV/HCV vulnerability in the US. Most counties are in coal country an RFA priority area.


application_id: 9985205
project_number: 5R44MH122117-03
administering_ic: NIMH
award_notice_date: 2020-07-24
opportunity_number: PA-18-574
application_type: 5
activity_code: R44
ic: MH
serial_number: 122117
program_official: GRABB, MARGARET CHRISTINE
project_start_date: 2016-04-15
project_end_date: 2023-07-31
study_section: Special Emphasis Panel[ZRG1-IMST-B(12)B]
contact_pi_person_id: 10138071
contact_pi: STONE, BARBARA JEAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-08-01
project_title:
An Innovative Device Integrating Cryopreservation Storage and Artificial Insemination of Mouse Sperm

project_abstract:
SUMMARYParaTechs Corporation aims to provide researchers with advanced technology and methods to simplifyprocedures for laboratory animal models. While actively supporting efforts to reduce replace and refine animaluse ParaTechs provides safe and efficient alternatives for surgical procedures. We have already brought tomarket a nonsurgical embryo transfer device (NSETTM) which replaces surgical embryo transfers with anonsurgical method that takes only seconds and does not require anesthesia. We have developed a newprotocol for non-surgical artificial insemination (AI) of mice which replaces existing protocols for surgical AI andis a technical advancement for existing nonsurgical AI protocols. We plan to use this newly developed protocolto revolutionize the process of archiving and global distribution of mouse models through a novel spermcryopreservation and strain recovery system.The use of mouse strains in research is one of the most important tools used to study mammalian gene function.While hundreds of thousands of mouse strains have been catalogued and cryopreserved sharing of strains isbecoming increasingly difficult as regulatory constraints and the cost of shipping live animals increase. We cansolve this problem and provide a technically superior alternative with the cryopreservation and insemination (C&I)device. This system will integrate storage and shipment of cryopreserved sperm with non-surgical AI. The devicewill be suitable for storage of cryopreserved sperm will be shippable will allow viable sperm recovery uponthawing and then will be used directly for non-surgical AI. This device will eliminate the need to perform in vitrofertilization (IVF) upon thawing of cryopreserved sperm; greatly reducing the number of mice required for theprocedure and replacing a surgical method of artificial insemination both of which promote animal health andwelfare.Therefore the goals of this project are to develop protocols for the C&I device to optimize efficiency and ease ofuse to test the parameters required for storage and shipping and expand utility of the device to embryo storageand transfer. This new technological breakthrough will provide an alternative to cryorecovery of mouse strainsby in vitro fertilization methods the currently preferred but technically challenging and labor intensive strainrecovery method. In doing so the C&I device will provide a substantial cost savings to researchers and aconvenient method for shipping and strain recovery. The C&I device will replace a technically challenging andlabor intensive recovery method culminating in a fast and easy way to share research models betweeninstitutions around the world.

project_terms:
Address;Age;Anesthesia procedures;Animal Experimentation;Animal Model;Animal Welfare;Animals;Archives;Artificial Insemination;Biotechnology;Breeding;Businesses;Catalogs;Cohort Studies;Collaborations;Communities;Consumption;Core Facility;Cost Savings;Cryopreservation;Development;Devices;Disease;Dry Ice;Embryo;Embryo Transfer;Fertilization in Vitro;Funding Opportunities;Genetic Drift;Goals;Health;Individual;Insemination;Institution;Laboratories;Laboratory Animal Models;Laboratory Animal Production and Facilities;Laboratory Animals;Laboratory Procedures;Laboratory Research;Laboratory mice;Liquid substance;Methods;Missouri;Modeling;Mouse Strains;Mus;Natural Disasters;Nitrogen;Operative Surgical Procedures;Phase;Pregnancy Rate;Price;Problem Solving;Procedures;Process;Protocols documentation;Recovery;Research;Research Personnel;Resources;Services;Shipping;Ships;Small Business Innovation Research Grant;Sperm Transport;System;Technology;Testing;Time;Transgenic Organisms;United States National Institutes of Health;Universities;Uterus;Workload;animal care;animal colony;animal facility;biobehavior;cost;design;falls;gene function;human disease;improved;innovation;mouse model;novel;preservation;pup;repository;sperm cell;sperm cryopreservation;sperm viability;tool;welfare

public_health_relevance:
NARRATIVEThe ability to genetically modify the laboratory mouse is now producing an ever-rising number of increasinglyvaluable and unique strains to investigate human disease. While maintaining these mouse strains has becomea significant budgetary commitment cryopreservation of strains in sperm repositories has proven successful asa means to permanently and economically preserve them. ParaTechs is developing a cryopreservation andinsemination (C&I) device for the purpose of integrating cryopreservation storage shipping and strain recoveryby non-surgical artificial insemination; providing a fast convenient and easy to use method in mice at aconsiderably reduced cost.


application_id: 9985093
project_number: 5F31DC017660-03
project_title: Connectivity of periperal taste neurons
administering_ic: NIDCD
award_notice_date: 2020-08-21
opportunity_number: PA-18-671
application_type: 5
activity_code: F31
ic: DC
serial_number: 017660
program_official: RIVERA-RENTAS, ALBERTO L
project_start_date: 2018-09-01
project_end_date: 2021-11-30
study_section: ZDC1-SRB-R(36)
contact_pi_person_id: 15039557
contact_pi: OHMAN, LISA C
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractWhile the function of taste neurons (that connect taste receptor cells to the brain) has been well-studiedalmost nothing is known about individual taste neuron morphology or peripheral connectivity. Specifically it isunclear how many taste receptor cells provide input to a single neuron or even if those receptor cells are all thesame type. This lack of knowledge contributes to our relatively poor understanding of peripheral taste codingmechanisms. This project will use a combination of sparse cell genetic labeling and serial blockface scanningelectron microscopy (SBF-SEM) to 1) examine the number of taste receptor cells likely contacted by chordatympani neurons of differing complexity 2) determine if individual neurons contact receptor cells of the sametype or more than one type. I will accomplish these goals via three specific Aims. In Aim 1 I will determine ifthere are any structural motifs present at synapses or non-synaptic structural connections using SBF-SEMwhich can also be identified in 3-D confocal images of sparsely labeled nerve fibers and taste receptor cells.The goal is to permit better interpretation of the anatomical relationships between receptor cells and nervefibers at the light level. In Aim 2 I will reconstruct separate fibers entering the taste bud using SBF-SEM whichwill determine the rules of connectivity of simply vs. sparsely branched fibers within the fungiform taste bud.These data will be compared with the contacts identified using image analysis software at the light levelbetween individual fibers entering the taste bud. In Aim 3 I will analyze the morphology of whole chordatympani nerve fibers innervating anywhere from 1 to 7 taste buds and relate their branching complexity to thenumber and types of peripheral contacts made with taste receptor cells. Together these experiments will testthe hypothesis that heavily branched neurons contact many more taste receptor cells of multiple typescompared to simply branched neurons which will contact only a few receptor cells of a single type. This projectwill be the first to examine the peripheral connectivity of individual chorda tympani neurons and may reveal ananatomical substrate for the physiological finding that some neurons are narrowly tuned (respond to one tastestimulus) whereas others are broadly tuned (respond to multiple taste stimuli). Determining the peripheralconnectivity of individual neurons will likely inform future experiments designed to look at taste coding. Thesebaseline data for the normal connectivity of the peripheral taste system can be used to compare the potentialdisruption of connectivity that may result from disease states or manipulations of molecular factors regulatingthe formation of these connections.

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

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


application_id: 9984862
project_number: 5R01CA208343-04
project_title: Altered Lipid Metabolism as a Novel Target for Colon Cancer Treatment
administering_ic: NCI
award_notice_date: 2020-07-31
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 208343
program_official: TIMMER, WILLIAM C
project_start_date: 2017-08-01
project_end_date: 2022-07-31
study_section: Clinical Oncology Study Section[CONC]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: GAO, TIANYAN
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Altered cellular metabolism has been widely recognized as an emerging hallmark of cancer. Althoughrecent advances in cancer metabolism research have begun to elucidate how metabolic changes supportcancer cell growth and survival alterations in fatty acid (FA) metabolism in cancer cells have received lessattention. Increasing evidence has suggested that increased FA biosynthesis is needed not only toaccommodate high rates of proliferation by providing building blocks for membrane synthesis but also toenhance the ability of cancer cells to defend against oxidative stress- or chemotherapy-induced cell death bychanging membrane lipid composition. Studies from our laboratories and others have demonstrated that FAsynthase (FASN) a key enzyme of de novo lipid biosynthesis is significantly upregulated in colorectal cancer(CRC). Our in vivo studies demonstrate that RNAi-mediated inhibition of FASN markedly reduces lung andhepatic CRC metastases and inhibits tumor angiogenesis. Collectively our studies indicate FASN may serveas a potential target for novel therapeutic agents. Recently several orally-available reversible potent andselective FASN small molecule inhibitors have been developed by our collaborator 3-V Biosciences. Theseagents have excellent pharmaceutical profiles and achieve antitumor effects at tolerated doses in a broadrange of tumors including non-small cell lung cancer ovarian and triple negative breast cancers. Thetranslational goal of our project is to define the metabolic adaptations that occur in colon cancer and toconduct a clinical trial to evaluate the effect of FASN inhibitor TVB-2640 on modulating cellular metabolismand proliferation in colon cancer patients. The central hypothesis for our proposal is that upregulation ofFASN expression and activity occurs in a subset of colon cancer patients; therefore these individuals wouldbenefit from a therapeutic approach that includes targeted inhibition of de novo lipogenesis. The followingSpecific Aims are proposed: 1) to determine the effect of altered FASN expression on metabolic reprogramingin colon cancer; 2) to delineate the anti-proliferative effect of FASN inhibition using patient-derived xenograft(PDX) models of colon cancer; and 3) to perform a pilot clinical trial in collaboration with 3-V Biosciences toassess pharmacodynamic effects on metabolic endpoints following short-term treatment with a novel FASNinhibitor (TVB-2640) prior to colon resection. Our highly collaborative group has the requisite expertiseinnovative model systems state-of-the-art technology and novel inhibitors to make rapid progress that willsignificantly advance our understanding of the FASN-mediated metabolic alterations of colon cancers andpotentially provide novel treatment strategies based on a more focused and personalized approach.

project_terms:
Acute;Address;Apoptosis;Attention;Behavior;Benign;Biological;Biological Models;Biological Sciences;Cancer Cell Growth;Cancer Etiology;Carnitine;Cell Death;Cell Proliferation;Cell Survival;Cells;Cessation of life;Clinical Trials;Collaborations;Colon;Colon Carcinoma;Colorectal Cancer;DNA Sequence Alteration;Development;Dose;Enzymes;Epithelial Cells;Etiology;Excision;Fatty Acids;Fatty-acid synthase;Future;Glucose;Glycolysis;Goals;Growth;Hepatic;Individual;Laboratories;Lead;Lipids;Lung;Malignant - descriptor;Malignant Neoplasms;Measures;Mediating;Membrane Lipids;Metabolic;Metabolism;Mitochondria;Mucous Membrane;Non-Small-Cell Lung Carcinoma;Oncogenic;Oral;Ovarian;Oxidative Stress;Palmitates;Patients;Pharmacodynamics;Pharmacologic Substance;Phospholipids;Production;RNA Interference;Research;Resected;Respiration;Signal Pathway;Slice;Techniques;Technology;Therapeutic;Therapeutic Agents;Tissues;Triglycerides;Tumor Angiogenesis;United States;Up-Regulation;Warburg Effect;Xenograft Model;Xenograft procedure;antitumor effect;base;beta catenin;cancer cell;cell growth;cell transformation;chemotherapy;colon cancer patients;colon cancer treatment;colorectal cancer metastasis;colorectal cancer progression;experimental study;extracellular;fatty acid biosynthesis;fatty acid metabolism;in vivo;inhibitor/antagonist;innovation;lipid biosynthesis;lipid metabolism;membrane synthesis;metabolomics;multidisciplinary;neoplastic;neoplastic cell;new therapeutic target;novel;novel therapeutics;overexpression;patient subsets;personalized approach;randomized placebo-controlled clinical trial;response;secondary endpoint;small molecule inhibitor;stable isotope;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor metabolism;tumorigenesis

public_health_relevance:
PROJECT NARRATIVEColorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Alteredcellular metabolism is required to drive tumorigenesis and progression. Our study will define the metabolicadaptations associated with increased fatty acid synthase (FASN) expression in colon cancer patients anddelineate the subset of patients who may benefit from treatment with FASN inhibitors.


application_id: 9984651
project_number: 1R21AI147139-01A1
project_title: Regulation of infection-associated protein expressed by the Lyme disease spirochete DnaA protein
administering_ic: NIAID
award_notice_date: 2020-02-14
opportunity_number: PA-19-053
application_type: 1
activity_code: R21
ic: AI
serial_number: 147139
suffix: A1
program_official: BOWDEN, NADINE
project_start_date: 2020-02-14
project_end_date: 2022-01-31
study_section: Special Emphasis Panel[ZRG1 IDM-B (80)]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACTVector-borne pathogens such as Borrelia burgdorferi the agent of Lyme disease produce different proteinsduring infection of the mammalian host and the arthropod vector. These include distinct surface proteins tointeract with the variety of tissues that are encountered. In addition vector-borne bacteria must sense whenthevectorisfeedingonahostandefficientlycoordinatetransmissionprocesses.We discovered that several key infection-associated proteins that are produced during tick feeding andtransmission can be induced in culture by increasing the rate of bacterial replication. A model proposes thatthis correspondstothedramatic increase in growth rate of B. burgdorferi whenatick begins tofeed onblood.We found that the master regulator of chromosomal replication the DnaA protein binds adjacent to thetranscriptional promoters of loci that encode two global regulatory proteins. Both of those regulatory proteinsdirecttheproductionofsurfaceproteinsthatcontributetomammalianinfectionprocesses.DnaAhomologsareknown to regulate transcription in E. coli and other bacterial species. We hypothesize that DnaA serves toconnectborrelialreplicationwithproductionofinfection-associatedproteins.The planned studies will critically test that hypothesis by identifying DnaA-binding sites throughout the B.burgdorferi genome by chromatin immunoprecipitation - sequencing (ChIP-Seq) characterizing new DnaA-regulatedlociandbiochemicallydefiningfactorsinvolvedwithDnaA-binding.Altogether results ofthese studies will characterizea novel regulon of theLyme diseasespirocheteprovidingsubstantialnewinsightonthebacteriasphysiologyandinfectiousmechanisms.

project_terms:
Affect;Affinity;Anti-Bacterial Agents;Antibiotics;Arthritis;Arthropod Vectors;Asia;Bacteria;Base Sequence;Binding;Binding Proteins;Binding Sites;Biochemical;Biology;Blood;Borrelia;Borrelia burgdorferi;Canada;Centers for Disease Control and Prevention (U.S.);Cessation of life;ChIP-seq;Consensus;DNA;Development;Disease;Escherichia coli;Europe;Facial paralysis;Failure;Funding;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genome;Growth;Human;Immunocompetent;Incidence;Infection;Investigation;Ligands;Link;Lyme Disease;Mammals;Membrane Proteins;Meningitis;Modeling;Nodal;Optic Neuritis;Order Spirochaetales;Organ;Physiology;Preventive vaccine;Process;Production;Promoter Regions;Proteins;Regulation;Regulon;Role;Series;Site;Symptoms;Testing;Ticks;Tissues;Virulence;Virulence Factors;Work;feeding;genetic regulatory protein;genome-wide analysis;human disease;insight;novel;pathogen;promoter;protein E;tick feeding;transmission process;treatment duration;vector;vector tick;vector-borne;vector-borne pathogen

public_health_relevance:
PROJECTNARRATIVEDuring transmission from tick-to-mammal the Lyme disease spirochete Borrelia burgdorferi produces adistinct repertoire of surface proteins that are critical for mammalian infection. Our studies indicate that themaster controller of B. burgdorferi chromosomal replication the DnaA protein is involved with regulation of atleast some of those transmission-induced proteins. The proposed studies will identify DnaA-binding sitesthroughout the B. burgdorferi genome functionally characterize novel DnaA-regulated loci and biochemicallydefinethemechanismsbywhichDnaAinteractswithitstargetDNAs.


application_id: 9984349
project_number: 5R01DK074720-13
project_title: Novel mechanisms involving complement cascade in stem cell trafficking
administering_ic: NIDDK
award_notice_date: 2020-07-02
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 074720
program_official: ROY, CINDY
project_start_date: 2007-03-01
project_end_date: 2022-06-30
study_section: Molecular and Cellular Hematology Study Section[MCH]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
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:
Modified Project Summary/Abstract SectionThe main hypothesis of this competing renewal is based on new exciting data that further supports the pivotalrole of the complement cascade (ComC) and other elements of innate immunity in the mobilization ofhematopoietic stem/progenitor cells (HSPCs). The ComC is activated by the i) classical ii) mannan-bindinglectin (Mbl) and iii) alternative pathways and as we already reported mice that lack the common distalcomponent of the ComC (C5/ mice) are poor mobilizers. To our surprise however we found that mice thatdo not activate the classical ComC (C1q/ mice) are normal mobilizers. This discrepancy is now explained byour latest results that show the pivotal involvement of the Mbl-dependent ComC pathway and not the classicalpathway in mobilization. We also recently found that two stress-induced enzymes heme oxygenase 1 (HO-1)and inducible nitric oxide synthetase (iNOS) are negative regulators of cell migration. Based on these findingswe have assembled a proposal that in a comprehensive way addresses the involvement of elements of innateimmunity (ComC Gr-1+ granulocytes/monocytes naturally occurring antibodies) in the mobilization of HSPCs.In three interrelated specific aims we address the crucial: i) inititation ii) amplification and execution phases ofmobilization. Specific Aim 1. The initiation phase of mobilization is explained by Mbl-mediated ComCactivation. We have maintained that the classical ComC activation pathway plays a crucial role in triggeringmobilization. However as we discovered recently it is not the classical but the Mbl pathway that is crucial inthis process. The main target cells for mobilizing agents are Gr-1+ cells which in addition to proteolytic andlipolytic enzymes also secrete ROS and danger-associated molecular pattern molecules (DAMPs). Whileproteolyic and lipolytic enzymes perturb the retention of HSPCs in bone marrow (BM) niches ROS-exposedneoepitope antigens bound by naturally occurring IgM antibodies and DAMPs released from Gr-1+ cells arerecognized by the circulating pattern recognition receptor (PRR) Mbl which via mannan-binding lectin serineproteases (MASPs) activates the ComC and coagulation cascade (CoaC). Specific Aim 2. The amplificationphase of mobilization - the generation of C5 convertase. Since C5 cleavage is crucial for egress of HSPCsfrom BM the main function of this phase is generation of C5 convertase activity. This enzyme is generated asa result of C3 cleavage which provides elements of classical C5 convertase and additionally by thrombinwhich has C5 convertase-like activity. The amplification phase is also modulated by a spontaneousamplification loop of C3 activation and by possible involvement of an alternative pathway of ComC activationand will be studied in detail in this aim. Specific Aim 3. Execution phase of ComC-mediated mobilization.Our recent results show that egress of HSPCs from BM is negatively controlled by HO-1 and iNOS which arenegative regulators of cell migration. We will focus on the molecular mechanisms of this phenomenon. It isexpected that these results will be translated into the development of better mobilization protocols.1

project_terms:
Address;Alternative Complement Pathway;Animal Model;Antibodies;Blood Circulation;Blood Vessels;Bone Marrow;Bone Marrow Transplantation;CXCR4 Receptors;CXCR4 gene;Cell Adhesion Molecules;Cell physiology;Cells;Chemotactic Factors;Circadian Rhythms;Coagulation Process;Complement;Complement 1q;Complement 3 Convertase;Complement Activation;Complement Factor H;Data;Defect;Development;Distal;Elements;Engraftment;Enzymes;Generations;Growth Factor;Hematology;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Mobilization;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Homing;Immunoglobulin M;Integrin alpha4beta1;Integrins;Ligands;Mannose Binding Lectin;Mediating;Molecular;Mus;Natural Immunity;Nitric Oxide;Nitric Oxide Synthase;Pathway interactions;Patients;Pattern;Pattern recognition receptor;Pharmacology;Phase;Physiological;Play;Process;Properdin;Protocols documentation;Reporting;Research;Role;Stress;Testing;Thrombin;Translating;Transplantation;Vascular Cell Adhesion Molecule-1;antigen binding;base;cell motility;conditioning;granulocyte;heme oxygenase-1;leukemia;mannose-binding protein-associated serine proteases;monocyte;neoantigens;novel;novel therapeutics;peripheral blood;pre-clinical;public health relevance;reconstitution;small molecule inhibitor;stem cells;trafficking

public_health_relevance:
Modified Public Health Relevance SectionIn this proposal we will focus on the role of a major component of innate immunity namely the complementcascade in the trafficking of hematopoietic stem/progenitor cells. This application will allow us to betterunderstand this process and will lead to the development of novel therapeutic strategies to treat patients withleukemia and inborn defects of hematopoiesis by employing hematopoietic stem cell transplants.2


application_id: 9984228
project_number: 5R21AG064626-02
project_title: Role of tau circular RNAs in tauopathies
administering_ic: NIA
award_notice_date: 2020-04-28
opportunity_number: PA-18-489
application_type: 5
activity_code: R21
ic: AG
serial_number: 064626
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2019-08-01
project_end_date: 2022-04-30
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
project_abstract:
Microtubule associated protein tau (encoded by the MAPT gene) is a critical component in the etiology ofAlzheimer's Disease (AD) and other tauopathies in which tau aggregates in neurofibrillary tangles.However the basic regulation of MAPT gene expression is still imperfectly understood. It is not clearwhat causes the formation of neurofibrillary tangles but tauopathic conditions show changes in taumRNA isoforms generated through alternative pre-mRNA processing. Furthermore mutationschanging alternative splicing of MAPT cause frontotemporal dementia underscoring the importance oftau pre-mRNA processing. We have identified human-specific circular RNAs (circRNAs) formed by thetau-encoding mRNA from the MAPT locus generated by backsplicing of exon 10. Backsplicing formingcircRNAs occurs when pre-mRNA forms loops which is aided by primate-specific Alu elements inhumans. The ground-breaking preliminary data demonstrate conclusive evidence of tau circRNAsderived from human brain samples. We hypothesize that Alu elements help forming human specificMAPT circRNAs that likely after RNA methylation could be translated into proteins containingmultimers of microtubule binding sites. We will use (a) minigenes in tissue culture for molecularmechanistic studies to test whether MAPT circRNAs are translated into proteins after RNA methylationand to test tau circRNA's interaction with other RNAs and proteins. These data will be correlated withassessments in human brain tissue across the disease spectrum from pathologically-confirmed normalMCI (mild cognitive impairment) and AD cases. To (b) test tau circRNA's physiological relevance wehave generated zebrafish lines expressing genomic parts of human MAPT that form circular RNAs inneurons and observed abnormal neurons after introduction of FTDP-17 mutants in constructs thatexpress only circRNAs. We will determine the expression of transgenic circRNAs their encodedproteins possible sequestration of other RNAs and proteins changes in neuron morphology taupathology and correlate these data with spatial memory tests that take stress into account. These arethe first reports and studies of human tau circular RNAs. These studies are significant as they couldprovide a novel human-specific molecular mechanism to alter MAPT gene expression and possibly anew mechanism to promote the formation of tau aggregates. Our studies capitalize on the excellentbrain bank at the University of Kentucky headed by Co-I Dr. Nelson and the zebrafish expertise of Co-I Dr. Blackburn.

project_terms:
Adenine;Adenosine;Alternative Splicing;Alu Elements;Alzheimer's Disease;Alzheimer's disease pathology;Amino Acids;Animal Model;Antisense Oligonucleotides;Autopsy;Binding;Binding Proteins;Binding Sites;Biological Assay;Biology;Brain;Cells;Cellular Stress;Clinical;Data;Development;Disease;Elements;Epigenetic Process;Etiology;Event;Excision;Exons;FTD with parkinsonism;Fishes;Freezing;Frontotemporal Dementia;Gene Expression;Generations;Genes;Genetic;Genomics;Human;Interdisciplinary Study;Kentucky;Knowledge;Lead;Letters;Link;MAPT gene;Mass Spectrum Analysis;Messenger RNA;Methylation;Microtubules;Modeling;Modification;Molecular;Molecular Weight;Morphology;Motor Neurons;Mutation;Nerve Degeneration;Neurodegenerative Disorders;Neurofibrillary Tangles;Neurons;Open Reading Frames;Pathologic;Pathology;Peptide Initiation Factors;Physiological;Play;Polyadenylation;Polymers;Primates;Protein Isoforms;Proteins;RNA;RNA Processing;RNA methylation;Reader;Regulation;Reporting;Research;Ribosomes;Role;Sampling;Site;Stress;Structure;Tauopathies;Terminator Codon;Testing;Transgenic Organisms;Translating;Translations;Universities;Zebrafish;biobank;brain tissue;circular RNA;mRNA Precursor;mild cognitive impairment;mutant;nervous system disorder;neurochemistry;neurofibrillary tangle formation;neuropathology;novel;novel therapeutics;overexpression;paired helical filament;programs;protein expression;recruit;spatial memory;tRNA Methyltransferases;tau Proteins;tau aggregation;tau function;tissue culture

public_health_relevance:
The microtubule associated protein tau is a protein central for the pathology ofAlzheimer's disease. We unexpectedly discovered that the tau gene generates circularRNAs and will analyze their generation and molecular function in cells and zebrafish.


application_id: 9983679
project_number: 5R01DK119619-03
project_title: Exercise-induced skeletal muscle exosomes promote adipocyte lipolysis
administering_ic: NIDDK
award_notice_date: 2020-08-11
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: DK
serial_number: 119619
program_official: HAFT, CAROL R
project_start_date: 2018-09-19
project_end_date: 2023-07-31
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
other_pis: PETERSON, CHARLOTTE A.
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SummaryExosomes are small extracellular vesicles that have emerged over the past few years as novel mediators ofintercellular communication. We recently reported that exosomes released from activated skeletal muscle stemcells regulate extracellular matrix remodeling during muscle hypertrophy through the transport of skeletalmuscle-specific miR-206 to fibroblasts. The discovery of this novel role for muscle stem cells inspired us tofurther explore if exosomes are released from muscle cells in response to resistance exercise and if so theirimpact on target tissues. Based on preliminary data we hypothesize that enhanced adrenergic signaling inadipose tissue in response to resistance exercise is mediated in part by exosomal muscle-specific miR-1activation of 3-adrenergic receptor (3-AR) expression. In particular we have developed a working model inwhich exercise causes skeletal muscle cells to release exosomes containing muscle-specific miR-1 thattransport miR-1 to adipocytes. As a result CAATT/enhancer binding protein alpha (C/EBP) activates 3-ARgene expression through miR-1-mediated repression of AP-2 thereby enhancing catecholamine sensitivity ofadipocytes and promoting the release of fatty acids and glycerol into the circulation as the result of increasedlipolysis. The purpose of the proposed studies is to test our working model by pursuing the following aims inboth mice and humans: Aim 1: Determine if exercise-induced exosomal miR-1 enhances adipocyte adrenergicsignaling through activation of 3-AR expression; Aim 2: Determine if human skeletal muscle fiber-derivedexosomes directly promote adipocyte lipolysis through enhanced -adrenergic signaling; Aim 3: Determine ifan acute bout of resistance exercise in humans promotes miR-1-mediated adipocyte lipolysis. Our preliminarydata provide the first evidence demonstrating that resistance exercise-induced exosomes mediate thebeneficial effect of exercise on adipose tissue metabolism. A better understanding of the role of exosomes inthe systemic adaptations that occur in response to resistance exercise are expected to provide thefundamental knowledge necessary to use exosomes as a platform for the delivery of exercise mimetics to treatobesity.

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

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


application_id: 9983555
project_number: 5U01AA026980-03
project_title: Alcoholic Hepatitis Network 3/9 University of Louisville
administering_ic: NIAAA
award_notice_date: 2020-06-25
opportunity_number: RFA-AA-18-002
application_type: 5
activity_code: U01
ic: AA
serial_number: 026980
program_official: GAO, PETER
project_start_date: 2018-08-01
project_end_date: 2023-06-30
study_section: ZAA1-JJ(01)R
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTAlcoholic hepatitis (AH) is a leading cause of liver-related morbidity and mortality with a remarkable paucity ofeffective therapeutics. This application represents a coordinated submission of several NIAAA-fundedconsortia that have come together as the Alcoholic Hepatitis Network (AlcHepNet). Collectively the networkwill synergize efforts and expertise to better understand AH and develop novel effective and safe therapies forsevere AH. Buttressing that goal the overarching aims of this new consortium are to: 1) perform studies tobetter understand the pathogenesis and main determinants of outcomes particularly in severe AH; 2) identifynovel targets for therapy of AH and 3) perform phase 2B studies of compounds that are already FDAapproved and available and can be repurposed as safe and effective therapies for severe AH. Under theumbrella of these larger aims the aims of this AlcHepNet proposal are to: Aim 1. Conduct a prospectivemulticenter observational study of patients with AH and suitable controls that serves as thefoundation for conducting novel mechanistic and therapeutic studies. We will consolidate and extend ourlongitudinal database containing 1) clinical and laboratory information and 2) bio-sample repository fromsubjects with AH of varying severity and matched controls. This database will serve three functions: (a) provideunique information on the outcomes and pathobiology of AH (b) support translational research designed toidentify novel targets for treatment and (c) serve as a catalyst to develop systems biology-based informatics-integrated databases that will serve as a resource for all researchers interested in AH; Aim 2. Perform amulticenter prospective randomized phase 2B clinical trial of granulocyte colony stimulating factor G-CSF versus Anakinra (plus zinc) versus standard medical therapy with Prednisone in patients withsevere AH. This aim will test the hypothesis that both active treatment arms with G-CSF and the IL-1 receptorantagonist Anakinra (plus zinc) are superior to the standard of care (i.e. Prednisone) in patients with severeAH. The choice of these agents is based on: 1) literature demonstrating a role for inflammation andinflammasome activation in severe AH 2) several pilot studies demonstrating therapeutic benefit with G-CSFand 3) interim analysis of an ongoing trial suggesting a mortality benefit with Anakinra in patients with AH. Thisphase 2B efficacy trial will be conducted across nine clinical centers and coordinated by two Data CoordinatingCenters (DCCs). The primary endpoint will be mortality at Day 90. The investigators and the AlcHepNet areuniquely positioned to perform the proposed study given the substantial breadth depth and history ofexpertise related to AH clinical trial conduct and related therapeutic development. By testing promisingtherapies for AH and collecting well-annotated patient samples and datasets this proposal will have a strongand lasting impact on the field.!

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

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


application_id: 9983539
project_number: 5U01AA026934-03
project_title: Pilot Trial UO1 DUR-928
administering_ic: NIAAA
award_notice_date: 2020-06-24
opportunity_number: RFA-AA-18-005
application_type: 5
activity_code: U01
ic: AA
serial_number: 026934
program_official: GAO, PETER
project_start_date: 2018-09-25
project_end_date: 2023-06-30
study_section: ZAA1-JJ(01)R
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AH is an acute form of alcoholic liver disease and includes a spectrum that ranges from mild injury to severelife threatening injury. The prevalence of AH has not been accurately determined; it is believed to occur in 10%to 35% of heavy drinkers. On histology AH is characterized by infiltration of the liver by inflammatory cells andhepatocellular injury. AH is usually associated with progressive fibrosis in the presence of continued alcoholabuse. No new drugs for AH have been successfully developed since the introduction of corticosteroids as atreatment in the early 1970s. Corticosteroids have been utilized as a standard of care in various treatmentguidelines for patients with severe AH. Pentoxifylline has also been used because of its safety but severalwell-conducted studies have not supported the efficacy of pentoxifylline for the treatment of severe AH.Importantly a recent study has questioned the efficacy of both prednisone and pentoxifylline in the treatment ofAH. Mortality at 6 months was similar in patients on either prednisone pentoxifylline or both as compared withplacebo. Therefore there is a need for novel therapies. DUR-928 is an endogenous intracellular regulatorymolecule and sulfated oxysterol: 5-cholesten-3 25-diol 3-sulfate (25HC3S). DUR-928 is under developmentfor multiple indications including treatment of chronic metabolic disease such as NAFLD/NASH and PSC andtreatment of acute organ injuries such as AKI and AH. DUR-928 is able to lower intracellular lipidaccumulation regulate inflammatory responses and improve cell survival. Based on the current accumulatedknowledge of DUR-928 biology we believe that DUR-928 represents a novel therapeutic agent for AH with anexcellent safety profile (is produced endogenously). In this PILOT UO1 we propose 2 independent but linkedstudies.Study #1: An open-label dose escalation study to assess the safety pharmacokinetics and efficacy of DUR-928 in patients with Moderate Alcoholic Hepatitis.Study #2: An open-label dose escalation study to assess the safety pharmacokinetics and efficacy of DUR-928 in patients with Severe Alcoholic Hepatitis.

project_terms:
25-hydroxycholesterol;ADD-1 protein;Acute;Acute Alcoholic Hepatitis;Acute Renal Failure with Renal Papillary Necrosis;Adrenal Cortex Hormones;Agonist;Alcohol abuse;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Anorexia;Apoptosis;Biology;Cell Nucleus;Cell Survival;Cholesterol;Cholesterol Homeostasis;Chronic;Clinical Data;Cytoplasm;Data;Development;Diet;Disease;Dose;Drug Kinetics;Enzymes;FDA approved;Failure;Fatty acid glycerol esters;Fibrosis;Glucocorticoids;Glycols;Hepatic;Hepatocyte;Hepatomegaly;Histology;Hospitals;Human;Hydroxylation;Icterus;In Vitro;Infection;Infiltration;Inflammatory;Inflammatory Response;Injury;Intracellular Accumulation of Lipids;Knowledge;Life;Link;Lipids;Liver;Liver Regeneration;Malaise;Malnutrition;Metabolic Diseases;Mitochondria;Morbidity - disease rate;Natural regeneration;Pathway interactions;Patients;Pentoxifylline;Placebos;Prednisone;Prevalence;Safety;Signal Pathway;Signal Transduction;Sterols;Sulfate;Syndrome;Systemic Inflammatory Response Syndrome;Therapeutic Agents;base;cell injury;effective therapy;hepatocellular injury;high risk;improved;in vivo;lipid biosynthesis;lipid metabolism;liver cell proliferation;macrophage;mortality;mouse model;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel therapeutics;open label;organ injury;overexpression;pilot trial;pre-clinical;preclinical study;standard of care;sulfotransferase;treatment guidelines

public_health_relevance:
Alcoholic Hepatitis (AH) is an acute form of alcoholic liver disease and includes a spectrum that ranges frommild injury to severe life threatening injury. Based on the current accumulated knowledge of DUR-928 biologywe believe that DUR-928 represents a novel therapeutic agent for AH with an excellent safety profile (isproduced endogenously). In this PILOT UO1 we propose 2 independent but linked studies in moderate andsevere AH.


application_id: 9983526
project_number: 5U01AA026936-03
project_title: Lipid metabolites can both potentiate and treat alcoholic hepatitis
administering_ic: NIAAA
award_notice_date: 2020-06-25
opportunity_number: RFA-AA-18-003
application_type: 5
activity_code: U01
ic: AA
serial_number: 026936
program_official: DUNTY, JR, WILLIAM
project_start_date: 2018-09-22
project_end_date: 2023-06-30
study_section: ZAA1-JJ(01)R
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: JOSHI-BARVE, SWATI
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Alcoholic Hepatitis (AH) is an important cause of morbidity mortality and health care costs. Only a limitednumber (<25% of those who drink heavily) develop this more advanced liver disease. Thus there must bemodifying factors that either prevent or facilitate disease activity/progression. Dietary fat represents a criticalmacronutrient disease modifier for AH. The American diet has increased dramatically in omega 6-polyunsaturated fat (PUFA) content and has a very imbalanced omega-6:omega-3 ratio. In pre-clinical rodentmodels dietary PUFA enriched in linoleic acid (LA) promotes alcohol-induced liver damage. Mice fed analcohol + high PUFA (LA) diet generate toxic oxidized products of linoleic acid metabolism (OXLAMs) as wellas a highly reactive and toxic aldehyde lipid peroxidation product (i.e. acrolein) which causes ER stress andliver injury. This high PUFA diet plus alcohol in rodents also causes gut dysbiosis and decreases levels of thecritical short chain fatty acid butyrate. We postulate that human subjects with AH will have (i) increasedlevels of the lipid peroxidation product acrolein (toxic aldehyde) (ii) increased levels of OXLAMs and(iii) altered gut flora with decreased fecal levels of butyrate and butyrate producing bacteria all ofwhich correlate with severity of liver injury. We also postulate that certain lipid products (resolvinsbutyrate) will be therapeutic in AH. We address this hypothesis with three specific aims using unique humansamples generated through the NIAAA-funded U01-consortium in AH.Specific Aim #1: Determine whether levels of acrolein metabolites and adducts in serum/urine/tissue areelevated in AH and correlate these levels with biomarkers of gut permeability hepatic cell death/injury anddisease severity.Specific Aim #2: Determine whether serum levels of OXLAMS are elevated in human AH and correlatethose levels with biomarkers of severity of AH hepatocyte death and gut permeability. Determine whetherserum levels of resolvins are decreased in AH and whether resolvin administration to AH blood ex vivodecreases proinflammatory cytokines.Specific Aim #3: Determine fecal levels of short-chain fatty acids (focusing on butyrate) in patients with AHand determine abundance of butyrate-producing bacteria in patients with acute AH and after recovery withabstinence. We will also determine the effects of different doses of butyrate on ex-vivo cytokine production inAH patients.!

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

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


application_id: 9983366
project_number: 3UT2GM130174-02S1
project_title: Southeast Xlerator Network
administering_ic: NIGMS
award_notice_date: 2019-09-05
opportunity_number: RFA-GM-18-001
application_type: 3
activity_code: UT2
ic: GM
serial_number: 130174
suffix: S1
program_official: ARORA, KRISHAN
project_start_date: 2018-09-01
project_end_date: 2021-08-31
study_section: Special Emphasis Panel[ZRG1-IMST-K(14)B]
contact_pi_person_id: 15333536
contact_pi: WILLMOT, JACQUELINE
other_pis: GIERSCH, RICHARD F;KRENTSEL, EUGENE ;MCCLURE, IAN D;SAUNDERS, ROBERT
congressional_district: 03
department: Unavailable
primary_duns: 080949252
primary_uei: JYN1A3M4LD29
duns_number: 080949252
uei: JYN1A3M4LD29
fips: US
organization_id: 10048196
organization_name: XLERATEHEALTH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402023346
organization_country: UNITED STATES
project_abstract:
The Southeast XLerator Network proposes to create a networked and easily accessible regionaltechnology transfer accelerator hub (XLerator Hub or Hub) to share best practicesdisseminate education content and offer products services facilities and other resourcesconnected through both physical and online platforms for innovators and trainees in the SoutheastIDeA states. Led by XLerateHealth LLC an SBA award-winning healthcare-focused technologyaccelerator the Hub will 1) bridge the divide between great ideas and the marketplace byleveraging and connecting existing resources and unique expertise assets across all participatingentities in the Southeast IDeA state region 2) fill the gaps that constitute barriers to efficientcommercialization among partner institutions and 3) deliver the necessary resources educationand business networks to foster and sustain a culture of entrepreneurship across the region. Thisproject will address significant disparities and lack of access to resources talent and capital inrespective local commercialization ecosystems for biomedical technologies that are pervasiveacross the Southeast IDeA state region making the rates of technology transfer andcommercialization of academic research discoveries in this region suboptimal. The Hubobjectives/ core functions are: 1. To improve knowledge and understanding by innovators about how technologies are brought to market. 2. To improve knowledge and understanding by accelerators and technology transfer offices about the unique commercialization pathways of various biomedical technologies 3. To facilitate access to technology/product development and commercialization resources required for early-stage technology advancement and later-stage product development 4. To help close the gap(s) in funding (a) between basic research discoveries and scientific proof of feasibility and (b) between exhaustion of grant funding and private capital required to generate products and revenues. 5. To commercialize new innovation in pharmaceuticals medical devices healthcare IT and electronics and other biomedical technologies through entrepreneurship licensing and partnerships with established companies and additionally commercialize the Hubs platform programs and materials through access by other regions.The impact of the Hub will be increased market-ready technologies and patents more successfulstartups and increased biomedical technology acceleration.

project_terms:
Acceleration;Address;Adopted;Advocate;Astronomy;Award;Basic Science;Biological Sciences;Biomedical Technology;Businesses;Capital;Development;Economic Development;Ecosystem;Education;Electronics;Entrepreneurship;Evaluation;Faculty;Fostering;Funding;Goals;Grant;Health Sciences;Healthcare;Incubators;Industry;Institution;Intellectual Property;Kentucky;Knowledge;Leadership;Learning;Legal patent;Licensing;Medical Device;Medical Technology;Mentors;Outcome;Pathway interactions;Pharmacologic Substance;Phase;Privatization;Process;Puerto Rico;Research;Resources;Services;Small Business Innovation Research Grant;Small Business Technology Transfer Research;Structure;Survival Rate;Talents;Techniques;Technology;Technology Transfer;Trainers Training;Training;Training Programs;Training and Education;United States National Institutes of Health;Universities;Vision;West Virginia;commercialization;design;education resources;exhaustion;experience;improved;innovation;inter-institutional;off-patent;operation;product development;programs;public-private partnership;success;technology development;tool

public_health_relevance:
Project NarrativeThis project will significantly enhance commercialization knowledge increase market-ready technologies and patents create more successful startups and as a resultaccelerate biomedical technology commercialization in the Southeast IDeA region.


application_id: 9983150
project_number: 5R01HL135000-04
project_title: Role of myocyte Na+ dysregulation in diabetic heart disease
administering_ic: NHLBI
award_notice_date: 2020-07-13
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 135000
program_official: BUXTON, DENIS B
project_start_date: 2017-08-01
project_end_date: 2023-07-31
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
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
arra_indicator: N
project_abstract:
ABSTRACTType-2 diabetes (T2D) heightens the risk of heart failure arrhythmias and sudden cardiac death even in theabsence of vascular complications. However the underlying mechanisms are poorly understood. We proposethat a critical contributor to diabetic heart disease involves myocyte Na+ dysregulation. Maintenance of cardiacNa+ homeostasis is vital for preserving heart function. Elevated myocyte Na+ concentration ([Na+]i) causesoxidative stress and augments the sarcoplasmic reticulum (SR) Ca2+ leak thus amplifying the risk forarrhythmias and promoting heart dysfunction. Using a rat model of late-onset T2D (the HIP rat) that displaysmyocardial dysfunction and arrhythmias we recently found that [Na+]i is increased in T2D hearts.Unexpectedly higher [Na+]i seems to be caused by enhanced Na+ entry through the Na+-glucose cotransporterisoform 1 (SGLT1) a previously ignored player in cellular Na+ homeostasis. Furthermore we found higherSGLT1 expression in hearts from patients with T2D compared to lean non-diabetic individuals and in heartsfrom diabetic HIP rats vs. control rats. Cardiac-specific SGLT1 overexpression was recently shown to causehypertrophy and left-ventricular dysfunction while SGLT1 activation has been linked to the cardiomyopathycaused by mutations in the gene encoding the 2 subunit of AMP-activated protein kinase. Thus the evidencethat enhanced SGLT1 activity damages the heart is mounting but little is known about the underlyingmechanisms and its role in diabetic cardiomyopathy. Based on these findings we hypothesize that SGLT1upregulation contributes to the multifactorial mechanism driving cardiac remodeling in T2D by perturbingmyocyte Na+ dyshomeostasis. To test this overall hypothesis we will i) assess the role of SGLT1 activation inthe myocyte [Na+]i rise and consequent oxidative stress larger SR Ca2+ leak and spontaneousafterdepolarizations in T2D ii) test whether SGLT1 upregulation is a maladaptation of the myocardium toimpaired insulin-dependent glucose uptake and iii) assess whether SGLT1 and [Na+]i are elevated in heartsfrom humans with T2D. Experiments will combine fluorescence imaging electrophysiology biochemistry invivo assessment of heart function pharmacological tools T2D and transgenic animal models and humanstudies. By integrating physiological and pharmacological analyses in rat and human hearts this project willestablish whether SGLT1 activation and Na+ overload are key events in the pathology of diabetic heart diseaseand will identify SGLT1 as a new therapeutic target for cardiac complications in T2D patients.

project_terms:
5'-AMP-activated protein kinase;Animal Model;Animals;Arrhythmia;Automobile Driving;Biochemistry;Blood Vessels;Cardiac;Cardiomyopathies;Diabetes Mellitus;Electric Stimulation;Electrophysiology (science);Event;Genes;Glucose;Heart;Heart Diseases;Heart failure;Homeostasis;Human;Hyperglycemia;Hypertrophy;Impairment;Individual;Insulin;Insulin Resistance;Kidney;Left Ventricular Dysfunction;Link;Maintenance;Mediating;Messenger RNA;Mitochondria;Modeling;Mus;Muscle Cells;Mutation;Myocardial;Myocardial dysfunction;Myocardium;Na(+)-K(+)-Exchanging ATPase;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oxidative Stress;Pathology;Patients;Pharmacology;Phase;Physiological;Prediabetes syndrome;Protein Isoforms;Proteins;Rattus;Regulation;Rest;Risk;Role;Sarcoplasmic Reticulum;Structure;Testing;Thinness;Tissues;Transgenic Animals;Transgenic Mice;Translating;Up-Regulation;Work;base;cardioprotection;db/db mouse;diabetic;diabetic cardiomyopathy;experimental study;fluorescence imaging;glucose uptake;heart damage;heart function;heart preservation;improved;in vivo;insulin sensitizing drugs;insulin signaling;new therapeutic target;non-diabetic;overexpression;prevent;sudden cardiac death;tool

public_health_relevance:
NARRATIVEType-2 diabetes heightens the risk of heart failure arrhythmias and sudden cardiac death but the underlyingmechanisms are poorly understood and there is no specific treatment for heart disease in patients withdiabetes. Proposed work seeks to test the hypothesis that enhanced activity of the Na+-glucose cotransporter 1and myocyte Na+ dysregulation are critical contributors to diabetic cardiomyopathy. Thus this work mayidentify novel therapeutic targets for cardioprotection that are specifically tailored to patients with type-2diabetes.


application_id: 9983143
project_number: 5K22HL141299-03
administering_ic: NHLBI
award_notice_date: 2020-07-31
opportunity_number: PAR-16-267
application_type: 5
activity_code: K22
ic: HL
serial_number: 141299
program_official: HUANG, LI-SHIN
project_start_date: 2018-08-20
project_end_date: 2023-07-31
study_section: NHLBI Mentored Transition to Independence Study Section[MTI(JA)]
contact_pi_person_id: 14386534
contact_pi: GORDON, SCOTT M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-08-01
project_title:
The Role of High Density Lipoprotein Associated Protease Inhibitor Activity in Protection Against Atherosclerosis.

project_abstract:
Project Summary and AbstractHigh density lipoproteins (HDL) have a well-established inverse correlation with the occurrence ofcardiovascular disease. However the functional activities of HDL which mediate this protection arenot well understood. HDL are micellar complexes composed of lipids and an array of differentproteins which are likely to confer specific functions to the HDL particles that carry them. Of morethan 85 identified HDL associated proteins over 20% have known functions related to proteaseinhibition the majority of these are members of the Serine Protease Inhibitor (SERPIN) family ofproteins. This proposal will examine the structural interaction between the most abundant HDL-boundSERPIN alpha-1-antitrypsin (A1AT) and HDL particles and also the functional consequences of thisinteraction. Dr. Gordon will use individual particle electron tomography a novel molecular imagingtechnique to determine the structural details of the interaction between A1AT and HDL and to identifythe region of the A1AT protein involved in binding. Using reconstituted HDL enriched with A1AT Dr.Gordon will investigate the capacity of these particles to reduce vascular protease activity andsubsequent atherosclerosis development in a mouse model. Additionally a novel HDL targeting smallpeptide mimetic of A1AT will be developed and evaluated for its capacity to prevent atherosclerosisdevelopment and to stabilize existing plaque in an effort to prevent thrombus formation andsubsequent cardiovascular events such as heart attack stroke or pulmonary embolism. This work has been proposed by Dr. Scott Gordon a postdoctoral fellow of the National HeartLung and Blood Institute at the National Institutes of Health as part of an NHLBI K22 CareerTransition Award. Dr. Gordon performed his graduate studies on the composition and function of HDLand has extended his previous work in the current proposal. A team of experienced mentors with avariety of skills related to aspects of this proposal has been assembled by Dr. Gordon to assist in thesuccessful completion of the proposed research as well as the successful transition of Dr. Gordoninto an independent tenure track academic faculty position at a major research university in theUnited States.

project_terms:
ATP binding cassette transporter 1;Active Biological Transport;Acute;Acute-Phase Reaction;Anti-Inflammatory Agents;Apolipoprotein E;Arterial Fatty Streak;Arteries;Atherosclerosis;Binding;Biological Assay;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Career Transition Award;Cause of Death;Cell Culture Techniques;Cholesterol;Complex;Coronary Angiography;Coronary Artery Bypass;Data;Developed Countries;Development;Dimensions;Elastases;Endothelium;Event;Faculty;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Histologic;Human;Imaging Techniques;In Vitro;Individual;Inflammation;Inflammatory Response;Infusion procedures;LDL Cholesterol Lipoproteins;Label;Leukocyte Elastase;Lipids;Lipoprotein Binding;Maps;Mass Spectrum Analysis;Measures;Mediating;Mentors;Methionine;Methods;Morphology;Mus;Myocardial Infarction;National Heart Lung and Blood Institute;Oxides;Peptide Hydrolases;Peptides;Pharmaceutical Preparations;Plasma;Plasma Proteins;Population;Positioning Attribute;Postdoctoral Fellow;Production;Property;Protease Inhibitor;Protein Family;Proteins;Pulmonary Embolism;Reporting;Research;Residual state;Risk;Role;Rupture;Serine Proteinase Inhibitors;Site;Site-Directed Mutagenesis;Small Interfering RNA;Stroke;Structure;Testing;Therapeutic;Thrombus;Tissues;Transference;United States;United States National Institutes of Health;Universities;Untranslated RNA;Up-Regulation;Variant;Vascular Endothelium;Work;alpha 1-Antitrypsin;base;cardiovascular risk factor;crosslink;cytokine;elastase inhibitor;electron tomography;experience;experimental study;genetic variant;human subject;in vivo;knock-down;macrophage;member;men;molecular imaging;mouse model;neglect;neutrophil;novel;overexpression;oxidation;particle;peptidomimetics;preservation;prevent;protein degradation;protein function;public health relevance;reconstitution;research clinical testing;skills;study population;tenure track;tool;transcytosis;uptake

public_health_relevance:
Public Health Relevance StatementCardiovascular disease is the leading cause of death in developed countries and atherosclerosis orhardening of the arteries is responsible for the occurrence of the majority of cardiovascular eventssuch as heart attack and stroke. High density lipoproteins (HDL) also known as the goodcholesterol have an established correlation with reduced risk of cardiovascular events. This proposalfocuses on a specific sub-population of HDL and its protective potential against atherosclerosis.


application_id: 9982965
project_number: 5R01EY021580-09
project_title: Deciphering Inhibition of Visual Plasticity by NgR1
administering_ic: NEI
award_notice_date: 2020-08-17
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: EY
serial_number: 021580
program_official: GREENWELL, THOMAS
project_start_date: 2012-05-01
project_end_date: 2022-07-31
study_section: Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section[SPC]
contact_pi_person_id: 10356866
contact_pi: MCGEE, AARON W
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractThe visual system exhibits a heightened sensitivity to the quality visual experience during an interval late indevelopment termed the `critical period'. Discordant vision during the critical period is the cause of amblyopia aprevalent visual disorder in children. Treatment of amblyopia is most effective in children before the close ofthe critical period. Subsequently the flexibility with brain circuitry diminishes in adulthood and effective therapyis more difficult. In a mouse model of amblyopia disrupting normal vision by closing one (monoculardeprivation MD) for the duration of the critical period but not thereafter decreases visual acuity and perturbsthe normal eye dominance of neurons in visual cortex. The nogo-66 receptor gene (ngr1) is required to close the critical period. In ngr1 mutant mice plasticityduring the critical period is normal but it is retained in adult mice. Importantly ngr1 mutant mice spontaneouslyrecover visual acuity in this model of amblyopia. Our overall hypothesis is that recovery of acuity and eyedominance are independent. In the proposed research we take advantage of this extended critical period inngr1 mice to identify with location and mechanisms of plasticity that mediate recovery of acuity and eyedominance with a combination of conditional mouse genetics behavioural assays electrophysiologysophisticated repeated in vivo calcium imaging and laser-scanning photostimulation circuit mapping. We willbegin to unravel how plasticity within visual circuitry mediates recovery of visual function following earlyabnormal vision (MD) as well as how this plasticity is restricted to the critical period with these experiments. Inaddition to improving understanding of how experience-dependent plasticity changes the function of braincircuits these studies may reveal new avenues for developing therapeutic approaches to treat amblyopia..

project_terms:
Address;Adult;Alleles;Amblyopia;Behavioral;Behavioral Assay;Binocular Vision;Brain;Calcium;Child;Childhood;Data;Development;Disease;Disinhibition;Electrophysiology (science);Exhibits;Eye;Frequencies;Head;Image;Interneurons;Knowledge;Lasers;Lateral Geniculate Body;Lazy Eyes;Location;Maps;Measures;Mediating;Mission;Modeling;Modification;Mus;Mutant Strains Mice;Neurons;Ocular Dominance;Parvalbumins;Phenotype;Population;Public Health;Receptor Gene;Recovery;Research;Scanning;Strabismus;Synapses;Synaptic plasticity;Testing;Thalamic structure;Therapeutic;Therapeutic Intervention;Time;Vision;Vision Disorders;Visual;Visual Acuity;Visual Cortex;Visual impairment;Visual system structure;Water;brain circuitry;critical period;effective therapy;excitatory neuron;experience;experimental study;flexibility;improved;in vivo calcium imaging;inhibitory neuron;monocular deprivation;mouse genetics;mouse model;neural circuit;optogenetics;postsynaptic;programs;response;spatial vision;targeted treatment;visual deprivation;visual plasticity;visual processing

public_health_relevance:
Project NarrativeAbnormal vision only during a critical period in childhood induces amblyopia also known as lazy eye adisorder comprising several deficits in spatial vision including poor acuity. The proposed research is relevant topublic health because knowledge of the neural circuits that mediate recovery of acuity and eye dominance willimprove our understanding of targets for therapeutic intervention. Thus the proposed research is relevant tothe mission of the both the NEI to increase understanding of the critical period in order to determine howexperience alters connectivity in the developing visual system.


application_id: 9982850
project_number: 5R01CA217934-04
project_title: (PQ9)A redox-mediated mechanism of chemotherapy-induced cognitive impairment
administering_ic: NCI
award_notice_date: 2020-07-14
opportunity_number: RFA-CA-15-008
application_type: 5
activity_code: R01
ic: CA
serial_number: 217934
program_official: CHEN, WEIWEI
project_start_date: 2017-09-15
project_end_date: 2022-07-31
study_section: ZCA1-RTRB-E(M2)
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: BONDADA, SUBBARAO ;BUTTERFIELD, D. ALLAN
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 SummaryThis application addresses the Provocative Question 9: "What are the molecular and/or cellular mechanismsthat underlie the development of cancer therapy-induced severe adverse sequelae?" focusing onChemotherapy-induced cognitive impairments (CICI). CICI is now a recognized toxicity syndrome that includesloss of executive function (confusion; memory issues) inability to multitask and impaired intellectualreasoning. While CICI caused by central nervous system (CNS)-directed therapies (such as radiation andintrathecal chemotherapy) is readily understood the mechanisms underlying a critical and shared toxicity ofchemotherapy that occurs after systemic cancer treatment with drugs that did not direct at the brain areunclear. The number of patients at risk for CICI from systemic therapy far exceeds the number of patientsexposed to CNS therapy but little is known about the mechanisms mediating the effect of systemic therapy onCICI and there is no clear vision of how to prevent this condition. We have previously shown that generationof reactive oxygen species (ROS) by cytotoxic chemotherapeutic drugs is an essential mediator of brain injuryeven though the drug itself did not get into the brain. It is also imperative to note that anticancer medicationsdesigned specifically to target cancer cells with specialized features such as the family of Bcl2 inhibitors alsogenerate ROS. However the effect of targeted therapy on CICI has never been addressed andconsequently their mechanisms of action are entirely unknown. The goal of this proposal is to test the overallhypothesis that therapy-induced ROS production in the target tissues leads to increased circulating TNFthrough extracellular vesicles (EVs)-mediated reactions and this pro-inflammatory cytokine crosses the bloodbrain barrier to elicit mitochondrial dysfunction and consequent neuronal injury leading to CICI. The followingspecific aims are designed to test the ROS hypothesis gain an understanding of the EVs-mediatedmechanisms and test the proof-of-concept in an experimental cancer therapy setting using two prototypechemotherapy agents (Doxorubicin and Venetoclax) that represent standard cytotoxic and experimentaltargeted drugs in a lymphoma model. Aim 1 will investigate the fundamental role of TNF in therapy-inducedneuronal injury to gain insights into mechanisms of CICI in the brain and demonstrate efficacy of chemotherapyin the presence of redox-active antioxidants. Aim 2 will determine the mechanistic links between circulatingextracellular vesicles and therapy-induced CICI. Aim 3 will define the cell(s) of origin of TNF produced duringchemotherapy that leads to cognitive impairment. These aims will be accomplished in vitro and in vivo usingstate-of-the-art technologies including magnetic resonance spectroscopy redox proteomics unique animalmodels and novel mitochondria targeting anti-oxidant MnP to ameliorate CICI without reducing the efficacy ofthe anti-cancer drugs. The results from this project will lay important groundwork for future clinical trials toimprove the quality of lives of cancer patients exposed to cytotoxic or targeted therapies.

project_terms:
4 hydroxynonenal;Address;Animal Model;Antibodies;Antineoplastic Agents;Antioxidants;Apoptotic;BCL2 gene;Biochemical;Blood - brain barrier anatomy;Blood Circulation;Brain;Brain Injuries;Cancer Patient;Cancer Survivor;Cells;Choline;Clinical;Clinical Trials;Cognition;Confusion;Cytotoxic Chemotherapy;Development;Doxorubicin;Drug Targeting;Drug usage;Etiology;Exposure to;Family;Functional disorder;Future;Generations;Goals;Immune;Impaired cognition;Impairment;In Vitro;Inflammatory;Injury;Intrathecal Chemotherapy;Knockout Mice;Link;Lymphoma;Lymphoma cell;Magnetic Resonance Spectroscopy;Mediating;Mediator of activation protein;Memory;Mitochondria;Modeling;Molecular;Mus;Neuraxis;Neuronal Injury;Nitrates;Oxidation-Reduction;Oxidative Stress;Pathology;Patients;Peripheral;Pharmaceutical Preparations;Plasma;Prevention;Production;Proteins;Proteomics;Publishing;Quality of life;Radiation;Reaction;Reactive Oxygen Species;Recommendation;Research;Respiration;Risk;Role;SOD2 gene;Symptoms;Syndrome;Systemic Therapy;TNF gene;Technology;Testing;Therapeutic Effect;Therapeutic Uses;Tissues;Toxic effect;Toxicity due to chemotherapy;Treatment Efficacy;United States;Vision;anti-cancer;antioxidant enzyme;blood-brain barrier permeabilization;cancer cell;cancer therapy;chemobrain;chemotherapy;cytokine;cytotoxic;design;executive function;experience;extracellular vesicles;improved;in vivo;inhibitor/antagonist;insight;macrophage;mimetics;mitochondrial dysfunction;multitask;neuron loss;nitration;novel;prevent;prototype;specific biomarkers;targeted treatment;tumor

public_health_relevance:
Project NarrativeChemotherapy-induced cognitive impairment (CICI) is a serious threat to the quality of life. This project isdesigned to identify practice-changing therapy by establishing a new paradigm which recognizes that ROS isthe initiator of CICI caused by both cytotoxic and targeted drugs. Results from these studies will lead to veryconcrete information potentially offering a specific course of action to develop effective clinical approachesspecifically designed to prevent CICI without reducing chemotherapeutic efficacy.


application_id: 9982439
project_number: 5R21MH119004-02
project_title: Informal Mentors and the HIV Care Engagement of Young Minority Men in the Southern U.S.
administering_ic: NIMH
award_notice_date: 2020-06-30
opportunity_number: PA-18-277
application_type: 5
activity_code: R21
ic: MH
serial_number: 119004
program_official: KAMATH, SUSANNAH M A
project_start_date: 2019-08-01
project_end_date: 2022-06-30
study_section: HIV/AIDS Intra- and Inter-personal Determinants and Behavioral Interventions Study Section[HIBI]
contact_pi_person_id: 11101853
contact_pi: STERRETT, EMMA M
other_pis: Not Applicable
congressional_district: 03
department: NONE
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 SOCIAL WELFARE/WORK
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Young Black men who have sex with men (YBMSM) ages 18 to 29 have been drastically affected by the HIVepidemic. Moreover HIV+ YBMSM have lower rates of engagement in the HIV Care Cascade compared toother sub-populations which includes the steps of being linked to care retained in care initiating andremaining adherent to antiretroviral therapy and achieving viral suppression. HIV+ YBMSM living in thesouthern United States (the South) are a particularly at-risk group as the South is the region in the U.S. withthe highest HIV mortality. Despite the profound disparities in HIV morbidity and mortality affecting HIV+YBMSM living in the South there is a dearth of interventions to increase HIV+ YBMSM engagement along theHIV Care Cascade. Informal mentors who provide social support and role-modeling can help encourage healthbehaviors such as safer sex practices and increased self-advocacy in the healthcare system amongadolescents and young adults in general. Importantly informal mentors are identified by many young MSM aspositive influences in their lives. Thus the inclusion of informal mentors already in the lives of HIV+ YBMSM insupporting HIV care engagement may be a promising strategy to reduce HIV disparities. Based on SocialAction Theory (SAT) and Mentoring Theory this exploratory R21 proposal seeks to examine the extent towhich informal mentors can impact contextual (e.g. employment) and individual (e.g. self-confidence) factorspredicted by SAT to be related to HIV care engagement among HIV+ YBMSM. Qualitative interviews will beused to explore ways informal mentors can impact factors important to the engagement of HIV+ YBMSM inHIV care. We will interview HIV+ YBMSM (n = 48) across both early and young adulthood and those engagedand not engaged in care as well as HIV+ YBMSM reporting they do not have an informal mentor to exploretheir perspectives regarding contextual and individual factors that affect HIV care engagement and the extentto which informal mentors have helped address those factors. In addition 24 dyads of HIV+ YBMSM andinformal mentors (n = 48 people) representing a variety of types of reported factors affecting HIV careengagement will discuss with each other ways that are acceptable to them both that mentors could helpaddress particular factors that have affected the likelihood of each HIV+ YBMSM to engage in HIV care.Finally based on the findings from the individual and dyadic interviews the research team will outline contentand format of an intervention involving informal mentors in supporting HIV+ YBMSM in engagement along theHIV Care Cascade. The team will elicit feedback on the intervention outline from a Community Advisory Boardand Expert Panel throughout the intervention outline development process. This study will provide data vital tosetting the stage for an R34 proposal to manualize and examine feasibility and acceptability of an HIV careengagement intervention that involves informal mentors for HIV+ YBMSM living in the South.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Adherence;Adolescent and Young Adult;Adult;Advocacy;Affect;Age;Appointment;Area;Behavior;Caring;Caucasians;Communities;Data;Death Rate;Development;Employment;Epidemic;Face;Family member;Feedback;Funding;Future;Gays;Goals;HIV;HIV Infections;Health behavior;Healthcare;Healthcare Systems;Heterosexuals;Homophobia;Incidence;Individual;Infrastructure;Intervention;Intervention Studies;Interview;Joints;Link;Mentors;Minority;Modality;Morbidity - disease rate;Motivation;Participant;Persons;Pharmaceutical Preparations;Predictive Factor;Process;Provider;Reporting;Research;Resources;Risk;Role;Safe Sex;Sampling;Services;Social Network;Social support;Structure;Testing;Training;Treatment outcome;United States;United States National Institutes of Health;Unsafe Sex;Viral;Vulnerable Populations;antiretroviral therapy;base;black men who have sex with men;emerging adult;experience;health disparity;improved;medication compliance;men;mortality;novel;novel strategies;response;role model;rural area;skills;social;suburb;theories;therapy development;treatment disparity;urban area;young adult;young men who have sex with men

public_health_relevance:
Project NarrativeYoung Black men who have sex with men (YBMSM) demonstrate the highest rates of new HIVinfections of any group in the U.S. and once infected have lower rates of linkage to careretention in care and viral suppression compared to their Caucasian counterparts. Informalmentors or adults who act as role models and provide social support are present in the lives ofmany YBMSM and are naturally occurring interpersonal resources that have been under-examined as potential supports for engagement in HIV care among HIV+ YBMSM. The goal ofthis exploratory study is to examine from the perspectives of both HIV+ YBMSM and informalmentors living in the Southern U.S. the extent to which it is feasible and acceptable for mentorsto impact contextual (e.g. employment) and individual (e.g. motivation) factors associated withengagement in HIV care as well as engagement behaviors along the HIV Treatment Cascadeamong HIV+ YBMSM.


application_id: 9982358
project_number: 5P30GM127211-03
project_title: Core D - Energy Balance and Body Composition Core
administering_ic: NIGMS
award_notice_date: 2020-07-29
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127211
project_start_date: 2018-08-01
project_end_date: 2023-07-31
study_section: ZGM1-RCB-3
subproject_number: 5342
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Energy Balance and Body Composition Core (Core D) serves investigators across the institution toquantify energy balance and body composition in mice. Accurate quantification of these parameters isessential for studies focused on obesity with wide-spread capabilities for metabolism-related studies. Thecore houses 24 LabMaster TSE chambers that quantify food and water intake physical activity and indirectcalorimetry in mice a common model for studies focused on the effect of diet or genetics on the developmentof obesity. The Core also houses an EchoMRI to quantify lean and fat mass and total body water inconscious mice. Both systems allow for non-invasive longitudinal assessment of energy balance and bodycomposition. Competent core staff maintain and oversee the use of the LabMaster TSE system and trainpersonnel in use of the EchoMRI. Core Directors assist in study design and data handling and analysis.Over 50 Principal Investigators use the LabMaster TSE system annually for studies on >700 mice/year whilethe EchoMRI is used by more than 25 laboratories annually. These systems are not duplicated at theinstitution or within the Commonwealth and are vital to our ability to reduce the epidemic of obesity inKentucky. In Phase III of the program we will broaden our focus to include obesity as a risk factor forcardiovascular diseases diabetes cancer and neurodegenerative diseases. This will increase use of thesystem to support an anticipated larger user base with targeted growth within these areas across theinstitution. We will also purchase a new system from institutional support that will markedly expandcapabilities of this core in quantifying energy metabolism in mice. Also during Phase III of the program thecore for this system including all equipment will be relocated to a modern animal care facility within a newresearch building that is dedicated to the study of these health disparities. We anticipate that this core willtransition to self-sustaining capacity over the course of Phase III support of the COCVD.

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


application_id: 9982356
project_number: 5P30GM127211-03
project_title: Core B - Analytical Core
administering_ic: NIGMS
award_notice_date: 2020-07-29
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127211
project_start_date: 2018-08-01
project_end_date: 2023-07-31
study_section: ZGM1-RCB-3
subproject_number: 5340
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Phase III Analytical Core will support research into mechanisms linking obesity lipid metabolism andhuman disease risk through continued use of facility core instrumentation and resources to develop andsupport a suite of analytical services tailored for studies of the relationship between diet obesity and diseasemechanisms using preclinical models and clinical approaches. In addition expansion of services in lipidomicsand stable isotope tracer studies will augment capabilities for small animal metabolic phenotyping. This corehas developed extensive instrumentation that enables quantitation of a broad range of small moleculesuntargeted profiling of lipids in complex mixtures targeted quantification of biomarkers linking obesity todisease and methods for studies of glucose and fatty acid metabolism. Each of these analytical capabilitiesare of direct relevance to studies focused on diet nutrition and obesity in disease development. This core hascontributed data for more than 110 peer reviewed publications since 2008 in high impact journals providedservices for more than 60 investigators and contributed to new grant awards in environmental sciences. Thecore is well equipped and with expanded services is anticipated to develop self-sustaining capacity in PhaseIII of the COCVD.

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


application_id: 9982355
project_number: 5P30GM127211-03
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2020-07-29
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127211
project_start_date: 2018-08-01
project_end_date: 2023-07-31
study_section: ZGM1-RCB-3
subproject_number: 5339
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Administrative Core of the Phase III Center of Biomedical Research Excellence (COBRE) on Obesity andCardiovascular Diseases (COCVD) will provide administrative oversight for the center. This core is Directed byDr. Lisa Cassis Program Director and Dr. Andrew Morris Program Coordinator who will collectively provideleadership oversight and coordination of the various activities associated with the COCVD to transition theCenter to self-sustaining capacity. This will include oversight of Core facilities and their administration fiscalaccounting programs for cores and pilot projects administrative oversight of the Pilot Project Programimplementation of strategies to assess core performance and increase core use assure adherence toregulatory guidelines and improve the research infrastructure.

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


application_id: 9982352
project_number: 5P30GM127211-03
project_title: Center of Research on Obesity and Cardiovascular Disease
administering_ic: NIGMS
award_notice_date: 2020-07-29
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127211
program_official: FRINCU, CRINA
project_start_date: 2018-08-01
project_end_date: 2023-07-31
study_section: ZGM1-RCB-3(C3)
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Phase III of the Center for Biomedical Research Excellence (COBRE) on Obesity and CardiovascularDiseases (COCVD) will further develop and expand upon obesity as an underlying risk factor for thedevelopment of cardiovascular diseases type 2 diabetes cancer and neurodegenerative diseases. Each ofthese diseases are rampant in Kentucky and obesity has been identified as a contributing risk factor for eachcondition. For Phase III of the COCVD we will transition the research core facilities developed during Phase Iand II of this program to independence. We will also support pilot project studies that include obesity as a riskfactor for disease development. We have experienced considerable success having supported 23 juniorinvestigators and 21 pilot project investigators who generated $52 million in extramural funding and publishedmore than 500 scholarly publications. Collectively our team has published more than 280 scholarly articlesthat directly cite COCVD support. We developed an analytical core that provides services in lipidomics andother small molecules a pathology core that provides specialized services to quantify adipose and other tissuemorphology and an energy balance and body composition core that is not duplicated in capacity across theinstitution or the Commonwealth. During Phase III of the COCVD we will transition each core to self-sustaining capacity and upgrade core equipment and use by continuing to provide high quality specializedservices and by expanding core capabilities through provision of additional services that relate obesity to otherdiseases (e.g. cancer). Transition to independence of COCVD cores will be facilitated by use of a vouchersystem to promote core use. We will also continue our strong tradition of pilot project funding which will beexpanded to include studies that focus on obesity as an underlying risk factor for not only cardiovasculardiseases but also type 2 diabetes cancer and neurodegenerative diseases. These areas have beendesignated as areas of strength across the institution (as each disease is a health disparity experienced byKentuckians) and are designated for growth within a new research facility that will focus on Kentucky's healthdisparities. The Administrative Core will oversee all administrative functions of the COCVD and in conjunctionwith the Program Coordinator and the Scientific Internal Advisory Committee will serve as the operational limbof the Center. An External Advisory Committee composed of experts in related fields will provide ongoingassessment and evaluation of the Center. Institutional commitment continues to be outstanding and issupplemented by strong evidence of programmatic growth of direct relevance to this Phase III COCVD.

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

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


application_id: 9982169
project_number: 5K99AG063994-02
project_title: Myonuclear Epigenetics of Skeletal Muscle Mass Regulation with Age
administering_ic: NIA
award_notice_date: 2020-06-22
opportunity_number: PA-18-398
application_type: 5
activity_code: K99
ic: AG
serial_number: 063994
program_official: WILLIAMS, JOHN
project_start_date: 2019-08-01
project_end_date: 2021-07-31
study_section: Biological Aging Study Section[NIA-B]
contact_pi_person_id: 14386396
contact_pi: MURACH, KEVIN
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTSkeletal muscle mass declines with age and simultaneously loses the ability to adapt to stressors. Reducedmuscle mass and function associated with aging ultimately leads to a loss of independence and mortalitycosting billions of dollars to the US economy every year. Understanding what contributes to muscle mass losswith age and what mediates the ability to enhance muscle mass with exercise or alternative therapeutics is ofcritical importance for developing effective countermeasures. The study of epigenetics and specifically DNAmethylation status has become increasingly popular in recent years since this level of regulation heavilydictates what genes are expressed and for how long. Skeletal muscle is multi-nucleated and ~50% of nuclei inthe muscle compartment are myonuclei. Little can be inferred about DNA methylation in muscle fibers withoutthe ability to specifically isolate myonuclei. We recently developed a genetically modified mouse model forlabeling skeletal muscle myonuclei and a workflow for purifying these labeled myonuclei for downstreamepigenetic applications. We also developed a translatable and reversible murine model of progressiveweighted wheel running (PoWeR) that elicits hypertrophy in muscles of different fiber type composition andfunction. Using these novel tools the purpose of this proposal is to provide the first muscle type-specific insightinto the epigenetic regulation of skeletal muscle mass with aging and determine whether early life stimuli affectmuscle adaptability later in life. I will profile myonuclear DNA using reduced representation bisulfite sequencingin order to explore global methylation status and focus in on ribosomeal DNA (rDNA) methylation sinceribosome biogenesis is strongly implicated in skeletal muscle mass regulation. In the mentored phase of thegrant I will learn the requisite epigenetic techniques for studying muscle mass regulation by evaluatingmyonuclear epigenetics during hypertrophy (PoWeR) and atrophy (hindlimb suspension). With these newlyacquired skills I will profile myonuclear DNA from oxidative and glycolytic muscles during the independentphase to provide a comprehensive epigenetic map of muscle aging. I will also PoWeR train mice early in life todetermine whether previous hypertrophy affects adaptability to that same stimulus later in life with the aim ofidentifying epigenetic cues for improving muscle adaptability in old age. My global hypotheses are thathypertrophy will be associated with muscle type-specific global and rDNA hypomethylation while unloadingand aging will be characterized by muscle type-specific hypermethylation. I also hypothesize that early lifeexercise will be associated with rDNA hypomethylation later in life which will associate with restoredhypertrophic adaptability in old age. The experiments in this proposal will provide a foundation for thedevelopment of epigenetic-based therapeutics aimed at skeletal muscle rejuvenation with aging. Furthermorethe training opportunity afforded by this project will facilitate my success as an independent researcher focusedon the epigenetics of muscle mass regulation during aging in skeletal muscle.

project_terms:
Address;Adult;Affect;Age;Aging;Atrophic;Biogenesis;Cell Nucleus;Cell Separation;Clinical;Cues;Custom;DNA;DNA Methylation;Data;Development;Enhancers;Epigenetic Process;Exercise;Fiber;Foundations;Functional disorder;Future;Genes;Genetic Transcription;Genome;Grant;Hindlimb Suspension;Human Genome;Hypermethylation;Hypertrophy;Intervention;Knowledge;Label;Learning;Life;Limb structure;Maps;Mediating;Memory;Mentors;Methylation;Mitotic;Modification;Mus;Muscle;Muscle Fibers;Muscle function;Muscular Atrophy;Nuclear;Phase;Phenotype;Plantaris muscle;Population;Protocols documentation;Quality of life;Regulation;Rejuvenation;Research;Research Personnel;Research Training;Ribosomal DNA;Ribosomal RNA;Ribosomes;Running;Science;Skeletal Muscle;Soleus Muscle;Stimulus;Techniques;Testing;Therapeutic;Time;Training;aged;base;bisulfite sequencing;career;combat;cost;dosage;epigenetic memory;epigenetic regulation;exercise training;experimental study;fall risk;genome wide methylation;improved;insight;loss of function;methylome;mortality;mouse genome;mouse model;muscle aging;muscle form;muscle hypertrophy;novel;reduced muscle mass;response;sedentary;skills;stressor;success;therapeutic target;tool;training opportunity;transcriptome

public_health_relevance:
PROJECT NARRATIVESkeletal muscle mass declines with age and simultaneously loses the ability to adapt to exercise whichcollaboratively leads to a loss of independence and mortality and costs billions of dollars to the US economyevery year. A major determinant of phenotype and plasticity is gene transcription that is in large part controlledby DNA methylation but essentially nothing is known about the epigenetic control of skeletal muscle massregulation with aging since isolating skeletal muscle nuclei has presented a significant challenge. Thetechniques developed for this project overcome this roadblock and mapping the myonuclear methylome inmuscles of different type and function in the context of exercise and aging will provide foundational insight forcombatting age-mediated skeletal muscle mass loss and dysfunction.


application_id: 9981811
project_number: 5U01DE025383-06
project_title: Roles for lymphocyte RANKL in periodontal complications of type 2 diabetes
administering_ic: NIDCR
award_notice_date: 2020-09-02
opportunity_number: PAR-15-192
application_type: 5
activity_code: U01
ic: DE
serial_number: 025383
program_official: CHANDER, PREETHI
project_start_date: 2016-07-01
project_end_date: 2023-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-S(02)S]
contact_pi_person_id: 6409370
contact_pi: NIKOLAJCZYK, BARBARA
other_pis: VAN DYKE, THOMAS ELLIOTT
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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Periodontitis fuels the inflammation of obesity-associated type 2 diabetes (T2D) associates with poor glycemiccontrol and increases T2D morbidity. New strategies are critically needed to counter sources of periodontalinfection and the resulting inflammation both of which are refractory to standard treatments in people withT2D. However mechanisms underlying the relationship between periodontitis and T2D remain poorlyunderstood impeding clinical progress. One unifying link between periodontitis and T2D is altered B cellfunction and recent collaborative work between Drs. Barbara Nikolajczyk and Thomas Van Dyke showed thatT2D-associated changes in B cells promote periodontitis. Our work further indicates that T cells cannot drivechronic periodontitis in T2D hosts in the absence of B cells despite evidence that T cells promote periodontitisin lean hosts. Taken together these findings support a model in which B cells support T2D-potentiatedperiodontitis while T cells dominate periodontitis in leans. Both B cells and T cells are major sources ofreceptor activator of nuclear factor kappa-B ligand (RANKL) a key driver of osteoclastogenesis andperiodontal bone loss. Obesity/T2D increases hematopoietic cell production of RANKL most likely throughincreasing concentrations of a number of cytokines (TNF IL-1 and IL-6) known to drive RANKL production.These data together with our demonstration that B cells are required for T2D-potentiated osteoclastogenesisand periodontitis support our central hypothesis: T2D cytokines specifically up regulate B cell RANKL functionwhich uniquely potentiates periodontal complications of T2D. Definitive analyses are needed to fill the criticalgaps in knowledge of how obesity-associated T2D impacts lymphocyte RANKL induction and function andwhether cellular sources of osteoclastogenic RANKL differ in T2D compared to lean hosts. We will use loss-and gain-of-function approaches in a standard mouse model of T2D coupled with a standard model of chronicperiodontitis to study development of T2D-potentiated periodontal disease. We will complement the diseaseetiology work in mice with analysis of gingiva from people with T2D to query mechanistic underpinnings ofchronic periodontitis. This strategy will identify drivers of both early and chronic phases of T2D-potentiatedperiodontitis to meet our long-term objective: to identify key factors that promote periodontitis in T2D comparedto non-T2D subjects and thereby pinpoint drug targets for future studies.

project_terms:
Acute Periodontitis;Address;Alveolar Bone Loss;Animal Model;B-Lymphocytes;Cell physiology;Chronic;Chronic Phase;Clinical;Complement;Complications of Diabetes Mellitus;Coupled;Data;Development;Disease;Drug Targeting;Etiology;FDA approved;Future;Gingiva;Goals;Hematopoietic Cell Production;High Fat Diet;Human;Hyperglycemia;Immunologics;Immunomodulators;Infection;Inflammation;Inflammatory;Interleukin-1 beta;Interleukin-10;Interleukin-6;Knowledge;Lesion;Link;Lymphocyte;Mediator of activation protein;Metabolic;Methods;Modeling;Morbidity - disease rate;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathogenesis;Pathogenicity;Periodontal Diseases;Periodontal Infection;Periodontitis;Play;Positioning Attribute;Production;Receptors Antigen B-Cell;Refractory;Regulation;Role;Source;Standard Model;Supporting Cell;T-Cell Receptor;T-Lymphocyte;TNF gene;TRANCE protein;Testing;Thinness;Time;Work;base;clinical application;clinical practice;cytokine;gain of function;glycemic control;high standard;human model;human subject;insight;mouse model;osteoclastogenesis;pathogen;standard care

public_health_relevance:
Project Narrative:Our proposed work will identify mechanisms by which lymphocytes (B cells and T cells) promote thepathogenic relationship between type 2 diabetes and periodontal disease. Identifying lymphocyte RANKL as akey mediator of type 2 diabetes-potentiated periodontal disease will pave the way for a greater understandingof disease pathogenesis and raise the possibility that FDA-approved immunomodulatory drugs that are beingtested as treatments for type 2 diabetes may positively impact periodontal complications.


application_id: 9981745
project_number: 5R01ES030019-02
project_title: Cell Survival Advantage in Cadmium Induced Carcinogenesis
administering_ic: NIEHS
award_notice_date: 2020-04-27
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: ES
serial_number: 030019
program_official: HUMBLE, MICHAEL C
project_start_date: 2019-08-01
project_end_date: 2021-03-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 7649061
contact_pi: DAMODARAN, CHENDIL
other_pis: Not Applicable
congressional_district: 03
department: UROLOGY
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 SummaryExposure to cadmium (Cd) is associated with a spectrum of human pathogenesis including the prostate cancer(CaP). A clear dose-response relation between Cd-exposure and abnormal prostate serum antigen (PSA) amarker for CaP have been reported in men exposed to Cd. However the molecular mechanism underlying themalignant cell transformation following Cd exposure is yet to be determined while the association between Cdand CaP in both pre-clinical and clinical models are well established. The goal of this application is toinvestigate the underlying mechanism of how Cd causes malignant cell transformation (from normal totransformed cells) and on the development of tumorigenesis by the Cd-transformed cells (transformedcells to tumorigenesis). Our preliminary results suggest that during cellular transformation Cd exposureinduced endoplasmic reticulum (ER)-stress which triggered the phosphorylation of stress transducers includingPERK and eIF2- resulted in the activation of ATF4 and initiate the induction of autophagy that protects Cd-damaged cells. Although induction of autophagy markers (Atg -12 and Atg-16L LC3B and Lamp1) were seenin Cd-treated cells the autophagy process is incomplete due to failure autophagosome and autolysosomefusion which allowed the damaged cell to proliferate for transformation. A massive accumulation of p62 in Cd-treated cells which also confirmed the defective autophagy. Silencing EGFR activation by siRNA orpharmacological inhibitors significantly inhibited the growth in transformed cells but not in Cd-treated normalcells or Cd- transforming cells suggesting that EGFR activation plays a critical role only after cellulartransformation. Xenograft tumor tissues generated by Cd-transformed cells expressed high levels of ATF-4EGFR p62 and LC3B in correlation with in vitro findings. Moreover increased expression of the proteins (ATF-4 EGFR p62 and LC3B) in human CaP specimens agreement with Gleason sum in comparison with benignprostatic hyperplasia and normal adjacent tissues. Based on the results we hypothesize that Chronic exposureof prostate epithelial cells to Cd causes ER-stress and subsequently defective autophagy leading to increasedsurvival of damaged cells that result in malignant cell transformation and in transformed cell EGFR activationplay a significant role in tumorigenesis. Three specific aims are proposed: Aim-1: To demonstrate that Cd causesER-stress which in turn induced defective autophagy during the transformation of prostate epithelial cells.Aim 2: Investigate the protective role of defective autophagy which increases the survival of Cd-damaged cellsduring the transformation of prostate epithelial cells. Aim-3: study Cd-induced tumorigenesis in mouse modelsand validate the molecular markers in human prostate specimens.

project_terms:
Agreement;Antigens;Antioxidants;Autophagocytosis;Autophagosome;Benign Prostatic Hypertrophy;Biochemical;Blood;Cadmium;Cell Survival;Cells;Chronic;Clinical;Complex;Development;Dose;Elements;Endoplasmic Reticulum;Epidermal Growth Factor Receptor;Epithelial Cells;Eukaryotic Initiation Factors;Exposure to;Failure;Gleason Grade for Prostate Cancer;Goals;Growth;Human;Human Papillomavirus;Human Pathology;In Vitro;Inductively Coupled Plasma Mass Spectrometry;Knockout Mice;Laboratories;Malignant - descriptor;Malignant neoplasm of prostate;Measures;Modeling;Molecular;Molecular Analysis;Normal Cell;Pathogenesis;Pathologic;Patients;Pharmacology;Phenotype;Phosphorylation;Phosphotransferases;Play;Process;Production;Proliferating;Prostate;Prostatic Neoplasms;Protein Family;Proteins;Reactive Oxygen Species;Reporting;Role;SNAP receptor;Serum;Signal Transduction;Small Interfering RNA;Soil;Specimen;Stress;Tissues;Transducers;Tumor Tissue;United States;Urine;Xenograft Model;activating transcription factor 4;base;cancer cell;carcinogenesis;cell injury;cell transformation;endoplasmic reticulum stress;inhibitor/antagonist;malignant phenotype;men;metallicity;metaplastic cell transformation;molecular marker;mouse model;overexpression;pre-clinical;protein expression;protein kinase R;response;sensor;superoxide dismutase 1;tumor growth;tumor xenograft;tumorigenesis;wasting

public_health_relevance:
Project NarrativeCadmium (Cd) is a non-essential metallic element that is found at varying levels in soil throughout the UnitedStates. Exposure to cadmium (Cd) is associated with a spectrum of human pathogenesis including theprostate cancer. The goal of this application is to investigate the underlying mechanism of how Cadmium (Cd)causes malignant cell transformation (from normal to transformed cells) and how transformed totumorigenesis (transformed cells to tumorigenesis). This study will highlight the better understanding of thecomplex interrelationship among prostate cancer phenotypes and the molecular cellular biochemical andpathological changes associated with cadmium and prostate cancer.


application_id: 9981741
project_number: 5R01ES027778-04
project_title: Mechanism for arsenic induced carcinogenesis
administering_ic: NIEHS
award_notice_date: 2020-07-29
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 027778
program_official: TYSON, FREDERICK L
project_start_date: 2017-08-01
project_end_date: 2022-07-31
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
arra_indicator: N
project_abstract:
AbstractChromosomal instability (CIN) contributes to carcinogenesis by promoting aneuploidy. Arsenic is well known toinduce aneuploidy however the molecular mechanism by which arsenic induces aneuploidy-mediatedcarcinogenesis is yet to be delineated. We have identified a miRNA (hsa-miR-186) that is overexpressed inarsenic-induced squamous cell carcinoma and that induces CIN when overexpressed in human keratinocytes.This miRNA is encoded within intron 9 of the ZRANB2 gene and is co-transcribed as part of the ZRANB2transcript. Such embedded microRNAs are processed out of the intronic RNA by the microRNA maturationmachinery. ZRANB2 encodes an alternative splicing factor containing two zinc fingers each with four-cysteinescoordinating the zinc. These types of zinc fingers are targets for arsenite displacement of zinc. We hypothesizethat chronic arsenic exposure disrupts ZRANB2 function by displacing zinc from the zinc fingers; cellularhomeostatic mechanisms induce ZRANB2 transcription; coincident increased hsa-miR-186 leads to CINcontributing to arsenic-induced carcinogenesis. This project will determine the role of hsa-miR-186 in arsenicinduced CIN in human keratinocytes and how ZRANB2 structure and function are modulated by arsenicexposure. The following specific aims will be pursued to test this hypothesis: 1. Determine role of hsa-miR-186in carcinogenic transformation of immortalized keratinocytes (HaCaT cells).; 2. Determine mechanism ofarsenite disruption of ZRANB2 structure and function; 3. Determine potential of hsa-miR-186 over-expressionto induce chromosomal instability and potential of arsenite to inhibit ZRANB2 directed splicing in primarykeratinocytes. Successful completion of these aims will demonstrate a novel mechanism for epigeneticresponse to the environmental stress of arsenic exposure and demonstrate that this response causeschromosomal instability (CIN) linked to arsenic-induced skin carcinogenesis. This mechanism likely plays arole in arsenic-induced carcinogenesis in other organs as well. Thus hsa-miR-186 could be a biomarker forarsenic induced internal cancers in arsenic exposed patients. Demonstration of arsenite-exposure disturbanceof mRNA splicing patterns will open a new area of research into mechanisms of arsenic induced disease.

project_terms:
Acute;Alternative Splicing;Aneuploidy;Area;Arsenic;Arsenites;Binding;Biochemical;Biological Assay;Biological Markers;Biophysics;CRISPR/Cas technology;Cell Culture Techniques;Cells;Chromosomal Instability;Chromosome abnormality;Chronic;Circular Dichroism;Cysteine;Data;Disease;Dose;Electrophoretic Mobility Shift Assay;Epigenetic Process;Fingers;Generations;Genes;Genetic Transcription;Health;Human;Incubated;Introns;Knock-out;Link;Malignant - descriptor;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Messenger RNA;MicroRNAs;Mitosis;Molecular;Monitor;Organ;Outcome;Patients;Pattern;Play;Process;RNA;RNA Splicing;Recombinants;Research;Role;Sampling;Signal Transduction;Skin;Skin Cancer;Skin Carcinogenesis;Squamous cell carcinoma;Stochastic Processes;Stress;Structure;Subfamily lentivirinae;Testing;Time;Transcript;Zinc;Zinc Fingers;arsenic-induced carcinogenesis;carcinogenesis;carcinogenicity;drinking water;experimental study;in vitro Model;in vivo Model;keratinocyte;novel;overexpression;response;tool;transcriptome sequencing;vector control

public_health_relevance:
NarrativeArsenic exposure via drinking water is a world-wide health problem. Skin is the major target organ of arsenicand skin cancer is a common outcome of chronic arsenic exposure. This application proposes to investigate anovel mechanism of arsenic-induced skin cancer.


application_id: 9981690
project_number: 5R21CA229057-03
project_title: A microreactor chip platform for quantitative analysis of unsaturated aldehydes in exhaled breath
administering_ic: NCI
award_notice_date: 2020-07-31
opportunity_number: RFA-CA-17-010
application_type: 5
activity_code: R21
ic: CA
serial_number: 229057
program_official: KRUEGER, KARL E
project_start_date: 2018-08-22
project_end_date: 2021-07-31
study_section: ZCA1-TCRB-W(M1)
contact_pi_person_id: 10807170
contact_pi: FU, XIAO-AN
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
project_abstract:
Project Title:A microreactor chip platform for quantitative analysis of unsaturated aldehydes in exhaled breath7. Project Summary/Abstract Lung cancer has the highest mortality of all types of cancer. Early lung cancer detection is a key factor forincreasing survival rates of lung cancer patients. The analysis of exhaled breath samples has great potential tobecome a powerful non-invasive screening and diagnostic tool for early lung cancer detection. A number ofrecent publications have indicated that certain volatile organic compounds (VOCs) in exhaled breath may belung cancer metabolic output. However there are some critical challenges for the analysis of breath VOCs thathinder the use of breath analysis technology for clinical applications. These challenges include trace levels ofVOCs in breath much lower than the detection limits of most current analytical instruments; the complexity ofsorting a large number of VOCs; and matrix interferences imparted by abundant and/or structurally similarVOCs unrelated to cancers. These challenges make it very difficult to identify true metabolic markers of lungcancers. We have developed a microreactor approach that uses a quaternary aminooxy coating for chemoselectivecapture of carbonyl compounds in exhaled breath. Four carbonyl compounds have been identified to havesignificantly higher concentrations in the breath of lung cancer patients than in the breath of healthy controlsubjects. However the slow reaction kinetics of the quaternary aminooxy coating with unsaturated aldehydesand unstable nature of these compounds make the microreactor technology inadequate for quantification ofkey unsaturated aldehydes in exhaled breath. Many unsaturated aldehydes in exhaled breath are related tolung cancer dysfunction-induced oxidative stress. Unfortunately there is no current technology that can beused to adequately measure unsaturated aldehydes in exhaled breath. The goal of this project is to develop a microreactor chip platform technology for quantitative analysis ofunsaturated aldehydes in exhaled breath for differentiation of early lung cancer from benign pulmonarynodules. The technology will overcome all critical challenges of current breath analysis technologies andenable quantitative analysis of unsaturated aldehydes. The goal will be fulfilled by the following two specificaims: Specific Aim 1. Develop a novel microreactor platform for accurate measurement of unsaturatedaldehydes in exhaled breath; Specific Aim 2. Establish novel algorithms for diagnosis of lung cancer by breathanalysis. The proposed microreactor chip platform for quantitative analysis of unsaturated aldehydes will betransformative because it will enable measurement and identification of lung cancer metabolic aldehydes andestablish a non-invasive tool for differentiation of lung cancer from benign pulmonary nodules. Themicroreactor chip enabled quantitative analysis of unsaturated aldehydes in breath can also be used with lowdose CT screening for detection of early lung cancer and differentiation of lung cancer from benign pulmonarynodules. The proposed technology will be superior to current breath analysis approaches because of fourcritical innovations: (1) diagnosis of lung cancer by quantitative measurement of cancer metabolic unsaturatedaldehydes in exhaled breath; (2) a novel microreactor for decreasing sample evacuation time; (3) optimizedchemoselective coatings for efficient capture of unsaturated aldehydes; and (4) separation of analyte adductsand quantitation by UHPLC-MS.

project_terms:
2-butenal;4 hydroxynonenal;Acrolein;Adult;Affect;Aldehydes;Algorithms;Ammonium;Benign;Breath Tests;Cancer Patient;Centers for Disease Control and Prevention (U.S.);Charge;Cigarette;Detection;Diagnosis;Diagnostic;Diagnostic Sensitivity;Early Diagnosis;Exhalation;Functional disorder;Goals;Hexenal;High Pressure Liquid Chromatography;Human;Ketones;Kinetics;Lung nodule;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Measurement;Measures;Metabolic;Metabolic Marker;Modality;Nature;Non-Malignant;Output;Oxidative Stress;Patients;Phase;Process;Publications;Reaction;Sampling;Scanning;Sensitivity and Specificity;Silicon;Smoker;Smoking;Sodium Chloride;Sorting - Cell Movement;Specificity;Statistical Data Interpretation;Structure;Survival Rate;Technology;Time;X-Ray Computed Tomography;adduct;base;cancer type;carbonyl compound;clinical application;computed tomography screening;cost effective;diagnostic accuracy;innovation;innovative technologies;instrument;low dose computed tomography;lung cancer screening;lung imaging;mortality;non-smoking;noninvasive diagnosis;novel;novel diagnostics;screening;success;tool;volatile organic compound

public_health_relevance:
8. Project Narrative Quantitative analysis of volatile organic compounds in exhaled breath has great potential to bedeveloped as a powerful noninvasive diagnostic tool for differentiation of lung cancer from benign pulmonarynodules. This project proposes to develop an innovative technology for quantitative analysis of unsaturatedaldehydes in exhaled breath for diagnosis of lung cancer. The approach is to investigate novel microreactorwith new quaternary aminooxy compound phase for chemoselective capture and preconcentration ofunsaturated aldehydes in exhaled breath.


