# projects

application_id: 10132725
project_number: 5F31EY030746-02
project_title: Superior Colliculus Interactions with the Parabigeminal Nucleus
administering_ic: NEI
award_notice_date: 2021-03-15
opportunity_number: PA-19-195
application_type: 5
activity_code: F31
ic: EY
serial_number: 030746
program_official: CLAYTON, EDWIN C
project_start_date: 2020-04-01
project_end_date: 2022-03-31
study_section: Special Emphasis Panel[ZRG1-F02B-E(20)L]
contact_pi_person_id: 14632518
contact_pi: WHYLAND, KYLE L
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/ABSTRACTRecent studies have implicated the superior colliculus (SC) and parabigeminal nucleus (PBG) as importantstructures involved in the selection and activation of visually-evoked defensive behaviors such as freeze andescape. However the precise role that the SC and PBG play in the initiation of visually-evoked behavior isunknown in part due to a gap in knowledge of the synaptic circuits that link the SC and PBG and the manner inwhich the PBG receives visual signals. The proposed project will address this gap by completing a detailedexamination of circuits that link the SC to the PBG. Aim 1 experiments will define the morphology and laminardistribution of SC cells that contain glutamic acid decarboxylase (GAD) or parvalbumin (PV) and send projectionsto the PBG. Aim 2 experiments will test whether these two cells types receive direct or indirect input from theretina and/or primary visual cortex. Aim 3 experiments will define the synaptic properties of SC-PBG connections.To investigate these circuits the proposed experiments use novel combinations of viral vector injections intransgenic mice immunohistochemistry in vitro whole cell recordings from identified cell types and optogeneticactivation of cell-type specific synaptic terminals. This combination of approaches will address fundamentalquestions regarding the circuity of the SC and PBG while providing the applicant with broad-based training inneuroscience.

project_terms:
Address;Antibodies;Behavior;Cell Nucleus;Cells;Contralateral;Data;Disease;Dyslexia;Exhibits;Freezing;Future;Glutamate Decarboxylase;Glutamates;Immunohistochemistry;In Vitro;Injections;Ipsilateral;Knowledge;Label;Light;Link;Morphology;Motion Perception;Motor;Mus;Neurosciences;Opsin;Output;Parvalbumins;Physiologic pulse;Play;Population;Presynaptic Terminals;Property;Retina;Role;Schizophrenia;Signal Transduction;Slice;Spatial Distribution;Stains;Structure;Synapses;Testing;Tissues;Training;Transgenic Animals;Transgenic Mice;Viral Vector;Virus;Visual;Visual Motion;Visual Pathways;Whole-Cell Recordings;Work;area striata;autism spectrum disorder;base;brain circuitry;cell type;experimental study;neural circuit;novel;optogenetics;postsynaptic;receptor;response;sensory stimulus;superior colliculus Corpora quadrigemina

public_health_relevance:
PROJECT NARRATIVE The results of these experiments will contribute to our understanding of the brain circuitryunderlying visual motion perception thus providing information relevant to the treatment of disorders inwhich visual motion processing is compromised such as dyslexia and schizophrenia. In addition theresults of these experiments will enhance our understanding of subcortical visual pathways which maybe altered in autism spectrum disorder.


application_id: 10132375
project_number: 5R01HL139748-04
project_title: Atherosclerosis Mechanisms: Angiotensin II production and action
administering_ic: NHLBI
award_notice_date: 2021-03-12
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 139748
program_official: HASAN, AHMED A K
project_start_date: 2018-05-01
project_end_date: 2023-03-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 9382938
contact_pi: LU, HONG SHEN
other_pis: DAUGHERTY, ALAN
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 The renin angiotensin system (RAS) plays a critical role in the development ofatherosclerosis. Mechanisms by which the RAS contributes to atherosclerosis have beenfocusing on effects of angiotensin II (AngII) production and its action through AT1a receptorswithin atherosclerotic lesions. On the basis of our preliminary data we challenge this conceptand propose a new hypothesis: Renal AngII production through a megalin-mediatedpathway in proximal convoluted tubules (PCTs) promotes atherosclerosis via its localstimulation of AT1a receptors. Angiotensinogen (AGT) the substrate of the RAS derivedfrom hepatocytes is filtered through glomeruli and retained by megalin a member of LDLreceptor superfamily in PCTs. Our protein sequence and structure analyses identified twoconserved sequences that may associate with its binding to megalin. Aim 1 will define howhepatocyte-derived AGT regulates renal AngII production and contributes to atherosclerosis.We will use site-mutagenesis surface plasmon resonance and cell culture system to determinehow AGT and megalin interact in vitro. Subsequently we will use an adeno-associated viral(AAV) system to manipulate conserved sequences of AGT in hepatocyte-specific AGT deficientmice to determine whether conserved sequences of AGT influence renal AngII production andatherosclerosis. Effects of megalin on renal AngII production and atherosclerosis will bedetermined using PCT-specific megalin deficient mice. Since AGT is cleaved by two criticalenzymes renin and angiotensin-converting enzyme (ACE) to produce AngII Aim 2 will firstdetermine whether renin or ACE derived from PCTs contributes to renal AngII production andatherosclerosis using PCT-specific renin and ACE deficient mice respectively. Studiesproposed in Aim 1 for AGT and megalin interaction and Aim 2 for the two enzymes (renin andACE) do not provide direct evidence whether AngII produced in PCTs contributes toatherosclerosis. To answer this question we will use a transgenic mouse model that hasrestricted production of AngII in PCTs. AngII promotes atherosclerosis through AT1a receptor-mediated mechanism. Therefore subsequent experiments will determine whether PCTs are thelocation for AT1a receptors to promote atherosclerosis. Completion of proposed studies willprovide evidence whether renal PCTs are the major source for each classic RAS component topromote atherosclerosis. Demonstration of this new concept may change our understanding ofthe AngII/AT1a receptor-mediated mechanisms of atherosclerosis which may also provideinsights into developing new therapeutic strategies.

project_terms:
Address;Amino Acid Sequence;Androgens;Angiotensin II;Angiotensin Type 1a Receptor;Angiotensinogen;Arterial Fatty Streak;Atherosclerosis;Binding;Breeding;Cell Culture System;Cleaved cell;Color;Conserved Sequence;Data;Development;Elements;Endocrine system;Endothelial Cells;Enzymes;Fibroblasts;Genes;Hepatocyte;Human;In Vitro;Infusion procedures;Kidney;LDL-Receptor Related Protein 2;Lesion;Leukocytes;Literature;Location;Low Density Lipoprotein Receptor;LoxP-flanked allele;Mediating;Methods;Mus;Mutagenesis;Nephrons;Pathway interactions;Peptidyl-Dipeptidase A;Pharmacology;Play;Production;Proteins;Renin;Renin-Angiotensin System;Reproducibility;Role;Site;Smooth Muscle Myocytes;Source;Surface Plasmon Resonance;System;Techniques;Testing;Therapeutic;Transgenes;Transgenic Mice;Viral;base;cell type;enzyme deficiency;experimental study;hypercholesterolemia;insight;member;mouse model;mutant;novel therapeutic intervention;prevent;promoter;protein structure;receptor;urinary

public_health_relevance:
Project NarrativeThe renin angiotensin system plays a critical role in the development of atherosclerosis. Thisproposal aims to understand the mechanisms and source of this hormonal system onatherosclerosis thereby providing new insights into developing potential therapeutic strategies.


application_id: 10131841
project_number: 5R01HL141343-03
project_title: Transcriptional Regulation of KCNH2
administering_ic: NHLBI
award_notice_date: 2021-03-05
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: HL
serial_number: 141343
program_official: SHI, YANG
project_start_date: 2019-03-08
project_end_date: 2023-02-28
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 7001509
contact_pi: DELISLE, BRIAN P
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SummaryCircadian rhythms help to match the optimal function of the cardiovascular system to the daily changes in theenvironment. Normal cardiovascular rhythms provide a physiological advantage to people. Unfortunatelynormal circadian signaling can also unmask a time-of-day pattern in adverse events like heart attack strokeand sudden death in patients with underlying cardiovascular disease.Emerging data now show that abnormal or unhealthy daily rhythms can create a negative impact on normalhealth too. For example shiftwork which repeatedly causes shifts in endogenous circadian rhythms is anindependent risk factor for cardiovascular disease.In mammals the suprachiasmatic nucleus (SCN) in the brain is the primary circadian pacemaker that helps toentrain endogenous rhythms to the environment. SCN rhythms are synchronized to the environment via lightand its signaling helps to coordinate the molecular rhythms in cells throughout the body. What is new aboutthis application is we determine how repeated changes in light cycle will impact molecular circadian signaling inthe heart.Most cells have a molecular clock signaling mechanism that cycles with a periodicity of ~24 hours. We foundgenetic disruptions in the molecular clock mechanism of heart cells (cardiomyocytes) primarily causesabnormal changes in cardiac electrophysiology by disrupting the regulation of ion channel function.The goal of this application is to determine how repeated shifts in the light cycle impact molecular clocksignaling in the mouse heart and its regulation on ion channel function.Aim 1. To identify new mechanisms with which the cardiac molecular clock regulates different ion channels.Aim 2. To determine how repeated changes in light impact molecular clock signaling in the heart and ionchannel regulation.This project creates new knowledge at the interface between chronobiology and cardiac electrophysiology.

project_terms:
ARNTL gene;Action Potentials;Adverse event;Arrhythmia;Biological Assay;Bioluminescence;Brain;Cardiac;Cardiac Electrophysiologic Techniques;Cardiac Myocytes;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Cells;Cessation of life;Chemistry;Chronic;Chronobiology;Circadian Rhythms;Cues;Data;Electrophoretic Mobility Shift Assay;Elements;Environment;Gene Expression;Genes;Genetic;Genetic Transcription;Goals;Half-Life;Health;Heart;Hour;Human;Hypothalamic structure;Incidence;Ion Channel;Knowledge;Kv channel-interacting protein 2;Label;Length;Light;Long QT Syndrome;Mammals;Measures;Messenger RNA;Molecular;Molecular Target;Mus;Myocardial Infarction;Patients;Pattern;Periodicity;Phase;Phenotype;Physiological;Pluripotent Stem Cells;Potassium Channel;Premature Mortality;Proteins;RNA;Regulation;Reporter Genes;Role;Signal Transduction;Stroke;Sudden Death;Telemetry;Testing;Time;Tissues;Transcript;Transcriptional Regulation;Transgenic Mice;Uridine;cardiovascular risk factor;chromatin immunoprecipitation;circadian;circadian pacemaker;heart cell;in vivo;insight;mRNA Stability;molecular clock;mouse model;premature;promoter;shift work;suprachiasmatic nucleus;transcription factor

public_health_relevance:
Project NarrativeThe molecular clock mechanism serves a ubiquitous cellular time-keeping function and it regulates the tissue-specific expression of many genes. Molecular clock signaling in cardiomyocytes controls the expression ofseveral K+ channel genes that are important for normal cardiac excitability. We are applying approachesdeveloped in chronobiology to study the regulation of cardiac K+ channels at an entirely new level.


application_id: 10131140
project_number: 5R13CA168316-09
project_title: Advancing Health Communication Research through the KCHC-DCHC Conference Series
administering_ic: NCI
award_notice_date: 2021-03-31
opportunity_number: PA-16-294
application_type: 5
activity_code: R13
ic: CA
serial_number: 168316
program_official: BLAKE, KELLY D
project_start_date: 2012-04-19
project_end_date: 2023-03-31
study_section: ZCA1-PCRB-G(O1)
contact_pi_person_id: 1974135
contact_pi: HARRINGTON, NANCY GRANT
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:
Abstract This R13 renewal application requests support to continue the highly successful Kentucky Conference onHealth Communication (KCHC)District of Columbia Health Communication (DCHC) scientific conferenceseries. The overall goal of the annual KCHC-DCHC conferences is to promote health communicationresearch and practice to advance our knowledge and understanding of communication and related social-behavioral sciences; such advances will through translational research subsequently enhance theeffectiveness of interventions designed to promote health and prevent illness. The specific aims are toexpand the impact and scholarly excellence of KCHC-DCHC by 1) enhancing dissemination through moreformal conference proceedings and an innovative online networking initiative; 2) increasing participation byearly career scientists graduate students and underrepresented groups through targeted recruitment andreduced registration rates for students; 3) enhancing training by building in structured mentoring sessions withsenior scholars; 4) increasing innovation and opportunities for research translation by scheduling specialsessions to promote academic and clinical research collaborations; 5) increasing international impact throughopportunities for discussion built into conference programming and increased promotion in internationalarenas; and 6) continuing emphasis on scholarly excellence by inviting distinguished speakers and makingscholarly awards. Across all six aims our goal is to positively influence the field of health communication andincrease its impact by promoting the career development of early career scientists encouraginginterdisciplinary research collaborations and enhancing dissemination and implementation of leading research.Our 2.5-day international interdisciplinary conference involves several disciplines representing communicationpublic health and other social behavioral and health sciences. Topics addressed include interventionsdesigned for health risk behavior reduction in areas such as cancer substance abuse and infectious disease;issues related to underserved populations health disparities and health literacy; interventions throughinterpersonal community media and new technology channels; and international health concerns includingpromoting the development of health communication programs in developing nations. Such communication-focused inquiry is now recognized as instrumental in promoting public health. Past conference attendance hasaveraged 250 participants. The audience primarily includes graduate postdoctoral and academic facultyresearchers as well as healthcare practitioners clinical researchers and representatives from non-profitorganizations and government agencies. We emphasize participation by graduate students and early careerscientists. This audience composition allows the conference series to support one of NIH's goals: to developmaintain and renew scientific humanresources that will ensure the Nation's capability to prevent disease.

project_terms:
Address;Area;Award;Behavioral Sciences;China;Clinical;Clinical Research;Clinical Sciences;Collaborations;Communicable Diseases;Communication;Communication Programs;Communication Research;Communities;Country;Decision Making;Developing Countries;Development;Diabetes Mellitus;Discipline;Disease;Dissemination and Implementation;District of Columbia;Effectiveness of Interventions;Ensure;Event;Faculty;Foundations;Funding;Germany;Goals;Government;Government Agencies;Growth;Health;Health Personnel;Health Promotion;Health Sciences;Healthcare;Human Resources;Interdisciplinary Study;International;Internet;Intervention;Kentucky;Knowledge;Life;Malignant Neoplasms;Mentors;Mission;Netherlands;Nonprofit Organizations;Participant;Patients;Personal Satisfaction;Public Health;Publications;Request for Applications;Research;Research Personnel;Risk;Risk Reduction Behavior;Role;Russia;Schedule;Scientist;Series;Social Sciences;Structure;Students;Substance abuse problem;Switzerland;Training;Translational Research;Underrepresented Populations;Underserved Population;United States National Institutes of Health;Universities;base;behavioral/social science;cancer risk;career;career development;design;disability;disorder prevention;experience;graduate student;health communication;health disparity;health goals;health information technology;health knowledge;health literacy;innovation;new technology;prevent;recruit;skills;substance abuse prevention;symposium;therapy design;tool

public_health_relevance:
Project NarrativeThe Kentucky Conference on Health Communication (KCHC)District of Columbia HealthCommunication (DCHC) conference series will advance health communication research andpractice to reduce the burden of pressing public health problems such as cancer diabetessubstance abuse and infectious disease. The conferences will advance health communicationresearch and practice through structured researcher and practitioner networking andcollaboration opportunities. The conferences will promote career development in the social andbehavioral sciences through involvement of early career scientists and graduate studentsincreasing the number of professionals with expertise in health communication.


application_id: 10131077
project_number: 5R01AG057187-05
project_title: Novel pathogenetic mechanism for hippocampal sclerosis a common Alzheimers mimic
administering_ic: NIA
award_notice_date: 2021-04-12
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 057187
program_official: OPANASHUK, LISA A
project_start_date: 2017-07-15
project_end_date: 2023-03-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Hippocampal sclerosis of aging (HS-Aging) is a major pathologic substrate of dementia but there currently areno validated strategies in the clinical setting to diagnose or treat the disease. HS-Aging affects ~15% ofelderly persons and is associated with substantial cognitive impairment. Our group has studied this areaextensively leading to the following major hypothesis: thyroid hormone (TH) dysregulation contributesto HS-Aging pathogenesis. This novel pathogenetic mechanism may provide the basis to diagnose HS-Aging during life using CSF analyses and to develop a therapeutic strategy. However critical knowledgegaps remain in terms of characterizing the specific association between TH dysfunction and brain pathologyand the potential to target the mechanism for therapeutic purposes. We propose a research program to fillthese knowledge gaps while testing key hypotheses via the following Specific Aims:Hypothesis 1: Clinical TH status is associated with presence and severity of HS-Aging pathology.Specific Aim 1: Test the hypothesis in a convenience sample (n=205 including cognitively intact and diversenon-HS-Aging dementia controls) from the University of Kentucky AD Center biobank. We will apply rigorousquantitative digital pathologic methods to assess TDP-43 pathology AD plaques/tangles and -synucleinopathy for correlation with clinical TH status: self-reported TH disease and TH medications are well-documented. As expected in aged persons more than 25% of the subjects exhibited clinical TH dysfunction.Hypothesis 2: CSF TH levels are associated with HS-Aging pathology and may provide a novel biomarker.Specific Aim 2: Evaluate TH (triiodothyronine or T3) in CSF as a clinical biomarker of HS-Aging. We willassess human CSF TH levels with direct correlation with various subtypes of pathology. We also will test THin clinical CSF from lumbar punctures correlated with established AD-related biomarkers (A and tau) andHS-Aging SNPs with the goal of developing a new method to diagnose HS-Aging in living persons. We haveobtained CSF from autopsied individuals (n=104) and clinical CSF samples (n=195) to accomplish this Aim.Hypothesis 3: Specific HS-Aging risk-associated gene variants induce altered brain TH levels with extensiveimpact on brain gene expression and orally available drugs can alter this pathogenetic mechanism.Specific Aim 3: Define gene expression changes relevant to TH and HS-Aging. We will analyze humangenomics databases to define how gene changes linked to HS-Aging risk contribute to variability in ABCC9and SLCO1C1 (a major brain TH transporter) expression. We will test human cells (cultured human hESCastrocytes and lymphoblastoid cells transformed with DNA from people with known genotypes and pathology)to determine the potential for manipulating the levels of ABCC9 of TH transporter SLCO1C1 and of other TH-regulated genes. Finally in mice we will test how TH-responsive gene expression neuropathology andneurobehavior are affected in vivo by treatment with TH and/or the ABCC9 agonist drug glimepiride.

project_terms:
ABCC9 gene;Affect;Age;Aging;Agonist;Alzheimer's Disease;Alzheimers disease biomarker;American;Area;Astrocytes;Autopsy;Behavior;Biological Markers;Biometry;Blood specimen;Brain;Brain Diseases;Brain Pathology;Cell Culture Techniques;Cells;Clinical;Cognitive;DNA;Data;Databases;Dementia;Development;Diagnosis;Disease;Elderly;Exhibits;Functional disorder;Future;Gene Expression;Genes;Genetic;Genotype;Glimepiride;Goals;Hippocampus (Brain);Hormone Responsive;Human;Impaired cognition;Individual;Infarction;Interdisciplinary Study;Kentucky;Knockout Mice;Knowledge;Life;Link;Metformin;Methods;Modeling;Morbidity - disease rate;Mus;Mutation;Neurofibrillary Tangles;Oral;Pathogenesis;Pathologic;Pathology;Patient Self-Report;Persons;Pharmaceutical Preparations;Pharmacology;Phenotype;Regulator Genes;Research;Research Personnel;Risk;Sampling;Severities;Spinal Puncture;Testing;Therapeutic;Thyroid Gland;Thyroid Hormones;Thyroxine;Transcript;Triiodothyronine;Universities;Widespread Disease;aged;base;biobank;cell transformation;clinical biomarkers;clinical center;cohort;dementia risk;digital;experimental study;genetic variant;genomic biomarker;hippocampal sclerosis;human embryonic stem cell;human genomics;in vivo;neurobehavior;neuropathology;novel;novel marker;prevent;programs;protein TDP-43;risk variant;synucleinopathy;therapeutic target

public_health_relevance:
PROJECT NARRATIVEWe are performing studies of a brain disease (hippocampal sclerosis of aging) thatmimics Alzheimer's disease in the clinical setting and which affects millions ofAmericans. Our group has studied this disease extensively leading to the followingmajor hypothesis: thyroid hormone dysregulation contributes to hippocampalsclerosis dementia. The experiments described in this proposal are necessary fordeveloping future clinical strategies aimed at detecting and ultimately preventing thisunderappreciated prevalent and high-morbidity brain disease.


application_id: 10130811
project_number: 1R01NS112304-01A1
project_title: Propriopsinal neuron function in normal and post-SCI locomotion
administering_ic: NINDS
award_notice_date: 2021-03-10
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: NS
serial_number: 112304
suffix: A1
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2021-03-15
project_end_date: 2026-01-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
other_pis: DANNER, SIMON MICHAEL;WHITTEMORE, SCOTT R
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Adult;Anatomy;Animals;Axon;Behavior;Biomechanics;Cervical;Characteristics;Computer Models;Computer Simulation;Contusions;Data;Data Set;Development;Dissection;Engineering;Forelimb;Gait;Goals;Hindlimb;Injury;Interneurons;Ipsilateral;Knowledge;Label;Lateral;Left;Limb structure;Locomotion;Mediating;Modeling;Molecular;Movement;Musculoskeletal System;Neurons;Physiological;Play;Population;Publishing;Rattus;Recovery;Role;Running;Sensory;Source;Speed;Spinal;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Structure;Structure-Activity Relationship;Synapses;Techniques;Testing;Thoracic spinal cord structure;Validation;Viral;Virus;Walking;animal data;base;biomechanical model;central pattern generator;design;experimental study;in silico;in vivo;kinematics;model development;neural circuit;neurotransmission;novel;novel therapeutics;predictive modeling;sensory input;tool


application_id: 10130446
project_number: 5R01AT009268-05
project_title: Mechanisms underlying anabolic effects of cyclic compressive loading in muscle
administering_ic: NCCIH
award_notice_date: 2021-03-12
opportunity_number: PA-14-168
application_type: 5
activity_code: R01
ic: AT
serial_number: 009268
program_official: TUTTLE, ALEXANDER H
project_start_date: 2017-04-01
project_end_date: 2023-09-30
study_section: Special Emphasis Panel[ZRG1-MOSS-R(02)M]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
other_pis: BUTTERFIELD, TIMOTHY ALAN
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The loss of skeletal muscle mass is a main contributor to disability in numerous disease states and is also apredictor of mortality and a major factor in the loss of independence in the elderly. We propose that massage isa novel intervention to attenuate acute muscle atrophy or aid with regrowth after muscle loss in patients whoare unable to perform exercise. Massage is a manual therapy modality extensively used clinically for pain reliefand as a modulator of immune responses; however very few investigations have addressed the actualunderlying mechanisms of the beneficial effects of massage mainly because of the lack of consistency in theapplied load. Using an innovative cyclic compressive loading (CCL) device for small rodents mimickingmassage with a well-defined load we showed that CCL elevated protein synthesis when administered duringdisuse or recovery after atrophy and enhanced the regrowth response in adult rats in the massaged limbwhile no effect was seen in unperturbed or aged rats. Surprisingly we also found a positive regrowth responsein the contralateral non-massaged limb. We suggest that protein synthesis is elevated throughmechanosensitive anabolic pathways such as the focal adhesion complexes including focal adhesion kinase(FAK) and integrin-linked kinase (ILK) in the massaged limb and that the growth effect in the non-massagedlimb is mediated by a neuronal cross-over effect or by systemically-mediated mechanisms. These preliminarydata led to following hypothesis: Massage in the form of CCL exerts an anabolic effect on muscledirectly through mechanosensitive pathways as well as indirectly by neurally or systemically mediatedmechanisms to enhance muscle size in perturbed growth states. We will use CCL in rats to study themuscle growth response using growth perturbations i.e. disuse atrophy and regrowth after atrophy. In Aim 1we will establish mechanisms for the attenuated growth response to CCL in muscles from aged compared toadult rats and test the hypothesis that muscles from aged rats show an attenuated response to CCL becauseof a stiffer extracellular matrix and a change in the pool of proteins synthesized. In Aim 2 the mechanosensitivepathways responsible for the growth response in skeletal muscle from adult rats after CCL will be investigatedwith particular attention to FAK and the role of satellite cells. In Aim 3 we will test the hypothesis that theincrease in protein synthesis and muscle size in the contralateral non-massaged limb after CCL is due to asensory feedback-regulated cross-over effect but will also investigate systemic-mediated actions such ascytokines and exosome-mediated transfer of miRNAs. Results from these studies will indicate whethermassage is a viable intervention for preventing the loss of muscle mass during disuse or promoting regrowth ofmuscle after atrophy while determining the underlying mechanisms for the beneficial anabolic effects.

project_terms:
Acquired Immunodeficiency Syndrome;Acute;Address;Adult;Aging;Animals;Atrophic;Attention;Attenuated;Biochemical Pathway;Biology;Clinical;Complementary Health;Complementary therapies;Complex;Congestive Heart Failure;Contralateral;Data;Development;Devices;Disease;Disuse Atrophy;Elderly;Endocrine;Exercise;Extracellular Matrix;Focal Adhesion Kinase 1;Focal Adhesions;Growth;Immune response;Immunomodulators;Integrative Medicine;Intervention;Investigation;Knowledge;Lead;Limb structure;Maintenance;Malignant Neoplasms;Manipulative Therapies;Massage;Mechanical Stimulation;Mechanics;Mediating;MicroRNAs;Modality;Morbidity - disease rate;Muscle;Muscle Weakness;Muscular Atrophy;NIH Program Announcements;Neurons;Pathway interactions;Patients;Periodicity;Play;Protein Biosynthesis;Proteins;Quality of life;Rattus;Recovery;Reproducibility;Research;Rodent;Role;Skeletal Muscle;Standardization;Symptoms;Testing;Therapeutic Intervention;aged;clinical pain;cytokine;direct application;disability;exosome;functional decline;innovation;integrin-linked kinase;mechanotransduction;mortality;muscle form;novel;pain relief;patient population;prevent;relating to nervous system;response;restoration;satellite cell;sensory feedback;skeletal muscle wasting

public_health_relevance:
The loss of muscle mass is a predictor of morbidity and mortality in multiple disease states and during agingand is highly correlated with quality of life. This research application proposes the use of massage as anintervention to decrease muscle atrophy during disuse and to increase the ability to regrow muscle size afterinactivity and will determine underlying mechanisms underlying these beneficial effects. Massage can bedirectly applied clinically for the maintenance and restoration of muscle size and strength in multiple patientpopulations and determining when it will be beneficial is of high significance.


application_id: 10129908
project_number: 5K07CA218247-05
project_title: Human Papillomavirus-Specific Biomarkers for the Prediction of Oropharyngeal Cancer Recurrence
administering_ic: NCI
award_notice_date: 2021-06-09
opportunity_number: PAR-16-284
application_type: 5
activity_code: K07
ic: CA
serial_number: 218247
program_official: BIAN, YANSONG
project_start_date: 2020-10-16
project_end_date: 2022-12-31
study_section: Career Development Study Section (J)[NCI-J]
contact_pi_person_id: 14510566
contact_pi: KUHS, KRYSTLE A.
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThis Career Development Award (CDA) is designed to provide Dr. Krystle A. Lang Kuhs with the necessary skills andmentorship to develop an independent research program focused on head and neck cancer prevention. The goals of herfuture research program are to improve patient outcomes by using molecular markers to: a) detect head and neck cancersearlier (secondary prevention); b) improve pre-treatment risk stratification to personalize therapy based on prognosis(tertiary prevention) and; c) detect recurrences earlier when highly-curative salvage surgery is still an option (quaternaryprevention). This is the natural next-step in Dr. Lang Kuhs career given that it builds upon her strengthens in cancerprevention basic science epidemiology oncogenic infections and biomarker development. However to achieve hercareer goals Dr. Lang Kuhs will need to address 3 main gaps in her training: 1) clinical epidemiology (patient populationexperience and clinical cohort building); 2) biomedical informatics (use of electronic health record [EHR] data); and 3)advanced biostatistics (risk prediction modeling). This training will be obtained through coursework seminars experientiallearning hands on training and mentorship. Dr. Lang Kuhs will be mentored by leading experts in molecular epidemiologyand cohort development (Dr. Wei Zheng) head and neck cancer immunology (Dr. Young Kim) and head and neck cancersurvivorship (Dr. Barbara Murphy). The research portion of this CDA will focus on human papillomavirus-drivenoropharyngeal cancer (HPV-OPC) a type of rapidly increasing head and neck cancer. While treatment of HPV-OPC is oftencurative it is associated with severe morbidity. Clinical trials are underway to investigate whether de-escalation oftreatment for HPV-OPC can decrease morbidity while still preserving high survival rates. However the most significantbarrier for the adoption of de-escalated treatment is the inability to identify patients at highest risk for recurrence. Theobjective of this research is to examine the potential utility of using HPV-specific biomarkers to identify patients at highestrisk for recurrence. This research will utilize banked biospecimens and EHR data to create a clinical cohort of HPV-OPCpatients to: 1) examine the association between HPV viral variants within OPC tumors and recurrence; 2) examine theassociation between pre-treatment HPV16 E6 seropositivity and E6 oncogene expression and risk recurrence; and 3)develop and refine protocols for expanded prospective collection of clinical data and biospecimens from OPC patients.The mentored training hands on experience and results gained from this CDA will position Dr. Lang Kuhs to successfullycompete for funding to establish an independent research program focused on developing biomarkers for the preventionof head and neck cancer.

project_terms:
Active Learning;Address;Adoption;Aftercare;Antibodies;Basic Science;Biological Markers;Biological Specimen Banks;Biometry;Cancer Patient;Cancer Survivorship;Cervical;Clinical;Clinical Data;Clinical Management;Clinical Trials;Collection;Data;Databases;Development;Diagnosis;Disease Management;Electronic Health Record;Enrollment;Epidemic;Epidemiology;Funding;Genome;Genomics;Goals;Head and Neck Cancer;Human Papilloma Virus Vaccine;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Immune response;Immunology;Incidence;Infection;Infrastructure;Institutional Review Boards;Joints;K-Series Research Career Programs;Knowledge;Lead;Mentors;Mentorship;Modality;Molecular;Molecular Epidemiology;Morbidity - disease rate;Oncogenes;Oncogenic;Oncoproteins;Operative Surgical Procedures;Oral;Outcome;Pathology;Patient Care;Patient-Focused Outcomes;Patients;Positioning Attribute;Prevention;Prognosis;Protocols documentation;Recurrence;Reporting;Research;Resource Sharing;Risk;Sampling;Secondary Prevention;Serum;Specimen;Survival Rate;Techniques;Tissues;Training;Treatment Protocols;Up-Regulation;Vaccinated;Variant;Viral;base;biobank;biomarker development;biomedical informatics;blood treatment;cancer prevention;cancer recurrence;cancer risk;carcinogenicity;career;clinical epidemiology;cohort;cytokine;design;experience;head and neck cancer patient;head and neck cancer prevention;high risk;improved;improved outcome;malignant oropharynx neoplasm;middle age;molecular marker;next generation sequencing;novel;novel marker;patient population;personalized medicine;preservation;programs;prospective;risk prediction model;risk stratification;sample collection;seropositive;skills;specific biomarkers;tertiary prevention;treatment response;treatment risk;tumor;tumor immunology;vaccine acceptance

public_health_relevance:
PROJECT NARRATIVEThe US is in the midst of a human papillomavirus-driven oropharyngeal cancer (HPV-OPC) epidemic and althoughtreatment is often curative it is associated with severe morbidity. This research has the potential to help identify HPV-OPC patients at highest risk for recurrence in order; a) to determine which patients should receive de-escalated treatmentprotocols so that treatment-related morbidity could be reduced for those at low risk of recurrence and b) to determinewhich patients should receive more aggressive post-treatment surveillance in order to detect recurrences earlier andimprove survival. Thus this CDA has the potential to significantly contribute toward our understanding of HPV-OPCrecurrence which could lead to improved clinical management of the disease decreased treatment-related morbidity andimproved survival post-recurrence.


application_id: 10129905
project_number: 5R25CA134283-10
project_title: University of Louisville Cancer Education Program
administering_ic: NCI
award_notice_date: 2022-03-31
opportunity_number: PAR-15-152
application_type: 5
activity_code: R25
ic: CA
serial_number: 134283
program_official: RADAEV, SERGEY
project_start_date: 2011-09-14
project_end_date: 2025-03-31
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID W
other_pis: KIDD, LA CREIS RENEE
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:
Cancer incidence morbidity and mortality in the Commonwealth of Kentucky are among thehighest in the nation. The University of Louisville Cancer Education Program recruits andmotivates outstanding undergraduate and health professional students to pursue further trainingand careers in cancer research. The program consistently recruits the best and brightestundergraduate and health science professional students from the University of Louisville andprestigious universities across the country. An impressive number of University of Louisvillefaculty members among its many colleges and schools contribute to this program. The Universityof Louisville Cancer Education program has surpassed all of its five year goals. The renewalapplication proposes an aggressive plan to reach even higher goals over the next five years. Wepropose to accomplish the objectives described in our renewal proposal via completion of six aims1) Recruit outstanding health professional and undergraduate students including targetenrollment of students from groups underrepresented in cancer research; 2) Provide hands-onparticipation in cancer research through the development completion and presentation of cancerresearch projects under the mentorship of research-intensive faculty members of the JamesGraham Brown Cancer Center; 3) Enrich the student participation with professional developmentand cancer research training activities and research seminars; 4) Require student presentation oftheir cancer research project to faculty judges and fellow students at annual scientificconferences; 5) Motivate students to attend and present their cancer research project at regionaland national scientific meetings; and 6) Evaluate student recruitment participation satisfactionplacement and other student outcomes against explicit benchmarks.

project_terms:
Benchmarking;Cancer Center;Cancer Research Project;Country;Development;Enrollment;Faculty;Goals;Health Professional;Health Sciences;Incidence;Kentucky;Malignant Neoplasms;Mentorship;Morbidity - disease rate;Outcome;Research;Schools;Student recruitment;Students;Training;Training Activity;Underrepresented Populations;Universities;anticancer research;cancer education;career;college;meetings;member;mortality;programs;recruit;research and development;satisfaction;science teacher;student participation;symposium;undergraduate student;university student

public_health_relevance:
Project NarrativeCancer incidence morbidity and mortality in the Commonwealth of Kentucky are among thehighest in the nation. The objective of the University of Louisville Program Cancer EducationProgram is to recruit train and motivate outstanding undergraduate and professional studentsto engage and present an outstanding cancer research project and to pursue further trainingand careers in cancer research.


application_id: 10129682
project_number: 1C06OD030129-01
project_title: University of Louisville Vivarium Construction
administering_ic: OD
award_notice_date: 2020-09-19
opportunity_number: PAR-20-086
application_type: 1
activity_code: C06
ic: OD
serial_number: 030129
program_official: CHEN, YONG
project_start_date: 2020-09-19
project_end_date: 2024-10-31
study_section: Scientific and Technical Review Board on Biomedical and Behavioral Research Facilities[STOD]
contact_pi_person_id: 8666997
contact_pi: SHERWOOD, LESLIE C.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROGRAM SUMMARY/ABSTRACTThe University of Louisville (UofL) is an Institution of Emerging Excellence (IEE) and one of 23states designated by the National Institutes of Health (NIH) as an Institutional DevelopmentAward (IDeA) state serving the research needs of medically underserved communities. As partof the IDeA state program UofL is the recipient of four NIH funded Centers of BiomedicalResearch Excellence (COBRE) projects to target local and regional health crises in Kentuckyand Appalachia. These include centers in 1) Diabetes and Obesity 2) Microbiome 3)Hepatobiology and Toxicology and 4) Cancer. UofL is also the recipient of NIH funding for theAlcohol Center and the Envirome Institute Superfund Research Center which studies theeffects of cigarette smoke e-cigarettes and other inhaled toxins on the cardiovascular system.UofL is requesting $8000000 to renovate the ninth floor of the A-Tower Research Building toprovide a centralized modern vivarium to house primarily rodent and aquatics species tosupport a broad range of research efforts. The proposed renovation will replace and consolidaterodent housing rooms on nine separate floors of the A-Tower and one room in the DentalSchool connected by a public pedway. The new facility will triple present animal housing spaceand improve efficiency for investigators by providing animal housing and procedural spacewithin the new facility. It will also isolate animals from public areas and provide a barrier level ofbiosecurity for rodent colonies. This innovative facility design maximizes flexibility for ourongoing needs and projected growth. The design features multi-purpose rooms that can beanimal housing or procedural space with minimal fixed equipment. The new facility alsoincludes specialized inhalation rooms and ABSL2 procedure space which is not currentlyavailable. The location of the A-Tower and its numerous enclosed connections to surroundingresearch buildings make it an ideal location for a centralized vivarium and an academicresearch hub. This new facility will provide essential support for the four NIH funded COBREgrants the Envirome Institute Superfund and over 80 investigators in at least thirteendepartments with combined NIH and other funding of over $25 million. This project will supportlong-term institutional research plans and provide long-term modern improvements to ourresearch infrastructure serving as a base for a broad range of investigators and their researchefforts institution-wide on a shared basis with a strong emphasis on clinical translationalresearch. In addition to having a local and regional impact despite being an IEE this projectalso has national impact through the support of our numerous COBRE and Superfund grants.

project_terms:
Alcohols;Animal Housing;Animals;Appalachian Region;Area;Award;Cardiovascular system;Centers of Research Excellence;Clinical;Communities;Dental Schools;Development;Diabetes Mellitus;Electronic cigarette;Equipment;Facility Designs;Floor;Funding;Grant;Growth;Health;Housing;Inhalation;Institutes;Institution;Kentucky;Location;Malignant Neoplasms;Modernization;Obesity;Procedures;Research;Research Infrastructure;Research Personnel;Rodent;Superfund;Toxicology;Toxin;Translational Research;United States National Institutes of Health;Universities;base;biosecurity;cigarette smoke;design;flexibility;improved;innovation;medically underserved;microbiome;programs


application_id: 10129546
project_number: 5P20GM125504-04
project_title: Characterization of the Impact of the Noncapped Alphavirus Genomic RNAs
administering_ic: NIGMS
award_notice_date: 2021-02-11
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
program_official: GAO, HONGWEI
study_section: ZGM1-RCB-3
subproject_number: 5121
contact_pi_person_id: 10849785
contact_pi: SOKOLOSKI, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-03-01
project_abstract:
Abstract: Alphaviruses are vector-borne pathogens that have proven capable of causing significant outbreaks of clinical disease. Currently there is an absolute lack of safe and approved antiviral therapies / vaccines. Thus research which defines the molecular basis of infection is essential and critically important to not only understanding alphaviral pathogenesis but to the development of innovative antiviral strategies. The overarching research objective of this proposal is to define the mechanism by which a novel alphavirus RNA species impacts infection and pathogenesis. The scientific premise and rationale supporting this objective are based upon a wealth of preliminary evidence which indicates that the production of noncapped genomic RNAs (ncgRNAs) is essential for alphaviral infection as evidenced by studies involving Sindbis virus (SINV) and Ross River virus. Nonetheless the extent to which the ncgRNAs impact viral infection is unknown and represents a critical gap in the knowledgebase. Thus we propose the following specific aims- i) To determine the mechanism with which the noncapped genomic vRNAs impact infection and ii) To define the impact of the noncapped genomic vRNAs on viral pathogenesis. To accomplish the first aim we will undertake an exhaustive molecular analysis of SINV infection to determine the mechanism by which the ncgRNAs effect viral infection. Specifically we will determine whether or not ncgRNA function is linked to its translatability via a novel IRES-based approach. In addition we will determine which viral process is negatively affected by ncgRNA reduction; and determine the molecular interactions required for ncgRNA function. The second aim uses a combinatorial approach of in vivo studies and IFN-competent tissue culture models to comprehensively define the contribution of the ncgRNAs to SINV pathogenesis. Briefly the contribution of the ncgRNAs to the induction of a detrimental neuroinflammatory response will be evaluated in depth histologically and at the transcriptomic and proteomic levels. Moreover the consequences of increasing and decreasing alphaviral capping efficiency on the host innate immune response will also be defined in highly tractable tissue culture models of infection. The proposed work is highly significant in that it seeks to characterize and define the molecular importance of a novel viral RNA species. Moreover the proposed research is conceptually and technically innovative as state-of-the-art techniques approaches and models of infection are used to delineate the contributions of the novel ncgRNA species to molecular infection and pathogenesis. The successful completion of this work will fundamentally expand the knowledgebase by eliminating the critical gap in understanding described above; in addition the proposed research has a high likelihood of leading to the identification of novel antiviral strategies.

project_terms:
Alphavirus;Antiviral Agents;Antiviral Therapy;Binding;Clinical;Development;Disease;Disease Outbreaks;Genomics;Histologic;Infection;Inflammation;Innate Immune Response;Interferons;Internal Ribosome Entry Site;Link;Modeling;Molecular;Molecular Analysis;Pathogenesis;Pathogenicity;Process;Production;Proteomics;RNA;Research;Ross river virus;Sindbis Virus;Techniques;Vaccines;Viral;Viral Pathogenesis;Virus Diseases;Work;base;combinatorial;defined contribution;exhaustion;genomic RNA;in vivo;innovation;knowledge base;microbiome research;negative affect;neuroinflammation;novel;response;tissue culture;transcriptomics;vector-borne pathogen;viral RNA


application_id: 10129313
project_number: 5R37CA227656-04
project_title: The phosphatase PRL3 as a MYC target and pro-survival oncogene in Acute Lymphoblastic Leukemia
administering_ic: NCI
award_notice_date: 2021-03-23
opportunity_number: PA-16-160
application_type: 5
activity_code: R37
ic: CA
serial_number: 227656
program_official: JHAPPAN, CHAMELLI
project_start_date: 2018-04-06
project_end_date: 2023-03-31
study_section: Cancer Molecular Pathobiology Study Section[CAMP]
contact_pi_person_id: 10310607
contact_pi: BLACKBURN, JESSICA S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThere is a great need for the development of molecularly targeted therapies in Acute Lymphoblastic Leukemia(ALL). The lack of targeted therapies for this disease is an important problem because ALL is primarily apediatric cancer and intensive rounds of general cytotoxic chemotherapy have severe and long-term adverseeffects in children. Additionally adults and children whose ALL does not respond to cytotoxic chemotherapy orwho develop relapse have a universally poor prognosis due to limited treatment options. The well-knowndrivers of ALL are mis-expressed transcription factors such as MYC which are not easily therapeuticallytargeted without undesirable side-effects on normal cells. Preliminary data which built on a novel in vivotransplantation screen in a MYC-induced ALL model in zebrafish demonstrated that the tyrosine phosphatasePRL3 collaborated with MYC to enhance leukemia progression. In vitro and in vivo studies using human cellsshowed that PRL3 is linked with MYC expression and plays a critical role in ALL survival. Phosphatases likePRL3 are most well-known as tumor suppressors and despite emerging evidence that some phosphataseshave oncogenic abilities there are currently no phosphatase inhibitors used in the clinic for cancer patientsand only one in clinical trial. The overall objective of this application is to clearly define the oncogenic role ofthe tyrosine phosphatase PRL3 in MYC-driven ALL and to establish that it is a novel molecular target in thisdisease. The central hypothesis is that PRL3 is a direct transcriptional target of MYC and synergizes withMYC to promote a pro-survival phenotype in ALL cells. The rationale for this research is that PRL3 belongs toa unique family of phosphatases that can be selectively inhibited; defining the mechanisms through whichPRL3 promotes ALL survival will provide a strong scientific rationale for the development of PRL and otherphosphatase inhibitors for use as targeted therapy for cancer patients. This hypothesis will be tested bypursuing three specific aims: 1) Define a mechanism through which MYC regulates PRL3 expression by usingenChIP and biochemical approaches to assess MYC interaction with a novel enhancer region near PRL3; 2)determine the pro-survival mechanisms that are controlled by PRL3 by utilizing an unbiased biotin ligaseapproach to identify PRL3 substrates in ALL cells; and 3) establish that small molecule inhibition of the PRLfamily is a potent therapeutic strategy in ALL by completing comprehensive pre-clinical testing of three newPRL inhibitors and a panel of FDA-approved tyrosine phosphatase inhibitors. This research is innovativebecause it departs from the status quo to use new methods to define an oncogenic role for a phosphatase incancer. The proposed research is also significant because it is expected to vertically advance and expandunderstanding of the role that phosphatases play in cancer progression. Ultimately this knowledge has thepotential to drive the development of a new class of targeted therapy for patients with acute lymphoblasticleukemia and other MYC-driven cancers.

project_terms:
Acute Lymphocytic Leukemia;Adult;Adverse effects;Apoptosis;Binding Sites;Biochemical;Biotin;Cancer Patient;Cells;Cessation of life;Child;Clinic;Clinical Trials;Cytotoxic Chemotherapy;DNA-Binding Proteins;Data;Defect;Development;Developmental Delay Disorders;Diagnosis;Disease;Disease Progression;Drug Targeting;Enhancers;FDA approved;Family;Gene Chips;General Population;Genes;Genetic Transcription;Growth;Human;Human Cell Line;In Vitro;Kinetics;Knowledge;Leukemic Cell;Life;Ligase;Link;MYC gene;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;Methods;Mission;Modeling;Molecular Target;Normal Cell;Nucleic Acid Regulatory Sequences;Oncogenes;Oncogenic;Organ;Outcomes Research;Pathway interactions;Patients;Phenotype;Phosphoric Monoester Hydrolases;Play;Preclinical Testing;Prognosis;Protein Array;Protein Tyrosine Phosphatase;Public Health;Regimen;Relapse;Research;Role;Sampling;Second Primary Cancers;Signal Pathway;Single Nucleotide Polymorphism;TP53 gene;Testing;Therapeutic;Transcriptional Regulation;Transplantation;Tumor Suppressor Proteins;Zebrafish;acute lymphoblastic leukemia cell;antileukemic activity;base;cancer type;chemotherapy;in vivo;inhibitor/antagonist;innovation;knock-down;leukemia;member;molecular targeted therapies;novel;patient derived xenograft model;pediatric patients;phosphatase inhibitor;preclinical trial;side effect;small molecule;targeted cancer therapy;targeted treatment;therapeutic target;transcription factor;translational impact;tumor progression

public_health_relevance:
PROJECT NARRATIVEThe proposed research is relevant to public health because the discovery of the mechanisms through whichthe tyrosine phosphatase PRL3 drives leukemia progression is expected to re-define the roles thatphosphatases can have in cancer. The proposed research is therefore relevant to the NCI mission because itwill provide a strong impetus for the development of phosphatase inhibitors which will be a new class oftargeted therapy for cancer patients.


application_id: 10129275
project_number: 5R21AI150085-02
administering_ic: NIAID
award_notice_date: 2021-02-24
opportunity_number: PA-19-053
application_type: 5
activity_code: R21
ic: AI
serial_number: 150085
program_official: MCGUGAN, GLEN C
project_start_date: 2020-03-20
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZRG1-IDM-M(02)]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY P.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-03-01
project_title:
Extragenic adaptation to the loss of a deubiquitinase affecting the T. gondii cell cycle and development

project_abstract:
Project SummaryThe cell cycle of protozoan parasite Toxoplasma gondii an important opportunistic pathogen in HIV-AIDSpatients is fundamentally distinct from that of typical eukaryotes. Replication in the actively growingtachyzoites in acute infection and within bradyzoites associated with chronic infection occurs by an internalbudding process termed endodyogeny. With endodyogeny each mother parasite produces 2 daughters percycle. In contrast the sexual cycle of the parasite a stage restricted to the feline gut occurs by a hybrid ofschizogony and endopolygeny which are typically associated with the malaria parasite and members of thegenus Sarcocystis respectively. These cell cycle architectures are associated with the generation of multipleprogeny per replicative cycle. We recently characterized a cell cycle regulated deubiquitnase TgOTUD3A(TgGT1_258780) the targeted disruption of which relaxed the restriction of tachyzoites replication toendodyogeny (2 progeny per cycle) to exhibit characteristics of both schizogony and endopolygeny-oftenwithin the same clonal vacuole. These mutant parasites generate 34 or 5 progeny per cycle to define themulti-daughter phenotype. In addition over 70% of TgOTUD3A tachyzoites ectopically express markersassociated with bradyzoites and induce the expression of genes typically associated with merozoties thestage associated with entry into the sexual cycle in cats. Complementation of the TgOTUD3A-KO failed torestore any of these phenotypes with whole genome sequencing revealing no credible mutations at thegenomic level. This suggested that a compensatory adaptation had occurred. Examination of the otherTgOTU family members revealed a selective transcriptional upregulation of two closely related familymember TgOTUD1B (TgGT1_237894) and TgOTUD1C (TgGT1_323200). It is likely that TgOTUD1A(TgGT1_207650) is similarly upregulated. This presents the possibility that one or more of the cell cycle anddevelopmental phenotypes attributed to the loss of TgOTUD3A may in fact be due to the upregulation of theClade D1 TgOTU members. To address this specific question we propose to functionally characterize theClade D1 TgOTU members and establish the consequence of both their ablation and regulatedoverexpression in the wild type and TgOTUD3A-KO background. In doing so we expect to gain insights intohow these deubiquitinases govern the selection of cell cycle architecture and control aspects of keydevelopmental transitions cementing an emerging association between these fundamental processes.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Address;Affect;Architecture;Biochemical;CRISPR screen;Cell Cycle;Cell Cycle Regulation;Cell Nucleus;Characteristics;Chronic Phase;Cloning;Clustered Regularly Interspaced Short Palindromic Repeats;Complement;Cytokinesis;Daughter;Development;Dissection;Dolichos;Ectopic Expression;Enzyme Kinetics;Epitopes;Eukaryota;Exhibits;Family;Family Felidae;Family member;Felis catus;Gap Junctions;Gene Expression;Generations;Genes;Genetic Transcription;Genomics;Growth;HIV;Hybrids;In Situ;Individual;Infection;Investigation;Lectin;Light;Link;Malaria;Mediating;Metabolism;Mitotic;Morphology;Mothers;Mutation;Nuclear;Organism;Parasites;Patients;Phenotype;Polyploidy;Process;Production;Quantitative Reverse Transcriptase PCR;Recombinants;Reporting;Role;Sarcocystis;Substrate Specificity;Surface;Toxoplasma;Toxoplasma gondii;Ubiquitin;Up-Regulation;Vacuole;Work;acute infection;asexual;chronic infection;fitness;genome sequencing;genome-wide;head-to-head comparison;insight;member;mutant;opportunistic pathogen;ovarian neoplasm;overexpression;promoter;scaffold;whole genome

public_health_relevance:
Project NarrativeThe loss of the deubiquitinase TgOTUD3A in Toxoplasma gondii tachyzoites initiates both thedysregulation of the cell cycle and a developmental shift characterized by a partial induction ofbradyzoite and merozoite activities. Dissection of the role of the induced Clade D1 OTUdeubiquitinases in these unusual phenotypes will be established.


application_id: 10128863
project_number: 1R21AI146542-01A1
project_title: Antimicrobial peptide mimetic activity against Candida auris
administering_ic: NIAID
award_notice_date: 2021-03-09
opportunity_number: PA-19-053
application_type: 1
activity_code: R21
ic: AI
serial_number: 146542
suffix: A1
program_official: LIU, BAOYING
project_start_date: 2021-03-11
project_end_date: 2023-02-28
study_section: Special Emphasis Panel[ZRG1 IDM-Y (82)]
contact_pi_person_id: 1891127
contact_pi: DIAMOND, GILL
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
project_abstract:
Project Summary / AbstractCandida auris is a recently emerged pathogenic fungus whose infections lead to high mortality in invasivenosocomial infections world-wide. The fungus can persist long-term and thus can often cause outbreaks. Inaddition C. auris exhibits high levels of resistance to all classes of antifungal drugs. Even those strains whichare initially susceptible to echinochandins the treatment of choice rapidly develop resistance. Thus there is anurgent need to develop new antifungal drugs to treat this pathogen. Antimicrobial peptides (AMPs) are naturallyoccurring broad-spectrum antimicrobial agents that have been examined recently for their utility as therapeuticantibiotics and antifungals. Chief among their strengths is that microbes do not generally develop resistance tothem. Unfortunately they are expensive to produce and are often sensitive to protease digestion. We haverecently demonstrated the potent antifungal activity of a series of inexpensive nonpeptidic compounds that mimicAMPs in both structure and activity. These AMP mimetics exhibit strong activity against C. albicans in bothplanktonic and biofilm forms as well as against drug-resistant non-albicans Candida clinical isolates. The activityis rapid and fungicidal against both blastoconidia and hyphal forms and resistant strains of Candida have failedto be generated suggesting that they are attractive candidates as drugs to treat C. auris infections. Most recentlyit was demonstrated that these mimetics exhibit potent in vivo activity in two mouse models of oral candidiasisand in a model of invasive candidiasis with low in vivo systemic toxicity. Indeed preliminary data show potentactivity of newly designed mimetics against C. auris in vitro. These initial results support the hypothesis thatthese compounds are active and non-toxic and can be developed into novel therapeutic antifungal agents totreat C. auris infections. In order to obtain sufficient data to investigate this in depth this exploratory studyproposes to examine the activity of AMP mimetics against C. auris. To address this two aims are proposed: 1)Quantify the antifungal activity of select AMP mimetics against C. auris clinical isolates and evaluatethe development of resistance in vitro; 2) Quantify the kinetics and activity of select AMP mimetics inmouse models of C. auris infection. Successful completion of these aims will provide the basis for futurestudies of these mimetic compounds as a treatment for C. auris and potentially other emerging fungalpathogens.

project_terms:
Address;Antibiotics;Antifungal Agents;Biological;Candida;Candida albicans;Candida auris;Candidiasis;Cations;Characteristics;Chemistry;Clinical;Communicable Diseases;Dangerousness;Data;Development;Digestion;Disease Outbreaks;Drug Kinetics;Drug resistance;Environment;Exhibits;Future;Goals;Hour;Immunocompromised Host;In Vitro;Individual;Industrial fungicide;Infection;Kidney;Kinetics;Lead;Membrane;Microbe;Microbial Biofilms;Modeling;Multi-Drug Resistance;Nosocomial Infections;Oral candidiasis;Peptide Hydrolases;Pharmaceutical Preparations;Publishing;Research;Resistance;Resistance development;Series;Structure;Testing;Therapeutic;Toxic effect;Toxicology;antimicrobial drug;antimicrobial peptide;base;design;dosage;effective therapy;experimental study;fungus;immunosuppressed;in vivo;mimetics;mortality;mouse model;multi-drug resistant pathogen;novel therapeutics;pathogen;pathogenic fungus;peptidomimetics;resistant strain;small molecule;synergism;systemic toxicity;treatment choice;treatment response

public_health_relevance:
Project NarrativeCandida auris is a recently identified often fatal fungal pathogen that is resistant to many standard antifungaldrugs. We hypothesize that a new class of molecules based on naturally occurring antimicrobial peptides whichexhibits potent activity against other species of Candida and to which fungi do not readily develop resistancecan be developed as a new treatment for this dangerous infectious disease. We propose to test these moleculesagainst C. auris to identify ones that could be further developed into new antifungal drugs.


application_id: 10128362
project_number: 5R01AI128818-05
project_title: Regulation of dermal gammadelta T cells by microbial pathogens/commensals in health and psoriasis
administering_ic: NIAID
award_notice_date: 2021-03-19
opportunity_number: RFA-AI-16-006
application_type: 5
activity_code: R01
ic: AI
serial_number: 128818
program_official: ROTHERMEL, ANNETTE L
project_start_date: 2017-04-20
project_end_date: 2024-03-31
study_section: Special Emphasis Panel[ZRG1-IDM-W(50)R]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Psoriasis is one of the most common immune-related chronic inflammatory skin disorders. Clinicalobservations suggest that streptococcal infection has an intimate relationship in triggering psoriasis onset andexacerbating chronic psoriasis. Humanized IL-12/IL-23 p40 IL-17A and IL-17 receptor mAbs have shownremarkable therapeutic efficacy for the treatment of chronic plaque psoriasis suggesting IL-23/IL-17 axis playsimportant roles in psoriasis pathogenesis. Our previous studies have demonstrated that dermal  T cells arethe major IL-17 producers in the skin and are critical in psoriasis pathogenesis. Dermal  T cells arephenotypically and functionally unique. However it is largely unknown how these cells are critically regulated inmice and humans particularly in the context of microbial infection and skin microbial commensal alteration. In the proposal we provided preliminary data suggesting that dermal  T cells play critical roles in skinimmune surveillance and inflammation. IL-1 signaling pathway plays a crucial role in regulating dermal  Tcell proliferation IL-17 production and probably trafficking in mice. Pathogen products stimulated skin cells toproduce IL-1. In addition we showed that skin microbiota from psoriatic skin has been substantially alteredcompared to that in healthy control skin. Human V9V2 T cells were capable of secreting IL-17 andsignificantly decreased in the peripheral blood of psoriatic patients but increased in psoriatic skin lesions andproduced large amounts of IL-17. Based on these preliminary findings we hypothesize that dysregulateddermal  T cells via IL-1 signaling by pathogen infection or skin microbiota alteration play an essentialrole in psoriasis pathogenesis. Three Aims are proposed to address this hypothesis. Aim 1 determines therole of IL-1 signaling in psoriasis immunopathogenesis. We will test the hypothesis that IL-1 signaling regulatespsoriasis immunopathogenesis through 1) directly activating dermal  T cells; 2) stimulating KC to secretechemokines which chemoattract more IL-17-producing  T cells from periphery into dermis thus amplifyingskin inflammatory cascade; 3) generating memory-like dermal  T cells for disease relapse. Aim 2 examineshow skin commensal microorganisms regulate dermal  T cell homeostasis in healthy skins and dermal  Tcell activation in skin inflammation. Aim 3 determines how human V9 T cells are regulated by pathogencomponents or skin microbiota alteration for expansion and IL-17 production. Human skin/SCID mousexenograft model will be established to determine the pathogenic roles of human V9 T cells and microbialinfection/commensal alteration in psoriasis pathogenesis. It is believed that this study will provide new insightsinto understanding the biology of dermal  T cell population and immuno-pathogenesis of psoriasis.

project_terms:
Address;Biology;CCL20 gene;Cells;Chronic;Chronic small plaque psoriasis;Clinical;Data;Dermal;Dermis;Development;Disease;Health;Homeostasis;Human;Immune;Immunologic Surveillance;In Vitro;Individual;Infection;Infiltration;Inflammation;Inflammatory;Interleukin-1;Interleukin-1 beta;Interleukin-12;Interleukin-17;Interleukins;Laboratories;Leukocytes;Memory;Modeling;Monoclonal Antibodies;Mus;Pathogenesis;Pathogenicity;Patients;Phase II Clinical Trials;Phenotype;Play;Population;Production;Psoriasis;Recurrent disease;Regulation;Role;SCID Mice;Signal Pathway;Signal Transduction;Skin;Source;Streptococcal Infections;T cell regulation;T-Cell Activation;T-Cell Proliferation;T-Lymphocyte;T-Lymphocyte Subsets;Testing;Treatment Efficacy;Xenograft Model;base;chemokine;chronic inflammatory skin;cytokine;individual patient;insight;interleukin-23;keratinocyte;microbial;microorganism;neglect;novel;pathogen;pathogenic microbe;peripheral blood;receptor;skin disorder;skin lesion;skin microbiota;trafficking; T cells

public_health_relevance:
Project NarrativeThis study will determine the regulation of dermal  T cells in mice and humans and explore itspathogenic role in skin inflammatory disease psoriasis particularly in the context of microbial infectionand skin commensal alteration. It is believed that these studies will provide new insight intounderstanding the pathogenesis of psoriasis and may help identify novel targets for its treatment.


application_id: 10127643
project_number: 5R01EB028792-02
administering_ic: NIBIB
award_notice_date: 2022-02-01
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: EB
serial_number: 028792
program_official: ANDERSON, AFROUZ AZARI
project_start_date: 2020-03-15
project_end_date: 2024-11-30
study_section: Imaging Guided Interventions and Surgery Study Section[IGIS]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-12-01
project_title:
Perioperative Diffuse Optical Imaging of Tissue Blood Flow and Oxygenation for Optimization of Mastectomy Skin Flap Viability

project_abstract:
ABSTRACTMastectomy is performed on approximately half of women with breast cancer. Postmastectomy breastreconstruction has benefits for body image sexuality self-esteem and quality of life. Poor clinical prognosesafter breast reconstruction often involve mastectomy skin flap necrosis (MSFN) or other complicationsassociated with the lack of blood flow and oxygenation to wound tissue volumes. MSFN and wound dehiscenceleads to a number of challenges including wound management problems delays to adjuvant therapy estheticcompromise implant extrusion patient distress and financial loss. A technology that allows surgeons toperioperatively assess and optimize preservation of skin flaps while avoiding complications is essential to ensuresuccessful clinical outcomes. Although alternative techniques have been explored to identify ischemic-hypoxictissues at risk of necrosis none have achieved universal acceptance as each technique has a few challengingissues that decrease its clinical usefulness. Moreover no single technique provides both blood flow andoxygenation information which are essential for precise assessment of skin flap viability. Our recent innovativedevelopment of near-infrared speckle contrast diffuse correlation tomography (scDCT) technique provides anoninvasive (dye-free) and noncontact means for continuous 2D/3D imaging of blood flow distributionsthroughout large/thick tissue volumes such as mastectomy skin flaps. We propose to extend this scDCTprototype to a next generation multi-wavelength scDCT (MW-scDCT) device for perioperative imaging of bothblood flow and oxygenation distributions in mastectomy skin flaps. New high-speed algorithms for 2D mappingand 3D image reconstruction will be developed to accommodate rapid online assessment of skin flaphemodynamics. This MW-scDCT system will be tested/optimized using standard tissue-simulating phantoms(Aim 1) and calibrated/validated against a commercial dye-based fluorescence angiography device (SPY Elite)in swine (Aim 2) and patients (Aim 3) undergoing mastectomy with expander-implant based breastreconstruction. The in vivo studies will determine the capability of our MW-scDCT for intraoperative prediction ofMSFN regions/volumes and postoperative optimization of incremental expander volumes to reduce risks ofMSFN and other complications. We expect that combined measurements of preoperative baseline andintraoperative alteration in skin flap flow and oxygenation will provide a more accurate assessment of skin flapviability than a one-time single-parameter measurement (i.e. blood flow blood oxygenation or fluorescenceperfusion). Study outcomes will provide the rationale for designing MW-scDCT guided clinical trials ofmastectomy with breast reconstruction to reduce postoperative complications and healthcare costs. Moreoverthis noninvasive (dye-free) noncontact continuous and cost-efficient imaging system has the potential forperioperative use in many other clinical settings especially where contact measurements may not be possiblesuch as for continual and longitudinal monitoring of burns wounds and other types of tissue flaps.

project_terms:
Adjuvant Therapy;Algorithms;Area;Blood;Blood capillaries;Blood flow;Body Image;Brain;Breast;Clinical;Clinical Trials;Color;Dermal;Development;Devices;Diagnosis;Diffuse;Distress;Dyes;Ensure;Esthetics;Excision;Family suidae;Fluorescence;Fluorescence Angiography;Health Care Costs;Heterogeneity;Human;Hypoxia;Image;Imaging Techniques;Implant;Incidence;Indocyanine Green;Interruption;Judgment;Laboratories;Lateral;Mammaplasty;Mastectomy;Measurement;Measures;Metabolic;Monitor;Necrosis;Operative Surgical Procedures;Optics;Outcome;Outcome Study;Oxygen;Patients;Pattern;Perfusion;Perioperative;Postoperative Complications;Postoperative Period;Quality of life;Risk;Rodent;Sexuality;Skin;Speed;Surgeon;Surgical Flaps;System;Techniques;Technology;Temperature;Testing;Thick;Three-Dimensional Image;Three-Dimensional Imaging;Time;Tissue imaging;Tissues;Woman;base;burn wound;clinical prognosis;cost efficient;design;diffuse optical spectroscopy and imaging;hemodynamics;image reconstruction;imager;imaging system;in vivo;innovation;malignant breast neoplasm;multimodality;next generation;non-invasive optical imaging;novel;operation;preclinical study;preservation;prevent;prototype;self esteem;surgery outcome;tissue reconstruction;tomography;translational study;wound;wound treatment

public_health_relevance:
PROJECT NARRATIVEClinical prognoses after surgical breast reconstruction often involve mastectomy skin flap necrosis or othercomplications associated with lack of blood flow and oxygenation to wound tissue volumes. The objective of thisproject is to design and optimize a novel noninvasive optical imaging technique which will enable rapid online3D imaging of both blood flow and oxygenation distributions throughout the entire volume of mastectomy skinflaps to perioperatively assess ischemic-hypoxic tissue regions/volumes. Outcomes from this translational studyin swine and patients undergoing mastectomy with expander-implant based breast reconstruction will provideessential information for intraoperative guidance of compromised tissue excision and postoperative optimizationof incremental expander fill volumes to reduce postmastectomy complications and healthcare costs.


application_id: 10127581
project_number: 5R01AR072061-05
project_title: Myostatin Alters Muscle Composition as The Result of an ACL Injury
administering_ic: NIAMS
award_notice_date: 2021-03-31
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AR
serial_number: 072061
program_official: CARIFI, EMILY FORAN
project_start_date: 2018-03-26
project_end_date: 2024-02-29
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 11267737
contact_pi: FRY, CHRISTOPHER
other_pis: Not Applicable
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: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractAnterior cruciate ligament (ACL) reconstruction surgery results in protracted quadriceps weakness that isassociated with poorer outcomes altered biomechanics and heightened risk of subsequent injuries. Littleprogress has been made in improving quadriceps strength and functional outcomes in the past decade.Alterations in the cellular and morphological composition of the knee extensor muscles contribute to weaknessfollowing an ACL reconstruction. ACL reconstruction induces expression of myostatin a negative regulator ofmuscle growth locally within the quadriceps. In addition to mitigating muscle regrowth myostatin alsopromotes connective tissue synthesis through activation of figrogenic cells within muscle. The objective ofthis proposal is to determine the time course of deleterious changes to the injured ligament and limb muscleand identify myostatin as integral in the etiology of protracted muscle weakness in individuals following an ACLtear. Aim 1 will evaluate the timeframe of myostatin induction within the injured ACL and quadriceps. Aim 2will determine the deleterious changes within the muscle using a mouse model of ACL injury and the efficacyof follistatin and a soluble form of the myostatin receptor (activin 2B receptor) to mitigate these maladaptations.Experiments in aim 3 will determine if the competitive inhibition of myostatin is capable of rescuing ACL injury-induced skeletal muscle weakness. Finally aim 4 will define if the acute induction of myostatin signalingfollowing an ACL injury in human subjects predicts reductions in muscle strength connective tissue infiltrationand dysregulation of skeletal muscle progenitor cells. The identification of myostatin as a therapeutic targetwill establish the basis for further research to mitigate myostatin signaling after ACL and other ligamentousinjuries to improve rehabilitative efforts and patient recovery.

project_terms:
ACVR2B gene;Activins;Acute;Anabolism;Animals;Anterior Cruciate Ligament;Atrophic;Biomechanics;Biopsy;Cell Proliferation;Cells;Cellular Morphology;Chronic;Clinical Trials;Collagen;Connective Tissue;Data;Degenerative polyarthritis;Development;Diffusion;Etiology;Extensor;Extracellular Matrix;Fibroblasts;Fibrosis;Follistatin;GDF8 gene;Goals;Growth;Human;Individual;Infiltration;Injury;Joints;Knee;Lead;Ligaments;Limb structure;Link;Measures;Modeling;Molecular;Mus;Muscle;Muscle Fibers;Muscle Weakness;Muscle satellite cell;Muscular Atrophy;Operative Surgical Procedures;Outcome;Patients;Pharmaceutical Preparations;Physical therapy;Physiological;Procedures;Public Health;Quality of life;Randomized;Reconstructive Surgical Procedures;Recovery;Rehabilitation therapy;Research;Risk;Saline;Signal Transduction;Skeletal Muscle;Testing;Time;Up-Regulation;anterior cruciate ligament injury;anterior cruciate ligament reconstruction;anterior cruciate ligament rupture;disability;experimental study;functional outcomes;healing;human subject;improved;ligament injury;limb injury;mouse model;muscle strength;premature;prevent;progenitor;quadriceps muscle;receptor;reconstruction;response;satellite cell;skeletal muscle weakness;stem cells;therapeutic target

public_health_relevance:
Project NarrativeAnterior cruciate ligament reconstructions are a common procedure resulting in significant quadriceps musclestrength loss which is linked to poorer functional outcomes. Increases in myostatin following anterior cruciateligament injury can impede muscle recovery by promoting alterations in the cellular and morphologicalcomposition of the muscle. The goal of this proposal is to determine the time course of deleterious changeswithin the injured limb muscle and identify myostatin as integral in the etiology of protracted muscle weaknessin individuals following an ACL tear and reconstruction.


application_id: 10126568
project_number: 1R21AG070909-01
administering_ic: NIA
award_notice_date: 2021-02-17
opportunity_number: PAR-19-071
application_type: 1
activity_code: R21
ic: AG
serial_number: 070909
program_official: MACKIEWICZ, MIROSLAW
project_start_date: 2021-03-01
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1 BDCN-A (55)]
contact_pi_person_id: 9426885
contact_pi: CHENG, QIANG
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
budget_start_date: 2021-03-01
project_title:
Gene Profile Analysis of Associations between Alzheimers Disease and Circadian Rhythmic Patterns of Human Brain Regions Using Machine Learning

project_abstract:
Project SummaryAlzheimers disease (AD) is the leading form of dementia and it has an increasing death rate throughout theworld. It gradually damages a patients memory speech thinking and ability to perform routine activities. Whilea few drugs may temporarily relieve some mild early AD symptoms they cannot stop or reverse cognitive andmemory impairment. Multiple studies have shown that circadian rhythm and AD have a close intricatebidirectional relationship. Accumulating evidence indicates that the disorder of circadian rhythm is not only apathological marker but a putative risk factor of AD. Improved understanding of the relationship between AD andthe circadian rhythm has the potential to guide the development of effective AD interventions or treatment.Timed gene expression data human brains are rare because of its highly invasive nature. In general brain geneexpression studies in neurodegeneration are based on post-mortem tissue samples with no or inaccurate if anytime labels. Currently there is a pending need for characterizing molecular mechanisms which underlie therelationship of AD with human brain circadian rhythms. However effective methods are yet to be developed toanalyze whole-genome gene expression data with none or inaccurate time labels to discover AD-specificdifferentiated circadian rhythmic patterns. Toward filling this urgent unmet need our overall aim is to developinnovative algorithms to discover circadian oscillation patterns based on genome-wide gene profile analysis andleverage them to identify and understand the associations of AD with circadian rhythms of different brain regions.This project will bridge a critical methodological gap to enable innovative discovery from untimed high-dimensional human brain data. It has a great potential to advance the understanding of the impact of circadianrhythm on AD and also provide researchers with a host of potential therapeutic targets for AD e.g. rhythmicsynchronization of brain regions to guide the development of future interventions.This project is highly innovative. For the first time gene profile analysis based on untimed expression data oftens of thousands of genes will be performed to pinpoint the AD-specific differentiated rhythmic patterns ofdifferent brain regions. To our knowledge this is the only capacity of its kind which permits the most directglimpse into the circadian events in the human brain at the brain region- or tissue-level. The algorithms will beused to find oscillation patterns and rhythmic correlations between brain regions for cohorts with or without ADand unique subsets of AD patients. Because a clear understanding between AD and the disturbances of humanbrain circadian rhythms is elusive deciphering oscillation patterns of brain regions and accounting for patientheterogeneity should advance our understanding of the complexity of AD and its intricate relationship withcircadian rhythms of regions.

project_terms:
Accounting;Age;Algorithms;Alpha Rhythm;Alzheimer's Disease;Alzheimer's disease patient;Alzheimer's disease risk;Artificial Intelligence;Autopsy;Brain;Brain region;Circadian Rhythm Disorder;Circadian Rhythms;Data;Data Set;Death Rate;Dementia;Demographic Factors;Development;Dimensions;Ensure;Ethnic Origin;Event;Future;Gender;Gene Expression;Genes;Goals;Heterogeneity;Human;Impaired cognition;Individual;Intervention;Label;Link;Machine Learning;Memory;Memory impairment;Methodology;Methods;Molecular;Mus;Nature;Nerve Degeneration;Outcome;Pathologic;Patients;Pattern;Periodicity;Pharmaceutical Preparations;Phase;Population Heterogeneity;Randomized;Reproducibility;Research Personnel;Retrospective Studies;Sample Size;Speech;Symptoms;Thinking;Time;Tissue Sample;Tissues;Translations;Validation;Work;base;circadian;cohort;comorbidity;design;effective therapy;gene expression database;genome-wide;genome-wide analysis;high dimensionality;human data;improved;innovation;large-scale database;patient subsets;secondary analysis;sex;success;therapeutic target;therapy development;treatment strategy;usability;whole genome

public_health_relevance:
PROJECT NARRATIVEThis R21 study is a retrospective study and we will conduct genome-wide analyses of secondary untimedgene expression data in existing large-scale databases of randomized cohorts for Alzheimers Disease (AD).The goal is to discover circadian oscillation patterns and using them to pinpoint associations of AD withcircadian rhythms of human brain regions to guide future development of interventions.


application_id: 10126418
project_number: 1K08DK124566-01A1
project_title: Muscle bone interaction and its role in diabetic bone disease of Type I diabetes
administering_ic: NIDDK
award_notice_date: 2021-02-23
opportunity_number: PA-19-117
application_type: 1
activity_code: K08
ic: DK
serial_number: 124566
suffix: A1
program_official: MALOZOWSKI, SAUL N
project_start_date: 2021-03-01
project_end_date: 2025-12-31
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 14779143
contact_pi: KALAITZOGLOU, EVANGELIA
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
project_terms:
20 year old;Activin Receptor;Address;Affect;Age;Animal Model;Antibodies;Basic Science;Biopsy;Bone Density;Bone Marrow Stem Cell;Bone Resorption;Cell Line;Cells;Childhood;Clinical;Clinical Research;Communication;Complication;Complications of Diabetes Mellitus;Data;Development;Diabetes Mellitus;Disease;Endocrine;Endocrinology;Environment;Equipment;Exhibits;FRAP1 gene;Foundations;Fracture;Fracture Healing;Functional disorder;Future;GDF8 gene;Gene Expression;Gene Proteins;General Population;Genes;Health;Hip Fractures;Hip region structure;Human;Hyperglycemia;Impairment;In Vitro;Incidence;Individual;Insulin;Insulin-Dependent Diabetes Mellitus;Intervention;Kentucky;Knowledge;Laboratories;Lead;Life;MAP Kinase Gene;Measures;Mechanics;Mediating;Mediator of activation protein;Mentors;Mus;Muscle;Muscle function;Musculoskeletal;Musculoskeletal Diseases;Musculoskeletal System;Nurses' Health Study;Osteoblasts;Osteocalcin;Osteocytes;Osteogenesis;Outcome;Pathway interactions;Pediatrics;Pharmacology;Phenotype;Physical Capacity;Population;Population Study;Positioning Attribute;Prevalence;Prevention;Program Development;Relative Risks;Research;Resources;Risk;Roentgen Rays;Role;Sampling;Scientist;Serum;Signal Pathway;Signal Transduction;Skeletal Muscle;Skeletal bone;Time;Trabecular Bone Score;Translational Research;Universities;Upper Extremity Fracture;Work;bone;bone cell;bone imaging;bone mass;bone turnover;career;career development;clinically significant;cost;diabetic;diabetic bone disease;diabetogenic;fracture risk;high risk;improved;in vivo;mineralization;mouse model;muscle form;negative affect;novel;osteoblast differentiation;paracrine;prevent;professor;prospective;receptor;reduced muscle mass;reduced muscle strength;skills;young adult


application_id: 10126135
project_number: 1R01AG070830-01
project_title: Contributions of astrocyte RelA signaling in aging-related neurodegenerative sequelae following TBI
administering_ic: NIA
award_notice_date: 2021-01-28
opportunity_number: PAR-19-070
application_type: 1
activity_code: R01
ic: AG
serial_number: 070830
program_official: OPANASHUK, LISA A
project_start_date: 2021-01-15
project_end_date: 2025-12-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 10594155
contact_pi: MORGANTI, JOSH
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Affect;Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease related dementia;Alzheimer's disease risk;Animal Model;Astrocytes;Automobile Driving;Behavioral;Brain;Calcium;Cells;Characteristics;Chronic;Complement;Complex;Data;Development;Disease;Environmental Risk Factor;Excision;Feedback;Functional disorder;Genetic Models;Gliosis;Heterogeneity;Human;Impaired cognition;Impairment;Incidence;Individual;Inflammation;Inflammatory;Inflammatory Response;Ischemia;Knockout Mice;Lead;Link;Mediator of activation protein;Memory impairment;Methods;Microglia;Modality;Modeling;Molecular;Multiple Sclerosis;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neuroglia;Neurons;Neurophysiology - biologic function;Outcome;Pathway interactions;Phenotype;Physiology;Populations at Risk;Predisposition;Prevention;Publishing;Risk;Rodent;Role;Signal Pathway;Signal Transduction;Slice;Spinal cord injury;Synapses;Synaptic plasticity;Testing;Time;Tissues;Transcriptional Activation;Trauma;Traumatic Brain Injury;age related;aged;aging brain;astrogliosis;cerebrovascular;conditional knockout;knowledge base;loss of function;male;mouse model;network dysfunction;neural circuit;neural network;neuroinflammation;new therapeutic target;novel;progressive neurodegeneration;protein profiling;relating to nervous system;response;response to injury;restoration;single-cell RNA sequencing;tau-1;transcription factor;transcriptome sequencing;transcriptomics;young adult


application_id: 10125203
project_number: 5R01NS112693-02
project_title: Mitochondrial Uncoupling Prodrug as a Translational Therapy for TBI
administering_ic: NINDS
award_notice_date: 2021-01-29
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 112693
program_official: UMOH, NSINI ALEASE
project_start_date: 2020-03-15
project_end_date: 2025-01-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: KILBAUGH, TODD JUSTEN
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
24-Dinitrophenol;Acute;Address;Adult;Aftercare;Aging;Anxiety;Axon;Behavior;Bioenergetics;Biological Assay;Biological Markers;Biosensor;Blinded;Blood Platelets;Brain;Brain Contusions;Brain Injuries;Chronic;Clinical;Clinical Pharmacology;Cognition;Cognitive;Cognitive deficits;Contusions;Data;Dinitrophenols;Dose;Drug Kinetics;FDA approved;Family suidae;Female;Goals;Healthcare;Homeostasis;Huntington Disease;Impaired cognition;Impairment;Individual;Injury;Inner mitochondrial membrane;Institution;Intervention;Link;Measures;Mediating;Membrane Potentials;Mitochondria;Mitochondrial Matrix;Morphology;Motor Activity;Movement;Mus;Neurons;Outcome;Oxidative Stress;Pediatric Hospitals;Pharmacodynamics;Pharmacological Treatment;Pharmacology;Philadelphia;Physiology;Pre-Clinical Model;Prodrugs;Production;Property;Protons;Publishing;Randomized;Reactive Oxygen Species;Recovery;Rodent;Scanning;Spinal cord injury;Stroke;Synapses;TBI treatment;Techniques;Testing;Therapeutic;Therapeutic Effect;Therapeutic Intervention;Time;Tissues;Translating;Translational trial;Translations;Traumatic Brain Injury;Traumatic Brain Injury recovery;Treatment Efficacy;United States;Work;behavior measurement;behavioral outcome;biosignature;clinically relevant;cognitive testing;cohort;design;dosage;efficacy evaluation;experimental study;improved;in vivo;innovation;male;mitochondrial dysfunction;mitochondrial membrane;mouse model;neurochemistry;neuroimaging;neurological recovery;neuropathology;neuroprotection;neurotropic;novel;novel marker;novel strategies;oxidative damage;porcine model;pre-clinical;preclinical efficacy;primary endpoint;repaired;residence;response;restoration;severe injury;sex;therapeutic evaluation


application_id: 10123557
project_number: 3U01AA026225-04S1
administering_ic: NIAAA
award_notice_date: 2020-08-26
opportunity_number: PA-18-591
application_type: 3
activity_code: U01
ic: AA
serial_number: 026225
suffix: S1
program_official: WANG, JOE
project_start_date: 2017-09-22
project_end_date: 2022-08-31
study_section: ZAA1(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_title:
Administrative Supplement Role of Gut Microbial Dysbiosis in Aging on HIV-associated in the Development of Alzheimer's DiseaseAssociated Dementia (ADRD).

project_abstract:
The goal of the active U01 is to examine the interactive effects of heavy alcohol use and HIV-1infection at the level of gut dysbiosis and permeability ensuing local and systemic inflammation andits pathogenic role in driving HIV infection and aging-associated neuroinflammation and cognitivedysfunction. This is being accomplished through longitudinal studies that systematically examine the role ofalcohol use and HIV-1 infection altered microbiome on HIV pathogenesis and development of neurocognitivedysfunction using 16S rRNA gene sequencing and Whole Genome Shotgun (WGS) metagenomic sequencinganalysis. The supplement is within the scope of the active award and extends the parent study byincluding an additional category of participants relevant to Alzheimers disease related dementia(ADRD). Specifically the proposed work is focused on amnestic mild cognitive impairment (aMCI) an earlystage of ADRD. Accordingly the study will include HIV-infected adults with heavy alcohol use andaMCI. There is supporting evidence from pre-clinical rodent studies and few human studies for the role of gutmicrobiota and peripheral inflammation in the development or progression of Alzheimers disease (AD).Notably there is a complete lack of comprehensive analysis and characterization of the gut microbial dysbiosisin heavy alcohol using HIV+ individuals with ADRD. By contrasting neurocognitive neuroimaging andbiospecimen indices between heavy alcohol using HIV+ individuals with aMCI and heavy alcohol using HIV+individuals without aMCI we will determine whether microbiome abnormalities contribute to the more severecognitive disturbances and possible development of ADRD. This will enable us to examine the effects of HIVand heavy alcohol use in individuals with and without aMCI/ADRD. Based on the one-year scope andbudgetary limits this supplemental study will differ from the parent project with respect to the inclusion of aMCIand only a single baseline assessment. These supplemental studies will leverage participant recruitmentvalidated clinical and demographic data biospecimen/biomarker collection and clinical expertise utilize fromour ongoing NIH sponsored longitudinal studies at the Universities of Louisville (UofL) and Florida (UF) with thefollowing specific aim: Determine HIV-1 infection- and heavy alcohol use-associated qualitative andquantitative changes in the gut microbiome (dysbiosis) and attendant intestinal permeability microbialtranslocation (MT) and peripheral inflammation in adults with Alzheimers disease related dementias(ADRD).

project_terms:
16S ribosomal RNA sequencing;Administrative Supplement;Adult;Age;Aging;Alcohol abuse;Alcohol consumption;Alcohols;Alzheimer's Disease;Alzheimer's disease patient;Alzheimer's disease related dementia;Amyloid deposition;Automobile Driving;Award;Biological Markers;Brain;Categories;Clinical;Cognition;Cognitive;Cognitive aging;Cognitive deficits;Collection;Data;Dementia;Development;Elderly;Encephalitis;Florida;Functional disorder;Goals;Grant;HIV;HIV Infections;HIV-1;Heavy Drinking;Human;Impaired cognition;Impairment;Individual;Infection;Inflammation;Inflammatory;Intestinal permeability;Lead;Learning;Longitudinal Studies;Memory;Metabolic;Nerve Degeneration;Neurobiology;Neurocognitive;Neurodegenerative Disorders;Parents;Participant;Pathogenesis;Pathogenicity;Pathologic;Pathology;Pathway interactions;Patient Recruitments;Peripheral;Permeability;Population;Preventive;Process;Reporting;Research;Risk;Risk Factors;Rodent;Role;Secondary to;Shotguns;Structure;Testing;Therapeutic;United States National Institutes of Health;Universities;Work;aging brain;amnestic mild cognitive impairment;base;cerebral amyloidosis;clinically relevant;combinatorial;dysbiosis;gut microbiome;gut microbiota;healthy aging;indexing;inflammatory marker;metagenomic sequencing;microbial;microbiome;microbiome alteration;modifiable risk;neuroimaging;neuroinflammation;outcome prediction;parent project;pre-clinical;preclinical study;premature;prevent;sex;whole genome

public_health_relevance:
The proposed supplemental work is focused on amnestic mild cognitive impairment(aMCI) an early stage of ADRD. Accordingly the study will include HIV-infected adultswith heavy alcohol use and aMCI.


application_id: 10123408
project_number: 3P20GM125504-03S1
project_title: Functional Microbiomics Inflammation and Pathogenicity
administering_ic: NIGMS
award_notice_date: 2020-06-26
opportunity_number: PA-18-591
application_type: 3
activity_code: P20
ic: GM
serial_number: 125504
suffix: S1
program_official: CUPIT, PAULINE
project_start_date: 2020-06-01
project_end_date: 2021-02-28
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractAlzheimers disease (AD) is a degenerative disease of the brain associated with aging which is responsible forprofound morbidity and mortality. Ninety-nine percent of cases are of unknown cause and not created by anabnormal gene. The disease progressively affects memory judgment abstraction perception visual-spatialabilities and language as well as other functions. There is also sterile inflammation of brain associated withthe progression of AD. The microbiota is being extensively studied and has been found to be critically importantfor health and disease. The role of the microbiota in AD is suggested by the early onset of olfactory dysfunctionin the disease as well as many other studies that document changes in microbiota associated with ageing andAD progression. Such microbiota changes are also observed in mouse models yet no clear candidate microbesfor promoting or delaying AD have been identified. We have established a Functional Microbiomics Core (FMC)at UofL that supports the work of many faculty by providing germ-free gnotobiotic mice as well as anaerobicculturing and characterization of microbiota signatures by 16S sequencing. In this administrative supplementwe propose to expand the FMC to include AD mouse models. We will rederive the well-established AD modelsAPP/PS1 and 3XTg-AD and maintain these as germ-free and test them in behavioral models. We will examinethe role of bacterial amyloids in seeding the brain AB by using the E.Coli strains expressing the amyloid proteincurli. In Aim2 we will recolonize the germ-free APP/PS1 mice with AD or control stool samples to generate stablehumanized microbiota mice that will serve as models for examining the promoting and protective roles of specificmicrobiota populations in AD. This work has important implications for all neurological conditions involvingmisfolded proteins and microbiota. The approaches outlined here will be highly productive and rewarding bothinterms of understanding disease mechanisms and developing novel preventive/therapeutic strategies.

project_terms:
16S ribosomal RNA sequencing;3xTg-AD mouse;APP-PS1;Administrative Supplement;Affect;Aging;Alzheimer like pathology;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease patient;Amyloid;Amyloid Proteins;Amyloid beta-Protein;Anaerobic Bacteria;Anatomy;Behavioral Model;Brain;Brain Diseases;Centers of Research Excellence;Cognitive;Core Facility;Degenerative Disorder;Dementia;Development;Diet;Disease;Disease Progression;Encephalitis;Endocrine;Escherichia coli;Etiology;Exposure to;Faculty;Functional disorder;Future;Gene Abnormality;Generations;Genetic;Germ-Free;Gnotobiotic;Goals;Health;Helicobacter;Histopathology;Immunologics;Impaired cognition;Inflammasome;Inflammation;Judgment;Kentucky;Language;Measures;Memory;Metabolic Pathway;Methods;Microbe;Modeling;Morbidity - disease rate;Mus;National Institute of General Medical Sciences;Neurodegenerative Disorders;Neurologic;Olfactory Pathways;Oral;Pathogenesis;Pathogenicity;Perception;Population;Prevention strategy;Preventive;Prevotella;Process;Production;Progressive Disease;Research;Rewards;Ribosomal RNA;Role;Sampling;Seeds;Services;Sterility;Testing;Therapeutic;Universities;Visuospatial;Volatile Fatty Acids;Work;brain pathway;cognitive ability;early onset;fecal transplantation;feeding;gut microbes;gut microbiota;microbiome research;microbiota;microbiota profiles;microbiota-gut-brain axis;misfolded protein;mortality;mouse model;neuroinflammation;novel;novel therapeutics;pathogen;relating to nervous system;stool sample

public_health_relevance:
Project NarrativeMicrobiota have been associated with health and disease under a wide variety of conditions includingAlzheimers disease. The goal of this proposal is to use germ-free mouse models of AD to develop a moreprecise understanding of how distinct microbes promote or delay the progression of AD.


application_id: 10123140
project_number: 1RF1AG070952-01
project_title: Dynamic GABA and Glutamate Neurotransmission in Alzheimers Disease and Aging
administering_ic: NIA
award_notice_date: 2021-02-12
opportunity_number: PAR-19-070
application_type: 1
activity_code: RF1
ic: AG
serial_number: 070952
program_official: DIBATTISTA, AMANDA
project_start_date: 2021-02-15
project_end_date: 2024-01-31
study_section: Special Emphasis Panel[ZRG1 BDCN-A (55)]
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY / ABSTRACTAlzheimers disease (AD) progression and normal aging are complex and often heterogeneous processesinvolving functional changes to neuronal and glial elements that are not just related to neuronal cell loss [1-4143]. Prior in vitro and in vivo data support that aberrant regulation of glutamate neuronal systems can be acontributor to neuronal degeneration in aging and likely a contributor to the age-dependent development of AD[1 4 6-8]. We think that because there is a dearth of treatment and monitoring options our study will help in thefuture development of therapeutics and non-invasive spectroscopic monitoring techniques for AD. Recently wehave successfully adapted our enzyme-based microelectrode arrays (MEAs) which are designed to preciselymeasure tonic and phasic neurotransmitter release in discrete brain structures in awake animals for use in agedrodents and AD mouse models [54-56 79 112]. A major knowledge gap in AD and aging involves changes inthe excitatory/inhibitory balance between glutamate (Glu) and GABA release and regulation [9-15]. We believethat the use of our new recording technology will improve our understanding of the glutamate/GABA interplay inan AD model and in normal aging. Our recent studies using this superior technology now allows themeasurements of tonic and phasic glutamate levels found that rats >18 months of age have normal or elevatedbasal Glu levels compared to younger rats. Thus some animals have elevated glutamate while others do not.As outlined in NIH Notice NOT-AG-18-051 & related announcement PAR-19-070 issues surrounding age andits role in dementia are critical in furthering our understanding of the metabolic and pathological changes thataffect signaling in neuronal circuits and networks. We will use young and aged normal and the APPNLh/NLh xPS1P264L/P264L knock-in mouse (APP/PS1 KI) that does not overexpress APP or PS1 or use artificial promotersmaking it an ideal system for the study of how aging affects the development of AD-related neuropathology [86-90]. We will use our novel methods to simultaneously record GABA and glutamate signaling in either the CA1region of the hippocampus or Frontal Cortex. We will first behaviorally characterize all animals so that we candetermine potential correlations between the behavioral performance of mice and glutamate and GABA releaseand/or regulation in the hippocampus (Morris water maze test) and frontal cortex (spatial memory variant ofMorris water maze test) [115] and performed as per [116]. Finally mice that are studied will undergo apathological examination to evaluate neurodegeneration by evaluating reactive gliosis may be present by lookingat Iba1 and GFAP. Collectively these studies will allow us to compare the effects of normal aging in male andfemale to the effects seen from a mouse model of AD on the balance of glutamate and GABA signaling and itsrelationship(s) to cognitive function in both male and female animals towards the development of noveltherapeutics to possibly treat the development and progression of AD.

project_terms:
APP-PS1;Address;Affect;Age;Age-Months;Aging;Alzheimer's Disease;Alzheimer's disease model;Animals;Behavioral;Brain;Cell Death;Cognition;Complex;Data;Dementia;Development;Disease Progression;Elements;Enzymes;Equilibrium;FDA approved;Female;Fostering;Future;Glial Fibrillary Acidic Protein;Gliosis;Glutamates;Goals;Hippocampus (Brain);Impaired cognition;Impairment;In Vitro;Individual;Knock-in Mouse;Knowledge;Measurement;Measures;Memantine;Memory;Metabolic;Methodology;Methods;Microelectrodes;Monitor;Mus;Mutation;Nerve Degeneration;Neurons;Noise;Pathologic;Patients;Performance;Pharmaceutical Preparations;Pharmacotherapy;Phase;Population;Prefrontal Cortex;Process;Property;Rattus;Regulation;Rodent;Role;Signal Transduction;Structure;System;Techniques;Technology;Testing;Time;United States National Institutes of Health;Variant;age related;aged;awake;base;cognitive function;design;excitotoxicity;familial Alzheimer disease;frontal lobe;gamma-Aminobutyric Acid;glutamatergic signaling;improved;in vivo;male;morris water maze;mouse model;neuron loss;neuronal circuitry;neuropathology;neurotransmission;neurotransmitter release;new therapeutic target;normal aging;novel;novel therapeutics;promoter;spatial memory;therapeutic development

public_health_relevance:
PROJECTIVE NARRATIVERecent data support that changes in the functional properties of glutamate and GABA neurotransmission in thehippocampus and frontal cortex in the CNS contribute to Alzheimers disease (AD) and age-related declines incognition and memory. A further understanding of the balance between glutamate levels and glutamate andGABA neurotransmission in vivo are needed from the frontal cortex and hippocampus in AD models and innormal aging. These studies will aid in the identification of targets and consistent comparable non-invasivespectroscopic monitoring techniques for existing FDA approved drugs as well as possibly new targets for drugsto treat AD to address the growing population with dementia.


application_id: 10123030
project_number: 5P40OD019794-07
project_title: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2021-03-05
opportunity_number: PAR-17-006
application_type: 5
activity_code: P40
ic: OD
serial_number: 019794
project_start_date: 2015-03-01
project_end_date: 2025-02-28
study_section: Special Emphasis Panel[ZRG1-GGG-D]
subproject_number: 7757
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
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:
APPLIED RESEARCH COMPONENT - PROJECT SUMMARYThis component addresses the significance and need to develop a protocol for cryopreserving axolotlgermplasm. The AGSC will work with the Aquatic Germplasm and Genetics Research Center at LouisianaState University (LSU) to develop a reproducible protocol for cryopreserving axolotl sperm. Early results arepresented to show that the AGSC has already initiated collaborative studies with the AGGRC to assess axolotlsperm viability and motility after overnight transport from Lexington to Louisiana. Building upon this work theAGSC will ship axolotl sperm to the AGGRC to identify optimal conditions for cryopreservation. After a workingprotocol has been established AGSC staff will visit the AGGRC to learn how to assess sperm quality andperform the cryopreservation procedure. Additionally AGGRC staff will help the AGSC develop a repositorystrategy for community-wide management of axolotl sperm. Upon returning to Lexington KY AGSC staff willimplement the protocol examine the viability of frozen sperm and then use cryopreserved sperm to re-deriveaxolotl stocks. Accomplishment of this objective will allow for more efficient management of axolotl stockswithin the AGSC and the broader axolotl community

project_terms:
Address;Ambystoma;Applied Research;Collaborations;Communities;Cryopreservation;Genetic;Genetic Research;Infrastructure;Knock-out;Learning;Louisiana;Methods;Modeling;Procedures;Protocols documentation;Reproducibility;Ships;Sperm Motility;Transgenic Organisms;Universities;Visit;Work;genetic resource;repository;sperm cell;sperm cryopreservation;sperm quality;sperm viability


application_id: 10123029
project_number: 5P40OD019794-07
project_title: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2021-03-05
opportunity_number: PAR-17-006
application_type: 5
activity_code: P40
ic: OD
serial_number: 019794
project_start_date: 2015-03-01
project_end_date: 2025-02-28
study_section: Special Emphasis Panel[ZRG1-GGG-D]
subproject_number: 7756
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
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:
RESOURCE COMPONENT - PROJECT SUMMARYThis component provides details about AGSC operations axolotl stocks and supplies and innovations inaxolotl care and genetic management. The host institution recently provided support to install new aquaticrecirculating systems to better ensure axolotl health and make husbandry more efficient. The AGSC currentlyhouses approximately 50% of the adult population in recirculating systems and will work toward the goal ofhousing 75% during the next funding period. A financial plan is described that will ensure long-termsustainability of axolotl stocks and move the AGSC each year towards greater self-sufficiency. Finally plansare presented to share methods protocols and data. The AGSC is a proven axolotl resource provider and willcontinue to ensure distribution and long-term sustainability of axolotl stocks to NIH investigators.

project_terms:
Adolescent;Adult;Ambystoma;Ambystoma mexicanum;Area;Awareness;Biomedical Research;Breeding;Caring;Collection;Communities;Computers;Custom;Data;Embryo;Ensure;Funding;Genetic;Goals;Health;Hour;Housing;IACUC;Informatics;Institution;International;Kentucky;Methods;Modeling;Newsletter;Online Systems;Population;Procedures;Protocols documentation;Provider;Research;Research Personnel;Research Support;Resources;Shipping;Site;System;Time;TimeLine;United States National Institutes of Health;Universities;Work;animal resource;cost;experience;innovation;knowledge base;learning strategy;meetings;operation;web site


application_id: 10122313
project_number: 2R01DK095662-10A1
project_title: The Role of Crypt Fissioning in IBD Ulcer Healing
administering_ic: NIDDK
award_notice_date: 2021-02-23
opportunity_number: PA-18-330
application_type: 2
activity_code: R01
ic: DK
serial_number: 095662
suffix: A1
program_official: SENGER, STEFANIA
project_start_date: 2021-02-24
project_end_date: 2025-01-31
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 1883566
contact_pi: BARRETT, TERRENCE A.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Biochemical;Biogenesis;Biopsy;Childhood;Chronic;Clinical;Clinical Data;Clinical Research;Colitis;Crohn's disease;Data;Disease;Disease Outcome;Disease remission;Drops;Epithelial Cells;Failure;Gene Expression;Generations;Genes;Genetic Transcription;Genetically Engineered Mouse;Goals;Human;In Vitro;Inflammation;Inflammatory Bowel Diseases;Injury;Intestines;Investigation;Knockout Mice;Leukocyte L1 Antigen Complex;Maintenance;Measures;Mitochondria;Modeling;Monoclonal Antibodies;Mucositis;Mucous Membrane;Mus;Operative Surgical Procedures;Outcome;Oxidation-Reduction;PTEN gene;Pathogenesis;Patients;Phosphatidylinositols;Phosphotransferases;Principal Investigator;Procedures;Refractory;Respiration;Respiratory Chain;Role;Signal Transduction;Site;TNF gene;Tattooing;Testing;Treatment Efficacy;Ulcer;Ulcerative Colitis;Visualization;WNT Signaling Pathway;Work;base;beta catenin;chronic ulcer;clinical phenotype;crypt cell;drug development;experience;healing;infliximab;intestinal epithelium;new therapeutic target;novel;novel strategies;prevent;programs;prospective;repaired;response;single-cell RNA sequencing;stem cells;therapeutic biomarker;therapeutic target;transcriptomics


application_id: 10122260
project_number: 1R01DE029498-01A1
project_title: Role of Notch-1/PLA2-IIA in oral dysbiosis inflammation and periodontal disease
administering_ic: NIDCR
award_notice_date: 2021-07-07
opportunity_number: PAR-19-172
application_type: 1
activity_code: R01
ic: DE
serial_number: 029498
suffix: A1
program_official: CHANDER, PREETHI
project_start_date: 2021-08-01
project_end_date: 2026-04-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 9641157
contact_pi: GONZALEZ, OCTAVIO ALBERTO
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
project_terms:
Address;Adverse effects;Agreement;Animal Model;Antimicrobial Effect;Antimicrobial susceptibility;Apoptosis;Autophagocytosis;Bacteria;Cell Culture Techniques;Cell Proliferation;Cell physiology;Cells;Clinical;Complex;Data;Development;Disease;Ecology;Enzymes;Epithelial;Epithelial Cells;Event;Exhibits;Firmicutes;Gene Expression;Gingiva;Health;Human;Immune;In Vitro;Inbred BALB C Mice;Infection;Inflammation;Inflammatory;Knowledge;Lead;Lesion;Mediating;Microbe;Modeling;Molecular;Mouse Strains;Mucosal Immunity;Mucous Membrane;Mus;Mutation;Natural Immunity;Oral;Oral health;PLA2G2A gene;Pathogenicity;Pathway interactions;Periodontal Diseases;Periodontitis;Phospholipase A2;Play;Porphyromonas gingivalis;Property;Proteobacteria;Public Health;Receptor Activation;Reporting;Research;Research Design;Resistance;Role;Surface;Testing;Time;Transgenic Mice;Variant;adaptive immunity;antimicrobial;base;bone loss;chemokine;chronic infection;chronic inflammatory disease;dysbiosis;gingipain;in vivo;innovation;macrophage;malignant mouth neoplasm;microbial;microbial community;microbiota;mouse model;nonhuman primate;notch protein;oral cavity epithelium;oral microbiome;oral pathogen;overexpression;pathogen;prevent;receptor;recruit;response


application_id: 10121748
project_number: 1R01AA028246-01A1
administering_ic: NIAAA
award_notice_date: 2021-03-15
opportunity_number: PA-18-390
application_type: 1
activity_code: R01
ic: AA
serial_number: 028246
suffix: A1
program_official: FREEMAN, ROBERT
project_start_date: 2021-03-15
project_end_date: 2026-01-31
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 14470701
contact_pi: RAY, ANNE ELIZABETH
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Alcohol consumption;Alcohols;Area;Behavior;Behavior Therapy;Behavioral;Clinical;Data;Data Collection;Development;Effectiveness;Ensure;Event;Feedback;Focus Groups;Future;Gold;Health;Heavy Drinking;Hybrids;Individual;Intervention;Link;Literature;Mind;Monitor;Motivation;National Institute on Alcohol Abuse and Alcoholism;Nature;Outcome;Participant;Pathway interactions;Pattern;Persons;Prevention strategy;Process;Public Health;Randomized Controlled Trials;Reporting;Research;Research Design;Risk;Sampling;Self Efficacy;Sex Behavior;Site;Students;System;Target Populations;Technology;Testing;Time;Universities;Unsafe Sex;Work;alcohol misuse;alcohol prevention;base;behavior change;binge drinking;college;design;diaries;drinking;eHealth;effectiveness evaluation;effectiveness implementation design;effectiveness implementation study;effectiveness implementation trial;evidence base;experience;flexibility;follow-up;formative assessment;group intervention;high intensity drinking;high risk;high risk sexual behavior;implementation determinants;implementation intervention;improved;innovation;intervention effect;programs;response;scale up;sex;sexual victimization;sexually active;success;university student;usability;web-based assessment


application_id: 10120628
project_number: 5R21AI150631-02
project_title: Role of amylopectin granules in chronic toxoplasmosis an HIV-AIDS defining infection
administering_ic: NIAID
award_notice_date: 2021-02-24
opportunity_number: PA-19-053
application_type: 5
activity_code: R21
ic: AI
serial_number: 150631
program_official: MCGUGAN, GLEN C
project_start_date: 2020-03-05
project_end_date: 2023-02-28
study_section: Special Emphasis Panel[ZRG1-AARR-Q(02)M]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY P.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryA distinguishing characteristic of tissue cyst forming Apicomplexa like Toxoplasma gondii is the accumulationof amylopectin (starch) granules (AG) within bradyzoites and their absence within the actively growingtachyzoite forms. As polymers of glucose AG functions as a battery serving as a reserve for energy productionand biosynthetic functions. Our recent work established that bradyzoites retain significant replicative potentialwithin tissue cysts in vivo. Notably most bradyzoite replication within tissue cysts occurs asynchronously withclustered bursts of growth interceded with non-replicative periods. While the specific signals triggering thesebursts remain unknown what is clear is that they would require substantial energy and metabolite inputs toexecute. Historical evidence and our findings reveal that AG levels within encysted bradyzoites are highlyvariable with clusters of parasites lacking AGs adjacent to others that are loaded with starch. This suggeststhat AG metabolism involving both synthesis and turnover are active within tissue cysts and may play a centralrole in the progression of chronic toxoplasmosis. We will directly address the dynamics and biologicalcontributions of AGs in the progression of the chronic infection at the level of individual bradyzoites using noveltools and concepts developed in our recently published work. The variable levels of AG within encystedbradyzoites suggest that both AG accumulation and depletion are under regulatory control. Indeed theenzymatic machinery required for both the synthesis and regulated turnover of starch are encoded in theToxoplasma genome. We will directly test the importance of AG in the acute infection the regulation of stageconversion and the establishment/ progression of the chronic infection by targeting the commitment enzyme forstarch synthesis the UDP-glucose pyrophosphorylase (TgUDP-GPP TgME49_218200) and the starchsynthase (TgSS TgME49_222800). Recent evidence suggests that despite being morphologically (though notbiochemically) detectable amylopectin may play a role in tachyzoite intermediary metabolism as well. Inaddition the contribution of AG's to reactivation the primary trigger of symptomatic disease in HIV-AIDS will beaddressed in the context of induced immune suppression. With the proposed studies we aim to dissect thepreviously unexplored role of AG in tachyzoites as factors in tachyzoite to bradyzoite conversion theprogression of the chronic infection and clinically critical reactivation in vivo. These studies will establish thegroundwork for targeting AG metabolism for therapeutic intervention in the chronic infection where the paucityof effective drugs remains a significant issue in the clinical context of HIV-AIDS.

project_terms:
Acquired Immunodeficiency Syndrome;Acute;Address;Amylopectin;Anabolism;Apicomplexa;Biochemical;Biochemistry;Biological;Biology;Characteristics;Charge;Chemicals;Chronic;Chronic Phase;Clinical;Cyst;Cytoplasmic Granules;Development;Disease;Energy-Generating Resources;Enzymes;Event;Future;Genome;Glucans;Glucose;Glucose-6-Phosphate;Glutamine;Glycogen;Glycogen (Starch) Synthase;Growth;HIV;Human;Immune system;Immunosuppression;Individual;Infection;Kinetics;Knock-out;Laboratories;Length;Link;Location;Maintenance;Mediating;Metabolism;Morphology;Parasites;Parasitic infection;Pharmaceutical Preparations;Phase;Phosphorylation;Physiological;Plants;Play;Polymers;Population;Process;Production;Publishing;Regulation;Resources;Role;Signal Transduction;Starch;Testing;Therapeutic Intervention;Tissues;Toxoplasma;Toxoplasma gondii;Toxoplasmosis;Uridine Diphosphate Sugars;Work;acute infection;asexual;chronic infection;crystallinity;glucose 1 phosphate;imaging approach;in vivo;insight;knock-down;metabolomics;mutant;novel;quantitative imaging;sugar nucleotide;tool;transmission process

public_health_relevance:
Project NarrativeThe accumulation of amylopectin(starch) granules (AGs) is a morphological characteristic of Toxoplasmagondii bradyzoites. Here we address the role of AG synthesis in the establishment and progression of thechronic infection leveraging our new insights into bradyzoites as dynamic replication competent entities. Inaddition we directly address the role of AG's immune suppression mediated reactivation the primary triggerof symptomatic disease in HIV-AIDS.


application_id: 10119801
project_number: 5P20GM121327-05
project_title: Circulating tumor cell-neutrophil clusters in breast cancer metastasis
administering_ic: NIGMS
award_notice_date: 2020-12-21
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: CALDWELL, SHEILA
project_start_date: 2017-03-01
project_end_date: 2021-12-31
study_section: ZGM1-RCB-6
subproject_number: 8283
contact_pi_person_id: 12106844
contact_pi: LIU, XIA X
other_pis: ZHOU, BINHUA P
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
More than 90% of cancer-related death is caused by spreading of tumor cells from the primary sites to  distant organs (metastasis). Triple-negative breast cancers (TNBCs) are more aggressive and metastatic than other types of breast cancers. To metastasize tumor cells have to enter into the blood vessels (circulation). It has been recognized that these circulating tumor cells (CTCs) contain a rare subset of metastasis-initiating cells with the ability to generate metastatic tumors. However the properties of these metastasis-initiating CTCs are largely unknown. Both my preliminary data and other studies have shown that neutrophils can interact with CTCs (CTC-neutrophil clusters) to facilitate metastasis but little is known about how they interact. By single-cell RNA sequencing I found that ICAM-1 was highly expressed in lung metastatic cells compared to the primary tumor cells in TNBCs. In addition knockdown of ICAM-1 inhibited self-renewal ability of tumor cells in vitro uPAR secretion and TNBC metastasis in vivo. It has been known that neutrophil-endothelial cell interactions are mediated by Mac-1 and ICAM-1 and uPAR pariicipates to the recruitment of neutrophils and facilitate Mac-1-mediated adhesion. Based on these findings I hypothesize that ICAM-1+ CTCs contain metastasis-initiating cells which secrete uPAR to recruit neutrophils and then associate with them through ICAM-1-Mac-1 interaction to promote metastasis. I propose to test this hypothesis in Aim1. Accumulating evidence indicate that neutrophils have both antimetastatic and pro-metastatic activities (plasticity). Inhibition of AloxS one of the key enzymes in the arachidonic acid (AA)-Alox5 metabolic pathway abrogates pro-metastatic activity of neutrophils and consequently reduces metastasis. In addition AA-cyclooxygenase (COX) metabolic product prostaglandin E2 (PGE2) is also involved in pro-tumor function of neutrophils. Interestingly both PLA2 (the initial enzyme of the AA metabolism) and Alox5 can increase Mac-1 expression and I have found that Mac-1 on circulating neutrophils from tumor bearing mice is upregulated. Based on these findings I hypothesize that AA metabolism regulates pro-metastatic activity of neutrophils and facilitates CTC-neutrophil interaction by upregulating Mac-1 expression. I will test this hypothesis in Aim2. The results from this proposal will not only reveal new mechanisms of metastasis but also have significant implication for understanding how AA metabolism regulates pro-metastatic function of neutrophils which will facilitate the development of the novel cancer immunotherapeutic strategies by targeting pro-metastatic neutrophils.

project_terms:
Adhesions;Arachidonic Acids;Blood Circulation;Blood Vessels;Breast cancer metastasis;Cancer Center;Cell Communication;Cells;Cessation of life;Data;Development;Dinoprostone;Distant;Endothelial Cells;Enzymes;In Vitro;Intercellular adhesion molecule 1;Kentucky;Macrophage-1 Antigen;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mus;Neoplasm Circulating Cells;Neoplasm Metastasis;Neutrophil Infiltration;Organ;Phospholipase A2;Primary Neoplasm;Property;Prostaglandin-Endoperoxide Synthase;Site;Testing;Universities;base;cancer immunotherapeutics;in vivo;knock-down;lung metastatic;malignant breast neoplasm;neoplastic cell;neutrophil;novel;self-renewal;single-cell RNA sequencing;triple-negative invasive breast carcinoma;tumor;tumor metabolism


application_id: 10119800
project_number: 5P20GM121327-05
administering_ic: NIGMS
award_notice_date: 2020-12-21
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: CALDWELL, SHEILA
project_start_date: 2017-03-01
project_end_date: 2021-12-31
study_section: ZGM1-RCB-6
subproject_number: 8282
contact_pi_person_id: 14584136
contact_pi: ZHU, CAIGANG
other_pis: ZHOU, BINHUA P
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Intra-vital metabolic microscopy to reveal head and neck cancer radiation resistance mechanism in small animal models

project_abstract:
Most deaths from head and neck squamous cell cancer (HNSCC) result from tumor recurrence following radiotherapy (RT). More than 75% of HNSCC patients receive RT as part of their care and over 50% of them are at risk for developing recurrence post RT. Radio-resistance (RR) leads to poor prognosis in head and neck squamous cell cancer (HNSCC) patients. The failure of RT has been attributed to hypoxia. However new studies found that RT-induced re-oxygenation rates alone cannot distinguish primary from recurring HNSCC tumors as some recurrent tumors also showed re-oxygenation after RT. Overexpression of RTinduced Hypoxia-Inducible Factor-1-alpha (HIF-1) has been shown to be associated with an increased risk of failure of RT. HIF-1 is known to regulate many growth factors to promote aerobic glycolysis and angiogenesis. We hypothesize that RT-induced HIF-1 expression and subsequent alterations in metabolism/vasculature underlie HNSCC RR. Unraveling metabolic traits of cells that evade RT and recur and the role of the supporting vasculature is critical to developing strategies to prevent HNSCC recurrence and improve patient survival. However there are surprisingly few techniques available to provide a systems level view of these hallmarks together in vivo. To fill these gaps I will build a portable multi-parametric microscope to measure the major axes of metabolism and vasculature in small animal models in vivo. I will then use these platforms to study the effect of radiation on HNSCC tumors and test our hypothesis on HNSCC RR development. This technology fills an important gap between in vitro studies on cells and whole body imaging and is complementary to metabolomics and immunohistochemistry (IHC). I envision that this system will be well suited to study tumor RR and recurrence in patient-derived xenograft (PDX) and organoid models which can faithfully recapitulate many micro-environmental features of patient tumors. Successful completion of the proposed studies will set the foundation for translating the optical technology to image patient derived tumor lines in PDX models allowing us identify predictors of recurrence and develop improved radiotherapeutics (HIF-1 inhibitors) for HNSCC.

project_terms:
Animal Model;Cancer Center;Cancer Patient;Caring;Cells;Cessation of life;Failure;Foundations;Growth Factor;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Hypoxia;Immunohistochemistry;In Vitro;Kentucky;Measures;Metabolic;Metabolism;Microscope;Microscopy;Modeling;Optics;Organoids;Patient imaging;Patients;Prognosis;Radiation therapy;Recurrence;Recurrent tumor;Resistance development;Risk;Role;System;Techniques;Technology;Testing;Translating;Tumor-Derived;Universities;aerobic glycolysis;angiogenesis;cancer recurrence;hypoxia inducible factor 1;improved;in vivo;in vivo Model;inhibitor/antagonist;metabolomics;overexpression;patient derived xenograft model;portability;prevent;radiation effect;radiation resistance;resistance mechanism;trait;tumor;tumor metabolism;whole body imaging


application_id: 10119769
project_number: 5P20GM121327-04
administering_ic: NIGMS
award_notice_date: 2020-03-04
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: CALDWELL, SHEILA
project_start_date: 2020-01-01
project_end_date: 2021-12-31
study_section: ZGM1-RCB-6(CI)
subproject_number: 8282
contact_pi_person_id: 14584136
contact_pi: ZHU, CAIGANG
other_pis: ZHOU, BINHUA P
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Intra-vital metabolic microscopy to reveal head and neck cancer radiation resistance mechanism in small animal models

project_abstract:
Most deaths from head and neck squamous cell cancer (HNSCC) result from tumor recurrence following radiotherapy (RT). More than 75% of HNSCC patients receive RT as part of their care and over 50% of them are at risk for developing recurrence post RT. Radio-resistance (RR) leads to poor prognosis in head and neck squamous cell cancer (HNSCC) patients. The failure of RT has been attributed to hypoxia. However new studies found that RT-induced re-oxygenation rates alone cannot distinguish primary from recurring HNSCC tumors as some recurrent tumors also showed re-oxygenation after RT. Overexpression of RTinduced Hypoxia-Inducible Factor-1-alpha (HIF-1) has been shown to be associated with an increased risk of failure of RT. HIF-1 is known to regulate many growth factors to promote aerobic glycolysis and angiogenesis. We hypothesize that RT-induced HIF-1 expression and subsequent alterations in metabolism/vasculature underlie HNSCC RR. Unraveling metabolic traits of cells that evade RT and recur and the role of the supporting vasculature is critical to developing strategies to prevent HNSCC recurrence and improve patient survival. However there are surprisingly few techniques available to provide a systems level view of these hallmarks together in vivo. To fill these gaps I will build a portable multi-parametric microscope to measure the major axes of metabolism and vasculature in small animal models in vivo. I will then use these platforms to study the effect of radiation on HNSCC tumors and test our hypothesis on HNSCC RR development. This technology fills an important gap between in vitro studies on cells and whole body imaging and is complementary to metabolomics and immunohistochemistry (IHC). I envision that this system will be well suited to study tumor RR and recurrence in patient-derived xenograft (PDX) and organoid models which can faithfully recapitulate many micro-environmental features of patient tumors. Successful completion of the proposed studies will set the foundation for translating the optical technology to image patient derived tumor lines in PDX models allowing us identify predictors of recurrence and develop improved radiotherapeutics (HIF-1 inhibitors) for HNSCC.

project_terms:
Animal Model;Cancer Center;Cancer Patient;Caring;Cells;Cessation of life;Failure;Foundations;Growth Factor;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Hypoxia;Immunohistochemistry;In Vitro;Kentucky;Measures;Metabolic;Metabolism;Microscope;Microscopy;Modeling;Optics;Organoids;Patient imaging;Patients;Radiation therapy;Recurrence;Recurrent tumor;Resistance development;Risk;Role;System;Techniques;Technology;Testing;Translating;Tumor-Derived;Universities;Xenograft Model;Xenograft procedure;aerobic glycolysis;angiogenesis;cancer recurrence;hypoxia inducible factor 1;improved;in vivo;in vivo Model;inhibitor/antagonist;metabolomics;outcome forecast;overexpression;portability;prevent;radiation effect;radiation resistance;resistance mechanism;trait;tumor;tumor metabolism;whole body imaging


application_id: 10119761
project_number: 5P20GM121327-04
administering_ic: NIGMS
award_notice_date: 2020-03-04
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: CALDWELL, SHEILA
project_start_date: 2020-01-01
project_end_date: 2021-12-31
study_section: ZGM1-RCB-6(CI)
subproject_number: 8281
contact_pi_person_id: 11588541
contact_pi: CHAISWING, LUKSANA
other_pis: ZHOU, BINHUA P
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Mitochondrial Heat Shock Protein 90 as a Novel Target for Radiation Resistant Prostate Cancer Treatment

project_abstract:
Radiation therapy is widely used to treat localized prostate tumors. However cancer cells often develop resistance to radiation through unknown mechanisms and pose an intractable challenge. Radiation resistance is highly unpredictable rendering the treatment less effective in many patients and frequently resulting in cancer recurrence. There is a dire need to uncover the molecular events that cause cells to become resistant in order to improve radiation therapy. In our in-depth investigations of radiation-resistant prostate cancer (RR-PCa) we found that mitochondrial heat shock protein 90 (mtHsp90) level and mitochondrial metabolism were aberrantly high when compared to radiosensitive PCa. mtHsp90 is a chaperone that maintains the stability of many diverse proteins including those that are necessary for tumor survival and metabolism. We further demonstrated that decreasing mtHsp90 protein level significantly restored the sensitivity of RR-PCa cells to radiation. Hence our overarching hypothesis is that mtHsp90 defines resistance of prostate cancer cells to radiation a premise that will be put under stringent testing in this proposal. Reactive oxygen species (ROS) are known to reduce the level of mtHsp90 by interfering with its transcriptional and post-translational levels. We screened 768 FDA-approved drugs in search of a potent drug that could raise the level of ROS but not be toxic to normal cells. We found Azithromycin (AZM) a macrolide antibiotic to be the most effective drug that selectively increases mitochondrial ROS and reduces mtHsp90 protein level. We further demonstrated that AZM enhances the death of cancer cells with radiation treatment. Encouraged by robust results we aim to advance our findings in this project test our hypotheses and develop a paradigm for adjuvant treatment that will ultimately enhance radiation therapy as a more effective procedure. The goals are: Aim 1 to determine the functional importance of mtHsp90 in RR-PCa cell survival and adaptive metabolisms Aim 2 to determine mechanistically how ROS down-regulates mtHsp90 protein level and sensitizes RR-PCa and Aim 3 to validate in preclinical models if AZM-generated ROS down-regulates mtHsp90 and enhances radiation treatment. The results will establish a novel link between mtHsp90 and RR-PCa. This study using state-of-the art metabolomics imaging techniques and model systems and has the potential to be translated into a clinical practice because AZM already has a good safety record. In the era of precision medicine we are confident of the prospects of our closely-focused studies which will push boundaries and make radiation therapy a better procedure and our approach will set a precedent for many cancer treatments where radiation therapy is preferred.

project_terms:
Adjuvant;Antibiotics;Azithromycin;Biological Models;Cancer Center;Cell Survival;Cells;Cessation of life;Event;FDA approved;Genetic Transcription;Goals;Heat-Shock Proteins 90;Imaging Techniques;Investigation;Kentucky;Link;Macrolides;Malignant neoplasm of prostate;Metabolism;Mitochondria;Molecular;Molecular Chaperones;Normal Cell;Patients;Pharmaceutical Preparations;Pre-Clinical Model;Procedures;Prostate Cancer therapy;Prostatic Neoplasms;Proteins;Radiation;Radiation Tolerance;Radiation therapy;Radiation-Sensitizing Agents;Reactive Oxygen Species;Resistance;Resistance development;Safety;Testing;Translating;Universities;cancer cell;cancer recurrence;cancer therapy;clinical practice;improved;metabolomics;mitochondrial metabolism;novel;precision medicine;prostate cancer cell;radiation resistance;radioresistant;tumor;tumor metabolism


application_id: 10119641
project_number: 2R01AG037868-06A1
project_title: Chronic Stress Glucocorticoids and Progesterone in Brain Aging
administering_ic: NIA
award_notice_date: 2021-09-14
opportunity_number: PA-19-056
application_type: 2
activity_code: R01
ic: AG
serial_number: 037868
suffix: A1
program_official: LARKIN, JENNIE
project_start_date: 2011-03-01
project_end_date: 2026-05-31
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 8915754
contact_pi: BLALOCK, ERIC
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Acceleration;Acute;Address;Age;Age-Months;Aging;Agonist;Astrocytes;Behavioral;Bilateral;Binding;Biological Assay;Biological Markers;Blood;Cells;Chronic;Chronic stress;Clinical;Cognitive;Corticosterone;Data;Dependence;Dimethyl Sulfoxide;Dose;Female;Gene Expression Profile;Genes;Genetic Transcription;Geriatrics;Glucocorticoid Receptor;Glucocorticoids;Gonadal Steroid Hormones;Health;Hippocampus (Brain);Hormone Responsive;Hormones;Hypertrophy;Immunohistochemistry;Intraperitoneal Injections;Knowledge;Label;Measures;Mediating;Mediator of activation protein;Microglia;Microinjections;Mifepristone;Modeling;Myelin;Neurons;Oligodendroglia;Oral;Outcome;Outcome Measure;Pharmacology;Phosphotransferases;Preparation;Process;Progesterone;Rattus;Research Support;Rodent Model;Role;Serum;Sex Differences;Signal Pathway;Signal Transduction;Slice;Stress;Stress Tests;System;Testing;Therapeutic Uses;Tissues;Up-Regulation;Viral;Work;acute stress;age effect;aged;aging brain;animal age group;anxiety-related behavior;base;biological adaptation to stress;cell type;cytokine;female sex hormone;glucocorticoid receptor alpha;gray matter;indexing;intervention effect;laser capture microdissection;mRNA Expression;male;morris water maze;nano-string;neuroinflammation;novel;novel strategies;overexpression;receptor;reproductive hormone;response;sex;transcriptome sequencing;treatment group;uptake;white matter


application_id: 10119608
project_number: 1K08DK123381-01A1
administering_ic: NIDDK
award_notice_date: 2021-03-19
opportunity_number: PA-19-117
application_type: 1
activity_code: K08
ic: DK
serial_number: 123381
suffix: A1
program_official: SASLOWSKY, DAVID E
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 9291843
contact_pi: JOPHLIN, LORETTA L.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Interaction of the Microtubule Cytoskeleton and Perilipin-2 Regulates Hepatic Lipid Droplets - a Potential Therapeutic Target for Fatty Liver Disease

project_abstract:
PROJECT SUMMARY/ABSTRACTThe overall objective of this research is to target hepatocyte lipid droplets (LDs) for the development oftherapeutic interventions for fatty liver disease. Hepatic steatosis fat accumulation within hepatocyte LDs is a keyprecursor for steatohepatitis which can lead to cirrhosis and hepatocellular cancer necessitating livertransplantation. Unfortunately hepatic steatosis also limits the number of donor livers acceptable for transplant asdonor livers with severe steatosis have a high risk of primary nonfunction. As such therapeutic strategies toreverse fatty liver are important for patients at risk for steatohepatitis and cirrhosis as well as to increase thedonor pool of viable livers for transplantation. Our work focused on hepatocyte LDs herein shows three keyobservations: a) perilipin-2 (PLIN2) a LD-associated protein which regulates fat storage and utilization co-localizes with and co-immunoprecipitates microtubules; b) microtubule disruption with nocodazole a bluntmicrotubule targeting agent (MTA) uncouples PLIN2 from the LD promotes LD fusion and yields delipidation (i.e.exocytotic secretion of LD contents) of steatotic hepatocytes with minimal cytotoxicity; and c) nocodazolepromotes fat loss from ex vivo liver tissue with no effect on tissue viability. Based on these preliminary data wepropose the CENTRAL HYPOTHESIS that hepatocyte LDs are regulated by an interaction between PLIN2 andthe microtubule cytoskeleton and that this interaction is a potential therapeutic target to decrease the lipid burden ofhepatocytes in fatty liver disease. Our SPECIFIC AIMS will test three hypotheses. FIRST we will test thehypothesis that microtubules directly interact with LD-associated PLIN2. SECOND we will test the hypothesisthat microtubule perturbation increases lipolysis and leads to delipidation of steatotic hepatocytes. FINALLY wewill test the hypothesis that treatment of ex vivo steatotic liver tissue and ex vivo perfusion of steatotic livers withMTAs will lead to delipidation of hepatocytes and improved liver function in a pre-clinical model of organ salvageand rehabilitation. This work will provide foundational information to the emerging field of LD biology and isprojected to demonstrate a novel cellular mechanism controlling hepatocyte LD dynamics and to identifytherapeutic strategies to defat steatotic livers. The candidate is a basic scientist and transplant hepatologistdedicated to improving the lives of patients with liver disease using a basic science approach. She is an AssistantProfessor of Medicine at Mayo Clinic with a mentorship team consisting of Drs. Vijay Shah and Greg Gores. She hasprotected time for research and training activities dedicated institutional funding for equipment and supplies anda robust career development plan with specific activities and benchmarks that will position her for anindependent research career. The comprehensive training plan will allow for the candidate to complete hercurrent research plan and seek independent investigator status where she will translate these and future studiesto human trials and future therapeutic interventions for patients.

project_terms:
Affect;Aftercare;Alcohols;American;Basic Science;Benchmarking;Binding;Biogenesis;Biology;Catabolism;Cell Survival;Cessation of life;Cirrhosis;Clinic;Co-Immunoprecipitations;Coupled;Cytoskeleton;Data;Development Plans;Disease;Dynein ATPase;Equipment and Supplies;Fatty Liver;Fatty acid glycerol esters;Foundations;Funding;Future;Goals;Hepatic;Hepatocyte;Human;Imaging Techniques;Lead;Lipids;Lipolysis;Liver;Liver Failure;Liver diseases;Malignant neoplasm of liver;Measures;Medicine;Mentorship;Metabolism;Microtubules;Modeling;Mus;Mutation;Nocodazole;Organ;Organ Model;Organelles;Patient-Focused Outcomes;Patients;Positioning Attribute;Post-Translational Protein Processing;Pre-Clinical Model;Prevalence;Primary carcinoma of the liver cells;Process;Proteins;Regulation;Rehabilitation therapy;Research;Research Activity;Research Personnel;Risk;Scientist;Steatohepatitis;Structure;Testing;Therapeutic;Therapeutic Intervention;Time;Tissue Viability;Tissues;Training;Training Activity;Translating;Transplantation;Tubulin;Work;base;career;career development;cytotoxicity;ex vivo perfusion;high risk;improved;improved outcome;knock-down;liver function;liver transplantation;mutant;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;perilipin;primary outcome;professor;targeted agent;therapeutic development;therapeutic evaluation;therapeutic target;trafficking;western diet

public_health_relevance:
PROJECT NARRATIVENon-alcoholic fatty liver disease (NAFLD) affects millions of Americans and can lead to cirrhosis liver cancerneed for liver transplantation and death. Excess fat stored within lipid droplets (LDs) of liver cells is responsiblefor this disease and this project aims to better understand LDs as a potential therapeutic target for NAFLD.


application_id: 10119363
project_number: 1R01AG066724-01A1
administering_ic: NIA
award_notice_date: 2020-12-24
opportunity_number: PA-17-088
application_type: 1
activity_code: R01
ic: AG
serial_number: 066724
suffix: A1
program_official: WILLIAMS, JOHN
project_start_date: 2021-01-01
project_end_date: 2025-11-30
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: KOSMAC, KATE
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Aging;Ankle;Area;Atrophic;Autophagocytosis;Biogenesis;Biological Markers;Biological Process;Biological Specimen Banks;Biopsy;Blood flow;Characteristics;Classification;Clinical;Clinical Trials;Data;Defect;Denervation;Development;Diagnosis;Diagnostic;Disease;Disease Progression;Effectiveness;Fiber;Foundations;Future;Gastrocnemius Muscle;Goals;Grouping;Impairment;Individual;Injury;Intervention;Ischemia;Lower Extremity;Measures;Medical;Mitochondria;Modeling;Morphology;Motor Neurons;Muscle;Muscle Fibers;Myopathy;Myosin Heavy Chains;Myosin Type I;NCAM1 gene;Outcome;Oxidative Stress;Participant;Pathology;Patients;Performance;Perfusion;Peripheral arterial disease;Pharmacology;Phase;Population;Property;Proteins;Reperfusion Injury;Reperfusion Therapy;Reporting;Sampling;Severity of illness;Skeletal Muscle;Stress Fibers;Supervision;Testing;Theoretical model;Training;Walking;biobank;cohort;coping;disability;efficacious intervention;exercise intervention;follow-up;functional adaptation;functional decline;functional disability;functional outcomes;improved;improved functioning;indexing;mitochondrial dysfunction;nerve supply;novel;oxidative damage;predictive modeling;preservation;prevent;reinnervation;response;tool


application_id: 10118384
project_number: 1R01DK124626-01A1
project_title: Mechanisms for activation of beige adipose tissue in humans
administering_ic: NIDDK
award_notice_date: 2020-11-27
opportunity_number: PA-18-330
application_type: 1
activity_code: R01
ic: DK
serial_number: 124626
suffix: A1
program_official: LAUGHLIN, MAREN R
project_start_date: 2020-12-01
project_end_date: 2025-11-30
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Adipocytes;Adipose tissue;Adrenergic Agonists;Adrenergic Receptor;Affect;Agonist;Antidiabetic Drugs;Beta Cell;Biochemical;Bladder;Body Weight decreased;Brown Fat;Cell physiology;Cells;Chronic;Conditioned Culture Media;Consumption;Development;Diabetes Mellitus;Elderly;Epidemic;FDA approved;Fatty acid glycerol esters;Fiber;Fibrosis;Gene Expression;Glucose;Glycosylated hemoglobin A;Health;Homeostasis;Human;In Vitro;Inflammation;Insulin;Insulin Resistance;Lipids;Lipolysis;Mammals;Measures;Mediating;Metabolic;Metabolic syndrome;Methods;MicroRNAs;Mus;Muscle;Muscle Cells;Muscle function;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Organ;Overactive Bladder;Participant;Peripheral;Pharmaceutical Preparations;Pharmacology;Physiological;Placebos;Plasma;Play;Prediabetes syndrome;Property;Proteins;Research;Research Project Grants;Rodent;Role;Skeletal Muscle;Smooth Muscle;Structure of beta Cell of islet;Therapeutic;Thinness;Tissues;Volatile Fatty Acids;adipokines;adult obesity;bile acid metabolism;blood glucose regulation;cell type;clinically relevant;combat;design;diabetic;exosome;fighting;glucose metabolism;glucose tolerance;glucose uptake;human study;improved;improved functioning;insulin secretion;insulin sensitivity;interest;mRNA Expression;new therapeutic target;novel strategies;obesity treatment;oral glucose tolerance;overtreatment;prevent;randomized trial;response;subcutaneous;transcriptome sequencing;uncoupling protein 1


application_id: 10118140
project_number: 5R03CA249111-02
project_title: A genomic locus associated with radiation resistance of oral cancer cells
administering_ic: NCI
award_notice_date: 2021-01-29
opportunity_number: PAR-18-021
application_type: 5
activity_code: R03
ic: CA
serial_number: 249111
program_official: PRASANNA, PAT G
project_start_date: 2020-03-03
project_end_date: 2023-11-30
study_section: ZCA1-SRB-K(J2)S
contact_pi_person_id: 6617337
contact_pi: IZUMI, TADAHIDE
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:
ABSTRACTWhile radiation treatment is the major adjuvant therapy for patients with advanced stages of oral squamouscell carcinoma (OSCC) the acquired resistance of OSCC cells against ionizing radiation (IR) reduces itsefficacy. It was reported that cancer stem-like cells (CSLCs) were more resistant to IR than other cells butthe mechanism by which CSLCs acquire IR resistance remains elusive. A crucial CSLC factor that drives IRresistance needs to be characterized as studies have failed to observe IR resistance of cells with knownCSLC markers such as CD133 and CD44. Recent evidence indicates that PRMT5 (protein arginine methyl transferase 5) is crucial not only formaintaining CSLC status but also for enhancing DNA double-strand break repair (DSBR) and thus may bean important target to increase efficacy of IR-based therapy. However the molecular alterations in OSCC thatincrease PRMT5 expression are not known. In addition DNA single-strand breaks (SSB) and oxidative DNAdamage are more abundantly produced by IR than DSB but whether high PRMT5 expression is alsoassociated with increased repair of these lesions has not been elucidated. The PRMT5 gene is in chromosome 14 where APE1 a crucial repair factor for oxidative DNA damage isclosely localized. By scrutinizing genomics data we found that expression of PRMT5 and APE1 are highlycoordinated which is likely caused by the local copy number variation. Furthermore we identify high levels ofboth PRMT5 and APE1 in OSCC as an important indication of poor radiotherapy outcomes. Theseobservations led us to the central hypothesis of this project that the expressional co-regulation of PRMT5and APE1 is caused by the local copy number variation in the OSCC tissues prior to radiotherapy and levelsof these genes synergistically influence cellular sensitivity against IR. In Aim 1 of this project we will analyzethe copy number variation (CNV) of the genomic region in OSCC tissues and the levels of PRMT5 and APE1proteins by immunohistochemistry to investigate whether (a) CNV at the gene level in this region occurs inearly OSCC development before radiotherapy and (b) the CNV is associated with the PRMT5 and APE1protein levels. In Aim 2 we will elucidate whether simultaneous knockdown or inhibition of PRMT5 and APE1effectively sensitizes OSCC cells to IR. The long-term goal of this project is to delineate the novel mechanism of the PRMT5-driven IR resistanceof cells by the gene level CNV which should help us develop not only a reliable biomarker but also a novelstrategy of synthetic lethality that effectively targets OSCC with high levels of PRMT5.

project_terms:
Address;Adjuvant Therapy;Arginine;Base Excision Repairs;Biological Markers;CD44 gene;Cell Line;Cell Maintenance;Cells;Chromosome 14;Copy Number Polymorphism;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Repair Pathway;DNA Single Strand Break;Development;Double Strand Break Repair;Down-Regulation;Female;Genes;Genomic Segment;Genomics;Goals;Immunohistochemistry;Incidence;Ionizing radiation;Kentucky;Lesion;Malignant Epithelial Cell;Malignant Neoplasms;Modeling;Molecular;Molecular Target;Oral Pathology;Oral Stage;Outcome;Patients;Pilot Projects;Protein-Arginine N-Methyltransferase;Proteins;Radiation therapy;Regulation;Reporting;Research;Resistance;Specimen;Survival Rate;Testing;Tissues;Transferase;Universities;base;cancer cell;cancer radiation therapy;endonuclease;genetic linkage;genomic data;genomic locus;improved;inhibitor/antagonist;insight;interest;knock-down;mRNA Expression;male;malignant mouth neoplasm;mortality;mouth squamous cell carcinoma;nano-string;novel;novel strategies;oxidative DNA damage;preservation;protein expression;radiation resistance;repaired;stem-like cell;tumor

public_health_relevance:
NARRATIVEThe objective of this proposal is to understand how a subpopulation of oral cancer cells becomes resistantto ionizing radiation. Accomplishing this project will help us develop strategies to improve oral cancerradiotherapy.


application_id: 10117692
project_number: 1R01CA249734-01A1
project_title: Targeting Lipid Metabolism in Colorectal Cancer
administering_ic: NCI
award_notice_date: 2021-03-17
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: CA
serial_number: 249734
suffix: A1
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 10755133
contact_pi: ZAYTSEVA, YEKATERINA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY Metastasis is the main cause of death from solid tumors including colorectal cancer (CRC). Our long-termgoal is to develop more selective therapeutic options to prevent or reduce the incidence of CRC metastasis byunderstanding how changes in fatty acid metabolism contribute to metastatic disease. Fatty acid synthase (FASN) a key enzyme of de novo lipid synthesis is significantly upregulated andactivated in CRC and its activity is associated with poor prognosis higher risk of disease recurrence and death.We identified FASN as a potential target for advanced CRC and showed that upregulation of this enzyme is akey mechanism supporting metastasis in CRC. However the underlying mechanisms of FASN regulation ofmetastasis and potential mechanism of resistance to FASN inhibition are not understood. The current applicationproposes a comprehensive research plan to study novel mechanisms of regulation of CRC metastasis by lipidmetabolism. Our preliminary data suggest that the primary product of de novo fatty acid synthesis palmitate isselectively used for sphingolipid synthesis. Overexpression of FASN selectively regulates activity of SphK1 andSphK2 and increases the level of sphingosine-1-phosphate (S1P) a bioactive sphingolipid implicated inmetastasis. Therefore in Aim 1 we will test the hypothesis that FASN enhances metastasis by upregulating theSphK/S1P axis and we will determine the contributions of SphK1 and SphK2 to CRC metastasis. Furthermore ourpreliminary studies show a correlation between expression of FASN and CD36 a fatty acid translocaseresponsible for exogenous FA uptake. Our data show that inhibition of FASN leads to upregulation of CD36 andit can be a potential mechanism of resistance to novel FASN inhibitors that are currently being tested in PhaseII clinical trials. Therefore in Aim 2 we will elucidate how FASN regulates CD36 and determine molecularmechanisms by which upregulation of CD36 contributes to CRC metastasis including the effect of CD36upregulation on sphingolipid metabolism and S1P synthesis. In Aim 3 we will test whether inhibition of FA uptakevia CD36 will increase efficacy of a novel FASN inhibitor TVB-3664 in CRC. We will utilize biological samples from patients human primary CRC cells tumor organoids established fromgenetically modified mice and CRC metastasis models which are the most advanced models for pre-clinicaltarget and drug evaluations. These models will be used in conjunction with state-of-the-art approaches includingtargeted and stable isotope-resolved metabolomics (SIRM) to evaluate the effect of alteration in lipid synthesisand FA uptake on cancer cell metabolism. These studies have a high translational impact since CD36 and FASNinhibitors are currently tested in multiple pre-clinical studies and Phase I-II clinical trials and there is urgent needfor more research and knowledge on their effects in CRC. Beside validation of FASN SphKs and CD36 astherapeutic targets in CRC the comprehensive analysis of metabolic and signaling pathways proposed in thecurrent application also have the potential to identify new druggable targets and therapeutic strategies for CRC.

project_terms:
Biological;Biological Assay;Biological Sciences;CD36 gene;Cancer Etiology;Cancer Patient;Cause of Death;Cecum;Cell Survival;Cessation of life;Clinical;Collaborations;Colorectal Cancer;Data;Development;Disease;Drug Evaluation;Drug Targeting;Environment;Enzymes;Fatty Acids;Fatty-acid synthase;Goals;Growth;Human;In Vitro;Incidence;Injections;Knowledge;Lipids;Literature;Liver;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Metastatic Neoplasm to the Liver;Metastatic Neoplasm to the Lung;Metastatic to;Modeling;Molecular;Morbidity - disease rate;Mus;Neoplasm Metastasis;Oncogenic;Oncology;Organ;Organoids;Outcome;Palmitates;Pathway interactions;Patients;Pharmacology;Phase I/II Clinical Trial;Phase II Clinical Trials;Pre-Clinical Model;Prognosis;Public Health;Recurrence;Regulation;Research;Role;Sampling;Signal Pathway;Signal Transduction;Solid;Solid Neoplasm;Specimen;Sphingolipids;Sphingosine;Testing;Therapeutic;Tumor Angiogenesis;United States;Up-Regulation;Validation;Woman;analog;antibody inhibitor;base;cancer cell;colorectal cancer metastasis;colorectal cancer progression;disorder risk;fatty acid metabolism;genetic approach;high risk;in vivo;inhibitor/antagonist;lipid biosynthesis;lipid metabolism;men;metabolomics;mortality;mouse model;neutralizing antibody;new therapeutic target;novel;novel therapeutic intervention;overexpression;patient derived xenograft model;preclinical study;prevent;resistance mechanism;response;sphingosine 1-phosphate;sphingosine kinase;stable isotope;targeted treatment;therapeutic target;transcriptome sequencing;translational impact;translocase;tumor;tumor metabolism;uptake

public_health_relevance:
PROJECT NARRATIVEColorectal cancer is the 2nd most common cause of cancer death among men and women in the Unites Stateswith a majority of the mortality associated with metastasis that has spread to other organs. We have proposedto investigate the mechanisms of how lipid metabolism promotes CRC metastasis. The completion of this studywill help to advance our knowledge of the contribution of lipid metabolism to CRC metastasis and to further guidethe development of novel therapeutic strategies to treat CRC and potentially other solid cancers.


application_id: 10116879
project_number: 5P20GM113226-05
project_title: Non-alcholic steatohepatitis-associated HCC and strategies of prevention and therapy
administering_ic: NIGMS
award_notice_date: 2020-03-09
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
program_official: BERNAL, FEDERICO
study_section: ZGM1-TWD-A(C1)
subproject_number: 7951
contact_pi_person_id: 9527186
contact_pi: LI, YAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-04-01
project_abstract:
Non-alcoholic steatohepatitis (NASH) a potential precursor of hepatocellular carcinoma (HCC) currently has no FDA-approved treatment. Recently the known beneficial effects of fibroblast growth factor (FGF)19 and FGF21 on metabolism suggest that endocrine FGFs and their derivatives carry great potential as novel therapeutics to treat metabolic conditions. Pharmacological application of endocrine FGF variants holds great promise as an effective therapeutic means for treating obesity diabetes and NASH. The Pegylated FGF21 (MS-986036) and FGF19 agonist (NGM282) have been studied in clinical phase II trials. Our preliminary studies show that the lack of FGF21 accelerates steatohepatities progression and HCC transformation. Overexpression of FGF19/FGF receptor 4 significantly correlated with epithelial cell adhesion molecule (EpCAM) as a marker of hepatic cancer stem cells within the fatty liver-steatosiscirrhosis-HCC sequence in clinical patients. It is also unknown as to the potential anticancer mechanisms by which FGF21 could negatively feedback on the Th17-IL-17 axis and the carcinogenetic signaling to abolish the carcinogenetic transformation from NASH to HCC. All the previous studies build upon this scientific premise which leads to our hypothesis that endocrine FGFs prevent NASH-HCC through negative feedback on the Th17-IL-17 axis to inhibit inflammation control lipolysis and excessive FFAs and eliminate the tumor initiating cells. The hypothesis will be tested in the following Specific Aims. Aim 1: To investigate the mechanism(s) of NASH-HCC transition in mice. 1) NASH-HCC model will be reproduced in C57BL/6J mice using high-fat diets (HFD) methionine-choline-deficient diets (MCD) and diethylnitrosamine (DEN); 2) NASH-HCC will be evaluated by histology NASH score and the biomarkers of inflammation and HCC. Aim 2: To explore the preventive/therapeutic effects of endocrine FGFs against NASH-HCC. Establishment of NASH-HCC in FGF21-KO and IL-17A mutant mice will address 1) whether FGF21 variant/FGF19 agonist can prevent WT IR and lipolysis and hepatic FFA-uptake thereby preventing the carcinogenetic lipid-signaling; 2) whether FGF21 can suppress Th17-IL-17A axis; 3) specific anticarcinogenetic signaling of FGF21 variant/FGF19 agonist to eliminate tumor-initiating cells. This proposal will study systemically the specific anticancer effect of endocrine FGF variants on NASH-HCC transition. The importance of this proposal is 1) to reveal therapeutic targets and the mechanism(s) during NASHHCC transition; 2) to explore pharmacological use of endocrine FGF variants against NASH-HCC.

project_terms:
Address;Agonist;Biological Markers;Cell Adhesion Molecules;Cells;Centers of Research Excellence;Clinical;Diabetes Mellitus;Diethylnitrosamine;Endocrine;Epithelial Cells;FDA approved;FGF19 gene;FGF21 gene;Fatty Liver;Feedback;Fibroblast Growth Factor;Hepatic;High Fat Diet;Histology;Inflammation;Interleukin-17;Lipids;Lipolysis;Malignant neoplasm of liver;Metabolic;Metabolism;Methionine;Modeling;Mus;Mutant Strains Mice;Obesity;Patients;Pharmacology;Phase II Clinical Trials;Prevention strategy;Prevention therapy;Preventive;Primary carcinoma of the liver cells;Signal Transduction;Steatohepatitis;Testing;Therapeutic Effect;Toxicology;Treatment Efficacy;Variant;anti-cancer;cancer stem cell;choline deficient diet;fibroblast growth factor receptor 4;nonalcoholic steatohepatitis;novel therapeutics;overexpression;prevent;therapeutic target;tumor;uptake


application_id: 10116878
project_number: 5P20GM113226-05
project_title: Role of acrolein in hepatic ER stress adn injury in alcoholic liver disease
administering_ic: NIGMS
award_notice_date: 2020-03-09
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
program_official: BERNAL, FEDERICO
study_section: ZGM1-TWD-A(C1)
subproject_number: 7950
contact_pi_person_id: 9367807
contact_pi: JOSHI-BARVE, SWATI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-04-01
project_abstract:
Alcohol consumption can cause alcoholic liver disease (ALD) which is a major cause of morbidity and mortality in the United States. Also it remains unclear why only some heavy drinkers develop clinically relevant ALD. Unfortunately there is no FDA-approved therapy for any stage of ALD and the pathogenesis of ALD is not fully understood. Therefore it is critical to investigate the underlying mechanisms and pathogenic mediators in order to identify novel targets and therapeutic strategies in ALD. Chronic alcohol consumption causes a prooxidant environment in the liver and increases hepatic lipid peroxidation (LPO) which produces lipid-derived aldehydes such as acrolein one of the most reactive and toxic aldehydes. Acrolein is primarily metabolized/cleared by conjugation to glutathione (GSH) catalyzed by glutathione-S-transferase-Pi (GSTP); unless removed acrolein can adversely impact key cellular functions. Acrolein can form covalent irreversible adducts with cellular molecules with detrimental consequences; such acrolein adducts are associated with several diseases. Our data show that acrolein exposure in hepatocytes causes endoplasmic reticulum (ER) stress GSH depletion and apoptosis all of which are recognized etiologic factors in ALD. Further our preliminary data show alcohol consumption downregulates GSTP and causes significant hepatic acrolein generation/accumulation which correlates with steatosis inflammation and liver injury in mice. This project will test our hypothesis that acrolein critically mediates alcohol-induced ER stress and liver injury thereby contributing to ALD pathogenesis. The proposed studies will help elucidate the molecular mechanisms of alcohol-induced liver injury and may help identify new therapeutic targets and potential interventions for ALD.

project_terms:
Acrolein;Alcohol consumption;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Aldehydes;Apoptosis;Cell physiology;Centers of Research Excellence;Data;Disease;Environment;Etiology;FDA approved;Generations;Glutathione;Hepatic;Hepatocyte;Inflammation;Injury;Intervention;Lipid Peroxidation;Lipids;Liver;Mediating;Mediator of activation protein;Molecular;Morbidity - disease rate;Mus;Pathogenesis;Pathogenicity;Role;Testing;Toxicology;United States;adduct;chronic alcohol ingestion;clinically relevant;endoplasmic reticulum stress;glutathione S-transferase pi;liver injury;mortality;new therapeutic target;novel;targeted treatment


application_id: 10116867
project_number: 5P20GM113226-05
administering_ic: NIGMS
award_notice_date: 2020-03-09
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
program_official: BERNAL, FEDERICO
study_section: ZGM1-TWD-A(C1)
subproject_number: 7948
contact_pi_person_id: 10972280
contact_pi: SONG, MING
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-04-01
budget_end_date: 2021-03-31
project_title:
Dietary Fructose-Induced Metabolic Reprogramming in Intestinal Epithelial Cells Results in Gut Microbiota Dysbiosis

project_abstract:
Nonalcoholic fatty liver disease (NAFLD) is now the most common liver disease in the US. The clinical burden of NAFLD is not restricted to liver-related morbidity or mortality but it also increases the risk of cardiovascular disease (CVD) type 2 diabetes and cancer. As yet there currently is no FDA-approved drug therapy. Thus NAFLD imposes an important health problem and huge economic burden in the US. Increased dietary fructose consumption is an important risk factor in the pathogenesis and progression of NAFLD. Emerging evidence supports the concept that gut microbiota dysbiosis and gut barrier dysfunction play critical roles in the development of NAFLD including dietary high fructose-induced NAFLD. However how dietary fructose intake alters the gut microbiome has not been elucidated. Cross-talk between host and gut microbiota is key for maintaining physiologic hypoxia in the intestinal epithelial cells which is important for a healthy gut and disease resistance. A balanced gut microbiota is characterized by the dominance of obligate anaerobic bacteria of Firmicutes and Bacteroidetes phyla whereas increased abundance of Proteobacteria is generally considered a signature of dysbiosis. Obligate anaerobic bacteria prevent pathogenic facultative anaerobic bacteria expansion in part by limiting the generation of hostderived nitrate and oxygen. Our preliminary data showed that male rats fed chronically with either 10% glucose (w/v) or 10% fructose (w/v) in the drinking water results in gut microbiota dysbiosis. We hypothesize that fructose metabolism in the intestinal epithelial cells results in metabolic reprogramming which switches the host metabolic pathway from mitochondrial -oxidation to glycolysis. This leads to the disruption of physiologic hypoxia and intestinal oxygenation thus inhibiting the growth of obligate anaerobic bacteria and facilitating the expansion of pathogenic bacteria. We will test our hypothesis in three specific aims. Aim 1. Determine whether fructose induces metabolic reprogramming in intestinal epithelial cells and determine if this results in gut microbiota dysbiosis. Aim 2. Determine whether modulation of glycolytic activity in intestinal epithelial cells alters gut microbiota composition. Aim 3. Determine whether fructose induced gut microbiota dysbiosis is mediated by HIF-1.

project_terms:
Anaerobic Bacteria;Bacteroidetes;Centers of Research Excellence;Chronic;Clinical;Consumption;Data;Development;Diet;Disease Resistance;Economic Burden;Epithelial Cells;FDA approved;Firmicutes;Fructose;Functional disorder;Generations;Glucose;Glycolysis;Growth;Health;Hypoxia;Intake;Intestines;Liver;Liver diseases;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Morbidity - disease rate;Nitrates;Non-Insulin-Dependent Diabetes Mellitus;Oxygen;Pathogenesis;Pathogenicity;Pharmacotherapy;Physiological;Play;Proteobacteria;Rattus;Risk Factors;Role;Testing;Toxicology;cardiovascular disorder risk;cross-species transmission;drinking water;dysbiosis;gut microbiome;gut microbiota;host microbiota;hypoxia inducible factor 1;intestinal epithelium;male;mortality;non-alcoholic fatty liver disease;oxidation;pathogenic bacteria;prevent


application_id: 10116681
project_number: 1R21NS120149-01
project_title: Role of senescent cells in pathogenesis of contusive spinal cord injury
administering_ic: NINDS
award_notice_date: 2020-09-22
opportunity_number: PA-18-358
application_type: 1
activity_code: R21
ic: NS
serial_number: 120149
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2020-09-30
project_end_date: 2023-08-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 7612305
contact_pi: HETMAN, MICHAL
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
After spinal cord injury (SCI) initial mechanical damage is followed by a secondary injury that exacerbatestissue destruction and functional deficits. In contusive thoracic SCI white matter damage which progresses forweeks post-injury is the critical anatomical determinant of locomotor dysfunction. Few targets have beenidentified whose manipulation reduces SCI-associated secondary injury with a therapeutic window of <12-24 h.Although locomotor recovery is observed in SCI rodents it is usually incomplete. The limits to recovery involveneuron and oligodendrocyte loss prolonged inflammatory responses vascular dysfunction lack of efficientregeneration and/or a finite capacity of synaptic plasticity. Breaking the ceiling of locomotor recovery inrodents remains a major challenge. Proliferating cells that accumulate DNA damage may undergo cellularsenescence. Senescence-associated induction of the cyclin-dependent kinases (CDK) inhibitors p21 and p16triggers permanent exit from the cell cycle. The senescence-associated secretory phenotype (SASP) involvessecretion of multiple cytotoxic pro-inflammatory mediators. Elimination of senescent cells (senolysis) improvesmany age-dependent pathologies and reduces neurodegeneration in mouse models of fronto-temporaldementia or -amyloidosis. In those cases improved outcomes were associated with elimination of senescentmicroglia/astrocytes or oligodendrocyte precursor cells (OPCs). As those glial cells proliferate in response toCNS injury their senescence is a likely by-product of trauma-induced gliosis. Our preliminary data revealincreased expression of cellular senescence markers at dpi 3 and 42 following T9 contusive SCI. Hence bypromoting neuroinflammation and tissue scarring senescent cells may increase white matter loss andcompromise neurorepair/neuroplasticity after contusive SCI. We hypothesize that accumulation of senescentcells after SCI contributes to progressive white matter loss and reduces recovery of locomotor function. In aim1 we will determine the identity and spatio-temporal distribution of senescent cells in the spinal cord of SCImice. In aim 2 we will test effects of pharmacological (2a) or pharmacogenetic (2b) senolysis on white mattersparing and hindlimb locomotor function after moderate T9 contusive SCI. Effects of senolysis will beevaluated by analyzing senescence markers neuroinflammation reactive gliosis apoptosis white mattersparing and hindlimb locomotion. These studies will conclusively evaluate the pathogenic significance of SCI-associated cellular senescence. As senolytic drugs are already in use in clinical trials for other diseases thesestudies may define a novel and readily translatable therapeutic treatment for both acute and chronic SCI-induced pathologies. Although it has been proposed that organismal aging may modify outcome of SCI thisapplication is focused on an entirely distinct issue that has not been previously addressed: the pathogenic roleof injury-induced cellular senescence.

project_terms:
Acute;Address;Aging;Amyloidosis;Anatomy;Anxiety;Apoptosis;Arthritis;Astrocytes;Atherosclerosis;Biological Assay;Blood Vessels;Cell Aging;Cell Cycle;Cells;Chronic;Cicatrix;Clinical;Clinical Trials;Contusions;Cyclin-Dependent Kinase Inhibitor 2A;DNA Damage;Dasatinib;Data;Diabetes Mellitus;Disease;Drug Combinations;Elements;Endothelial Cells;Environment;Fibroblasts;Frontotemporal Dementia;Functional disorder;Ganciclovir;Gliosis;HSV-Tk Gene;Herpes Simplex Infections;Hindlimb;Human;Inflammation Mediators;Inflammatory Response;Injury;Locomotion;Locomotor Recovery;Luciferases;Mechanics;Mediator of activation protein;Microglia;Modeling;Monitor;Mus;Natural regeneration;Nerve Degeneration;Neuroglia;Neuronal Plasticity;Neurons;Obesity;Oligodendroglia;Outcome;Pathogenesis;Pathogenicity;Pathology;Pericytes;Permeability;Pharmaceutical Preparations;Pharmacogenetics;Pharmacology;Phase;Phenotype;Proliferating;Quercetin;Recovery;Recovery of Function;Renilla Luciferases;Reporter Genes;Reporting;Rodent;Role;Sorting - Cell Movement;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Synaptic plasticity;Testing;Therapeutic;Thoracic spinal cord structure;Thymidine Kinase;Tissues;Transgenic Organisms;Trauma;Vascular Diseases;Wild Type Mouse;age related;cell type;central nervous system injury;cytotoxic;effective therapy;improved;improved outcome;in situ imaging;mouse model;neuroinflammation;new therapeutic target;novel;oligodendrocyte precursor;oncoprotein p21;precursor cell;promoter;red fluorescent protein;response;senescence;spatiotemporal;white matter;white matter damage

public_health_relevance:
Project narrativeCurrently there are no clinically effective treatments to improve outcome after traumatic spinal cord injury(SCI). This proposal will examine the role of novel candidate mediators of secondary tissue damage and/ordysfunctional neurorepair following SCI. Hence new therapeutic targets may be identified to enhancefunctional recovery after SCI.


application_id: 10116381
project_number: 5R01EY012716-22
project_title: Circuit Assembly in the developing thalamus
administering_ic: NEI
award_notice_date: 2021-02-22
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: EY
serial_number: 012716
program_official: GREENWELL, THOMAS
project_start_date: 2001-05-01
project_end_date: 2023-08-31
study_section: Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section[SPC]
contact_pi_person_id: 1864719
contact_pi: GUIDO, WILLIAM
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/AbstractThe thalamic reticular nucleus (TRN) is a shell like structure that surrounds the dorsal thalamus and serves asa key inhibitory interface for the bidirectional signaling between thalamus and the neocortex. Together withinputs from thalamus cortex and cholinergic nuclei of brainstem and basal forebrain the TRN regulates manyaspects of sensory motor and cognitive processing. When the connections between these structures aredisrupted by disease degeneration or trauma they have devastating consequences. In fact many adult andchildhood neurological disorders have at their core a disturbance in TRN signaling and circuitry. Despite itskey role in thalamocortical function remarkably little is known about how reticular circuitry emerges duringdevelopment and becomes operational. To address this substantive gap in knowledge we developed a robustmouse model as an experimental platform to visualize manipulate and dissect emergent and developingreticular circuitry. We plan to conduct anatomical electrophysiological and optogenetic experiments ingenetically modified mice that allow for the visualization and experimental manipulation of specific cell typesarising from the TRN first-order thalamic sensory nuclei layer VI of cortex and cholinergic nuclei of brainstemand basal forebrain. The goals of this proposal focus on three unanswered questions about TRN development.First how are the sensory sectors of TRN established; do inputs from primary sensory thalamic nuclei andcorresponding regions of cortex innervate TRN diffusely and then segregate to form modality specificdomains? Second what is the sequence and pattern of driver and modulator innervation of TRN; do driver-likeinputs from sensory thalamic nuclei such as the dorsal lateral geniculate nucleus arrive prior to modulatoryinput from cortex or brainstem and basal forebrain? Third how and when do feed-forward and feedbackcircuits linking TRN to thalamus and cortex emerge during development to control thalamocortical signaling?Finally for each of these questions we plan to take a loss of function approach to assess whether the absenceof sensory input (vision) affects the development form and function of reticular circuitry. These studies willprovide valuable information about the organizing principles that guide the emergence of reticular circuitry inthe neonatal brain and perhaps reveal a new understanding into childhood disorders that result from abnormalpatterns of connectivity.

project_terms:
Acute;Address;Adult;Affect;Anatomy;Area;Attention;Attention Deficit Disorder;Axon;Biological Models;Brain;Brain Stem;CRH gene;Cell Differentiation process;Cell Nucleus;Childhood;Childhood Neurological Disorder;Cognitive;Conscious;Cre driver;Deafferentation procedure;Decision Making;Development;Development Plans;Diffuse;Disease;Dorsal;Electrophysiology (science);Epilepsy;Failure;Feedback;Gap Junctions;Generations;Genetic;Glutamates;Goals;In Vitro;Injections;Knowledge;Lateral Geniculate Body;Light;Link;Modality;Motor;Mus;Nature;Neocortex;Neurons;Pathway interactions;Pattern;Play;Preparation;Reporter;Retinal Ganglion Cells;Role;Schizophrenia;Sensory;Series;Signal Transduction;Sleep;Sleep Disorders;Slice;Source;Structure;Synapses;Testing;Thalamic Nuclei;Thalamic structure;Tomatoes;Trauma;Viral;Vision;Visual;Visual Cortex;Visualization;Wakefulness;autism spectrum disorder;awake;basal forebrain;basal forebrain cholinergic neurons;cell type;cellular development;cholinergic;cognitive function;developmental disease;experimental study;in vivo;insight;loss of function;mouse model;mutant;neonatal brain;nerve supply;nervous system disorder;optogenetics;postnatal;postsynaptic;response;retinogeniculate;sensory input

public_health_relevance:
NarrativeThe TRN is a critical nexus between thalamus and cortex and the connections betweenthese structures are essential for many aspects of sensory and motor processing as wellas the generation of synchronous rhythms that define different levels of consciousness.When these connections are disrupted by a developmental anomaly disease or traumathey have devastating consequences and lie at the core of many childhood and adultdisorders including epilepsy sleep disorders schizophrenia autism and attention deficitdisorders. Thus these studies will provide valuable information about how thedeveloping brain forms precise patterns of connections and offer further insight into thestudy and treatment of developmental and neurological disorders that result from theformation of abnormal patterns of connectivity.


application_id: 10115956
project_number: 5P20GM113226-05
project_title: Effects of Dietary Fat on the Hepatotoxicity of Environmental Arsenic
administering_ic: NIGMS
award_notice_date: 2020-03-09
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
program_official: BERNAL, FEDERICO
study_section: ZGM1-TWD-A(C1)
subproject_number: 7873
contact_pi_person_id: 1902836
contact_pi: WATSON, WALTER H
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-04-01
project_abstract:
One of every three American adults is obese and is afflicted with some form of non-alcoholic fatty liver disease(NAFLD). The majority of obese individuals will have steatosis (fatty liver) but only about 20% will have themore serious condition of steatohepatitis (fatty liver with inflammation and liver injury). There is still no FDA-approvedtherapy for any stage of NAFLD. Therefore it is critical that we understand the multiple factors thatpromote progression from steatosis to steatohepatitis in NAFLD. Our previous studies have shown thatconsumption of arsenic-contaminated drinking water is an important risk factor for progression of NAFLD.Preliminary proteomic analysis demonstrated that the abundance of a number of proteins that are controlled atthe transcriptional level by HNF-4a was decreased in the livers of mice with arsenic-enhanced NAFLD.Mechanistic studies showed that the expression of this zinc finger transcription factor was not altered but thatits DNA binding activity was inhibited at the post-translational level. HNF-4a is known to be regulated by posttranslationalmodifications (PTMs) and arsenic has the potential to affect zinc binding cysteine oxidationarginine methylation and lysine acetylation. Very little is known about how PTMs of HNF-4a are regulated orhow disruption of these regulatory processes contributes to liver disease. To follow up on these importantfindings the objective of the current proposal is to delineate the mechanisms by which environmental arsenicexposure promotes the progression from steatosis to steatohepatitis in mice fed a Western-style diet that ishigh in saturated fat. The central hypothesis to be tested is that alterations in HNF-4a-mediated geneexpression induced by arsenic play a critical role in the progression of NAFLD from steatosis to steatohepatitisin this model. This hypothesis will be tested in three Specific Aims. First we will define the specific molecularinteractions of arsenic with the zinc finger domain of HNF-4a. Second we will analyze the mechanisms bywhich arsenic affects PTMs of HNF-4a and how these changes translate into altered DNA binding activity andtransactivation potential. Third we will define the post-translational modifications of hepatic HNF-4a in mice feda high fat diet and exposed to arsenic-contaminated drinking water and relate these changes to the occupancyof HNF-4a-response elements in genes involved in lipid metabolism and inflammation. This model ofinflammatory liver injury is relevant to the United States population where high fat diets are common andarsenic exposure levels are typically below the threshold for overt hepatotoxicity. The new information obtainedfrom these studies will delineate pathways that are altered by arsenic and that are important in the etiology ofNAFLD.

project_terms:
Acetylation;Adult;Affect;American;Animal Model;Arginine;Arsenic;Arsenites;Benign;Binding;Cells;Centers of Research Excellence;ChIP-seq;Chemicals;Cirrhosis;Clinical;Consumption;Cysteine;DNA;DNA Binding;DNA Binding Domain;Diet;Dietary Fats;Disease;Disease Progression;Disease model;Environment;Etiology;Exposure to;FDA approved;Fatty Liver;Fatty acid glycerol esters;Fibrosis;Gene Expression;Genes;Genetic;Genetic Transcription;Hepatic;Hepatotoxicity;High Fat Diet;In Vitro;Incubated;Individual;Inflammation;Inflammatory;Injury;Knowledge;Liver;Liver diseases;Lysine;Mediating;Methylation;Modeling;Modification;Mus;Obesity;Pathway interactions;Pharmacology;Play;Population;Post-Translational Protein Processing;Process;Proteins;Proteomics;Response Elements;Risk Factors;Role;Signal Pathway;Steatohepatitis;Techniques;Testing;Tissues;Toxic effect;Toxicology;Transactivation;Translating;United States;Zinc;Zinc Fingers;cell injury;contaminated drinking water;drinking water;experimental study;follow-up;genetic regulatory protein;innovation;lipid metabolism;liver injury;non-alcoholic fatty liver disease;novel;oxidation;promoter;response;saturated fat;transcription factor;transcriptome sequencing


application_id: 10115632
project_number: 5R01CA213990-05
project_title: Transcriptional Regulation of Immunosuppressive Macrophages by c-Maf in Cancer
administering_ic: NCI
award_notice_date: 2021-04-06
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 213990
program_official: XI, DAN
project_start_date: 2017-02-06
project_end_date: 2023-07-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Immunosuppressive macrophages have been linked to cancer-related inflammation and therapeuticresistance in cancer including chemotherapy and immunotherapy thus representing attractive therapeutictargets. Macrophages can be polarized into extreme M1 or M2 phenotype depending on the environmentalcues. Although macrophage phenotype within the tumor microenvironment is more complicated it is clearthat immunosuppressive tumor-associated macrophages (TAM) phenotypically more resemble M2-likemacrophages. In the preliminary studies we discovered that transcription factor c-Maf is highly expressed inmouse and human polarized M2 macrophages and immunosuppressive TAM. In addition natural productyeast-derived particulate -glucan treatment significantly downregulates c-Maf expression leading toenhanced T cell responses in mice. We also demonstrated that M1 and M2 macrophages have distinctmetabolic profiles and c-Maf regulates many genes related to glycolysis. Based on these preliminary studieswe hypothesize that transcription factor c-Maf is an essential controller and a metabolic checkpointfor immunosuppressive TAM functional activity. Three Aims are proposed. Aim 1 determines thecellular and molecular mechanisms by which c-Maf is regulated in immunosuppressive TAM. We willinvestigate whether tumor secreted factors regulate c-Maf expression in TAM. We will also determine howthe Raf-1 kinase pathway regulates c-Maf and c-Maf-related gene expression. Finally we will test whetherloss of function of c-Maf in TAM significantly delays tumor progression and metastasis. Aim 2 determineswhich TAM metabolic pathway(s) is regulated by c-Maf using systems metabolomics approach. We will firstdetermine TAM metabolic pathways using Stable Isotope Resolved Metabolomics (SIRM) approach.Furthermore we will determine which metabolic pathways are regulated by c-Maf. Finally we will determinethe causative role of metabolic reprogramming in -glucan-mediated TAM functional conversion. Aim 3determines whether the dectin-1 agonist -glucan modulates TAM function of human non-small cell lungcancer (NSCLC) via the c-Maf pathway. We will determine whether -glucan treatment downregulates c-Maf expression and alters c-Maf-regulated genes in human NSCLC TAM. We will also determine whetherhuman TAM functions are reversed upon -glucan treatment. Finally we will examine whether -glucantreatment in patients with NSCLC downregulates c-Maf expression and alters monocyte suppressivefunction. The overall goal of this proposal is to understand the transcriptional regulation ofimmunosuppressive TAM by c-Maf and establish the transcription factor c-Maf as a novel target for humancancer immunotherapy.

project_terms:
Agonist;Anti-Inflammatory Agents;Arginine;Cell Survival;Cell physiology;Clinical Research;Cues;Data;Dinoprostone;Essential Amino Acids;Gene Expression;Generations;Genes;Genetic Transcription;Glucose;Glutamine;Glycolysis;Goals;Human;IRF4 gene;Immunosuppression;Immunotherapy;Infiltration;Inflammation;Interleukin-10;Interleukin-12;Leukocytes;Link;MHC Class II Genes;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitogen-Activated Protein Kinase Kinases;Modeling;Molecular;Mus;Natural Products;Neoplasm Metastasis;Network-based;Nitric Oxide;Non-Small-Cell Lung Carcinoma;PPAR gamma;PTGS2 gene;Particulate;Pathway Analysis;Pathway interactions;Patients;Phenotype;Play;Population Heterogeneity;Prognosis;Prostaglandin-Endoperoxide Synthase;Proto-Oncogene Proteins c-raf;Reactive Oxygen Species;Regulation;Role;Signal Transduction;System;T cell response;TNF gene;Testing;Transcriptional Regulation;Tumor Burden;Tumor-associated macrophages;Vascular Endothelial Growth Factors;Yeasts;arginase;bZIP Domain;base;beta-Glucans;c-myc Genes;cancer immunotherapy;chemotherapeutic agent;chemotherapy;cytokine;dectin 1;density;effector T cell;factor C;fibrosarcoma;immunosuppressive checkpoint;immunosuppressive macrophages;inhibitor/antagonist;innovation;loss of function;macrophage;metabolic profile;metabolomics;monocyte;novel;stable isotope;therapeutic target;therapy resistant;transcription factor;transcriptome;tumor;tumor microenvironment;tumor progression

public_health_relevance:
Project NarrativeThis study will determine the mechanisms by which transcription factor c-Maf regulates cancer-elicitedimmunosuppressive macrophages via the transcriptional regulation and metabolic reprograming. Thesuccessful completion of this study may provide an innovative approach for cancer immunotherapy.


application_id: 10115016
project_number: 5R01DA047368-03
project_title: A Translational Determination of the Mechanisms of Maladaptive Choice in Opioid Use Disorder
administering_ic: NIDA
award_notice_date: 2021-02-22
opportunity_number: PA-18-060
application_type: 5
activity_code: R01
ic: DA
serial_number: 047368
program_official: FEDOTA, JOHN RAPHAEL
project_start_date: 2019-04-15
project_end_date: 2024-02-29
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: BECKMANN, JOSHUA ;WESLEY, MICHAEL J
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Opioid use disorder (OUD) is characterized by the decision to use opioids at the expense of other activities.Lab-based efforts to address this problem have therefore included opioid choice self-administration proceduresthat incorporate a non-drug alternative to model this defining feature. Studies using these procedures havetypically scheduled competing reinforcers so that the probabilities are certain. However such deterministicoutcomes are not representative of real-world experiences in which the consequences from drug-related choicesare often unpredictable. Importantly decision-making in a dynamic uncertain context significantly alters thevalue of choice options and requires continuous updating of option values which engages learning processesand related corticostriatal networks that function abnormally in OUD. Decision-making in dynamic environmentshas been successfully modeled using probabilistic reinforcement-learning choice (PRLC) tasks. The integrationof these tasks with reinforcement-learning (RL) computational modeling has been used to capture moment-to-moment changes in the mechanisms of dynamic choice and the application of neuroscience techniques hasbegun to identify the underlying neurobiology. This approach has uncovered biologically-based decision-makingabnormalities in multiple brain disorders but has yet to be systematically applied to the experimental study ofOUD The translation of combined RL and neuroscience approaches to OUD is logical considering themaladaptive choice behavior that typifies the disorder the varying reinforcement probabilities in opioid usersnatural environments and the learning impairments that have been documented in individuals with OUD. Thusthere are critical gaps in our understanding of the mechanisms underlying dynamic opioid use decisions and astrong scientific premise for applying an RL framework to fill these gaps. This project proposes rigorous PRLCtasks RL modeling neurorecording/fMRI neuroimaging techniques and complementary translational studydesigns in rats and humans. The first set of cross-species experiments will demonstrate the impact of opioidexposure and withdrawal on dynamic decision-making and reveal the neurobehavioral and neurobiologicalprocesses underlying abnormal task performance. The second set of experiments will use a PRLC task in whichintravenous remifentanil a prototypical opioid agonist with a favorable safety profile is available as an alternativeto a non-drug reinforcer to determine the behavioral and neural profiles associated with drug choice as well asthe increases and decreases in drug choice that occur during withdrawal and in the presence of a largemagnitude alternative reinforcer respectively. This project will have a significant impact on the field byestablishing the experimental application of reinforcement-learning theory to the study of maladaptive dynamicdrug-use decision-making in OUD to reveal behavioral and neural mechanisms that can be targeted for futureprevention and treatment development.

project_terms:
Abate;Abstinence;Address;Animals;Area;Back;Behavioral;Behavioral Mechanisms;Biological;Brain Diseases;Brain region;Choice Behavior;Chronic;Clinical;Cognition;Computer Models;Cues;Decision Making;Disease;Drug usage;Environment;FDA approved;Fibrinogen;Food;Foundations;Functional Magnetic Resonance Imaging;Future;Half-Life;Human;Impairment;Individual;Intravenous;Knowledge;Learning;Mental disorders;Methods;Modeling;Neurobiology;Neurologic;Neurosciences;Opioid;Opioid agonist;Outcome;Oxycodone;Performance;Pharmaceutical Preparations;Postdoctoral Fellow;Prevention;Prevention strategy;Probability;Procedures;Process;Psychological reinforcement;Rattus;Research;Research Design;Safety;Schedule;Self Administration;Signal Transduction;Task Performances;Techniques;Time;Translating;Translations;Update;Withdrawal;base;experience;experimental study;human subject;innovation;neuroadaptation;neurobehavioral;neuroimaging;neuromechanism;non-drug;novel;opioid exposure;opioid use;opioid use disorder;opioid user;opioid withdrawal;participant safety;reinforcer;relating to nervous system;remifentanil;theories;therapy development;translational study;treatment strategy

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


application_id: 10114980
project_number: 5R01CA207772-05
project_title: Roles of Hsp47 in breast cancer progression
administering_ic: NCI
award_notice_date: 2021-02-02
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 207772
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2017-03-03
project_end_date: 2022-08-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Despite recent advance in early diagnosis and adjuvant therapy treatment of triple negative breastcancer (TNBC) remains a significant challenge because of the high incidence of metastasis and relapse aftertreatment. Signaling from extracellular matrix (ECM) an essential component of the tumor microenvironmentis required for TNBC progression and metastasis. However it is not known how cancer cell-deposited ECMproteins and ECM signaling in cancer cells are regulated and promote TNBC metastasis/relapse. We recentlyidentified Hsp47 as a hub of the ECM transcription network. Hsp47 is a molecular chaperon that regulatessecretion and deposition of ECM proteins. Increased Hsp47 expression has been detected in TNBC and isassociated with cancer metastasis. Silencing Hsp47 restrains the aggressive phenotype of TNBC cells in 3Dculture and inhibits tumor growth and lung colonization in the xenograft model indicating that increased Hsp47expression is crucial for the TNBC progression. EMT promotes cancer progression by enhancing cancer celldissemination and endowing cancer cells with stemness properties that favor successful colonization indistant organs and contribute to chemoresistance. Platelet adhesion and activation are required for cancer cellcolonization at the distal sites. We found that silencing Hsp47 in metastatic breast cancer cells significantlyreduced platelet adhesion. These results suggest that Hsp47 promotes TNBC metastasis/relapse by inducingEMT and platelet recruitment. In Aim 1 we will investigate the molecular mechanism by which Hsp47 regulatesEMT and stemness properties. In Aim 2 we will determine the cellular mechanism by which Hsp47 promotescolonization of breast cancer cells at the secondary organs. In Aim 3 we will define the roles of Hsp47 inpromoting cancer metastasis and chemoresistance in TNBC. This investigation will change the currentconcept of ECM microenvironment in cancer metastasis by revealing new roles of cancer cell-derived collagenin inducing cancer cell-platelet interaction and metastasis. Characterization of Hsp47 as a hub ofcollagen/DDR2 signaling will identify a novel pathway to inhibit TNBC progression and chemoresistance.

project_terms:
Adhesions;Adjuvant Therapy;Aftercare;Binding;Biology;Blood Circulation;Blood Platelets;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Epithelial Cells;Breast cancer metastasis;Cancer Relapse;Cell Survival;Cells;Chemoresistance;Clinical;Coculture Techniques;Collagen;Collagen Receptors;Deposition;Development;Disseminated Malignant Neoplasm;Distal;Distant;Early Diagnosis;Epithelial;Event;Extracellular Matrix;Extracellular Matrix Proteins;Extravasation;Gene Silencing;Genetic Transcription;Growth;Human;Incidence;Investigation;Knowledge;Lung;Mesenchymal;Metastatic breast cancer;Microfluidics;Migration Assay;Modeling;Molecular;Molecular Chaperones;Mus;Neoplasm Metastasis;Oncogenes;Organ;Pathologist;Pathway interactions;Phenotype;Platelet Activation;Positioning Attribute;Production;Prognosis;Prognostic Marker;Property;Proteins;Proteomics;Regulation;Relapse;Research;Role;Signal Transduction;Site;Stromal Cells;System;Techniques;Testing;Tissue Microarray;Tumor Tissue;Up-Regulation;Xenograft Model;base;breast cancer progression;cancer cell;carcinogenesis;chemotherapeutic agent;chemotherapy;discoidin domain receptor 2;experimental study;imaging system;in vivo;loss of function;lung colonization;malignant breast neoplasm;multidisciplinary;nano;novel;protein expression;recruit;self-renewal;stemness;therapeutic target;three dimensional cell culture;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;tumor progression

public_health_relevance:
Defining roles of Hsp47 and collagen signaling in regulating platelet recruitment and cell plasticity will fill criticalgaps in our knowledge of the tumor microenvironment and cancer metastasis. The study of Hsp47 in regulatingDDR2 will identify a novel pathway regulating oncogene DDR2 and may characterize a potential strategy tosensitize TNBC to chemotherapy.


application_id: 10114544
project_number: 1R15GM140427-01
project_title: Identifying and characterizing translation of circular RNAs using high-throughput sequencing data
administering_ic: NIGMS
award_notice_date: 2021-09-17
opportunity_number: PAR-18-714
application_type: 1
activity_code: R15
ic: GM
serial_number: 140427
program_official: YUAN, JEAN
project_start_date: 2021-09-21
project_end_date: 2023-07-31
study_section: Molecular Genetics A Study Section[MGA]
contact_pi_person_id: 14867184
contact_pi: PARK, JUW WON
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 MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Title: Identifying and characterizing translation of circular RNAs using high-throughput sequencing dataProject DescriptionThe purpose of this research is to improve our understanding of a recently discovered circular form of RNA (circularRNA or circRNA) using high-throughput sequencing data to identify and characterize the translation of these structuresover a variety of contexts. Over the past two decades studies have discovered a special form of alternative splicing (AS)that produces a circular form of RNA. This stands in contrast to normal AS which produces a linear form of RNA.Although these circRNAs have garnered considerable attention in the scientific community for their biogenesis andfunctions the focus of these studies has been on the regulatory role of circRNAs with the assumption that circRNAs arenon-coding. As non-coding RNAs they may regulate mRNA transcription tumor initiation and translation by spongingmiRs and RNA-binding proteins (RBPs). In addition to these regulatory roles of circRNAs however recent studies haveprovided strong evidence for their translation. The translation of circRNAs is expected to have an important role inpromoting cancer cell growth and activating molecular pathways related to cancer development. In some cases includingour preliminary bioinformatics studies translation of circRNAs is shown to be efficiently driven by an internal ribosomalentry site (IRES). The development of a computational tool for identifying and characterizing translation of circRNAsusing high-throughput sequencing and IRES will increase identifiable proteins translated from circRNAs. In turn it willhave a substantial impact on helping researchers understand the functional role of proteins derived from circRNAs. One ofthe major application of RNA sequencing (RNA-seq) a powerful technology for analysis of eukaryotic transcriptomescoupled with ribosome profiling (Ribo-seq) is to find evidence for the translation of novel (or unannotated) mRNAtranscripts. Since circRNAs are novel transcripts RNA-seq provides a perfect platform for genome-wide detection ofcircRNAs while Ribo-seq provide evidence for the translation of circRNAs. Our own preliminary result from rat brainRNA-seq and rat liver Ribo-seq data has identified 3 circRNAs with evidence of translation. Guided by these data thecurrent proposal will (Aim 1) develop a novel computational method for identifying and characterizing translationof circRNAs by coupling RNA-seq and Ribo-seq data and (Aim 2) develop a new web resource for aggregatingcataloging and visualizing translational information of circRNAs derived from publicly available RNA-seq andRibo-seq datasets. This proposal will accomplish the objectives of the R15 AREA grant in: (i) supporting meritoriousresearch; (ii) strengthening the research environment of non-research intensive institutions; and (iii) engagingundergraduate/graduate students in bioinformatics research. The proposed work would act as a foundation for theapplicant to establish a program of research aimed at facilitating translated circRNA studies using high-throughputsequencing data. In turn this would provide researchers with critical information regarding translated circRNAs inexisting high-throughput sequencing datasets. Finally the proposed research will be used as a vehicle to engageundergraduates in multi-disciplinary bioinformatics research and better enable students from Kentucky a traditionallyunderrepresented state in bioinformatics to successfully participate in advanced biomedical research.

project_terms:
Alternative Splicing;Area;Attention;Binding;Binding Sites;Biogenesis;Bioinformatics;Biomedical Research;Brain;Cancer Cell Growth;Cataloging;Collection;Communities;Complex;Computing Methodologies;Coupled;Coupling;Data;Data Set;Databases;Deposition;Detection;Development;Disease;Drops;Environment;Faculty;Foundations;Future;Gene Expression;Genetic Transcription;Genetic Translation;Genomics;Goals;Grant;High-Throughput Nucleotide Sequencing;Human;Institution;Internal Ribosome Entry Site;Kentucky;Liver;Malignant Neoplasms;Messenger RNA;MicroRNAs;Molecular;Pathway interactions;Porifera;Proteins;Publishing;RNA;RNA Sequences;RNA-Binding Proteins;Rattus;Research;Research Personnel;Resources;Ribosomes;Role;Scientist;Structure;Students;Technology;Tissues;Transcript;Translating;Translations;Universities;Untranslated RNA;Work;ZIKV infection;Zika Virus;circular RNA;college;computerized tools;cost;cost effective;experience;genome-wide;graduate student;improved;multidisciplinary;nerve stem cell;next generation sequencing;novel;online resource;programs;ribosome profiling;tool;transcriptome;transcriptome sequencing;tumor initiation;undergraduate student;user-friendly;web portal

public_health_relevance:
Over the past two decades studies have discovered a special form of mechanism that produces a circularform of RNA (circRNA). The purpose of this research is to identify and characterize translated circRNAsusing next generation sequencing technology. This research will provide researchers with criticalinformation regarding the translated circRNAs in existing sequencing datasets in addition to enhancingresearch experiences in multi-disciplinary bioinformatics research among college undergraduates inUniversity of Louisville.


application_id: 10112952
project_number: 5P20GM130456-02
administering_ic: NIGMS
award_notice_date: 2021-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9
subproject_number: 8072
contact_pi_person_id: 10451500
contact_pi: VENDITTO, VINCENT JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-02-01
project_title:
Understanding the role of anti-apolipoprotein A-I antibodies in atherosclerotic cardiovascular disease

project_abstract:
PROJECT SUMMARY / ABSTRACT  PROJECT 4The identification of autoantigens in atherosclerotic plaques has prompted investigation of the antibody-mediatedpathogenesis of cardiovascular disease (CVD). Detailed characterization of the antigen epitope specificityantibody subclass and receptor engagement will enhance the understanding of CVD and guide therapeuticdevelopment. One target of IgG antibody induction in patients is apolipoprotein A-I (ApoA-I) the major protein ofhigh density lipoprotein (HDL). Although anti-ApoA-I antibodies have been identified in mice and human subjectsthe role of these antibodies have not been elucidated. Furthermore the immunologic impact of antibodies boundto ApoA-I in an immune complex (ApoA-I/IgG ICs) is unclear. The long-term goal is to develop novel peptideand antibody therapeutics based on mechanistic insight from mice to reduce the burden of CVD in patients. Toachieve this goal the overall objectives of this proposal build from our observations in human subjects tocharacterize the molecular components of the anti-ApoA-I antibody response in mice and correlate theircharacteristics with cellular interactions functional outcomes and atherosclerosis progression. The hypothesisis that anti-ApoA-I antibodies exhibit both pro- and anti-inflammatory effects depending on the antibodycharacteristics (i.e. subclass epitope specificity Fc receptor interaction) leading to exacerbation or suppressionof atherosclerosis. The rationale for this proposed research is that understanding one component of the immuneresponse associated with CVD will promote improved patient outcomes through novel therapeutic strategies.Encouraged by strong preliminary data this hypothesis will be tested through two specific aims: 1) Elucidatethe molecular components and functional implications of antibodies targeting peptide epitopes derived fromApoA-I; and 2) Determine if ApoA-I/IgG ICs mediate an anti-inflammatory phenotype by engaging with theinhibitory Fc receptor using in vitro assays and in vivo studies in atherosusceptible mouse models. In the firstaim a structure immunogenicity relationship will be generated by correlating in silico modeling biophysicalcharacterization and immunogenicity studies of known peptide epitopes derived from ApoA-I. These data will becorrelated with antibody profiles and subclass composition of the antibody response toward ApoA-I. In thesecond aim the mechanistic impact of anti-ApoA-I antibodies will be determined by characterizing cellpolarization in the presence of specific anti-ApoA-I profiles and inducing antibody profiles in atherosusceptiblemice lacking Fc receptors. The innovation and significance of the proposed work is driven by the novelimmunomodulation strategies that will improve our understanding of antibody-mediated immune responseswhich will guide continued efforts to develop novel immunotherapies through coordination with the CPRI COBREto decrease the burden of CVD in patients.

project_terms:
Address;Anti-Inflammatory Agents;Antibodies;Antibody Response;Antibody Therapy;Antigen-Antibody Complex;Antigens;Antiinflammatory Effect;Apolipoprotein A-I;Arterial Fatty Streak;Atherosclerosis;Autoantibodies;Autoantigens;Biology;Blood Circulation;Cardiovascular Diseases;Cells;Centers of Research Excellence;Cessation of life;Characteristics;Chemicals;Consumption;Coronary Arteriosclerosis;Coupled;Data;Development;Disease Progression;Epitopes;Evaluation;Exhibits;Fc Receptor;Female;Foundations;Goals;Health;High Density Lipoproteins;Human;IgG1;IgG4;Immune;Immune response;Immunization;Immunoglobulin G;Immunologics;Immunotherapy;Investigation;Kentucky;Laboratories;Link;Mass Spectrum Analysis;Mediating;Mission;Modeling;Molecular;Mus;Myocardial Infarction;Outcome;Pathogenesis;Patient-Focused Outcomes;Patients;Peptide antibodies;Peptides;Pharmacologic Substance;Phenotype;Prevention;Procedures;Proteins;Reporting;Research;Role;Specificity;Structure;TLR4 gene;Testing;Universities;Work;athero susceptible;base;biophysical properties;cancer immunotherapy;cardiovascular disorder risk;functional outcomes;human subject;immunogenic;immunogenicity;immunomodulatory therapies;immunoregulation;improved;in silico;in vitro Assay;in vivo;innovation;insight;macrophage;male;mouse model;novel;novel therapeutic intervention;polarized cell;receptor;success;therapeutic development;treatment strategy;western diet


application_id: 10112950
project_number: 5P20GM130456-02
project_title: Chemical biology of type IV secretion systems
administering_ic: NIGMS
award_notice_date: 2021-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9
subproject_number: 8071
contact_pi_person_id: 11309989
contact_pi: SHAFFER, CARRIE
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 SUMMARYBacteria have evolved specialized nanomachines to deliver microbial cargo across the cell envelope. Oneversatile translocation apparatus the type IV secretion system (T4SS) can be strategically deployed to injectmacromolecular substrates into target bacterial or eukaryotic recipient cells. Despite their importance in bacterialpathogenesis and dissemination of antibiotic resistance determinants the mechanisms by which the T4SSassembles and transports payload remain largely undefined. To address this knowledge gap the long-term goalof this proposal is to develop and apply robust molecular tools to accelerate fundamental studies of T4SSnanomachines. The cag T4SS of the gastric bacterium Helicobacter pylori has emerged as an important systemfor understanding how a single molecular machine can transport diverse cargo into target cells. Whereas someT4SS have the capacity to secrete hundreds of proteins or DNA-protein complexes into the host cell the abilityto translocate a diverse repertoire of lipid nucleic acid protein and polysaccharide substrates distinguishes thecag T4SS from other systems. Notably the bacterial oncoprotein CagA is rapidly delivered to host gastric cellsvia cag T4SS mechanisms. Translocated H. pylori effector molecules activate innate defenses and dysregulatesignaling pathways that influence progression of gastric disease; consequently colonization by cag T4SS-positive H. pylori significantly augments the risk for gastric cancer. As a result of its central role in bacterialpathogenesis the T4SS represents an ideal target for antimicrobials. In this application we propose to identifyand mechanistically characterize novel small molecule-based T4SS modulators. Iterative structure-activityrelationship studies will be used to develop chemical scaffolds and pharmacophores with optimized anti-virulencepotential. Probe development will take advantage of expertise and assay platforms in the Shaffer lab and willleverage synergistic resources in the proposed CPRI Computational Core (ligand-binding model developmentrational design virtual screening) CPRI Translational Core (high throughput assay support novel compoundrepositories and ADMET profiling) and the Organic Synthesis Core (medicinal chemistry and scale-up).Prioritized and validated chemical probes will be used in conjunction with biochemical and genetic approachesto interrogate cag T4SS regulation and dynamic steps in substrate translocation. Using a similar multidisciplinaryapproach we will determine how the H. pylori cag T4SS apparatus assembles at the bacteria-host cell interface.Collectively these studies will stimulate new basic research directions and will provide important insight into howthe T4SS nanomachine orchestrates the delivery of specific molecular cargo to target cells to drive microbialpathogenesis. Furthermore this work will generate powerful chemical tools that are broadly applicable toinfectious disease research and will identify potent lead compounds with the potential to disarm T4SS functionin a variety of medically-relevant pathogens.

project_terms:
2-hydroxypyridine;Address;Antibiotic Resistance;Bacteria;Bacterial DNA;Bacterial Genome;Basic Science;Biochemical;Biochemical Genetics;Biogenesis;Biological;Biological Assay;Biology;C10;Cells;Cellular biology;Centers of Research Excellence;Chemicals;Clinical;Collaborations;Complement;Complex;DNA;Destinations;Development;Discipline;Engineering;Epithelial Cells;Escherichia coli;Eukaryotic Cell;Exhibits;Faculty;Fostering;Foundations;Genetic;Goals;Helicobacter pylori;Impairment;Infection;Infectious Diseases Research;Knowledge;Lead;Libraries;Ligand Binding;Lipids;Lipopolysaccharide Biosynthesis Pathway;Mechanics;Mediating;Medical;Microscopy;Molecular;Molecular Machines;Molecular Probes;Nucleic Acids;Nucleoproteins;Oncoproteins;Organic Synthesis;Outcome;Pathogenesis;Pathogenicity Island;Peptidoglycan;Pharmaceutical Chemistry;Pharmacologic Substance;Phenotype;Pilum;Plant Model;Play;Polysaccharides;Prokaryotic Cells;Proteins;Regulation;Research;Research Design;Resolution;Resources;Rhizobium radiobacter;Risk;Role;Series;Signal Pathway;Stomach;Stomach Diseases;Structure;Structure-Activity Relationship;System;Systems Biology;Therapeutic;Toxin;Type IV Secretion System Pathway;Validation;Virulence;Work;antimicrobial;appendage;base;carcinogenicity;cell envelope;design;extracellular;genetic approach;high throughput screening;inhibitor/antagonist;innovation;insight;interdisciplinary approach;invention;malignant stomach neoplasm;microbial;microbiome;model development;mutant;nanomachine;novel;pathogen;pathogenic bacteria;pharmacophore;protein complex;repository;response;scaffold;scale up;screening;small molecule;system architecture;tool;tumorigenic;virtual screening


application_id: 10112948
project_number: 5P20GM130456-02
project_title: Quantitative mechanical phenotyping of bacterial biofilms on implant surfaces
administering_ic: NIGMS
award_notice_date: 2021-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9
subproject_number: 8070
contact_pi_person_id: 14741591
contact_pi: GRADY, MARTHA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT  PROJECT 2Bacteria accumulation on medical devices puts a patient at serious risk for infection and could be life threatening.Eradication of established biofilm-forming infections remains difficult in part because the accumulated bacteriaare physiologically and metabolically distinct from the planktonic cells (floating single cells) of the same organism.Despite intense efforts in the field biofilm level response to treatments and changes in environment has beenhindered by the lack of robust quantitative and accurate biofilm characterization techniques that can be directlycorrelated to medical device surfaces. Furthermore antibiotic penetration in implant-associated biofilms istypically limited due to the dense and complex matrix of biofilms. The overall goal of this project is to developcomplementary techniques that yield quantitative information on biofilm adhesion and deformability. Our workinghypothesis is that changes in these two mechanical properties i.e. adhesion and deformability of biofilms is adirect marker of disease progression. The development of tools that can quantitatively characterize themechanical properties of biofilms and corresponding material surfaces that control bacterial adhesionpossiblyin a species-specific mannerwill have a significant impact on medical device compatibility. Aided by access tothe CPRI Translational and Computational Cores the proposed research will first develop a film adhesionmeasurement technique for evaluation of biofilms to determine the association between biofilm antibioticresistance and adhesion strength (AIM 1). Parallel to exploration of the role of biofilm adhesion we will leverageour unique characterization suite that includes a rare confocal-atomic force microscopy platform to evaluate therelationship between biofilm deformability and antibiotic resistance (AIM 2). Lastly we will evaluate nanoparticlemobility assays as a measure of biofilm confinement and develop computational models regarding drug carrierdiffusion (AIM 3). Our expectation is that the results and tools developed here will guide us and others to logicallydesign medical devices with a decreased propensity for the genesis of therapeutic-resistant biofilm infections.

project_terms:
3-Dimensional;Adhesions;Adhesives;Amputation;Anti-Bacterial Agents;Antibiotic Resistance;Antibiotic Therapy;Antibiotics;Arthrodesis;Atomic Force Microscopy;Bacteria;Bacterial Adhesion;Biological Assay;Biology;Cells;Centers of Research Excellence;Cessation of life;Chemicals;Chemistry;Complex;Computer Models;Cues;Data;Development;Devices;Diffuse;Diffusion;Disease;Disease Marker;Disease Progression;Drug Carriers;Endocarditis;Enterococcus faecalis;Environment;Evaluation;Failure;Film;Goals;Image;Implant;Infection;Inflammation;Label;Lasers;Lead;Life;Literature;Malignant Neoplasms;Mammalian Cell;Measurement;Measures;Mechanics;Medical Device;Medical Device Designs;Medical Device Safety;Metabolic;Methods;Microbial Biofilms;Modeling;Nosocomial Infections;Organism;Outcome;Patients;Penetration;Pharmacologic Substance;Phenotype;Physiological;Polymers;Property;Quantum Dots;Research;Resistance;Role;Spectrum Analysis;Structure;Surface;System;Teacher Professional Development;Techniques;Therapeutic;Thinness;biomaterial compatibility;expectation;extracellular;implant associated infection;implantable device;improved;indexing;infection risk;innovation;interdisciplinary collaboration;mechanical properties;microorganism interaction;nanoparticle;novel;particle;screening;stem;tool;tool development;treatment response;veterinary science


application_id: 10112947
project_number: 5P20GM130456-02
administering_ic: NIGMS
award_notice_date: 2021-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2021-08-31
study_section: ZGM1-RCB-9
subproject_number: 8069
contact_pi_person_id: 11956743
contact_pi: AWUAH, SAMUEL GORMAN
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: 2021-02-01
project_title:
Gold-based pharmacophore synthetic strategies as a basis for transcription factor modulator discovery

project_abstract:
PROJECT SUMMARY/ABSTRACT  PROJECT 1 Transcription factor (TF) deregulation underlies numerous diseases including cancer; however the selective targeting of TFs with small molecule probes/leads remains elusive. Our research program seeks to exploit the unique spatial properties and chemical reactivity of gold-based [Au(I) and Au(III)] complexes as a basis for TF probe/lead modulator discovery. Specifically we seek to develop novel and efficient reaction methods to rapidly construct diverse Au-based pharmacophore libraries and to leverage these unique compound sets and a streamlined screening strategy to discover selective modulators of the model oncogenic transcription factor c- MYC. This study will develop a generalizable platform to target undruggable targets such as protein-protein interfaces or TFs using caged gold centers via two ways: i) directly ligate gold to specific amino acids or ii) covalently modify specific amino acids by transfer of coordinated ligands via reductive elimination in a manner similar to chemistry performed by transition metal-based catalysts. The studies will extend the breadth of stable gold ligands through optimization of Au catalytic processes advance our understanding of the tunable reactivity and bioorthogonality of Au-based pharmacophores and potentially set the stage for a generalized strategy to target undruggable proteins. A primary innovation of the proposed studies is the potential to dramatically alter via covalent modification protein surface structure/electronics and thereby influence function.  CPRI mentorship and research support cores will further facilitate this project in a number of key ways. Specifically the Computational Core will assist in the development of new predictive structure-activity relationship (SAR) models for Au-based probes and computational c-MYC/MAX-ligand structural models to guide probe design; the Translational Core will facilitate assay development validation and implementation (and eventually first in animal assessments including PK and ADMET); and the COBRE for Molecular Medicines Organic Synthesis Core will strategically support ligand synthesis/scale-up. This will also be augmented by a COBRE mentorship team with extensive expertise in transcription factor lead discovery cancer biology and pharmaceutical science.

project_terms:
3-Dimensional;Affinity;Amino Acids;Animals;Area;Auranofin;Binding;Binding Sites;Biochemical;Biological Process;Cancer Biology;Cells;Centers of Research Excellence;Chemicals;Chemistry;Complex;Computer Models;Cysteine;DNA Binding;Data;Development;Disease;E-Box Elements;Electronics;Evaluation;Exhibits;FDA approved;Gene Expression Regulation;Genetic Transcription;Glutathione;Goals;Gold;Heterodimerization;Histidine;Individual;Laboratories;Lead;Libraries;Ligands;Lysine;Malignant Neoplasms;Medical;Membrane Proteins;Mentorship;Methods;Modeling;Modification;Molecular;Molecular Medicine;Natural Products;Nature;Nitrogen;Nucleic Acids;Oncogenic;Organic Synthesis;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Post-Translational Protein Processing;Process;Property;Proteins;Reaction;Regulation;Research;Research Support;Rheumatoid Arthritis;Safety;Science;Selenocysteine;Side;Site;Structural Models;Structure;Structure-Activity Relationship;Surface;System;Testing;Transition Elements;Validation;assay development;base;c-myc Genes;catalyst;cellular targeting;cytotoxicity;design;functional group;improved;inhibitor/antagonist;innovation;interest;metal complex;novel;pharmacophore;programs;protein phosphatase inhibitor-2;protein protein interaction;scale up;screening;small molecule;success;therapeutic target;time use;transcription factor


application_id: 10112943
project_number: 5P20GM130456-02
project_title: Computational Core
administering_ic: NIGMS
award_notice_date: 2021-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9
subproject_number: 8068
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Artificial Intelligence;Basic Science;Biology;Biomedical Research;Centers of Research Excellence;Chemicals;Clinical;Clinical Research;Complement;Complex;Computer Hardware;Computer software;Computing Methodologies;Consultations;DNA;Data Analyses;Development;Devices;Diffusion;Disease;Doctor of Philosophy;Excretory function;Faculty;Gap Junctions;Goals;Gold;Health;Individual;Infrastructure;Kentucky;Lead;Leadership;Ligands;Macromolecular Complexes;Mentors;Mentorship;Metabolism;Methods;Modeling;Molecular;Molecular Medicine;Organic Synthesis;Pharmacologic Substance;Pilot Projects;Process;Proteins;Protocols documentation;Research;Research Design;Research Personnel;Research Support;Resources;Science;Scientist;Services;Structure;Techniques;Toxic effect;Training;Translational Research;Universities;Validation;absorption;base;career development;clinical application;design;experimental study;faculty research;innovation;intermolecular interaction;models and simulation;molecular dynamics;molecular modeling;multidisciplinary;nanoparticle;particle;pre-clinical;prevent;primary outcome;protein complex;simulation;stem;synergism;tool;virtual screening


application_id: 10112942
project_number: 5P20GM130456-02
project_title: Translational Core
administering_ic: NIGMS
award_notice_date: 2021-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9
subproject_number: 8067
contact_pi_person_id: 8227789
contact_pi: LEGGAS, MARKOS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adhesions;Animals;Basic Science;Biological Assay;Biology;Biomedical Research;Centers of Research Excellence;Chemicals;Clinical;Clinical Research;Collection;Complement;Consultations;Data Analyses;Development;Devices;Disease;Doctor of Philosophy;Drug Kinetics;Excretory function;Faculty;Gap Junctions;Goals;Health;In Vitro;Infrastructure;Kentucky;Lead;Leadership;Libraries;Mentors;Mentorship;Metabolism;Methods;Microbial Biofilms;Modeling;Molecular Medicine;Natural Products;Organic Synthesis;Pharmacologic Substance;Pilot Projects;Reporter;Research;Research Design;Research Personnel;Research Support;Resources;Science;Scientist;Services;Toxic effect;Translational Research;Type IV Secretion System Pathway;Universities;Validation;absorption;antimicrobial;base;career development;clinical application;cytotoxicity;design;experimental study;faculty research;immunoregulation;innovation;instrumentation;multidisciplinary;pre-clinical;prevent;primary outcome;screening;screening services;stem;synergism;tool;transcription factor


application_id: 10112939
project_number: 5P20GM130456-02
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2021-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9
subproject_number: 8066
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT  ADMINISTRATIVE COREWe propose to establish a Center of Biomedical Research Excellence (COBRE) in Pharmaceutical Researchand Innovation at the University of Kentucky (UK). CPRI will serve as a comprehensive multidisciplinary centerfocused on translational chemical biology [the nexus of chemical biology (the application of chemical biologyprinciples to develop validated probe/models to advance our understanding of biology) and pharmaceuticalscience (the application of pharmaceutical principles to advance leads/materials/devices that address unmetclinical needs)]. The COBRE will leverage and develop unique translational chemical biology research supportinfrastructure/expertise to facilitate junior faculty mentorship and career development innovative biomedicalresearch probe/tool/model/materials development and validation and the early advancement of potentialtranslatable assets. Within this context the CPRI Administrative Core will support center communicationcoordination oversight and integration of all COBRE operations activities projects pilots and research supportcores. The Core will provide fiscal management and resource oversight overall coordination of mentoring andcareer development activities resource allocation and program evaluation to ensure program effectiveness.The Administrative Core will also facilitate interactions with related UK programs and centers to foster synergyand coordination of resources. The Core will facilitate the Centers engagement of junior faculty researchersand mentors from UK Colleges (Agriculture Food & Environment; Arts and Sciences; Engineering; Medicine;Pharmacy and others) to create a vibrant center that seamlessly integrates resources personnel and knowledgeacross disciplinary boundaries and fosters scientific innovation and career development.

project_terms:
Address;Agriculture;Arts;Biological;Biology;Biomedical Research;Cancer Center;Cardiovascular Diseases;Career Mobility;Centers of Research Excellence;Chemicals;Clinical;Clinical Sciences;Communication;Decision Making;Development;Development Plans;Devices;Discipline;Disease;Education;Engineering;Ensure;Evaluation;Faculty;Fostering;Gap Junctions;Goals;Health;Human Resources;Infrastructure;Kentucky;Knowledge;Leadership;Medicine;Mentors;Mentorship;Modeling;Molecular Medicine;Obesity;Oral;Outcome;Pharmacologic Substance;Pharmacy facility;Process;Program Effectiveness;Program Evaluation;Research;Research Personnel;Research Priority;Research Support;Resource Allocation;Resource Sharing;Resources;Science;Structure;Systemic disease;Translational Research;Translations;Universities;Validation;base;career;career development;clinical application;clinical center;college;faculty research;food environment;improved;innovation;interdisciplinary collaboration;multidisciplinary;operation;outreach;prevent;primary outcome;programs;stem;success;supportive environment;synergism;tool;tumor metabolism


application_id: 10112923
project_number: 5P20GM130456-02
project_title: Center of Biomedical Research Excellence in Pharmaceutical Research and Innovation
administering_ic: NIGMS
award_notice_date: 2021-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
program_official: FRINCU, CRINA
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9(C1)
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Area;Biology;Biomedical Research;Cardiovascular Diseases;Centers of Research Excellence;Chemicals;Clinical;Collaborations;Communicable Diseases;Communication;Core Facility;Development;Devices;Discipline;Disease;Education;Environment;Faculty;Fostering;Funding;Gap Junctions;Goals;Health;Infrastructure;Kentucky;Malignant Neoplasms;Mentors;Mentorship;Modeling;Molecular Medicine;Organic Synthesis;Outcome;Pharmacologic Substance;Pharmacy facility;Phase;Pilot Projects;Research;Research Personnel;Research Project Grants;Research Support;Science;Scientist;Testing;Therapeutic;Translational Research;Translations;Universities;Validation;career development;clinical application;college;experience;faculty research;innovation;interdisciplinary collaboration;interest;multidisciplinary;pre-clinical;pre-clinical research;prevent;tool


application_id: 10112795
project_number: 5R01AG064234-02
project_title: Regulation of Microglial Activation State by a Lipid Transporter
administering_ic: NIA
award_notice_date: 2021-01-28
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AG
serial_number: 064234
program_official: OPANASHUK, LISA A
project_start_date: 2020-03-01
project_end_date: 2024-12-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 2275110
contact_pi: BIEBERICH, ERHARD
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
ATP binding cassette transporter 1;Affect;Agonist;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease patient;Amyloid beta-Protein;Anti-Inflammatory Agents;Astrocytes;Autopsy;Brain;Ceramides;Chronic;Clinical;Clinical Data;Complex;Conflict (Psychology);Data;Disease;Drug Kinetics;Exposure to;Extracellular Space;Goals;Homologous Gene;Immune;Impaired cognition;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Inorganic Phosphate Transporter;Investigation;Knockout Mice;Lipids;MAPT gene;Mediating;Microglia;Mus;NF-kappa B;Nerve Degeneration;Neuraxis;Neurodegenerative Disorders;Neurofibrillary Tangles;Neuroglia;Onset of illness;Pathogenesis;Pathology;Pathway interactions;Peptides;Phagocytosis;Phenotype;Play;Procedures;Process;Proteins;Public Health;Regulation;Reporting;Research;Role;Senile Plaques;Signal Pathway;Signal Transduction;Sphingosine-1-Phosphate Receptor;Stimulus;Testing;Therapeutic;amyloid pathology;astrogliosis;cell type;cognitive function;extracellular;genome wide association study;improved;mouse model;neuroinflammation;novel;novel therapeutic intervention;p38 Mitogen Activated Protein Kinase;pre-clinical;response;sphingosine 1-phosphate;sphingosine kinase;tau Proteins


application_id: 10112254
project_number: 5P20GM125504-04
project_title: Modulation of respiratory melioidosis inflammation
administering_ic: NIGMS
award_notice_date: 2021-02-11
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2023-02-28
study_section: ZGM1-RCB-3
subproject_number: 8246
contact_pi_person_id: 10426217
contact_pi: WARAWA, JONATHAN MARK
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:
Burkholderia pseudomallei (Bp) is an antibiotic resistant Select Agent bacterial pathogen and the causativeagent of the disease melioidosis with endemicity in tropical regions worldwide. Bp is infectious by several routesof entry into a host with inhalation representing an important route of entry and furthermore Bp exhibit a stronglung tropism regardless of the route of entry. Respiratory melioidosis is an acute inflammatory disease of thelung which progresses into a fatal systemic disease involving all major organs. Bp is a facultative intracellularpathogen which employs the Type 3 Secretion System cluster 3 (T3SS3) to mediate vacuolar escape of Bp fromphagocytes allowing for subsequent outgrowth of the bacteria in the host cytoplasm. Importantly the specifichost cells which support the intracellular lifestyle of Bp have not been well characterized.A critical gap in our understanding of Bp pathogenesis is the identification of which host cell types facilitate areplicative niche for Bp. Identification of these host environments will further provide key insights into which hostcells mount an inflammatory response against Bp. It is furthermore poorly understood as to whether the cytokinestorm mounted as a response to respiratory melioidosis contributes to morbidity as recent evidence suggeststhat excessive neutrophil recruitment is associated with reduced host survival. This suggests thatimmunomodulation of the innate immune response may represent an excellent method of providing noveltherapeutics for a disease which has no licensed vaccine and minimal treatment options due to inherentgenome-encoded antibiotic resistance. We provide preliminary data which demonstrate the therapeutic efficacyof inhaled slow-release IL-12 particles to provide full protection against a lethal Bp respiratory challengeOur central hypothesis is that the host innate immune response to lethal respiratory melioidosis is driven by apoorly-controlled intracellular bacterial proliferation where immunomodulation represents an effective method ofcombating disease. In Specific Aim 1 we will identify the replicative niche of Bp in the lung. We hypothesize thatspread of Bp to secondary phagocytes is the leading cause of sepsis/death associated with respiratorymelioidosis. In Specific Aim 2 we will determine the contribution of host innate immune cells to inflammation. Wehypothesize that the late-arriving myeloid component causes lethality via the inflammatory mediators theyproduce. In Specific Aim 3 we will determine the mechanism of microparticulate IL-12 therapeutic efficacy ofrespiratory melioidosis.Modification of the state of inflammation of respiratory melioidosis may provide effective control of disease byeither encouraging early clearance of pathogen through promoting early inflammation or by improving outcomethrough modulating late inflammation.

project_terms:
Acute;Antibiotic Resistance;Bacteria;Burkholderia pseudomallei;Cells;Cessation of life;Cytoplasm;Data;Disease;Environment;Exhibits;Genome;Immune;Inflammation;Inflammation Mediators;Inflammatory Response;Inhalation;Innate Immune Response;Interleukin-12;Life Style;Lung;Mediating;Melioidosis;Methods;Modification;Morbidity - disease rate;Myelogenous;Neutrophil Infiltration;Organ;Pathogenesis;Pathogenicity;Phagocytes;Route;Secondary to;Sepsis;Systemic disease;Treatment Efficacy;Tropism;Type III Secretion System Pathway;Vaccines;cell type;cytokine release syndrome;disorder control;immunoregulation;improved outcome;inflammatory lung disease;insight;microbiome research;novel therapeutics;particle;pathogen;pathogenic bacteria;respiratory;response


application_id: 10112253
project_number: 5P20GM125504-04
project_title: Pathogenesis of Yersinia pestis infection during intracellular infection
administering_ic: NIGMS
award_notice_date: 2021-02-11
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2023-02-28
study_section: ZGM1-RCB-3
subproject_number: 8245
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT: Yersinia pestis is a facultative intracellular pathogen that causes the human disease known as plague. Growingevidence indicates that intracellular growth in macrophages is important for Y. pestis virulence. Uponphagocytosis Y. pestis alters the maturation of the phagosome to generate a protective compartment within thecell known as the Yersinia containing vacuole (YCV). Key steps in the generation of the YCV include inhibitionof YCV acidification expansion into a spacious vacuole and acquisition of the autophagic markers. Howeverthe mechanisms used by the bacterium to subvert the normal phagosome maturation process and generate theYCV have not been defined. Our long term goals are to elucidate the mechanisms by which Y. pestis evadesmacrophage killing and define the contribution of intracellular survival to Y. pestis virulence. Recently wediscovered that Y. pestis manipulates the host endocytic recycling pathway to survive in macrophages.Moreover we have demonstrated that Y. pestis recruits Rab1 Rab4 and Rab11 to the YCV. Importantly wealso discovered that Y. pestis manipulation of Rab11b disrupts global endocytic recycling in the macrophage.Together these data suggest the hypothesis that Y. pestis specifically targets and recruits Rab11 to the YCV toavoid phagolysosome maturation and generate a replicative niche within macrophages. Furthermore wehypothesize that disruption of cellular trafficking during the YCV biogenesis process also disrupts TLR-4trafficking and immune signaling during intracellular infection. Here we propose to expand on these initial findingsto further define how Y. pestis manipulates Rab11 and the host recycling machinery to generate the YCV.Specifically we will answer two key questions. First how does Y. pestis recruit Rab11 to the YCV (Aim 1)?Second how does Rab11 recruitment impact the remodeling of the YCV (Aim 2)? Specifically what othercomponents of the recycling pathway does Rab11 recruit to the YCV and do these components directly contributeto YCV biogenesis and intracellular survival? Furthermore as TLR-4 recruitment to the phagosome is dependenton Rab11 how does YCV biogenesis and Rab11 manipulation by Y. pestis impact TRL-4 trafficking andinflammatory signaling? Answering these questions will fill a critical gap in our understanding of how Y. pestis isable to subvert normal phagosome maturation and survive within this intracellular niche. Furthermore throughunderstanding how Y. pestis manipulates the host recycling and inflammatory pathways we can gain novelinsight into the interactions between these pathways in the context of normal cell biology.

project_terms:
Bacteria;Biogenesis;Bubonic Plague;Cells;Cellular biology;Data;Development;Fleas;Generations;Goals;Growth;Immune signaling;Infection;Inflammation;Inflammatory;Inflammatory Response;Innate Immune Response;Integration Host Factors;Link;Mediating;Molecular;Normal Cell;Pathogenesis;Pathogenicity;Pathway interactions;Phagocytosis;Phagolysosome;Phagosomes;Pharmacology;Plague;Process;Proteins;RNA interference screen;Recycling;Research Personnel;Signal Transduction;Testing;Type III Secretion System Pathway;Vacuole;Virulence;Yersinia;Yersinia pestis;base;defined contribution;human disease;insight;macrophage;microbiome research;novel;overexpression;pathogen;recruit;response;trafficking;transmission process


application_id: 10112252
project_number: 5P20GM125504-04
project_title: Novel synthetic analogue of microbial metabolite Urolithin A mitigates inflammatory bowel diseases
administering_ic: NIGMS
award_notice_date: 2021-02-11
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2023-02-28
study_section: ZGM1-RCB-3
subproject_number: 8243
contact_pi_person_id: 9246960
contact_pi: JALA, VENKATAKRISHNA RAO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract Inflammatory Bowel Diseases (IBDs) which include f ulcerative colitis and Crohns disease affect asmany as 1.4 million people in the USA. Chronic inflammation and microbial dysbiosis are major features of IBDs.Beneficial effects rendered by healthy dietary practices are not uniform among individuals and are attributed tovariations in gut microbiota and their active metabolites. To overcome the challenge of inter-individual differencesin gut microbiota their metabolites and poor bioavailability here we propose direct usage of microbialmetabolites to maintain gut immune homeostasis to mitigate IBDs. Urolithin A (UroA) is one of such beneficialmicrobial metabolite derived from ellagic acid and ellagitannins major polyphenolic components of berries andpomegranate. Based on UroA structure we developed novel potent structural analogue UAS03 which exhibitedincreased anti-inflammatory and gut barrier functional activities compared to parent UroA compound. Thecurrent proposal investigates the molecular and cellular mechanisms of UAS03 and its therapeutic efficacies inIBD pre-clinical models. Our preliminary results showed that the oral administration of UAS03 mitigated colitis in dextran sodiumsulphate (DSS)- or 246-Trinitrobenzenesulfonic acid (TNBS) induced murine colitis even at 10 fold lower dosecompared to UroA. UAS03 significantly inhibited lipopolysaccharide (LPS)-induced increase in inflammatorymediators in immune cells and epithelial cells with 10 fold higher efficacy than UroA. Further treatment withUAS03 reduced intestinal permeability by up-regulating junctional proteins through activation of nuclear factor(erythroid-derived 2)-like 2 (Nrf2)-hemoxygenase (HO1) pathways in epithelial cells. Based on these results wepropose two-pronged beneficial activities of UAS03 and UroA where these compounds protect the host fromexternal challenges by protecting gut barrier function and dampening inflammatory activities. In this proposal wewill test the hypothesis that treatment with UAS03 an effective analogue of a microbial metabolite protectsfrom IBD development by reducing barrier dysfunction and inflammation. In Aim 1 we will investigate howUSA03/UroA increase gut barrier function in a Nrf2-dependent manner by upregulating junctional proteins aswell as molecular events involved anti-inflammatory activities of UAS03. In Aim 2 therapeutic efficacies ofUAS03 and UroA will be examined in acute chronic and spontaneous IBD pre-clinical models. In Aim 3 wepropose to identify the bacteria responsible for UroA production and test their pro-biotic activities in colitis models.The successful completion of proposed studies will allow understanding of UAS03 and UroA mechanisms ofactions and establishes the basis for therapeutic usage in IBDs.

project_terms:
Acids;Acute;Affect;Anti-Inflammatory Agents;Bacteria;Benzopyrans;Berry;Biological;Biological Availability;Cells;Chemopreventive Agent;Chronic;Clinical;Colitis;Crohn's disease;Data;Development;Diet;Dietary Intervention;Dietary Practices;Disease;Disease model;Dose;Down-Regulation;Ellagi-Tannins;Ellagic Acid;Epithelial Attachment;Epithelial Cells;Erythroid;Event;Exhibits;Functional disorder;Glycols;Goals;Heme;Homeostasis;Human;Ileitis;Immune;In Vitro;Indigenous;Individual;Individual Differences;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Bowel Diseases;Interleukin-1;Interleukin-6;Intestinal permeability;Lipopolysaccharides;Measures;Mediating;Modeling;Molecular;Mus;Nuclear;Oral Administration;Oxygenases;Parents;Pathogenicity;Pathway interactions;Phenotype;Phytochemical;Pilot Projects;Pomegranate;Pre-Clinical Model;Probiotics;Production;Proteins;Risk;Role;Sampling;Sodium Dextran Sulfate;Structure;T-Lymphocyte;TNF gene;Testing;Therapeutic;Therapeutic Uses;Tight Junctions;Time;Treatment Efficacy;Trinitrobenzenesulfonic Acid;Ulcerative Colitis;Variant;Wild Type Mouse;analog;bacterial metabolism;base;chemokine;comparative efficacy;dysbiosis;efficacy evaluation;gastrointestinal epithelium;gut bacteria;gut microbiota;in vivo;in vivo Model;inter-individual variation;macrophage;microbial;microbiome research;microbiota metabolites;molecular targeted therapies;novel;preservation;protective effect


application_id: 10112250
project_number: 5P20GM125504-04
project_title: Functional Microbiomics Core-Bodduluri
administering_ic: NIGMS
award_notice_date: 2021-02-11
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2023-02-28
study_section: ZGM1-RCB-3
subproject_number: 8242
contact_pi_person_id: 6074575
contact_pi: BODDULURI, HARIBABU
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:
Biomedical research areas including the study of metagenomics inflammation and pathogenesis are resourceand technology intense. All COBRE-supported investigators require state of-the-art resources to successfullycompete with investigators from other resource-rich institutions for NIH support. The primary goal of theFunctional Microbiomics Core (FMC) is to establish an integrated service center that functions as a criticalresource for all Microbiome Inflammation and Pathogenicity COBRE investigators. Since all the COBRE projectsutilize mouse models to explore the inter-relationships between inflammation and pathogenesis and thecontribution of microbiota to this process the development of a facility to house and maintain germ-free andgnotobiotic mice is crucial to the FMC. An anaerobic culture facility will support research on gnotobiotic mice thatrequires specific colonization with fecal transplants or defined anaerobic bacteria. Further in Aim 2 we proposeto establish an integrated metagenomics center for microbiota. This facility will prepare genomic DNA followingunified protocols and generate 16S rRNA gene amplicon sequences and provide bioinformatics support for allmicrobiota analysis. The FMC will also support all COBRE projects with analysis of their biological samples forinflammatory markers as well as histopathological examination of tissue sections. Education and training of juniorinvestigators and the university wide research community in microbiota research is an important goal of the FMC.Towards this goal the FMC will organize seminars as well as informal meetings that will serve as a forum forhighlighting the scientific and technical advances in the field. Finally the FMC plans to become an independentservice center at UofL to support the needs of all researchers in this area of research

project_terms:
Address;Adopted;Anaerobic Bacteria;Area;Attention;Award;Bioinformatics;Biological;Biomedical Research;Centers of Research Excellence;Clinical;Communities;Continuing Education;Core Facility;Data Analyses;Development;Dietary Intervention;Disease;Equipment;Extramural Activities;Fee-for-Service Plans;Fostering;Funding;Generations;Genomic DNA;Genomics;Germ-Free;Gnotobiotic;Goals;Health;Housing;Human Resources;Incubators;Individual;Infection;Inflammation;Inflammation Mediators;Institution;Kentucky;Laboratories;Mentors;Metagenomics;Methodology;Mission;Mus;Outcome;Pathogenesis;Pathogenicity;Phase;Pilot Projects;Process;Protocols documentation;Research;Research Personnel;Research Support;Resources;Ribosomal RNA;Sampling;Services;Sterility;Techniques;Technology;Tissues;Training;Training and Education;Translational Research;United States National Institutes of Health;Universities;Work;animal facility;base;biosafety level 3 facility;experimental study;fecal transplantation;histopathological examination;inflammatory marker;innovation;interest;investigator training;meetings;member;metabolomics;microbial;microbiome;microbiome research;microbiota;mouse model;pathogen;programs;protocol development;rRNA Genes;social health determinants;social relationships;success;tool


application_id: 10112249
project_number: 5P20GM125504-04
project_title: COBRE-Administrative Core
administering_ic: NIGMS
award_notice_date: 2021-02-11
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2023-02-28
study_section: ZGM1-RCB-3
subproject_number: 8241
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Louisville (UofL) COBRE in Functional Microbiomics Inflammation and Pathogenicitycomprises a multidisciplinary group of investigators addressing thematic aspects of microbiome inflammationand pathogenicity studies. The UofL is uniquely poised to investigate these problems in a coordinated andefficient fashion and the COBRE is horizontally integrated with a number of UofL funded initiatives and grantapplications in related areas. The departments of Oral Immunology and Infectious Diseases Microbiology andImmunology and Bioengineering all contribute to the cross-disciplinary nature of the center. These units haveestablished records of federal funding mentoring junior faculty graduate student training and collaborativeinteractions across campus. This application is led by well-qualified and well-funded Center Directors. There arefive outstanding PI-mentees with senior established funded mentoring teams. Our proposed COBRE will havea major positive impact on research throughout UofL and will help recruit and retain faculty. The germ freeanimal facility to be established will be one of only a few in the country. Many of the projects address chronicinflammatory diseases that occur at disproportionately high incidence in minority communities. Other projectsinvolving plague and melioidosis have national and international significance. The Administrative Core willprovide overall governance and will ensure that the COBRE projects and cores work together in a cohesive andcoordinated manner. All projects and cores will utilize the Administrative Core. The Specific Aims are: to providea formal governance structure to allow coordination direction and prioritization of activities including budgetissues ensuring the quality of all functions; to evaluate progress; to resolve any conflicts as they arise; to providea formalized process for mentoring junior faculty; to provide a mechanism to replace mentees as they becomeindependent; to provide a mechanism to replace any key individuals who may leave; to provide pilot funding forjunior faculty to ensure a pipeline of investigators; to provide biostatistical and bioimaging support; and todisseminate pertinent information resulting from the COBRE activities.

project_terms:
Acute;Address;Applications Grants;Area;Biological Warfare;Biomedical Engineering;Biometry;Bubonic Plague;Budgets;Burkholderia pseudomallei;Centers of Research Excellence;Communicable Diseases;Conflict (Psychology);Country;Disease;Disease Outcome;Ensure;Faculty;Funding;Germ-Free;Goals;Guidelines;Health;Human;Human Microbiome;Immunology;Incidence;Individual;Inflammation;Inflammatory;Inflammatory Response;Interdisciplinary Study;International;Location;Melioidosis;Mentors;Microbiology;Modality;Natural Immunity;Pathogenicity;Plague;Play;Population;Process;Records;Regulation;Research;Research Personnel;Role;Structure;Universities;Work;Yersinia pestis;animal facility;bioimaging;chronic inflammatory disease;cohesion;graduate student;host-microbe interactions;immune system function;microbiome;microbiome research;microbiota;minority communities;multidisciplinary;nature center;new technology;new therapeutic target;oral immunology;oral infection;pathogen;recruit;student training;underserved community


application_id: 10112248
project_number: 5P20GM125504-04
project_title: Functional Microbiomics Inflammation and Pathogenicity
administering_ic: NIGMS
award_notice_date: 2021-02-11
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
program_official: CUPIT, PAULINE
project_start_date: 2018-03-01
project_end_date: 2023-02-28
study_section: ZGM1-RCB-3(C1)
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
In the past few decades the fields of microbiology and immunology have undergone a renaissance driven inpart by technological advances which have shaped our understanding of microbes as components of complexpolymicrobial interactive communities. This microbiome can play a role in a number of fundamental aspects ofhuman health and disease in many instances through the interface with host innate immunity. The immunesystem functions to restrict the potential for damage caused by the microbiota while simultaneously minimizingdestructive inflammatory responses. Disruption of the intensity duration or physical location of inflammationhowever can contribute to disease. Advances in our understanding of the microbiome along with a realizationthat inflammatory processes are at the core of a number of common diseases necessitates a cross-disciplinaryperspective that accommodates the host-microbe interaction in toto. The major goal of this COBRE is toestablish a thematic multidisciplinary research center for the study of the interface between the microbiomeinflammation and pathogenicity. We have assembled a team of junior investigators with complementaryexpertise and outstanding potential and have partnered these project leaders with well-qualified and dedicatedmentors. An integrated set of complementary projects will make novel connections between inflammatoryprocesses and bacterial pathogenicity and establish the basis for the development of novel therapeutics anddelivery methods. We will create a multidisciplinary program in research education mentoring and careerdevelopment that will facilitate and accelerate the transition of junior faculty to independent extramural fundedstatus. Research will be support by a Functional Microbiomics Core that will provide germ free animal facilitiesanaerobic culture capability microbiome sequencing and bioinformatics assay of inflammatory markers andpathology services. An Administrative Core will co-ordinate activities and provide additional biostatistical andbioimaging support along with a Pilot Project program to ensure a pipeline of investigators. Institutionalcommitment will also help ensure long term sustainability of the thematic research program.

project_terms:
Anaerobic Bacteria;Anti-Inflammatory Agents;Area;Autoimmune Diseases;Basic Science;Bioinformatics;Biological Assay;Biometry;Centers of Research Excellence;Chronic;Colorectal Cancer;Communities;Complex;Dentistry;Development;Disease;Distant;Ecology;Education;Engineering;Ensure;Environment;Equilibrium;Evaluation;Extramural Activities;Faculty;Funding;Germ-Free;Goals;Health;Health Sciences;Homeostasis;Human;Human Microbiome;Immune response;Immune system;Immunologist;Immunology;Indigenous;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Infrastructure;Interdisciplinary Study;International;Lead;Location;Mentors;Methods;Microbe;Microbiology;Monitor;Mucous Membrane;Natural Immunity;Normal tissue morphology;Outcomes Research;Parkinson Disease;Pathogenicity;Pathology;Pathway interactions;Periodontitis;Physiology;Pilot Projects;Play;Positioning Attribute;Postdoctoral Fellow;Process;Recovery;Renaissance;Research;Research Infrastructure;Research Personnel;Research Priority;Research Project Grants;Resources;Rheumatoid Arthritis;Role;Scientist;Services;Shapes;Site;Specificity;Structure;Surface;System;Talents;Teacher Professional Development;Therapeutic Agents;Time;Tissues;Training;Universities;animal facility;autism spectrum disorder;bioimaging;career development;chronic infection;dysbiosis;graduate student;host-microbe interactions;immune system function;inflammatory marker;intercellular communication;medical schools;microbial;microbial community;microbiome;microbiome research;microbiome sequencing;microbiota;multidisciplinary;nervous system disorder;novel;novel therapeutics;pathogen;programs;recruit;response;tool

public_health_relevance:
The University of Louisville COBRE in Functional Microbiomics Inflammation and Pathogenicity is a uniquethematic research center. COBRE scientists comprise a multidisciplinary group of senior mentors and juniorinvestigators on a pathway to independence who are focusing on diseases that involve complex interactionsbetween microbial challenge and host inflammatory responses. Outcomes of this research may lead to thedevelopment of novel therapeutic agents and delivery systems to protect against a number of chronic and difficultto treat conditions.


application_id: 10112180
project_number: 5R01AR070313-05
project_title: Macrophage phenotype orchestrates mammalian tissue regeneration
administering_ic: NIAMS
award_notice_date: 2021-02-18
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AR
serial_number: 070313
program_official: BELKIN, ALEXEY
project_start_date: 2017-03-13
project_end_date: 2023-02-28
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
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
project_abstract:
ABSTRACT/PROJECT SUMMARYDespite clinical advances the fact remains that humans cannot regenerate injured tissue. Instead tissuetrauma stimulates inflammation which in turn induces fibrosis and ultimately the formation of scar tissue.Trauma-induced inflammation is primarily regulated by macrophages; key regulators of fibrosis. Althoughcurrent therapies to control human fibrotic diseases include agents that target macrophages new data indicatethese treatments negatively impact regenerative ability. This outcome results from our lack of knowledge abouthow macrophages regulate endogenous tissue regeneration. A mammalian model of tissue regeneration isnecessary to directly study how macrophages regulate the injury response to fill this knowledge gap. Thediscovery that African spiny mice (Acomys) can regenerate complex tissues of the external ear including skinhair follicles nerves muscle and cartilage provides such a model. Furthermore because laboratory miceproduce scar tissue in response to an identical injury this comparative system provides a unique opportunity todirectly study how macrophage phenotypes regulate regeneration and scarring. The long-term goal is todevelop clinical interventions that stimulate regeneration and inhibit fibrosis. The objective of this proposal is toidentify macrophage subtypes that regulate regeneration and manipulate inflammation to stimulateregeneration in response to injury. This proposal tests the central hypothesis that specific macrophagesubtypes stimulate a regenerative extracellular environment and that phenotype switching from one state toanother is critical to the outcome of injury. This hypothesis is based upon published and preliminary studiesindicating general macrophage phenotypes are associated with regeneration that Acomys and Mus exhibitdifferent cytokine and inflammatory gene profiles and that production of a regenerative or scarring extracellularenvironment corresponds to specific macrophage phenotypes observed in Acomys or Mus. Guided by strongpreliminary data this hypothesis will be tested by pursuing the following two specific aims: (1) identify specificmacrophage phenotypes that regulate tissue regeneration and scarring in Acomys and Mus. Parallel in vivoand in vitro studies will integrate the timing and extracellular influence of macrophage subtypes andmacrophage origin using newly developed regeneration assays; and (2) test the role of macrophage-producedarginase on tissue regeneration through the use of a newly identified immunomodulatory agent and geneticallyengineered mice with macrophages that lack arginase. The approach is innovative in the applicant's opinionbecause it departs from the status quo of investigating wound healing and instead focuses on understandingendogenous tissue regeneration in a unique model of mammalian tissue regeneration. The proposed researchis significant because it is expected to provide new and fundamental insight into how macrophages coordinatethe inflammatory and immune reaction to stimulate a regenerative response to injury.

project_terms:
Acomys;Address;African;Azithromycin;Biological Assay;Cartilage;Cicatrix;Clinical;Complex;Data;Disease;Ear;Environment;Epithelial;Exhibits;External Ear;Extracellular Matrix;Fibroblasts;Fibrosis;Genes;Genetic Transcription;Genetically Engineered Mouse;Genomics;Goals;Granulation Tissue;Hair follicle structure;Human;Immunomodulators;In Vitro;Inflammation;Inflammatory;Injury;Intervention;Knowledge;Laboratory mice;Mammals;Medicine;Modeling;Molecular;Mus;Muscle;Musculoskeletal structure;Natural regeneration;Nerve;Outcome;Pathology;Phenotype;Process;Production;Proteomics;Public Health;Publishing;Regenerative response;Research;Role;Skin;System;Testing;Time;Tissue Model;Tissues;Trauma;Work;Wound models;arginase;base;comparative;cytokine;disability;extracellular;healing;immunoreaction;improved functioning;in vivo;inhibitor/antagonist;injured;injury and repair;innovation;insight;macrophage;novel;organ regeneration;recruit;regenerative;response;response to injury;skin regeneration;stem;targeted agent;tissue regeneration;tissue trauma;wound;wound healing

public_health_relevance:
PROJECT NARRATIVEAlthough humans cannot regenerate damaged tissue the African spiny mouse can naturally regenerate skinhair follicles nerves muscle and cartilage. Thus the proposed research is relevant to public health becausestudying the cellular mechanisms that regulate endogenous regeneration is expected to generate novel clinicalapproaches to restore damaged tissue. Stimulating natural tissue regeneration greatly improves thefunctionality of injured tissue and will help reduce the burden human disability.


application_id: 10111576
project_number: 5R01NS101105-05
project_title: Promoting and understanding recovery of breathing after chronic spinal cord injury
administering_ic: NINDS
award_notice_date: 2021-02-17
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 101105
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2017-03-15
project_end_date: 2023-02-28
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8838438
contact_pi: ALILAIN, WARREN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT More than 50% of all spinal cord injuries occur at the cervical level. At this level are the phrenic motorneurons which innervate the diaphragm. Therefore injuries at this level can lead to the inability to breathe.The overall objective of this grant proposal is to examine the changes which take place chronically in thephrenic circuitry of the cord in response to cervical spinal cord injury and investigate and optimize potentialtherapies that can restore breathing long after injury. Through these studies an effective intervention can betranslated to a significant population of the spinal cord injured community. In this proposal we will utilizechronic cervical spinal cord-hemisected animals which have half of the diaphragm paralyzed. In our earlierstudies we observed that enzymatic (chondroitinase ABC) removal of extracellular matrix molecules calledchondroitin sulfate proteoglycans which block plasticity regeneration and sprouting led to restoration offunction of the once paralyzed hemidiaphragm when administered at or near the time of injury. Recovereddiaphragmatic activity was rhythmic and synchronized. In stark contrast when the spinal cord of chronicallyinjured animals was stimulated with chondroitinase ABC and intermittent hypoxia training chaotic andunstructured activity resulted suggesting slowly developing and potentially maladaptive responses to injury.However the use of chondroitinase alone at chronic stages can promote normal rhythm and dramaticallyenhance properly patterned functional recovery. This grant proposal seeks to: 1) understand the time courseand carefully describe the maladaptive processes that take place; 2) understand the mechanisms underlyingthe production of this newly discovered atypical activity at chronic time points; and 3) learn how to overcomethese negative responses to injury so that interventions and rehabilitative strategies can become moreeffective thereby leading to improved functional outcomes. Overall these studies will provide insight on thebasic mechanisms that underlie maladaptive as well as functionally beneficial plasticity that can lead to robustfunctional respiratory motor recovery at chronic stages of spinal cord injury.

project_terms:
Acute;Americas;Anatomy;Animals;Applications Grants;Behavior;Breathing;Cervical;Cervical spinal cord injury;Cervical spinal cord structure;Chondroitin ABC Lyase;Chondroitin Sulfate Proteoglycan;Chondroitinases;Chronic;Communities;Equilibrium;Excision;Extracellular Matrix;Health Care Costs;Hypersensitivity;Hypoxia;Injury;Intervention;Investigation;Knowledge;Lead;Learning;Length;Measures;Mechanical Ventilators;Mediating;Modeling;Motor;Motor Activity;Motor Neurons;Natural regeneration;Paralysed;Patients;Pattern;Periodicity;Play;Population;Positioning Attribute;Process;Production;Quality of life;Recovery;Recovery of Function;Regimen;Rehabilitation therapy;Research;Respiratory Diaphragm;Role;Saline;Serotonin;Spinal Cord;Spinal cord injury;Subgroup;Testing;Therapeutic Intervention;Time;Training;Translating;United States;Work;effective intervention;experimental study;functional outcomes;health management;improved;inhibitor/antagonist;injured;insight;motor recovery;motor rehabilitation;neurotransmission;normoxia;novel therapeutics;optimal treatments;preservation;prevent;receptor;rehabilitation strategy;respiratory;response;response to injury;restoration;serotonin receptor;side effect;success

public_health_relevance:
PROJECT NARRATIVEPublic Relevance: There are near 260000 people in the United States of America that have a spinal cord injury with atleast 12000 new cases each year and more than half of all those injuries are at the cervical level which canresult in the patient's inability to breathe. Extreme measures such as the use of mechanical ventilators areoften needed to enable them to survive leading to millions of dollars in health care costs and a decreasedquality of life. The main objective of this grant proposal is to investigate and optimize novel therapies that canrestore the ability to breathe and improve functional outcomes in chronic cases of cervical spinal cord injury.


application_id: 10111499
project_number: 5R01DA043519-05
administering_ic: NIDA
award_notice_date: 2021-02-25
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DA
serial_number: 043519
program_official: HIGHSMITH, KEISHER S
project_start_date: 2017-05-01
project_end_date: 2025-02-28
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 3100162
contact_pi: BADA, HENRIETTA S.
other_pis: LEGGAS, MARKOS
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
budget_start_date: 2021-03-01
project_title:
Non-opiate treatment after prenatal opiate exposure to Prevent Postnatal Injury to the Young Brain (No-POPPY)

project_abstract:
ABSTRACTThe number of newborns that develop the constellation of drug withdrawal symptoms or Neonatal AbstinenceSyndrome (NAS) in the US has increased to epidemic proportions. The pharmacologic treatment of NAS withmorphine or methadone is highly concerning as it corresponds with a timeframe of rapid postnatal brain development. The negative effects of opioids on the developing brain include decreased neurogenesis synaptogenesis and corticogenesis decreased brain size and decreased brain volumes in older children with prenatalopiate exposure. Furthermore response of neonates to treatment is highly variable and limited pharmacogenetic and metabolic activity data which can be used to optimize therapy in this population pose additionalchallenges in using any drug to treat NAS. Collectively these issues present a critical need to evaluate andoptimize the use of a non-opioid drug for treatment of NAS. The long term goals of our research is to establishthe best pharmacological treatment for NAS and determine how pharmacologic treatment of NAS affects long-term developmental outcomes. The objective of this application is to evaluate the effectiveness of clonidine an2 adrenergic receptor agonist as a treatment for neonates with NAS in a randomized clinical trial. Our central hypothesis is that clonidine will effectively treat drug withdrawal manifestations in neonates. Preliminaryclinical evidence supports this hypothesis. Clonidine has previously been reported by us and others as a singledrug therapy for NAS in small number of infants with relief of withdrawal symptoms and as an effective adjunctive treatment when giving chloral hydrate or morphine. The rationale for the proposed research is that oncewe understand how clonidine can be used optimally in the clinic to treat NAS a safe medication will be available and it could potentially minimize complications associated increased length-of-stay in the hospitalhealthcare costs and the deleterious opiate assaults on the developing brain that continue with postnatal opiateadministration. To test our central hypothesis and accomplish the objective of this application we plan to pursue the following three specific aims: 1) To determine whether the treatment of NAS with a non-opiate medication clonidine will be more effective than morphine. 2) To determine whether treatment of NAS with clonidinewill result in better early childhood outcomes than those treated with morphine. 3) To determine how infantswith NAS metabolize morphine and clonidine. With respect to expected outcomes this proposal will provideprospective evidence: a) regarding the potential of clonidine treatment to treat NAS; b) regarding how opioidand non-opioid exposure affect early childhood development; c) regarding factors that influence response totreatment. These results are expected to have an important positive impact because they have the potential toprovide fundamental information regarding the metabolic ontogeny of infants exposed to opioid drugs andmost importantly to improve the long-term outcomes of children born to addicted mothers.

project_terms:
Abstinence;Adrenergic Agonists;Affect;Aftercare;Age;Analgesics;Brain;Cells;Child;Child Behavior Checklist;Chloral Hydrate;Chronic;Clinic;Clinical;Clonidine;Cognitive;Collaborations;Data;Development;Drug Kinetics;Drug Withdrawal Symptoms;Epidemic;Exposure to;Genetic;Goals;Growth;Health;Health Care Costs;Hospitals;Infant;Informal Social Control;Injury;Laboratory Study;Language;Length of Stay;Life;Metabolic;Methadone;Mission;Modeling;Morphine;Mothers;Motor;Narcotics;Neonatal;Neonatal Abstinence Syndrome;Neurons;Newborn Infant;Norepinephrine;Opioid;Opioid Receptor;Outcome;Performance;Pharmaceutical Preparations;Pharmacogenetics;Pharmacological Treatment;Pharmacology;Pharmacotherapy;Pilot Projects;Population;Pregnancy;Problem behavior;Property;Public Health;Randomized Clinical Trials;Reflex action;Reporting;Research;Stress;Testing;Time;United States National Institutes of Health;Withdrawal;Withdrawal Symptom;assault;brain size;brain volume;cost;drug withdrawal;early childhood;effectiveness evaluation;effectiveness testing;fetal opioid exposure;heroin use;improved;individual response;neonate;neurobehavioral;neurogenesis;non-opioid analgesic;noradrenergic;opioid exposure;opioid use;pharmacodynamic model;postnatal;prevent;prospective;response;standard of care;synaptogenesis;treatment duration;treatment optimization;treatment response

public_health_relevance:
PROJECT NARRATIVEThe proposed research is relevant to public health because it will investigate the treatment of newborn drugwithdrawal or neonatal abstinence syndrome afflicting infants born to mothers who used heroin or opioid painkillers (prescribed or non-prescribed) during pregnancy. Instead of treating infants with opioids to alleviateintense drug withdrawal symptoms the project will test the effectiveness of a non-opioid medication and inaccompanying laboratory studies it will determine how genetics and metabolic maturity of neonates affectindividual response to treatment. This study is relevant to NIH's mission because it has the potential to improvethe short- and long-term health outcomes of these neonates.


application_id: 10111484
project_number: 5F30CA232550-03
project_title: The role of MIF in mitochondrial metabolism and M2-TAM polarization
administering_ic: NCI
award_notice_date: 2021-02-16
opportunity_number: PA-18-673
application_type: 5
activity_code: F30
ic: CA
serial_number: 232550
program_official: BIAN, YANSONG
project_start_date: 2019-03-01
project_end_date: 2023-02-28
study_section: Special Emphasis Panel[ZRG1-F09C-Q(20)L]
contact_pi_person_id: 15053134
contact_pi: NOE, JORDAN T
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThe role of MIF in mitochondrial metabolism and M2-TAM polarization. Tumor-associated macrophages (TAMs) promote intratumoral microvessel density increase tumorstromal matrix remodeling and potently suppress anti-tumor immunity in late-stage cancer patients. Althoughsubstantial research has identified how M2 TAM polarization promotes tumor progression much less is knownabout how TAMs obtain this M2 phenotype within tumor microenvironments. Metabolic reprogramming is acritical determinant of macrophage polarization as recent studies demonstrate that M2 TAMs adopt an oxidativephosphorylation/mitochondrial metabolic phenotype and uniquely respond to metabolites within the tumormicroenvironment. This proposals long-term objective is to investigate the mechanisms by which macrophagemigration inhibitory factor (MIF) dictates lactate-enhanced M2 polarization. Our preliminary studies demonstratethat M2 macrophages metabolize extracellular lactate to pyruvate which in turn is oxidized in the mitochondriaand is both necessary and sufficient to significantly enhancing Th2 cytokine-dependent M2 TAM polarization.Our data further indicates that MIF promotes mitochondrial metabolism which is required for maximallactate/pyruvate-enhanced M2 polarization and acquisition of pro-tumorigenic phenotypes. Two aims areproposed to test our hypotheses: Specific Aim 1: Delineate the mechanistic effectors of lactate/pyruvate toHIF1-dependent M2-macrophage polarization. Objective: To use a combination of metabolic flux analysesmetabolomics gene expression assays transgenic mice and mechanistic studies to answer three primaryquestions: 1) Whether M2 macrophages actively metabolize lactate; 2) Which metabolic pathways are utilizedto accomplish this and; 3) How is lactate metabolism mechanistically linked to M2 polarization Specific Aim 2:Determine the mechanistic contributions of MIF in lactate/pyruvate-mediated M2 TAM polarization.Objective: Use mutant MIF protein re-expression small-molecule rescue studies flow cytometry and geneexpression assays to make three determinations: 1) Whether MIF dictates mitochondrial biogenesis andmetabolism in M2 macrophages; 2) Whether and how MIF influence mitochondrial metabolism by binding toCSN5 and regulating NRF2 stability and; 3) If MIF is functionally linked to lactate-amplified HIF1 stability andensuing M2 polarization.

project_terms:
Adopted;Anaerobic Bacteria;Binding;Biogenesis;Biological Assay;COPS5 gene;Cancer Patient;Citric Acid Cycle;Clinical;Complex;Data;Development;Diagnosis;Electron Transport;Exhibits;Flow Cytometry;Fumarates;GA-binding protein transcription factor;Gene Expression Profiling;Genetic;Hypoxia Inducible Factor;IL4 gene;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Incidence;Interleukin-4;Laboratories;Lead;Link;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Migration Inhibitory Factor;Mitochondria;Modeling;Molecular Target;Mus;Neoplasm Metastasis;Oxidative Phosphorylation;Oxides;Oxygen Consumption;Pathway interactions;Patients;Phenotype;Process;Production;Proteins;Pyruvate;Pyruvate Metabolism Pathway;Reporter;Research;Resistance;Role;Solid;Solid Neoplasm;Stimulus;Stromal Neoplasm;Succinate Dehydrogenase;Survival Rate;Testing;Transgenic Mice;Tumor Immunity;Tumor-Derived;Tumor-associated macrophages;Unresectable;Warburg Effect;adenoviral-mediated;angiogenesis;anti-tumor immune response;cancer cell;cancer type;cytokine;density;expression vector;extracellular;gene product;glucose metabolism;improved;macrophage;melanoma;metabolic phenotype;metabolomics;mitochondrial metabolism;mortality;mutant;neoplasm immunotherapy;novel therapeutics;response;small molecule;transcription factor;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions;tumorigenic;uptake

public_health_relevance:
Project NarrativeThe role of MIF in mitochondrial metabolism and M2-TAM polarization. Patients diagnosed with unresectable stage IV melanoma have a median survival rate of 6-10 months.Despite encouraging improvements in overall survival in patients receiving immunotherapies for melanomamany patients are unresponsive to these therapies. As tumor-associated macrophages (TAMs) polarized to anM2 phenotype promote both tumor progression and resistance to the latest immunotherapies investigatinghow TAMs acquire an M2 polarization phenotype may lead to the identification of molecular targets for thedevelopment of new and highly improved tumor immunotherapies.


application_id: 10109963
project_number: 5R01AG053585-05
project_title: Reversing Microvascular Dysfunction in Advancing Age
administering_ic: NIA
award_notice_date: 2021-02-19
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 053585
program_official: GAO, HONGWEI
project_start_date: 2017-03-01
project_end_date: 2023-02-28
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 8957618
contact_pi: LEBLANC, AMANDA JO
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Coronary blood flow (BF) reserve (or the ability of the small coronary vessels to increase BF inresponse to increased workload) declines in senescent animals and humans and may contribute in theincreased risk for cardiovascular disease (CVD) as a person ages. In addition to this baselinedeterioration of coronary microvascular function there are some distinct gender-related symptoms ofCVD that have gone untreated. As many as 50% of women referred for evaluation of myocardialischemia do not have obstructive coronary disease (like most men) but are frequently associated withcoronary microvascular dysfunction/ischemia. Unfortunately most traditional therapeutic treatments ofCVD and myocardial ischemia were designed to address symptoms displayed by a majority of men(with obstructive large coronary vessels) but these methods are not applicable to treating women withmicrovascular ischemia. To address the clinical need for an effective microvessel-targeted therapy wedeveloped an adipose-derived stromal vascular fraction (SVF) cell therapy and demonstrated that thecells improved the microvascular coronary blood flow (CBF) and vasoactivity in aged rats. Furthermorethe therapeutic use of SVF cells improves tissue perfusion independent of vessel density. Building onthis observation additional findings have determined that the intravenous (i.v.) delivery of autologousSVF cells reduced the resting tone of peripheral vasoactive arteries due to the injected SVF cellsspontaneously populating the walls of these arteries in a hydrogen-peroxide-dependent manner.Therefore we hypothesize that the i.v. delivery of freshly isolated adipose SVF cells will improve CBFin aged female rats by populating the walls of small coronary arteries/arterioles promoting vesselrelaxation. To test this we will use an aged female rat model combined with transgenic reporter-basedcell tracking and functional assessment approaches to determine if coronary microvascular dysfunctioncan be reversed through SVF cell injection (Aim 1) to determine the effect of SVF cell incorporation onvascular network function (Aim 2) and which cell population from the SVF is contributing to the reversalof coronary microvascular dysfunction (Aim 3). To date there a lack of cellular therapy designed totreat dysfunctional coronary microvessels as a result of advanced age and this particular autologouscellular therapy has high clinical potential with findings applicable to a broad array of othermicrovascular disorders. In addition we foresee our findings to have broad therapeutic relevance andprovide new insight into the dynamics of vessel wall homeostasis and microvascular disease.

project_terms:
Address;Adipocytes;Adipose tissue;Age;Aging;Animals;Arteries;Autologous;Blood Pressure;Blood Vessels;Blood flow;Cardiac;Cardiovascular Diseases;Catheters;Cell Fraction;Cell Therapy;Cell physiology;Cells;Clinical;Coronary;Coronary Arteriosclerosis;Coronary Vessels;Coronary artery;Coronary heart disease;Deterioration;Disease;Elderly;Endothelial Cells;Evaluation;Exhibits;Female;Functional disorder;Gender;Heart;Homeostasis;Human;Hydrogen Peroxide;ITGAM gene;Impairment;Individual;Injections;Intravenous;Ischemia;Mediating;Mediator of activation protein;Methods;Microspheres;Microvascular Dysfunction;Modeling;Molecular;Monitor;Mus;Muscle Tonus;Myocardial Infarction;Myocardial Ischemia;Oxidative Stress;Pathway interactions;Patient-Focused Outcomes;Perfusion;Peripheral;Persons;Pharmaceutical Preparations;Pharmacology;Population;Postmenopause;Publishing;Rattus;Reactive Oxygen Species;Regulation;Relaxation;Reporter;Rest;Role;Safety;Signal Transduction;Skin;Stromal Cells;Surface;Symptoms;Telemetry;Testing;Therapeutic;Therapeutic Uses;Time;Tissues;Transgenic Organisms;Trees;Tunica Adventitia;Ultrasonography;Vascular Diseases;Vascular Smooth Muscle;Woman;Workload;age related;aged;arteriole;base;cardiovascular disorder risk;cell type;coronary vasculature;density;design;effective therapy;experimental study;heart function;improved;improved outcome;in vivo;insight;intravital microscopy;juvenile animal;macrophage;macrovascular disease;men;molecular drug target;older men;older women;pressure;regenerative cell;repaired;response;senescence;targeted treatment;therapy design

public_health_relevance:
NarrativeTo date there are no known treatments to improve coronary microvascular dysfunction that occurs inadvancing age. The purpose of this study is to evaluate the safety and efficacy of a regenerative cell-based therapy to repair or restore coronary microvascular function potentially through theincorporation of injected regenerative cells into the vascular wall. This study will improve ourunderstanding of age-related cell therapy and the mechanism for which cell type in adipose tissuemediates vascular dysfunction reform upon incorporation.


application_id: 10109336
project_number: 1R21AI156332-01
project_title: F-18 fluorodeoxysorbitol for detecting response of bacterial infection to treatment
administering_ic: NIAID
award_notice_date: 2021-03-15
opportunity_number: PA-19-053
application_type: 1
activity_code: R21
ic: AI
serial_number: 156332
program_official: XU, ZUOYU
project_start_date: 2021-03-16
project_end_date: 2023-02-28
study_section: Imaging Guided Interventions and Surgery Study Section[IGIS]
contact_pi_person_id: 7606517
contact_pi: NG, CHIN K
other_pis: Not Applicable
congressional_district: 03
department: RADIATION-DIAGNOSTIC/ONCOLOGY
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):Bacterial infections cause significant mortality and morbidity worldwide despite the availability of antibiotics.Antibiotic resistance is one of the most urgent threats to the public's health. Klebsiella microbes are gram-negative bacteria that have the inherent adaptive ability to resist treatment and also pass along genetic materialthat facilitates drug resistance in other bacteria. Klebsiella pneumoniae (Kp) infection has created a tremendousclinical problem for many hospitals worldwide. As of today none of the current convention methods can provideearly specific diagnosis and rapid monitoring of infections in the clinic. Consequently treatment is often delayedor indefinite. The long-term goal is to develop a novel pathogen-specific and non-invasive whole-body imagingtechnique to guide patient management monitor treatment efficacy and speed drug development.The objective of this proposal is to validate F-18 fluorodeoxysorbitol (FDS) as an imaging tool for monitoringtreatment efficacy and identifying drug resistant Kp from drug sensitive Kp. The central hypothesis is that FDSis a promising PET imaging agent with simple chemistry optimal pharmacokinetics and high specificity andsensitivity for predicting treatment response to bacterial infection. The rationale underlying this proposal is thatits completion will contribute to accurate diagnosis for guiding effective treatment. The central hypothesis will betested by pursuing two specific aims: 1) Identify the optimal imaging time of FDS for 2 drug-resistant and 2 drug-sensitive Kp strains in a clinically relevant preclinical mouse model of lung infection 2) Determine the ability ofFDS PET imaging to differentiate treatment response between drug-resistant Kp strains and drug-sensitive onesin mice of lung infection. We will pursue these aims by using novel and more clinically relevant Kp mouse modelsof lung infection and a double-blinded strategy to mimic actual clinical patient situation.The proposed studies are significant and innovative because FDS PET imaging can be validated to be a usefultool to triage drug options by predicting early treatment response to bacterial infection and thus avoiding themisuse and overuse of antibiotics. The results will have an important positive impact immediately in that they willestablish an imaging technique for better understanding of bacterial infection guiding patient management andassisting drug development because they lay the groundwork to develop a suite of techniques for bettertreatment of Kp drug-resistant infections.

project_terms:
Antibiotic Resistance;Antibiotics;Bacteria;Bacterial Antibiotic Resistance;Bacterial Infections;Bacterial Pneumonia;Bioluminescence;Biopsy;Carbapenems;Categories;Ceftriaxone;Chemistry;Clinic;Clinical;Clinical Trials;Communicable Diseases;Development;Diagnosis;Discipline of Nuclear Medicine;Disease Progression;Double-Blind Method;Drug Kinetics;Drug resistance;Early treatment;Escherichia coli;Future;Genetic Materials;Goals;Gram-Negative Bacteria;Health;Hospitals;Human;Image;Imaging Device;Imaging Techniques;Imaging technology;Infection;Inflammation;Klebsiella;Klebsiella pneumoniae;Knowledge;Label;Leukocytes;Location;Lung;Lung infections;Magnetic Resonance Imaging;Methods;Microbe;Modeling;Monitor;Morbidity - disease rate;Multi-Drug Resistance;Mus;Outcome;Oxyquinoline;Patient imaging;Patients;Pharmaceutical Preparations;Pharmacotherapy;Physicians;Positron-Emission Tomography;Pre-Clinical Model;Prediction of Response to Therapy;Public Health;Publishing;Reporting;Research;Research Proposals;Rodent;Sensitivity and Specificity;Signal Transduction;Site;Source;Specialist;Speed;Sterility;Stress;Techniques;Testing;Thigh structure;Time;Treatment Cost;Treatment Efficacy;Treatment outcome;Triage;Work;X-Ray Computed Tomography;accurate diagnosis;antibiotic resistant infections;antimicrobial;base;carbapenem resistance;cellular imaging;clinically relevant;diagnostic platform;dosage;drug development;drug-sensitive;effective therapy;emerging pathogen;evidence base;fluorodeoxyglucose;imaging agent;improved;innovation;interest;microbial;mortality;mouse model;non-invasive imaging;novel;novel therapeutics;pathogen;pre-clinical;resistant Klebsiella pneumoniae;resistant strain;response;symposium;tool;treatment planning;treatment response;whole body imaging

public_health_relevance:
Project NarrativeThis research proposal is directly relevant to public health and would advance the capability of infectious diseasespecialists to detect early response to treatment for patients with bacterial infection. This proposal to furthervalidate F-18 fluorodeoxysorbitol (FDS) as a potential PET imaging agent for gram-negative bacteria byunderstanding its ability to triage drug options could potentially allow clinicians to quickly change the treatmentplan thereby minimizing patient stress improving survival and reducing treatment costs.


application_id: 10108115
project_number: 1R35HL155649-01
project_title: Determinants of Aorta Heterogeneity
administering_ic: NHLBI
award_notice_date: 2021-02-25
opportunity_number: RFA-HL-20-011
application_type: 1
activity_code: R35
ic: HL
serial_number: 155649
program_official: CHARETTE, MARC F
project_start_date: 2021-06-01
project_end_date: 2028-05-31
study_section: Special Emphasis Panel[ZHL1 CSR-I (O2)]
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Aneurysm;Aorta;Aortic Diseases;Atherosclerosis;Basic Science;Biological;Biology;Brain;Cell physiology;Cells;Characteristics;Clinical;Data;Disease;Dissection;Embryo;Extracellular Matrix;Funding;Heterogeneity;Inflammation;Kidney;Length;Life;Lipoproteins;Lung;Magnetic Resonance Imaging;Medical;Metabolism;Molecular;Operative Surgical Procedures;Organ;Pathogenesis;Patient observation;Pharmaceutical Preparations;Proteomics;Reagent;Research;Rupture;Scientist;Signal Pathway;Skin;Specificity;Structure;Syndrome;Techniques;Therapeutic;Tissues;Training;Translational Research;Ultrasonography;bone;extracellular;flexibility;insight;intravital microscopy;mouse model;next generation;novel;programs;single-cell RNA sequencing;tool;transcriptomics


application_id: 10108026
project_number: 1R03OD030603-01
project_title: Improving Deposition Quality and FAIRness of Metabolomics Workbench
administering_ic: OD
award_notice_date: 2020-09-18
opportunity_number: RFA-RM-19-012
application_type: 1
activity_code: R03
ic: OD
serial_number: 030603
program_official: KINSINGER, CHRISTOPHER
project_start_date: 2020-09-18
project_end_date: 2022-08-31
study_section: Special Emphasis Panel[ZRG1 ETTN-B (53)]
contact_pi_person_id: 9542008
contact_pi: MOSELEY, HUNTER NATHANIEL
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:
Improving Deposition Quality and FAIRness of Metabolomics WorkbenchPROJECT SUMMARY (30 lines) The practical reuse of genomics and transcriptomics datasets is well-demonstrated due to the use ofuniversal gene identifiers that facilitate matching of features across these datasets high feature coveragestandardized metadata and data deposition formats and a maturity in deposition quality and consistency.However metabolomics datasets are much harder to reuse due to the lack of standardization metabolitefeature identification heterogeneity in feature coverage and high variability in deposition quality andconsistency. Therefore it is much harder to both find relevant metabolomics datasets from repositorieslike Metabolomics Workbench (MWbench) and effectively reuse these datasets to generate and/or testhypotheses. To address these difficulties in reusing metabolomics datasets deposition quality must beimproved. Furthermore methods that enable the effective search and harmonization of MWbench studies areneeded especially for integrative multi-omics analyses. We are the developers of the only set of available open-source tools for parsing generating and validating mwTab formatted repository files. Our experience developingand utilizing this open-source mwtab Python package makes us uniquely qualified to develop methods toimprove both deposition and FAIRness of MWbench studies. Also we have provided periodic feedback toMWbench based on systematic evaluations of the repository to enable the improvement of this growing publicresource (2). Therefore we propose to develop methods and open-source tools that will improve depositionquality and FAIRness of MWbench through the following specific aims: Aim 1: Enable comprehensive capturedeposition and validation of metabolomics experimental data and metadata; Aim 2: Improve the FAIRness ofMetabolomics Workbench while demonstrating effective multi-omics integration with the Genotype-TissueExpression Project (GTEx). The major innovations that this proposal will develop are: i) effective metadatacapture methods from unstructured formats ii) advanced search methods for relevant MWbench studies thatcan filter on metadata quality iii) effective harmonization methods for MWbench studies iv) new omicsintegration approach to detect human gene-metabolite associations and v) new tools that facilitate publicdeposition with high-quality metadata with InChI tags and in mwTab format for quicker easier deposition. The significance of this proposal is in developing methods and tools that: a) comprehensivelycapture validate and deposit metadata-rich metabolomics data b) improve the FAIRness of MWbench datasetsespecially reuse c) enable integration of MWbench and GTEx datasets to generate biomedically-relevant humangene-metabolite associations and d) enable interpretation of gene-metabolite associations within molecularinteraction networks. These new tools will enhance the utility and usage of Metabolomics Workbenchwhile demonstrating multi-omics integration with the Genotype-Tissue Expression Project.

project_terms:
Address;Archives;Binding;Chemicals;Data;Data Analyses;Data Set;Databases;Deposition;Development;Documentation;Evaluation;Feedback;Genes;Genomics;Genotype-Tissue Expression Project;Heterogeneity;Human;Human Biology;International;Knowledge;Laboratories;Libraries;Life;Management Information Systems;Meta-Analysis;Metabolic;Metabolism;Metadata;Methods;Periodicity;Process;Pythons;Resources;Standardization;Testing;Validation;base;data submission;experience;gene product;human disease;improved;innovation;metabolomics;multiple omics;open source;public repository;repository;small molecule;tool;transcriptomics

public_health_relevance:
PROJECT NARRATIVE (3 sentences)We will develop methods and tools needed to effectively archive and use public biomedical datasets describingthe thousands of small biomolecules (metabolomics) involved in human biology and disease. We will usethese methods to demonstrate the integration and reuse of thousands of datasets in both the MetabolomicsWorkbench and the Genotype-Tissue Expression Project to derive new biomedical knowledge that describeshow gene-products relate to the small molecules generated in metabolism i.e. the chemical processes of life.


application_id: 10107753
project_number: 5R21AI147139-02
project_title: Regulation of infection-associated protein expressed by the Lyme disease spirochete DnaA protein
administering_ic: NIAID
award_notice_date: 2021-01-29
opportunity_number: PA-19-053
application_type: 5
activity_code: R21
ic: AI
serial_number: 147139
program_official: BOWDEN, NADINE
project_start_date: 2020-02-14
project_end_date: 2024-01-31
study_section: Special Emphasis Panel[ZRG1-IDM-B(80)S]
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
arra_indicator: N
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;tick transmission;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: 10104957
project_number: 1K01HL149984-01A1
project_title: Pharmacological Mechanistic Insights into Thoracic Aortic Aneurysm
administering_ic: NHLBI
award_notice_date: 2020-12-18
opportunity_number: RFA-HL-19-026
application_type: 1
activity_code: K01
ic: HL
serial_number: 149984
suffix: A1
program_official: HUANG, LI-SHIN
project_start_date: 2020-12-18
project_end_date: 2025-11-30
study_section: Special Emphasis Panel[ZHL1 CSR-Z (O1)]
contact_pi_person_id: 14305741
contact_pi: SHEPPARD, MARY BURCHETT
other_pis: Not Applicable
congressional_district: 06
department: FAMILY MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Adrenergic Receptor;Aneurysm;Angiotensin Receptor;Animal Model;Aorta;Aortic Aneurysm;Aortic Diseases;Aortic Rupture;Area;Atenolol;Attenuated;Basic Science;Biological Assay;Blood Vessels;Cause of Death;Cell Fractionation;Cell membrane;Cellular Membrane;Chest;Cholesterol;Cholesterol Homeostasis;Clinic;Clinical Research;Confocal Microscopy;Cultured Cells;Data;Diagnosis;Disease;Dissection;Elastin;Etiology;FBN1;Faculty;Farnesyl Transferase Inhibitor;Fluorescence-Activated Cell Sorting;Funding;Future;Gel;Gelatinase A;Genetic Diseases;Genetic Predisposition to Disease;Goals;Growth;Human;Hydroxymethylglutaryl-CoA reductase;Hypertension;Immunohistochemistry;Incubated;Infusion procedures;Kentucky;Laboratories;Laboratory Study;Lead;Learning;Leukocytes;Life;Losartan;Marfan Syndrome;Matrix Metalloproteinases;Measurement;Measures;Medical Genetics;Medicine;Mentors;Microscopy;Mus;Operative Surgical Procedures;Patients;Pharmaceutical Preparations;Pharmacology;Physicians;Plasma;Pravastatin;Production;Proteins;Publications;RAS inhibition;Ras/Raf;Regimen;Renin-Angiotensin System;Research;Research Personnel;Research Project Grants;Retrospective Studies;Risk;Scientist;Senior Scientist;Signal Transduction;Signaling Molecule;Smooth Muscle Myocytes;Syndrome;Techniques;Testing;Therapeutic Uses;Thoracic Aortic Aneurysm;Tissues;Training;Transforming Growth Factor beta;Ultrasonography;United States National Institutes of Health;Universities;Vascular Diseases;Vascular Smooth Muscle;Work;base;career;clinically relevant;college;experimental study;farnesyl pyrophosphate;farnesylation;in vivo;insight;interest;mouse model;new therapeutic target;novel therapeutics;pre-clinical research;prevent;professor;repaired;sexual dimorphism;skills;standard of care;translational study;ultra high resolution


application_id: 10104266
project_number: 1R34MH124799-01
administering_ic: NIMH
award_notice_date: 2021-03-15
opportunity_number: RFA-MH-18-706
application_type: 1
activity_code: R34
ic: MH
serial_number: 124799
program_official: ROONEY, MARY
project_start_date: 2021-03-15
project_end_date: 2024-02-29
study_section: Special Emphasis Panel[ZMH1 ERB-K (09)]
contact_pi_person_id: 10775786
contact_pi: LEVINSON, CHERI ALICIA
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-03-15
project_title:
A Pilot Randomized Control Trial of a Relapse Prevention Online Exposure Protocol for Eating Disorders and Mechanisms of Change

project_abstract:
PROJECT SUMMARY/ABSTRACTEating disorders (EDs) are chronic and disabling; most individuals never achieve full remissioneven after intensive treatment and 50% of those who access intensive treatment will relapsewithin 6-months of discharge. These high relapse rates occur often and contribute to the pooroutcomes seen in EDs. Importantly existing treatments to not differ from control treatments inthe ability to alter cognitive ED pathology which is the primary remaining symptomatology atdischarge from intensive care. ED relapse-prevention treatments are urgently needed that candisrupt the persistent cycle of admission and discharge from intensive treatment and that areexplicitly targeted at core cognitive-affective pathology. Our scientific premise developed fromour past work is that the application of an online exposure protocol will engage fear extinction -improving outcomes enhancing full recovery and decreasing the likelihood of relapse. Ourstudy goals are to (1) develop and test the acceptability feasibility and preliminary efficacy of arandomization of an online exposure relapse-prevention protocol that can be delivered post-acute treatment versus a writing control treatment and (2) to test if this treatment targets fearextinction which is a core aspect of ED cognitive-affective pathology. These goals will ultimatelylead to a highly deployable and accessible online treatment targeted at core ED mechanisms.The proposed research uses highly innovative methods; we will use an all remote technology-based approach combining an online treatment with mobile technology that assesses the targetof fear extinction. The combination of an online treatment with mobile assessment allows forthe first time the creation of an engaged and targeted treatment which can rapidly bedisseminated during a critical period of care. Specific aims are to (1) collect preliminary data onthe feasibility and acceptability of the randomization of two treatment conditions after dischargefrom intensive ED treatment: a relapse-prevention online exposure protocol (n=65; ROEP) anda control treatment writing condition (n=65) (2) To test for differences between ROEP andcontrol treatment for the prevention of relapse and preliminary change on clinical ED outcomes(3) To examine if ROEP targets fear extinction and if fear extinction is associated with relapseand ED outcomes and (3b) To test if baseline differences in fear conditioning relate to changein ED outcomes across treatment. The proposed research has clinical impact. Ultimately thisproposal will lead directly to the creation and dissemination of a highly user-friendly easilyaccessible and deployable intervention that can prevent relapse in the EDs which will decreasemortality morbidity and the high costs associated with chronic treatment.

project_terms:
Acute;Address;Admission activity;Adult;Affective;Aftercare;Anorexia Nervosa;Anxiety;Behavior;Behavioral;Bulimia;Caring;Cellular Phone;Chronic;Clinical;Cognition;Cognition Disorders;Cognitive;Communities;Data;Diagnosis;Diagnostic;Dimensions;Disease remission;Eating Disorders;Exhibits;Extinction (Psychology);Food;Fright;Goals;Hospitalization;Hospitals;Individual;Inpatients;Intensive Care;Intervention;Lead;Learning;Literature;Measures;Medical;Methods;Morbidity - disease rate;Outcome;Participant;Pathology;Prevention Protocols;Prevention program;Protocols documentation;Randomized;Recovery;Relapse;Research;Service delivery model;Severities;Shapes;Symptoms;Technology;Testing;Time;Treatment Efficacy;Treatment outcome;United States National Institutes of Health;Validation;Variant;Weight;Weight Gain;Work;Writing;acceptability and feasibility;base;conditioned fear;control trial;cost;cost outcomes;critical period;dietary restriction;disorder later incidence prevention;evidence base;hospital readmission;improved outcome;individual variation;innovation;medical complication;mobile computing;mortality;prevent;public health relevance;recruit;relapse prediction;remote therapy;severe mental illness;smartphone Application;smartphone based assessment;symptomatology;targeted treatment;therapy design;user-friendly

public_health_relevance:
PROJECT NARRATIVEThis project will collect data on the feasibility acceptability efficacy and target engagement andvalidation of an online relapse-prevention treatment for eating disorders delivered afterdischarge from acute treatment. The proposed research has significant public health relevanceas it will directly lead to a highly accessible and deployable treatment that can decrease eatingdisorder relapse and the high societal burden associated with eating disorders. The proposedresearch is relevant to NIHs strategic aim 4.3 as it will lead to the creation of an innovativeevidence-based service delivery model using technology that can be easily disseminated tocommunities in need during a critical period of transition of care.


application_id: 10103812
project_number: 5R01DK112034-05
project_title: Mechanisms regulating neurotensin secretion and function
administering_ic: NIDDK
award_notice_date: 2021-02-02
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 112034
program_official: SERRANO, JOSE
project_start_date: 2017-02-01
project_end_date: 2022-01-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Neurotensin (NT) is a tridecapeptide localized to specialized enteroendocrine (EE) cells predominantlyin the small bowel. The most potent stimulus for NT release is the ingestion of dietary fats. NT facilitates freefatty acid (FFA) absorption in the proximal intestine stimulates growth of colorectal pancreatic and breastcancers that have the high affinity NT receptor 1 (NTR1) and contributes to lipid metabolism and glucosecontrol although its precise role in these processes has not been delineated. Recently a large populationstudy identified a significant association of increased fasting pro-NT (a stable NT precursor fragment producedin equimolar amounts relative to NT) levels with the development of diabetes increased risk of cardiovasculardisease and mortality and increased risk of breast cancer in women. Together these findings identify animportant role for NT in lipid metabolism and moreover links increased NT levels to various metabolicdiseases and increased morbidity and mortality. Epidemiological evidence clearly shows direct linkage between overnutrition and obesity; however themolecular mechanisms linking adiposity to overnutrition remain unknown. In exciting recent findings wedemonstrate that NT deficiency (using an NT knockout mouse model) protects against obesity insulinresistance and non-alcoholic fatty liver disease (NAFLD) associated with high fat consumption; we furtherdemonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FFAabsorption through a mechanism involving NTR1 and NTR3/sortilin. Conversely the overexpression of NT inDrosophila midgut EE cells increases lipid accumulation in the midgut fat body and oenocytes (hepatocyte-likecells). Remarkably in humans we show that increased levels of pro-NT strongly predict new onset obesity ina graded manner which is independent of body mass index (BMI) and insulin resistance. Therefore thecentral hypothesis for our current proposal is that FFA-mediated NT release by EE cells through a cross-talkmechanism involving AMPK activation mTOR inhibition and ERK1/2 activation promotes intestinal absorptionof FFAs acting through NTR1 and/or NTR3 and the inhibition of intestinal AMPK. Moreover we speculate thatthe overconsumption of dietary fats which leads to excess NT secretion results in obesity (from continued fatstorage) and metabolic disorders (e.g. hepatic steatosis and insulin resistance). To examine our long-termgoal of better defining intestinal NT secretion and function we have assembled a multidisciplinary and highlycollaborative team with defined expertise in NT physiology and function; metabolism and systemsbiochemistry; Drosophila genetics; and biostatistics/computational biology. Ultimately our findings will: i)significantly advance the fields of GI physiology endocrinology and metabolism; ii) change existing paradigmsregarding the systemic effects of NT; and iii) revolutionize our concept of gut hormones and their role inobesity and metabolic diseases.

project_terms:
5'-AMP-activated protein kinase;Adipose tissue;Affinity;Amino Acids;Assimilations;Attenuated;Biochemistry;Biometry;Body mass index;Breast Cancer Risk Factor;Cells;Clinical;Colorectal Cancer;Complex;Computational Biology;Consumption;Development;Diabetes Mellitus;Dietary Fats;Digestion;Distant;Drosophila genus;Endocrinology;Enterocytes;Enteroendocrine Cell;Epidemiology;Epigenetic Process;FRAP1 gene;Fasting;Fat Body;Fatty Liver;Fatty acid glycerol esters;Food;Future;Gastrointestinal Physiology;Genes;Genetic;Goals;Growth;Hepatocyte;High Fat Diet;Homeostasis;Hormones;Human;Ingestion;Innovative Therapy;Insulin Resistance;Intestinal Absorption;Intestinal Mucosa;Intestines;Knockout Mice;Laboratories;Lead;Length;Link;Lipids;Liver;MAPK3 gene;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Mediating;Metabolic Diseases;Metabolism;Midgut;Molecular;Morbidity - disease rate;Mus;Neurotensin;Neurotensin Receptors;Nonesterified Fatty Acids;Nutrient;Obesity;Overnutrition;Peptides;Physiology;Play;Population Study;Process;Protein Kinase;Regulation;Role;Signal Pathway;Signal Transduction;Site;Small Intestines;Stimulus;Stomach;System;Time;Transgenic Organisms;Woman;absorption;base;blood glucose regulation;cardiovascular disorder risk;cell motility;diet-induced obesity;epidemiology study;lipid metabolism;mTOR inhibition;malignant breast neoplasm;mortality;mouse model;multidisciplinary;non-alcoholic fatty liver disease;novel;overexpression;receptor;response;sortilin;uptake

public_health_relevance:
Project NarrativeOur recent findings have shown that neurotensin (NT) a 13-amino acid peptide localized predominantly to thesmall bowel acts as a thrifty gene to absorb ingested fats; NT deficiency in mice protects against obesityinsulin resistance and hepatic steatosis associated with high fat diet consumption. Moreover we made thenovel observation that elevated NT levels in humans is strongly predictive of future obesity. Our currentstudies which define the mechanisms regulating NT secretion and intestinal function will significantly impactthe fields of GI physiology and metabolism and may eventually lead to innovative therapies for diet-inducedobesity and resultant metabolic disorders based on inhibition of NT signaling.


application_id: 10102306
project_number: 1U18DA052319-01
project_title: Validation of ghrelin hydrolysis as an effective approach to treatment of substance use disorders
administering_ic: NIDA
award_notice_date: 2020-09-17
opportunity_number: RFA-DA-20-025
application_type: 1
activity_code: U18
ic: DA
serial_number: 052319
program_official: CONRAD, CHRISTOPHER GARNER
project_start_date: 2020-09-30
project_end_date: 2022-09-29
study_section: Special Emphasis Panel[ZDA1 SKM-D (06)]
contact_pi_person_id: 10880007
contact_pi: ZHENG, FANG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
About 10 percent of American adults have struggled with substance use disorders (SUDs). In some SUDssuch as cocaine and methamphetamine (METH) use disorders there are no approved medications. For othersubstances such as alcohol nicotine and opioids there are approved medications available but relapse ratesare high. It is highly desirable to develop improved treatments for SUDs. Recently reported studies have revealedan interesting role of ghrelin in drug abuse and award-relevant behaviors. Ghrelin known as a 28 amino-acidpeptide (GSSFLSPEHQKAQQRKESKKPPAKLQPR) acylated at Ser3 by a fatty acid is produced in the stomachand travels to the brain through blood circulation. In the brain ghrelin acts on ghrelin (or growth hormonesecretagogue) receptor (GHSR) to stimulate the mesolimbic dopamine reward pathway and increase rewardingbehaviors in rodents. Ghrelin receptor antagonism has been shown to attenuate METH- amphetamine-cocaine- nicotine- fentanyl- morphine- and alcohol-induced rewarding effects. For example administration ofa selective GHSR antagonist significantly and dose-dependently attenuated morphine-induced conditionedplaced preference (CPP) and dopamine sensitization and attenuated METH self-administration tendency torelapse and METH-induced CPP. In addition pretreatment with a selective GHSR antagonist significantly anddosedependently reduced the manifestation of fentanylCPP and reduced the fentanylseeking/relapselikebehavior in rats. In fact GHSR antagonism is one of the NIDAs 10 Most-Wanted targets for opioid user disordermedication development. On the other hand GHSR possesses a naturally high constitutive activity (in theabsence of ghrelin ligand) representing 50% of its maximal activity. Due to the ghrelin receptors diverseregulatory roles associated with its constitutive activity GHSR antagonism could also result in unwanted adverseeffects. Thus alternative strategies targeting ghrelin itself could be a more interesting approach. Howeverwhether targeting ghrelin itself would be effective to attenuate the drug rewarding effects remains controversialin literature as ghrelin levels before and after treatment were not measured in previous animal studies usingghrelin sequestering approaches. It is unknown whether any of the previously used approaches was able todecrease the ghrelin level significantly enough to attenuate the substance reward. We propose to develop andtest an efficient ghrelin hydrolase which can be used as a safe and effective ghrelin modulator to attenuatesubstance rewarding effects as effective as a GHSR antagonist but without interacting with any brainreceptors/transporters and to treat SUDs including METH and opioid use disorders etc. Accomplishment of thisinvestigation will determine whether ghrelin itself is a truly effective target and whether the specific ghrelinhydrolase as a ghrelin modulator is truly effective for treatment of SUDs. If the answers are all positive (asanticipated according to our preliminary data; see below) the effective ghrelin hydrolase (recombinant protein)to be developed and tested may also serve as a promising therapeutic candidate for treatment of SUDs.

project_terms:
Acute;Adult;Adverse effects;Affect;Aftercare;Alcohol consumption;Alcohol dependence;Alcohol or Other Drugs use;Alcohols;American;Amino Acids;Amphetamines;Animals;Attenuated;Award;Behavior;Binding;Biological Assay;Blood Circulation;Brain;Butyrylcholinesterase;Chimeric Proteins;Chronic;Cocaine;Cocaine Dependence;DR1 gene;Data;Dependence;Development;Disease;Dopamine;Dopamine Receptor;Dose;Drug Exposure;Drug abuse;Esthesia;Euphoria;Fatty Acids;Feeling;Fentanyl;G-Protein-Coupled Receptors;Gastric Acid;Human;Human Engineering;Hydrolase;Hydrolysis;Hyperactive behavior;Hypesthesia;In Vitro;Ingestion;Investigation;Lead;Ligands;Literature;Methamphetamine;Morphine;Motor Activity;Mus;National Institute of Drug Abuse;Neurons;Nicotine;Octanoic Acids;Opioid;Pathway interactions;Peptides;Perception;Pharmaceutical Preparations;Physiological;Play;Presynaptic Terminals;Prevalence;Process;Production;Property;Proteins;Protocols documentation;Rattus;Receptor Signaling;Recombinant Proteins;Relapse;Reporting;Research;Rewards;Rodent;Role;Self Administration;Side;Signal Transduction;Site-Directed Mutagenesis;Stimulus;Stomach;Structure;Substance Use Disorder;Substance of Abuse;Synapses;System;Testing;Travel;Validation;Withdrawal;Work;alcohol reward;base;cocaine overdose;cocaine use;conditioned place preference;design;dimer;dopamine system;dopamine transporter;dopaminergic neuron;drug reward;effective therapy;enzyme activity;ghrelin;ghrelin receptor;growth hormone secretagogue receptor;improved;in vivo;methamphetamine use;mutant;novel therapeutic intervention;novel therapeutics;opioid use disorder;opioid user;pleasure;protein expression;protein purification;receptor;receptor expression;response;success;therapeutic candidate

public_health_relevance:
Accomplishment of this investigation will validate a potentially promising new target and may eventuallylead to development of a novel therapeutic approach to treatment of substance use disorders.


application_id: 10101624
project_number: 5R03AI148828-02
project_title: Examination C. pneumoniae-specific Incs by employing C. trachomatis L2 genetic tools
administering_ic: NIAID
award_notice_date: 2021-01-15
opportunity_number: PA-19-052
application_type: 5
activity_code: R03
ic: AI
serial_number: 148828
program_official: VINCENT, LEAH REBECCA
project_start_date: 2020-02-06
project_end_date: 2022-07-31
study_section: Special Emphasis Panel[ZRG1-IDM-B(80)]
contact_pi_person_id: 9776107
contact_pi: WOLF, KATERINA
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractMembers of the genus Chlamydia are Gram-negative bacteria that cause various acute as wellas chronic diseases in humans. Although chlamydiae share numerous aspects of their typicalbacterial life style such as intracellular developmental cycle and the preference to primarilyinvade epithelial cells these human pathogens employ sophisticated species-specific strategiescontributing to an extraordinary diversity in tissue tropism and disease manifestation. C.trachomatis infects mucosal surfaces of the human urogenital tract or columnar epithelial cellsof the eye. Chlamydia-mediated genital infections represent the leading cause of bacterial STDsin the United States with 1708569 infections reported to the CDC in 2017. C. pneumoniaeinfects mucosal surfaces of the human respiratory tract causing pneumonia bronchitispharyngitis and sinusitis. Epidemiological data suggest that most people are infected andreinfected throughout life. Infections with both chlamydial species can often lead to thedevelopment of various chronic diseases. Genome sequencing of several members of thegenus Chlamydia revealed that there are only a few C. trachomatis genes with no homologs inthe genome of C. pneumoniae whilst C. pneumoniae contains ~200 genes not found in C.trachomatis. It is highly likely that those genes unique to C. pneumoniae significantly contributeto the particular tissue tropism of this organism. In this grant we propose to utilize C.trachomatis L2 as a surrogate microorganism together with recently developed approaches forgenetic manipulation of this chlamydial species in investigating unique host-cell interactions ofthree C. pneumoniae-specific inclusion membrane proteins (Incs). Initially we would focus onCP0641 CP0401 and CP0707 putative Incs because our preliminary data demonstrated that adomain(s) of each proposed Inc is exposed to the eukaryotic host cytoplasm. Due to theunavailability of reliable genetic manipulation tools for generating mutations in C. pneumonaieemploying C. trachomatis L2 as a surrogate microorganism may prove useful for studying notonly C. pneumonaie-specific genes but also genes from other chlamydial species.

project_terms:
Acute;Alzheimer's Disease;Animal Model;Asthma;Atherosclerosis;Biotinylation;Bronchitis;Cell Communication;Cells;Centers for Disease Control and Prevention (U.S.);Chimeric Proteins;Chlamydia;Chlamydia trachomatis;Chlamydiaceae;Chlamydophila pneumoniae;Chronic Disease;Chronic Obstructive Airway Disease;Columnar Epithelium;Complex;Cytoplasm;Data;Detection;Development;Disease;Endometritis;Epithelial Cells;Eukaryotic Cell;Exposure to;Eye;Family;Genes;Genetic;Genome;Goals;Gram-Negative Bacteria;Grant;Human;Immune Sera;Infection;Invaded;Investigation;Label;Laboratories;Lead;Life;Life Style;Mass Spectrum Analysis;Mediating;Medical;Membrane;Membrane Proteins;Mucous Membrane;Multiple Sclerosis;Mutation;Organ;Organism;Oryctolagus cuniculus;Pelvic Inflammatory Disease;Peroxidases;Pharyngitis;Play;Pneumonia;Protein Analysis;Proteins;Reiter Disease;Reporting;Reproducibility;Respiratory System;Role;Salpingitis;Sarcoidosis;Sinusitis;Streptavidin;Subcellular structure;Surface;System;Tetracyclines;Tissues;United States;Woman;Work;Yeasts;acute infection;community acquired pneumonia;comparative;epidemiologic data;genetic approach;genetic manipulation;genital infection;genome sequencing;human pathogen;hydrophilicity;member;microorganism;mutant;novel strategies;pathogen;pathogenic bacteria;preference;promoter;tissue tropism;tool;urogenital tract;vector;yeast two hybrid system

public_health_relevance:
PROJECT NARRATIVE (RELEVANCE)Organisms of the family Chlamydiaceae include significant human pathogens C. pneumoniaeand C. trachomatis. In this proposal we intend to utilize recently developed genetic manipulationapproaches for C. trachomatis L2 in investigation of C. pneumonaie-specific Incs where C.trachomatis L2 will be employed as a surrogate organism for identification and characterizationof eukaryotic target molecules interacting with CP0401 CP0641 and CP0707 putative Incs.


application_id: 10098068
project_number: 5R01NS092680-05
project_title: ER Ca2+ store mediated white matter injury
administering_ic: NINDS
award_notice_date: 2021-02-14
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 092680
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2017-05-01
project_end_date: 2023-07-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 11601659
contact_pi: STIRLING, DAVID PAUL
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract: Protecting white matter following SCI is a major goal to improve neurological recovery followingspinal cord injury (SCI). Whether the axoplasmic reticulum (AR) the major endomembrane system and Ca2+store within axons contributes to secondary bystander central myelinated fiber degeneration following SCIremains unknown. Furthermore the role of the AR's major release channels ryanodine receptors (RyR) andinositol 145-trisphophate receptors (IP3R) in white matter injury remain poorly understood; however ourpreliminary data support an important role for RyR in mediating secondary degeneration of axons following aclinically-relevant contusion SCI in vivo. Our overall objective is to protect central myelinated fibers followingSCI by targeting AR Ca2+ release channels. We will test the following hypothesis within this proposal. RyRand IP3R mediate intra-axonal Ca2+ store release of Ca2+ within spinal axons and cause secondary axonaldegeneration following contusion SCI. Therefore inhibiting Ca2+ store mediated Ca2+ release by targeting RyRor upstream signaling pathways that converge on RyR and IP3R will protect white matter following SCI. Ourspecific aims are to: 1. Determine the role of RyR and IP3R in secondary axonal degeneration followingcontusion SCI in real-time. 2. Determine the role of upstream signaling pathways in AR Ca2+ release inreal-time. 3. Evaluate clinically relevant approaches to inhibit AR-mediated intra-axonal CICR toimprove neurological recovery following contusion SCI. To accomplish this goal we will utilize two-photonmicroscopy combined with an ultrafast resonant scanner (capable of collecting images at up 420 frames persecond) to assess axonal swelling spheroid formation axonal retraction degeneration (Advillin-Cre: tdTomatotransgenic mice) axonal Ca2+ wave generation and Ca2+ accumulation in axons (Advillin-Cre: tdTomato:CaMP6f and Thy1GCaMP6f transgenic mice) myelin integrity (fluorescent lipophilic dyes) and changes in AR(e.g. ER tracker dyes and 3D electron microscopy) as these dynamic events are unfolding in real-time in vivofollowing a contusion SCI. The technology and approach proposed may help advance the field as live imagingof axons over time allows unequivocal determination of the fate of injured axons and whether they can berescued in real-time with treatment. Furthermore it allows direct visualization of myelin and the fate of this vitalelement simultaneously with axons as these events are unfolding in the injured spinal cord. This proposal isinnovative and uses advanced imaging techniques to explore overlooked areas of SCI research. The approachtaken may also unveil potential novel therapeutic targets and clinically relevant treatments (e.g. FDA approvedcarvedilol) to promote neurological recovery after SCI. The underlying mechanisms of white matter injury mayalso be relevant to multiple sclerosis and other neurological diseases.

project_terms:
3-Dimensional;AVIL gene;Area;Atrophic;Axon;Behavioral;Binding Proteins;Calcium;Data;Degenerative Disorder;Distal;Dyes;Electron Microscopy;Elements;Event;FDA approved;Fiber;Gait;Generations;Goals;Human;ITPR1 gene;Image;Imaging Techniques;Injury;Inositol;Intervention;Kainic Acid Receptors;Knockout Mice;Mediating;Modeling;Molecular;Morphology;Multiple Sclerosis;Mus;Myelin;Nature;Neurologic Deficit;Pathologic;Pathology;Patients;Pharmacology;Process;Recovery;Recovery of Function;Reproducibility;Research;Reticulum;Role;Ryanodine Receptors;Secondary to;Signal Pathway;Signal Transduction;Site;Spinal;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Stroke;Swelling;System;Technology;Testing;Therapeutic;Time;Transgenic Mice;Visualization;Wallerian Degeneration;Work;axon injury;axonal degeneration;carvedilol;clinically relevant;effective therapy;functional outcomes;genetic approach;improved;in vivo;injured;innovation;kinematics;lipophilicity;loss of function;nervous system disorder;neurological recovery;new therapeutic target;novel;novel therapeutics;oxidation;preservation;prevent;receptor;serial imaging;spinal tract;two photon microscopy;white matter;white matter injury

public_health_relevance:
Project NarrativePatients with spinal cord injury often suffer from permanent neurological deficits due to loss of white matteraxons and there are currently no effective therapies to treat these problems. The molecular mechanisms thatcause secondary bystander axonal loss following spinal cord injury are poorly understood; however growingscientific evidence suggests a key role of pathological calcium in this process. This proposal will explore onepotential molecular mechanism through which the axon's major calcium store calcium release receptors mightexert such damaging effects.


application_id: 10094072
project_number: 5R01HL141081-04
administering_ic: NHLBI
award_notice_date: 2021-02-19
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 141081
program_official: WONG, RENEE P
project_start_date: 2018-04-01
project_end_date: 2023-02-28
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 12204790
contact_pi: MOORE IV, JOSEPH B
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
budget_start_date: 2021-03-01
project_title:
The Role of Cardiomyogenic Lineage Commitment in Cardiac Mesenchymal Cell-Mediated Extracellular Vesicle Signaling and Cardiac Repair

project_abstract:
Clinical trials for cell therapy reveal only modest benefits on cardiac function in heart failure (HF) patients leaving the future of this therapeutic modality uncertain. Despite years of research on the topic the celltherapy field remains engrossed in controversies regarding the mechanism(s) of action of donor cells and thecell type best suited to promote cardiac repair. Two competing hypotheses have been forwarded to explain themechanisms underlying cell therapy-mediated cardiac repair namely donor cell direct differentiation(contributing to new cardiac parenchyma) and paracrine signaling (promotion of endogenous repairmechanisms through cytokine and/or extracellular vesicle (EV) secretion). Given that donor cell populationsexhibit poor rates of retention and limited long-term persistence after delivery in HF models paracrine signalingis viewed as a major mechanism of cell-mediated cardiac repair. However there is also evidence implicating alink between therapeutic efficacy and donor cell cardiovascular fate decisions; although the mechanismsremain unknown. It is known that different cell types possess distinct trophic factor secretion profiles andparacrine signaling activities. Thus we posit that cardiovascular cell lineage commitment-dependent variationsin paracrine signaling are likely to have a significant impact on donor cell reparative capacity in cell-mediatedcardiac repair. Further as EVs have been identified as important mediators of progenitor cell-induced cardiacregeneration we hypothesize that donor cell cardiomyogenic lineage commitment regulates the expressionand synthesis of EV-resident cardiotrophic factors which mediate cardiac repair. To test this hypothesis wewill use genetic and pharmacologic approaches for enhancing cardiogenic factor expression to assess theeffects of cardiomyogenic lineage commitment on the reparative capacity of cardiac mesenchymal cells(CMCs) and lineage-dependent adaptations in CMC EV signaling. Aim 1 will interrogate the impact of genetic-and pharmacologic-mediated induction of cardiogenic factor expression on CMC cardiovascular lineagecommitment and EV paracrine signaling. Aim 2 will assess the effect of cardiomyogenic lineage commitmenton the reparative capacity of CMCs following administration in a chronic infarct model. Aim 3 will evaluate theconsequences of EV administration derived from nave and cardiomyogenic lineage-committed CMCs oncardiac repair. The results of this project will establish an unidentified link between progenitor cellcardiovascular lineage commitment and modifications in EV secretion/paracrine signaling as well as elucidatenovel targets and pathways that may be exploited to enhance the efficacy of cell therapy.

project_terms:
Affect;Azacitidine;Biological;Bone Marrow;Cardiac;Cardiovascular system;Cell Lineage;Cell Survival;Cell Therapy;Cell Transplantation;Cells;Characteristics;Chronic;Clinical Trials;Competence;Congestive Heart Failure;Dependence;Development;Exhibits;Future;GATA4 gene;Genetic;Goals;Heart;Heart failure;Human;In Vitro;Infarction;Injections;Injury;Left Ventricular Function;Light;Link;Mediating;Mediator of activation protein;Mesenchymal;Methods;Modality;Modeling;Modification;Muscle Cells;Myocardial Infarction;Nude Rats;Paracrine Communication;Pathway interactions;Patients;Pharmacology;Population;Production;Rattus;Research;Role;Signal Transduction;Structure;Testing;Therapeutic;Tissues;Treatment Efficacy;Variant;Ventricular;Ventricular Remodeling;Work;arteriole;cardiac regeneration;cardiac repair;cell type;cytokine;early phase clinical trial;extracellular vesicles;heart function;improved;neovascularization;novel;pre-clinical;release factor;repaired;reparative capacity;retention rate;stem cells;transcription factor

public_health_relevance:
Cell therapy is a promising approach to repair the human heart after a heart attack. Unfortunately ourunderstanding of how cell therapy actually works to repair dead or dying heart tissue after a heart attack islimited. This project seeks to identify the essential characteristics and/or reparative factors released fromdonor cells that contribute to their ability to improve heart function after injury.


application_id: 10093135
project_number: 5R01NR016262-05
project_title: Corazn de la Familia (Heart of the Family)
administering_ic: NINR
award_notice_date: 2021-02-01
opportunity_number: PA-14-142
application_type: 5
activity_code: R01
ic: NR
serial_number: 016262
program_official: BYNUM, SHALANDA A
project_start_date: 2017-03-02
project_end_date: 2023-12-31
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 9701191
contact_pi: MUDD, GIA
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTHispanics have significantly higher rates of type 2 diabetes (T2D) and cardiovascular disease (CVD) riskburden compared to non-Hispanic whites. Dramatic increases in rates of type 2 diabetes and cardiovasculardisease in U.S. Hispanics are anticipated as the population ages and acculturation lends to engagement inunhealthy behaviors. Culturally appropriate lifestyle modification strategies are needed for effective riskreduction. Most lifestyle modification strategies have focused on individuals and sustained engagement inhealthy behaviors is seldom achieved. Respectful of the Hispanic cultural value of familismo prioritizing of thewell-being of the family over that of the individual we propose to conduct a family dyad-focused interventionthat addresses family members as active participants in a lifestyle intervention for Hispanics with high risk forT2D or CVD. Corazn de la Familia (Heart of the Family) is a promotores- (community health workers)facilitated intervention that integrates evidence-based education and health behavior skills development withsocial support strategies through the involvement of family members. We will conduct a randomized controlledtrial using a 2-group design and compare the short-term and long-term impact of the family dyad-focusedactive intervention to an individual-focused control condition on biological and behavioral T2D and CVD riskfactors. Furthermore we will determine how each active intervention dyad members engagement in healthylifestyle behaviors and level of support for their partners engagement in healthy lifestyle behaviors affects theirown and their partners outcomes. Guided by community-based participatory research principles ourcommunity-academic partnership was formed in response to needs recognized by Hispanic residents ofKentucky for socioculturally tailored health promotion programs to reduce T2D and CVD risk. Hispaniccommunity partners have been integrally involved in all phases of sociocultural tailoring and pilot testing theCorazn de la Familia intervention. The result of the work of our community-academic partnership is a familydyad-focused intervention that provides a unique approach to sustain engagement in healthy lifestylebehaviors to reduce T2D and CVD risk among at-risk Hispanics. Further this community-based interventionhas significant potential for broad implementation to successfully address T2D and CVD health disparitiesacross U.S. Hispanic communities.

project_terms:
Acculturation;Address;Adult;Affect;Age;Behavior;Behavioral;Biological;Blood Pressure;Body mass index;Cardiovascular Diseases;Cause of Death;Communities;Community Health Aides;Complement;Diabetes Mellitus;Diagnosis;Dietary Practices;Disease;Education;Effectiveness;Environment;Ethnic group;Family;Family member;Glycosylated hemoglobin A;Health;Health Promotion;Health behavior;Heart;Heart Diseases;High Prevalence;Hispanics;Hypertension;Immigrant;Individual;Intervention;Kentucky;Length;Life;Life Style Modification;Linear Regressions;Lipids;Logistic Regressions;Modeling;Morbidity - disease rate;Non-Insulin-Dependent Diabetes Mellitus;Not Hispanic or Latino;Nutritional;Obesity;Outcome;Outcome Measure;Participant;Pattern;Personal Satisfaction;Phase;Physical activity;Population;Population Growth;Prevention;Public Health;Randomized;Randomized Controlled Trials;Research;Risk;Risk Behaviors;Risk Factors;Risk Reduction;Social support;Testing;Time;Tobacco use;Work;base;behavior influence;behavioral outcome;cardiovascular disorder risk;cardiovascular health;community based participatory research;comparison intervention;cultural values;design;disorder risk;evidence base;family support;health disparity;healthy lifestyle;high risk;hypercholesterolemia;indexing;innovation;intervention effect;lifestyle intervention;medically underserved population;member;mortality;prevent;primary outcome;programs;residence;response;secondary outcome;skill acquisition;skills;social culture;socioeconomics;success

public_health_relevance:
PROJECT NARRATIVEUsing a community-based participatory research approach this is a community-academic partnership initiativeto reduce type 2 diabetes and cardiovascular disease risk in Hispanic community members with high risk forthese diseases. The promotores (community health workers) facilitated intervention engages family dyads tosupport healthy lifestyle behaviors among dyad members integrating skills-based risk reduction approacheswith social support strategies. Successful implementation has significant potential to reduce type 2 diabetesand cardiovascular disease risk among U.S. Hispanic adults and family members.


application_id: 10093114
project_number: 5P20GM135004-02
project_title: Overcoming resistance to cancer immunotherapy by targeting MDSC-derived adenosine
administering_ic: NIGMS
award_notice_date: 2021-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-4
subproject_number: 8112
contact_pi_person_id: 10807180
contact_pi: YADDANAPUDI, KAVITHA
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_terms:
5'-Nucleotidase;Adenosine;Adopted;Advanced Malignant Neoplasm;Attenuated;CD8-Positive T-Lymphocytes;CD8B1 gene;CREB1 gene;Cancer Center;Cancer Model;Cancer Patient;Cattle;Cell physiology;Cell surface;Cells;Child;Clinical;Consumption;Critical Pathways;Cyclic AMP;Data;Dinoprostone;Disease;Enzymes;Epidermal Growth Factor Receptor;FDA approved;Frequencies;Generations;Goals;Homing;Human;Immune;Immune Cell Suppression;Immune checkpoint inhibitor;Immune system;Immunotherapeutic agent;Immunotherapy;Impairment;Implant;In Vitro;In complete remission;Inosine;Knock-out;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mediator of activation protein;Molecular;Mus;Myeloid-derived suppressor cells;Non-Small-Cell Lung Carcinoma;Nonmetastatic;Nucleosides;Outcome;PD-1 inhibitors;Pathway interactions;Patients;Polyethylene Glycols;Prostaglandin Inhibition;Purine Nucleosides;Regulation;Resistance;STAT3 gene;Severe Combined Immunodeficiency;Signal Pathway;Signal Transduction;T-Cell Activation;T-Lymphocyte;Testing;Transgenic Model;Tumor Immunity;Tumor-Derived;adenosine deaminase;anti-CTLA4 antibodies;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;cancer immunotherapy;clinically relevant;conditional knockout;effector T cell;enzyme replacement therapy;extracellular;improved;in vivo;inhibitor/antagonist;insight;monocyte;mouse model;neoplastic cell;novel;objective response rate;pembrolizumab;programmed cell death ligand 1;response;therapeutic target;therapy development;therapy resistant;transcription factor;tumor;tumor growth;tumor immunology;tumor microenvironment


application_id: 10093112
project_number: 5P20GM135004-02
administering_ic: NIGMS
award_notice_date: 2021-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-4
subproject_number: 8111
contact_pi_person_id: 10517640
contact_pi: WATSON, COREY TAYLOR
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-02-01
project_title:
Defining tumor-infiltrating B cell signatures associated with T cell mediated antitumor immunity in human lung adenocarcinoma

project_abstract:
Lung cancers are the most common malignancies and are the leading cause of cancer-related deaths worldwide.Immunotherapies are transforming treatment regimes and trials conducted in lung cancer have alreadydemonstrated improvements in long-term survival outcomes. However existing therapies are not effective in allpatients stressing a need to better characterize the complex molecular and immunological processes associatedwith treatment responsiveness and disease progression. Although T cells have been the primary target ofimmunotherapies in lung cancer there is a growing appreciation that T cell-mediated anti-tumor immunity canbe influenced by actions of other immune cells within the tumor microenvironment (TME). Tumor-infiltrating(TI) B cells have been shown to have dual roles in tumor progression generally but in non-small cell lungcancers (NSCLC) specifically adenocarcinomas (LUAD) particular B cell subsets have been shown to bothpromote T cell anti-tumor responses and positively impact long-term survival outcomes. Indications of a role forspecific antibody (Ab) responses in LUAD have also recently been reported including evidence of focused tumorantigen-specific responses. However characterizations of anti-tumor B cells and their functional signatures havebeen limited by the study of only a small number of pre-selected surface markers in relatively small numbers ofpatients. Nonetheless it is evident that B cell-mediated roles in LUAD tumor progression are variable amongpatients and indicates that a more comprehensive and integrated characterization of TI B cell phenotypicvariation and the associated effects on the anti-tumor T cell response has great potential to inform ourunderstanding of disease progression as well as the development of novel potentially personalized therapies.The overall goal of this proposal is to define TI B cell signatures that are associated with the T cell-mediatedanti-tumor response in human lung cancer. To achieve this goal we will leverage several cutting-edgetechniques to first comprehensively profile lymphocytes (B and T cells) in tumor and paired normal tissues froma large cohort of early-stage LUAD patients including the first pairing of this type of data with Ab repertoiresequencing as a means to interrogate critical functional Ab response signatures in LUAD B cells. Importantlythe single-cell profiling approach proposed will leverage B cell markers already determined to be associated withlong-term LUAD survival outcomes so that distinct functional B cell profiles and their associations with TI T cellscan be identified specifically in the context of disease progression (Aim 1). These large-scale statisticalassociations will be validated and then serve as a framework for conducting functional in vitro culture and serum-based analyses to assess whether prognostically favorable B cell subsets identified have distinct functionalphenotypes associate with tumor antigen-specific Ab responses and have differential effects on T cell activationand effector function (Aim 2). Successful completion of this project will facilitate novel discovery and biomarkerscritical for the development of novel therapeutics in human lung cancer.

project_terms:
Adenocarcinoma;Antibodies;Antibody Repertoire;Antibody Response;Antigen Presentation;Antigen-Antibody Complex;Antigens;Antitumor Response;B-Cell Activation;B-Cell Neoplasm;B-Lymphocyte Subsets;B-Lymphocytes;Biological Assay;Biological Markers;CD8B1 gene;Cancer Center;Cancer Etiology;Cell physiology;Cell surface;Cells;Cessation of life;Clinical;Coculture Techniques;Complex;Data;Data Set;Development;Disease Progression;Exhibits;Foundations;Frequencies;Funding;Future;Generations;Goals;Human;IgE;Immune;Immunoglobulin G;Immunoglobulin M;Immunologics;Immunotherapy;In Vitro;Individual;Lung Adenocarcinoma;Lung Neoplasms;Lymphocyte;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Molecular;Nature;Non-Small-Cell Lung Carcinoma;Normal tissue morphology;Outcome;Pathogenesis;Patient-Focused Outcomes;Patients;Peripheral;Phenotype;Plasmablast;Population;Prevalence;Process;Regulatory T-Lymphocyte;Reporting;Role;Secure;Serum;Stress;Structure of parenchyma of lung;Surface;T cell response;T-Cell Activation;T-Cell Proliferation;T-Lymphocyte;T-Lymphocyte Subsets;Techniques;Testing;Transcript;Treatment Efficacy;Treatment outcome;Tumor Antigens;Tumor Immunity;Tumor-Infiltrating Lymphocytes;Variant;Work;base;biomarker panel;cancer immunotherapy;cohort;design;effective therapy;effector T cell;exhaustion;improved;insight;novel;novel therapeutics;outcome prediction;patient stratification;peripheral blood;personalized medicine;phenotypic biomarker;phenotypic data;prognostic;response;survival outcome;therapy design;tumor;tumor immunology;tumor microenvironment;tumor progression


application_id: 10093109
project_number: 5P20GM135004-02
project_title: Ongoing inflammation following chemotherapy induces immunosuppression
administering_ic: NIGMS
award_notice_date: 2021-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-4
subproject_number: 8109
contact_pi_person_id: 9855558
contact_pi: DING, CHUANLIN
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_terms:
Address;Antioxidants;Bone Marrow;Breast Cancer Patient;Breast Cancer cell line;CX3CL1 gene;Cancer Center;Cells;Centers of Research Excellence;Chemotherapy-Oncologic Procedure;Clinical;Clinical Management;Data;Dose;Fluorouracil;Granulocyte-Macrophage Colony-Stimulating Factor;Hematopoiesis;Hematopoietic stem cells;Human;Immune response;Immune system;Immunity;Immunocompetence;Immunosuppression;In Vitro;Inflammation;Inflammatory;Intercellular adhesion molecule 1;Investigation;Mitochondria;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;Oxidative Phosphorylation;Paclitaxel;Peripheral;Pharmaceutical Preparations;Pharmacotherapy;Production;Reactive Oxygen Species;Recruitment Activity;Regimen;Role;Side;Stromal Cells;Testing;Time;Tissues;Tumor Immunity;Tumor-Derived;Tumor-associated macrophages;Up-Regulation;anti-tumor immune response;antitumor effect;base;cancer immunotherapy;cancer therapy;chemokine;chemotherapy;combinatorial;cytokine;design;gemcitabine;in vivo;monocyte;neoplastic cell;novel;novel therapeutic intervention;receptor;response;tumor;tumor immunology;tumor microenvironment;tumor progression


application_id: 10093049
project_number: 5R01EY030933-02
project_title: Blood outer retina barrier regulation
administering_ic: NEI
award_notice_date: 2021-01-15
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: EY
serial_number: 030933
program_official: SHEN, GRACE L
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 1877760
contact_pi: DEAN, DOUGLAS CHASE
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adaptor Signaling Protein;Age;Animal Model;Apical;Arrestins;Automobile Driving;Back;Binding;Birth;Blood;Blood Circulation;Cell Death;Cells;Choroid;Clathrin;Complex;Cone;Cytoplasm;Cytoskeletal Modeling;DNA;Dark Adaptation;Development;Disease;Disease Progression;Down-Regulation;Endocytosis;Environment;Epigenetic Process;Epithelial Cells;Event;Face;Family;Family suidae;Feedback;Feeds;GLUT 4 protein;Gene Expression;Genes;Glucose;Glucose Transporter;Hypoglycemia;Injections;Insulin;Integrins;Investigation;Label;Light;Link;Lipids;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic;Metabolic Pathway;Metabolism;Modeling;Mus;Mutation;Neurons;Nutrient;Pathway interactions;Peripheral;Phagocytosis;Phosphatidylserines;Phosphorylation;Photoreceptors;Proteins;Reading;Regulation;Resolution;Retina;Retinal Pigments;Retinitis Pigmentosa;Rod;Rod Outer Segments;Signal Pathway;Signal Transduction;Starvation;Structure of retinal pigment epithelium;Surface;TXNIP gene;Time;Transplantation;Vision;Visual;Work;alpha ketoglutarate;coated pit;cofactor;epigenome;experimental study;functional loss;glucose metabolism;glucose transport;glucose uptake;histone demethylase;inhibitor/antagonist;loss of function;macrophage;metabolome;mutant;overexpression;prevent;receptor;recruit;response;restoration;retinal rods;scaffold;subretinal injection;uptake


application_id: 10093003
project_number: 5R01DC017025-04
project_title: ATP-purinergic mechanisms underlying noise-induced cochlear synaptopathy and hearing loss
administering_ic: NIDCD
award_notice_date: 2021-02-12
opportunity_number: PAR-16-170
application_type: 5
activity_code: R01
ic: DC
serial_number: 017025
program_official: CYR, JANET
project_start_date: 2018-03-22
project_end_date: 2023-02-28
study_section: Special Emphasis Panel[ZRG1-IFCN-Y(56)]
contact_pi_person_id: 8536073
contact_pi: ZHAO, HONG-BO
other_pis: Not Applicable
congressional_district: 06
department: OTOLARYNGOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARY The long-term goal of this project is to investigate mechanisms underlying noise-induced cochlearsynaptopathy and hidden hearing loss. Noise is a common risk factor for hearing loss. Recent studieshave demonstrated that even a single episode of noise overexposure induces transient hearing lossi.e. temporal threshold shift (TTS) noise-exposed animals could have no hair cell loss but haveextensive spiral ganglion neuron (SG) and synapse degeneration. In particular low spontaneous rate(LSR) auditory nerves and their synaptic connections with inner hair cells are preferentially lost. Thenoise-exposed animals and humans demonstrate normal hearing threshold and sensitivity (i.e.hidden hearing loss) in the early stage but will eventually exhibit other hearing disorders and hearingloss. Currently the underlying mechanism for such cochlear synaptopathy remains unclear. Noise stimulates hair cell and neuron over-activation and increases K+ efflux that leads toincreasing extracellular K+ concentration. It is well-established that high extracellular K+ can inducetoxicity leading to second cell death in the brain following injury and stroke. We hypothesize thathigh excess extracellular K+ following noise exposure can also cause SG synapse and neurondegeneration in the cochlea. We previously found that ATP purinergic P2X receptors in the cochleaare required for sinking K+ to re-enter into cells. A recent study also demonstrated that P2X2receptors are necessary for the development of TTS. In addition we found that P2X2 mutation canincrease susceptibility to noise and induce hearing loss. These studies indicate that P2X receptorsmay have a critical role in noise-induced cochlear synaptopathy and hidden hearing loss. In thisproject we will first test whether high extracellular K+ can cause SG synapse and neurondegeneration (Specific Aim 1 SA1). Then we will identify and characterize P2X receptor expressionin SG neurons including LSR and HSR (high spontaneous rate) fiber synaptic endings and testwhether P2X receptors can mediate K+-sinking in the SG neurons. In SA3 we will test whetherdeficiency of P2X receptors can induce and exacerbate cochlear synaptopathy and hearing lossfollowing noise exposure and high-K+ challenge. Completion of these studies will directly reveal themolecular mechanism underlying noise-induced cochlear synaptic degeneration and hidden hearingloss. These novel studies will also open a new therapeutic avenue for targeting noise-induced hearingloss and cochlear synaptopathy.

project_terms:
Acoustic Nerve;Address;Animals;Apoptosis;Apoptotic;Area;Astrocytes;Auditory Threshold;Auditory system;Brain;CASP3 gene;Cell Death;Cells;Cessation of life;Cochlea;Data;Development;Exhibits;Fiber;Gap Junctions;Gene Family;Generations;Genetic;Goals;Hair Cells;Hearing problem;Homogeneously Staining Region;Human;Injury;Inner Hair Cells;Mediating;Microscopy;Molecular;Mutation;Nerve Degeneration;Nerve Fibers;Neurons;Noise;Noise-Induced Hearing Loss;Optics;P2X-receptor;Pathway interactions;Play;Postsynaptic Membrane;Predisposition;Protein Isoforms;Purinoceptor;Research;Resolution;Risk Factors;Role;Stroke;Synapses;Techniques;Technology;Testing;Therapeutic Intervention;Toxic effect;cochlear synaptopathy;extracellular;hearing impairment;hidden hearing loss;light microscopy;normal hearing;novel;novel therapeutics;public health relevance;receptor;receptor expression;receptor function;reconstruction;spiral ganglion

public_health_relevance:
Public Health Relevance Statement: In this proposal we will define novel purinergic mechanism underlying noise-inducedcochlear synaptopathy and hidden hearing loss using multiple state-of-the-art techniques. Thiswill enhance our understanding of genetic causes underlying noise-induced hearing loss. Thisstudy will provide invaluable clues for developing and applying protective and therapeuticinterventions for noise-induced hearing loss in particular hidden hearing loss.


application_id: 10092953
project_number: 5R03AI151621-02
project_title: Engineered promoters for finely tuned gene expression in Chlamydia
administering_ic: NIAID
award_notice_date: 2021-01-15
opportunity_number: PA-19-052
application_type: 5
activity_code: R03
ic: AI
serial_number: 151621
program_official: VINCENT, LEAH REBECCA
project_start_date: 2020-02-01
project_end_date: 2022-04-30
study_section: Special Emphasis Panel[ZRG1-IDM-B(80)S]
contact_pi_person_id: 7726964
contact_pi: FIELDS, KENNETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Chlamydia trachomatis represents a significant health concern world-wide. A substantialburden exists due to the prevalence and the combined health and socioeconomic impact ofacute and chronic disease. Chlamydiae are obligate intracellular parasites that undergo acomplex developmental cycle and this biology has historically impeded rapid progress inunderstanding pathogenesis. Recently the ability to transform Chlamydia with exogenous DNAhas greatly facilitated advances in understanding the molecular mechanisms underpinning thesuccess of chlamydial infection. For example ectopic expression of chlamydial genes hasprovided insight into intracellular localization and function. As studies become moresophisticated however current promoter systems are often proving inadequate to addressphysiologically relevant biology. Progress is particularly hindered by limited choices in tightly-regulated inducible promoters. We propose to address deficiencies by developing reagents formore finely tuned gene expression in Chlamydia. We will exploit advances in synthetic biologyand rational design to engineer a suite of tightly regulated and tunable promoters. Preliminarydata showing the efficacy of the approach are presented herein. We propose to validate andfurther develop these technologies. At the end of these studies we will have established newapproaches that will benefit the entire Chlamydia research community and advance the utility ofectopic gene expression to study chlamydial infection biology.

project_terms:
Acute Disease;Address;Area;Attention;Binding Sites;Biological Assay;Biology;Chemicals;Chlamydia;Chlamydia Infections;Chlamydia trachomatis;Chronic Disease;Communities;Complex;Consensus Sequence;Coupled;DNA;Data;Development;Ectopic Expression;Elements;Engineering;Epithelial Cells;Gene Deletion;Gene Expression;Gene Silencing;Generations;Genes;Genetic;Genetic Transcription;Goals;Gram-Negative Bacteria;Health;Infection;Insertional Mutagenesis;Metabolism;Methodology;Modeling;Molecular;Mutagenesis;Pathogenesis;Physiological;Physiology;Plasmids;Prevalence;Proteins;Reagent;Reproducibility;Research;Sexually Transmitted Agents;Sexually Transmitted Diseases;System;Techniques;Technology;Testing;Transcription Initiation Site;Virulence;Work;base;design;experience;flexibility;functional group;gene product;genetic manipulation;inducible gene expression;innovation;insight;member;new technology;novel;novel strategies;obligate intracellular parasite;promoter;protein expression;protein function;socioeconomics;success;synthetic biology;tool;transcription factor

public_health_relevance:
Chlamydia trachomatis an agent of sexually transmitted disease has recently become tractablefor genetic manipulation. This proposal contains work designed to develop more sophisticatedmethodologies and reagents to enable controlled expression of genes. This will enable morerigorous and reproducible approaches for the study of Chlamydia pathogenesis.


application_id: 10092819
project_number: 5R01CA217255-05
project_title: Studies to understand and exploit 10-membered enediyne biosynthesis
administering_ic: NCI
award_notice_date: 2021-02-17
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 217255
program_official: FU, YALI
project_start_date: 2017-03-01
project_end_date: 2023-02-28
study_section: Special Emphasis Panel[ZRG1-BCMB-U(02)M]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: PHILLIPS, GEORGE NEAL;VAN LANEN, STEVEN GARY
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe 10-membered enediynes [exemplified by calicheamicin (CLM) esperamicin (ESP) and dynemicins (DYN)]are arguably among the most renowned natural products (NPs) discovered to date by virtue of theirunprecedented complex molecular architectures notable anticancer and anti-infective potencies and in the caseof CLM demonstrated clinical utility. The current study builds on a longstanding collaborative effort ofachievement and discovery relating to key aspects of 10-membered enediyne biosynthesis as well as parallelinnovative efforts to co-opt key biosynthetic catalysts for synthetic applications. The studies put forth will takeadvantage of this strong foundation and a powerful combination of genetic biochemical chemical and proteinstructural tools to elucidate the remaining unusual biosynthetic transformations and to exploit select catalysts forenediyne non-native modification. Specifically aims 1 and 2 will focus on extending our understanding of thefundamental steps of enediyne core biosynthesis common to CLM/DYN/ESP DYN anthraquinone biosynthesisand a selected set of unique tailoring reactions (CLM/ESP thiosugar sulfur installation and aminopentose N-alkylation ESP C6-hydroxylation and O-glycosylation). In parallel aim 3 will focus on tactical structural studiesto augment both aims 1 and 2 and the structural study of unknowns to facilitate functional annotation. Additionalstudies in aim 2 with key catalysts and corresponding non-native substrates are designed to assess the potentialfor strategic installation of chemoselective handles to enable novel approaches for facile mild bioconjugation ofCLM to tumor-targeting mAbs (in collaboration with Pfizer).

project_terms:
Achievement;Alkylation;Amines;Anabolism;Anthraquinones;Anti-Infective Agents;Antibodies;Antitumor Natural Products;Architecture;Biochemical;Biogenesis;Bioinformatics;Biotin;Chemical Structure;Chemistry;Clinical;Collaborations;Complement;Complex;Crystallization;Cyclization;Development;Dynemicin;Enzymatic Biochemistry;Enzymes;Family member;Foundations;Genetic;Hybrids;Hydroxylation;Iodination reaction;Ligands;Mixed Function Oxygenases;Modality;Modification;Molecular;Monoclonal Antibodies;Natural Products;Nucleotides;Polyenes;Proteins;Reaction;Reagent;Route;Series;Structure;Sulfur;Trisaccharides;analog;anti-cancer;base;cancer therapy;catalyst;chemical genetics;clinical development;design;enzyme pathway;genetic approach;glycosylation;glycosyltransferase;innovation;insight;non-Native;novel;novel strategies;oxidation;polyketide synthase;prototype;structural biology;structural genomics;sugar;targeted agent;thiosugar;tool;tumor

public_health_relevance:
PROJECT NARRATIVEThis proposal seeks to study a prioritized set of highly unique enzyme-catalyzed transformations involved inthe biosynthesis of antitumor natural products (10-membered enediynes) and develop new strategies toconjugate 10-membered enediynes to tumor-targeting agents. The proposed studies will advance ourfundamental understanding of natural product biosynthesis and provide strategies for enhancing the clinicalutility of enediynes in the treatment of cancer.


application_id: 10091382
project_number: 5R01AG038651-08
project_title: Role of impaired cognitive states & risk factors in conversion to mixed dementias
administering_ic: NIA
award_notice_date: 2021-02-11
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AG
serial_number: 038651
program_official: ANDERSON, DALLAS
project_start_date: 2011-09-01
project_end_date: 2024-01-31
study_section: Neurological, Aging and Musculoskeletal Epidemiology Study Section[NAME]
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: ABNER, ERIN ;YU, LEI
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractPopulation demographic trends suggest an expected dramatic increase in age-associateddementias and a looming public health crisis. Current emphasis is on disease prevention with afocus on older adults who express early cognitive impairment. The SMART (Statistical Modelingof Aging and Risk of Transitions) has successfully harmonized data from nine differentlongitudinal studies on aging involving records on 5032 subjects with 1657 having autopsyinformation. We propose to identify authoritatively the roles of diabetes and hypertension on theoccurrence and duration of pre-dementia states as well as mixed pathology. The project hasshown that self-reported diabetes is not a risk for Alzheimer pathology but is a risk forcerebrovascular pathology that subjective memory complaints are a risk for a future cognitiveimpairment and that transitioning to a subjective complaint or even to mild cognitive impairmentis no guarantee of future dementia. The SMART renewal proposes to obtain Medicare claimsdata on its participants to determine the severity of diabetes hypertension and othercomorbidities that have not been investigated such as renal disease with a focus on improvingthe prediction of who is at risk for a transition to an impaired cognitive state and mixed dementiapathology. This will be accomplished through the following specific aims:Aim 1. Update and extensively revise the existing SMART project database with additionalparticipant data; obtain and integrate linked Medicare claims data; assess agreement betweenself-reported medical history and claims data. Aim 2. Investigate the relationship of HTN T2DMand multimorbidity in advanced old age with AD and non-AD neuropathologies. Aim 3. Investigatethe relationship of HTN T2DM and multimorbidity in advanced old age with cognitive statesincluding subjective memory complaints mild cognitive impairment and dementia.

project_terms:
Academic Medical Centers;Adult;Affect;Age;Age of Onset;Aging;Agreement;Alzheimer's Disease;Alzheimer's disease diagnosis;Alzheimer's disease pathology;Alzheimer's disease risk;Americas;Area;Autoimmune Diseases;Autopsy;Brain;Cerebrovascular Disorders;Cessation of life;Chronic Disease;Clinical;Cognitive;Conflict (Psychology);Data;Databases;Dementia;Diabetes Mellitus;Diagnosis;Elderly;Factor Analysis;Female;Funding;Future;Goals;Grant;Health Sciences;Hypertension;Impaired cognition;Impairment;Individual;Infarction;Investments;Kentucky;Kidney Diseases;Knowledge;Life;Link;Longitudinal Studies;Lung diseases;Medical Genetics;Medical History;Medicare;Medicare claim;Memory;Microvascular Dysfunction;National Institute on Aging;Non-Insulin-Dependent Diabetes Mellitus;Oregon;Paper;Participant;Pathology;Patient Self-Report;Population;Primary Prevention;Probability;Public Health;Records;Research;Research Personnel;Risk;Risk Factors;Role;Sample Size;Secondary Prevention;Severities;Statistical Models;Universities;Update;Washington;age related;care costs;cerebrovascular pathology;clinical Diagnosis;cognitive testing;comorbidity;data harmonization;data integration;dementia risk;disorder prevention;follow-up;human old age (65+);improved;mild cognitive impairment;mixed dementia;multiple chronic conditions;neuropathology;sex;trend

public_health_relevance:
Project NarrativeWith the graying of America the cost of caring for older adults with dementia will risesubstantially over the next few decades. Current emphasis in the field is on primary andsecondary prevention. This project will study diabetes and hypertension as risk factors forvarious forms of dementia inducing pathology as well as the impaired clinical states thatprecede diagnosed dementia.


