# projects

application_id: 11013390
project_number: 5K23MH126211-04
project_title: A Precision Medicine Approach to Target Engagement for Emotion Regulation
administering_ic: NIMH
award_notice_date: 2025-01-27
opportunity_number: PA-20-206
application_type: 5
activity_code: K23
ic: MH
serial_number: 126211
program_official: CHAVEZ, MARK RAY
project_start_date: 2022-01-01
project_end_date: 2025-01-02
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
contact_pi_person_id: 14333057
contact_pi: SOUTHWARD, MATTHEW WAYNE
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:
Emotion dysregulation is a transdiagnostic maintenance factor involved in a wide array of costly anddebilitating psychiatric disorders. Although numerous full-model behavioral health treatments have beendesigned to improve patients emotion regulation capacities these treatments consist of multiple componentsmaking it difficult to discern which are active mechanisms leading to reductions in negative emotion intensity.Further it is unclear whether the delivery of these evidence-based components can be tailored to the individualpatient. The proposed Mentored Patient-Oriented Research Career Development Award (K23) is a four-yearplan to support the applicants long-term career goal of becoming a clinical scientist with expertise in (1)identifying active mechanisms of emotion regulation interventions for psychopathology (2) tailoring theseinterventions to individual patients and (3) developing scalable interventions for wide dissemination. Theapplicants training and career thus far are aligned with these long-term goals. Throughout his graduate workhe conducted studies testing emotion regulation mechanisms in transdiagnostic samples and used thisinformation to explore for whom these mechanisms were most impactful. The immediate goals of the K23award are for the applicant to become skilled at intensive longitudinal experimental designs to disaggregatebetween- from within-person mechanisms of change and enhance his proficiency in conducting and analyzingmultimethod assessments of emotion regulation. This proposal uses a two-phase approach to address thesegoals. In line with an experimental therapeutics approach the goal of Phase 1 is to compare the effects ofteaching one or three emotion regulation skills on daily changes in negative emotion intensity amongparticipants with elevated emotion dysregulation. The first goal of Phase 2 is to apply a personalizationalgorithm based on Phase 1 data to an independent sample to determine which baseline participantcharacteristics predict greater reductions in negative emotion intensity in each experimental condition. Thesecond goal of Phase 2 is to compare the effects of teaching participants emotion regulation skill(s) accordingto their optimal or non-optimal delivery condition based on the personalization algorithm. The training planclosely matches the proposed research and long-term goals including (a) developing advanced understandingin statistical methods to test between- and within-person mechanisms of emotion regulation interventions (b)gaining proficiency in applying novel personalization algorithms and (c) enhancing expertise in theimplementation and analysis of multimethod assessments of emotion regulation skills. The broader aim of thisresearch and training is to address the need for more efficient personalized and scalable interventions fortransdiagnostic psychiatric conditions in line with the NIMH strategic plan. This study will answer importanttheoretical and practical questions about the efficacy of different emotion regulation mechanisms on clinicaloutcomes that may promote the development of more targeted and disseminable interventions.

project_terms:
Address;Aftercare;Algorithms;Anger;Anxiety;Articulation;Behavioral;Behavioral Model;Borderline Personality Disorder;Characteristics;Clinical;Consensus;Data;Dedications;Development;Diagnostic;Disease;Disease remission;Ecological momentary assessment;Educational process of instructing;Emotional;Emotional disorder;Emotions;Explosion;Goals;Influentials;Intervention;Intervention Strategies;Investigational Therapies;Learning;Machine Learning;Maintenance;Mediating;Mental Health;Mental disorders;Mentored Patient-Oriented Research Career Development Award;Methods;Multimedia;National Institute of Mental Health;Nature;Outcome;Participant;Patient Representative;Patient Self-Report;Patient-Focused Outcomes;Patients;Persons;Phase;Population;Process;Productivity;Psychopathology;Randomized;Reporting;Research;Research Domain Criteria;Role;Sampling;Scientist;Signal Transduction;Statistical Methods;Strategic Planning;Symptoms;Techniques;Testing;Therapeutic;Time;Training;Trauma;Work;behavior measurement;behavioral health;career;cost;depressive symptoms;design;efficacious intervention;emotion dysregulation;emotion regulation;emotional experience;emotional functioning;evidence base;experience;functional outcomes;health care availability;health care service;improved;in vivo;indexing;individual patient;longitudinal design;novel;precision medicine;prospective;response;skills

public_health_relevance:
The proposed study is designed to first test whether teaching people with emotion dysregulation asingle emotion regulation skill in depth or multiple emotion regulation skills in less depth leads to greaterdecreases in daily negative emotion intensity. Second using data from an initial sample we will prospectivelyassign an independent sample of participants to receive their predicted optimal or non-optimal skill condition todetermine if it is feasible and efficacious to match the participants to a single- or multiple-skill condition. Resultsof these studies may identify the mechanisms by which emotion regulation interventions impact emotionalfunctioning and allow for the development of personalized evidence-based and scalable emotion regulationinterventions.


application_id: 11012377
project_number: 5K01AG070279-03
project_title: Cognitive Aging Trajectories in Survivors of Trauma
administering_ic: NIA
award_notice_date: 2025-01-23
opportunity_number: PA-20-190
application_type: 5
activity_code: K01
ic: AG
serial_number: 070279
program_official: TREVINO, MELISSA
project_start_date: 2023-05-15
project_end_date: 2028-01-31
study_section: Career Development For Early Career Investigators Study Section [AGCD-2]
contact_pi_person_id: 8923142
contact_pi: LAWRENCE, KAREN ANN
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 SOCIAL WELFARE/WORK
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Dementia and the prodromal stages of cognitive decline together affect approximately 25-30% of older adultsacross the United States (U.S.). Posttraumatic Stress Disorder (PTSD) has been linked to a 111% increasedrisk of developing dementia of any type even after controlling for potential confounders such as traumatic braininjury (TBI). Therefore PTSD may be an important target for early prevention of cognitive decline and potentialprogression to dementia. Most studies on PTSD and cognition have used a cross-sectional study design andhave not examined important potential effect modifiers (e.g. sex and APOE4 carrier status) leaving a gap inour fundamental understanding of the effect of PTSD on longitudinal trajectories of cognitive functioning.Further although PTSD is more prevalent in women most research on PTSD and cognition has beenconducted in men. This proposal is of timely public health importance as the pre-pandemic lifetime prevalenceof PTSD in the U.S. was 6% but post-pandemic epidemiological findings have indicated a rise toapproximately 32% among young adults. COVID-19 events have also resulted in PTSD symptoms withoutmeeting Diagnostics and Statistical Manual of Mental Disorders 5th edition (DSM-5) Criterion A. Thereforecritical research gaps in our understanding of the effect of PTSD on cognitive aging include: 1) prospectiveinvestigation wherein temporal sequencing and rate of cognitive decline can be evaluated in the context ofPTSD 2) testing the potential modifying effects of sex and APOE4 carrier status on the relationship betweenPTSD status and cognitive decline and 3) understanding whether Criterion A is necessary when determiningthe relationship between PTSD and cognitive decline. Aims 1 and 2 will leverage existing data from theNational Alzheimer's Coordinating Center (NACC). In adults aged 55+ years multilevel modeling andinteraction analyses will determine the impact of PTSD status on trajectories rate and temporal sequence ofdomain-specific cognitive decline and will test sex and APOE4 carrier status as potential effect modifiers. ForAim 3 men and women participants aged 65+ with and without Criterion A trauma will be recruited andmultiple regression will be used to unambiguously clarify if PTSD severity (Criteria B through E) is associatedwith cognitive functioning without meeting Criterion A. This K01 award will provide training and mentorship inaging health cognitive aging sex-specific health effects of PTSD neuropsychology of PTSD longitudinalstudy design and advanced statistics and propel the PI to become an independent investigator with expertisein the effects of traumatic stress and biopsychosocial factors on cognitive aging with a sex-specific focus andin alignment with Goals B-3 B-4 and F-4 of NIAs Strategic Directions 2020-2025.

project_terms:
Accidents;Address;Adult;Affect;Aging;Alzheimer's Disease;Alzheimer's disease related dementia;Anxiety;COVID-19;COVID-19 pandemic;Clinical;Clinical Sciences;Cognition;Cognitive;Cognitive aging;Cross-Sectional Studies;DSM-V;Data;Data Collection;Dementia;Diagnosis;Diagnostic;Diagnostic and Statistical Manual of Mental Disorders;Disasters;Epidemiology;Episodic memory;Event;Funding;Goals;Health;Impaired cognition;Incidence;Intervention;Investigation;Kentucky;Link;Medical;Mental Depression;Mentored Research Scientist Development Award;Mentors;Mentorship;Modeling;Modification;National Center for Advancing Translational Sciences;Neuropsychology;Participant;Pharmaceutical Preparations;Post-Traumatic Stress Disorders;Prevalence;Prevention;Psychologist;Public Health;Recording of previous events;Research;Research Design;Research Personnel;Risk;Risk Factors;Severities;Sex Differences;Short-Term Memory;Survivors;Symptoms;Testing;Training;Translational Research;Trauma;Traumatic Brain Injury;United States;Universities;War;Woman;Women's prevalence;aged;apolipoprotein E-4;biopsychosocial factor;carrier status;clinical center;cognitive function;cohort;comorbidity;dementia risk;disability;executive function;first responder;functional decline;human old age (65+);longitudinal design;meetings;men;mild cognitive impairment;military veteran;multilevel analysis;older adult;pandemic disease;post-pandemic;pre-clinical;pre-pandemic;processing speed;prospective;recruit;sex;sexual assault;statistics;traumatic stress;young adult

public_health_relevance:
PROJECT NARRATIVEPTSD prevalence is high and PTSD increases the risk of dementia. The proposed research will: a) investigatethe impact of PTSD on the rate of domain-specific cognitive decline b) test potential effect modifiers includingsex of the relationship between PTSD and rate of cognitive decline and c) determine the association betweencognitive functioning and PTSD severity with and without Criterion A trauma. Successful completion of thisproject has important public health implications including indicating whether PTSD should be considered atarget for the early prevention of cognitive decline that may lead to dementia and increasing understanding ofsex differences in the relationship between PTSD and cognitive decline.


application_id: 11011811
project_number: 2R35GM130349-06
project_title: Functional Analysis of Programmed Genome Rearrangement
administering_ic: NIGMS
award_notice_date: 2025-01-17
opportunity_number: PAR-22-180
application_type: 2
activity_code: R35
ic: GM
serial_number: 130349
program_official: VATAKIS, DIMITRIOS NIKOLAOS
project_start_date: 2019-02-01
project_end_date: 2029-12-31
study_section: Maximizing Investigators' Research Award A Study Section[MRAA]
contact_pi_person_id: 9381521
contact_pi: SMITH, JERAMIAH JAMES
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:
My laboratorys research interests are focused on understanding how changes in genome sequence structureand function arise: both in the context of changes that accumulate over deep evolutionary time and in the contextof changes that occur during the development of cell lineages. An individuals genome provides a complete setof instructions for completing development regulating physiology and passing heritable information to the nextgeneration. These instructions are encoded in the linear sequence of DNA molecules and are modulated byepigenetic modifications in the context of higher-order structures. Alterations at any scale can severely impactan individuals health or ability to reproduce. It is therefore not surprising that life has evolved a variety ofmolecular pathways that contribute to the maintenance of genome integrity. Studying these diverse mechanismscan provide critical comparative perspective on the cellular molecular and evolutionary underpinnings of humangenome biology and has the potential to reveal new approaches to modulating related pathways in human.Following this philosophy my lab has sought to understand the functional and evolutionary mechanisms thatunderlie the remarkable diversity of genome biologies that exist among deep vertebrate lineages. This worktakes advantage of the deep evolutionary history of key vertebrate groups (including lamprey hagfish andsalamander) and exceptional aspects of their genome biologies (e.g. programmed DNA loss and reprogrammingduring development/regeneration) to gain new inroads toward understanding vertebrate genome biology. Our recent work has largely focused on dissecting the causes and consequences of programmed genomerearrangement (PGR) in the sea lamprey (Petromyzon marinus). In lampreys PGR involves changes in thephysical structure (and content) of the genome that occur in a highly predictable and programmatic mannerduring early development. These changes result in the reproducible loss of a specific subset of genes from allsomatic cell lineages. In total ~20% of the lampreys genome is eliminated from somatic cells and retained onlyby germ cells. Recent progress in this line of research has substantially improved our understanding of thestructure of eliminated chromosomes allowed us to trace the origins and evolution of eliminated genes provideda more integrative understanding of PGR in the context of early embryonic reprogramming and identifiedcellular/developmental pathways that contribute to later stages of PGR. However the pathways that achieveinitial targeting of sequences for elimination and their differential behavior during cell division remain elusive. Proposed studies aim to further this line of research address several outstanding challenges with respect toPGR. These include identification of the pathways that that mediate 1) the targeting of sequences for elimination2) the differential migration of eliminated chromatin and 3) the stable packaging of eliminated DNA. In additionour recent work has highlighted the necessity of 4) resolving how PGR integrates with other mechanisms ofembryonic reprogramming that direct the early development of germline and soma.

project_terms:
Address;Behavior;Biology;Cell Lineage;Cell division;Chromatin;Chromosomes;DNA;DNA Sequence;Development;Embryo;Epigenetic Process;Event;Evolution;Funding;Genes;Genome;Germ Cells;Germ Lines;Hagfish;Health;Heritability;Higher Order Chromatin Structure;Human;Human Genome;Individual;Instruction;Laboratory Research;Lampreys;Life;Maintenance;Mediating;Modification;Molecular;Natural regeneration;Pathway interactions;Petromyzon marinus;Philosophy;Physiology;Recording of previous events;Reproducibility;Research;Salamander;Somatic Cell;Structure;Time;Work;comparative;genome integrity;improved;interest;migration;neuronal cell body;next generation;novel strategies;pluripotency;tumorigenesis;vertebrate genome

public_health_relevance:
Lamprey is a vertebrate that undergoes developmentally programmed genome rearrangements which result inthe reproducible elimination of ~20% of the genome from nearly all somatic cell lineages (this material is retainedonly in the germline). Our proposed studies will allow us to unravel the mechanisms by which lamprey physicallyreengineers its genome and understand how elimination mechanisms are integrated with other epigeneticreprogramming events that define early vertebrate development. If funded these studies will contribute to ourfundamental understanding of cellular mechanisms that contribute to stability and change in vertebrate genomestructure as well as gene regulatory changes that mediate the development of germ cells epigeneticmaintenance of pluripotency and oncogenesis.1


application_id: 11011484
project_number: 5R37CA278989-02
project_title: Mechanistic and structural insights into a new pro-metastatic collagen glucosyltransferase
administering_ic: NCI
award_notice_date: 2025-01-06
opportunity_number: PA-20-185
application_type: 5
activity_code: R37
ic: CA
serial_number: 278989
program_official: COUCH, JENNIFER A
project_start_date: 2024-01-16
project_end_date: 2028-12-31
study_section: Tumor Evolution, Heterogeneity and Metastasis Study Section[TEHM]
contact_pi_person_id: 14359954
contact_pi: GUO, HOUFU
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:
Lung cancer is the primary cause of cancer death in western countries including the United States.Kentucky leads the nation both in lung cancer incidence and mortality. Lung cancer-related mortality is mainlydue to metastasis. During metastasis malignant tumors accumulate collagen fibrils to drive cancer celldissemination and impede the influx of anti-tumor immune cells. The long-term goal of our laboratory is todetermine the roles of collagen and collagen-modifying enzymes in metastasis to inform new therapeuticdevelopment. Toward that goal we found that the collagen lysyl hydroxylase 2s long alternatively splicedisoform b (LH2b) carrying an extra motif encoded by exon 13a is a previously undetected collagenglucosyltransferase (GGT). GGT plays a major role in LH2s pro-metastatic activity. High expression levels ofLH2b predict a worse prognosis while the expression levels of LH2s short alternatively spliced isoform a(LH2a) without exon 13a are not prognostic. These findings provide a novel basis for the observation made byour group and many others that high LH2 expression has poor-prognostic value and drives the growth andmetastasis of multiple cancer types including lung cancer breast cancer and sarcoma. Thus LH2 GGT is anew therapeutic target of interest. However how LH2 GGT drives cancer metastasis is unclear and LH2 GGTinhibitor is not available deficiencies that can be addressed only by gaining mechanistic insight into thestructure-function of LH2 GGT. To elucidate how LH2 GGT enzymatic activity is structurally regulated we solved 3 collagen GGTstructures including LH2 GGT and its mimiviral homolog. Our results suggested that LH2b forms a dimer witha continuous collagen-binding site and binds UDP-glucose cooperatively. Based on these findings wehypothesized that LH2bs unique structural features allow it to modify tumor stroma and drive metastasis. Bytesting this hypothesis we will gain insights into 1) to what extent LH2b overexpression and LH2b-mediatedcollagen glucosylation happen in human lung cancer; 2) why LH2b drives tumor progression; 3) how LH2bGGT function is regulated; 4) what are LH2b GGTs pro-metastatic structural features. The findings from thiswork will advance the understanding of the relevance and mechanism of LH2b in tumor progression andidentify the structural features of LH2b GGT that drive cancer progression. Such insights will inform LH2b GGTcancer biology and inhibitor development.

project_terms:
2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine;Active Sites;Address;Affinity;Alleles;Alternative Splicing;Anabolism;Binding;Binding Sites;Biological Assay;Cancer Biology;Cancer Etiology;Cancer Patient;Cells;Cessation of life;Clustered Regularly Interspaced Short Palindromic Repeats;Collagen;Collagen Fibril;Country;Cysteine;Development;Dimerization;Disulfides;Enzymes;Epithelial Cells;Epithelium;Exons;Glucose;Glucosyltransferase;Goals;Growth;Homologous Gene;Human;Hydrophobicity;Incidence;Kentucky;Knock-out;LHX2 gene;Laboratories;Link;Lung;Malignant Breast Neoplasm;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mesenchymal;Mesenchymal Cell Neoplasm;Modeling;Mus;Mutate;Mutation;Nature;Neoplasm Metastasis;Normal tissue morphology;Osteoblasts;Play;Prognosis;Protein Isoforms;Proteins;Reporting;Role;Sarcoma;Structure;Surface;Testing;Tissues;Tumor Promotion;Tumor-infiltrating immune cells;United States;Work;cancer cell;cancer invasiveness;cancer type;clinical application;dimer;glycosylated collagen;inhibitor;insight;interest;mRNA Expression;mortality;mutant;new therapeutic target;novel;novel therapeutics;overexpression;prognostic value;therapeutic development;therapeutic target;tumor;tumor progression;tumorigenesis

public_health_relevance:
We recently found that high expression of the collagen-modifying enzyme lysyl hydroxylase 2 (LH2) drives lungcancer metastasis due to a previously undetected collagen glucosyltransferase (GGT) activity. Based on ournew mechanistic and structural insights into LH2 GGTs pro-metastatic activity we hypothesize that the uniquestructural features of LH2 GGT underlie its pro-metastatic activity. If our hypothesis is proven true thesefindings will inform LH2b GGT inhibitor development and could have broad clinical applicability because LH2has been implicated in the metastasis of multiple cancer types.


application_id: 11010937
project_number: 2R35GM131807-06
project_title: Hedgehog Signaling in Development and Metabolism
administering_ic: NIGMS
award_notice_date: 2025-01-31
opportunity_number: PAR-22-180
application_type: 2
activity_code: R35
ic: GM
serial_number: 131807
program_official: XU, JIANHUA
project_start_date: 2019-09-01
project_end_date: 2030-01-31
study_section: Special Emphasis Panel[ZRG1 CDB-L (55)]
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract:Hedgehog (Hh) signaling controls growth and patterning during embryonic development and homeostasis inadult tissues. Dysregulation of Hh signaling is implicted in many human disorders including several types ofcancer. Hh binding to the 12-transmembrane protein Patched (Ptc) elicits intracellular signaling by relievingPtc-mediated inhibition of the 7-transmembrane protein Smoothened (Smo). Despite significant progress keyquestions persist regarding the mechanisms by which Ptc inhibits Smo in the absence of Hh and how Hhstimulation alleviates this inhibition. In the past years this team has generated new insights into Hh signalingmechanisms including: 1) Smo phosphorylation by multiple kinases which leads to Smo cell surfaceaccumulation and signaling activity; 2) Smo sumoylation induced by Hh which activates Smo; 3) Smoubiquitination that downregulates Smo cell surface accumulation and promotes Smo endocytosis; and 4) Smoactivation by Phosphatidyl-inositol 4-phosphate (PI(4)P) and phosphatidic acid (PA) through direct interactionwith Smo C-tail and transmembrane helixes respectively. The goal of this research program is to understandhow Hh signals are sensed and transmitted to control downstream biological events that ultimately govern cellgrowth and patterning. Proposed studies use a combination of genetic and biochemical approaches to build onprior contributions and to transition to newly emergent avenues of inquiry. The knowledge gained from theproposed studies will provide novel insights into mechanisms surrounding Smo suppression by Ptc andactivation by cholesterol PI(4)P and PA. In addition expected outcomes will provide novel insights into humandevelopmental disorders and adult neurodegenerative diseases and will promote development of diagnostictools and novel therapeutic approaches to transform current concepts of Hh signaling in cancer andneurodegenerative diseases.

project_terms:
Adult;Basal cell carcinoma;Binding;Biochemical;Biological;Cell surface;Cholesterol;Development;Disease;Embryonic Development;Endocytosis;Erinaceidae;Event;Genetic;Goals;Growth;Homeostasis;Human;Integral Membrane Protein;Investigation;Knowledge;Malignant Neoplasms;Mediating;Medulloblastoma;Membrane;Metabolism;Mutation;Neurodegenerative Disorders;Outcome;Pattern;Phosphatidic Acid;Phosphorylation;Phosphotransferases;Process;Proliferating;Proteins;Research;Role;Signal Transduction;Sumoylation Pathway;System;Tail;Tissues;Ubiquitination;cancer type;cell growth;developmental disease;diagnostic development;diagnostic tool;human disease;insight;novel;novel therapeutic intervention;patched protein;phosphatidylinositol 4-phosphate;programs;public health relevance;smoothened signaling pathway;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCEHedgehog (Hh) signaling is known for its role in directing processes such as cell growth proliferation anddifferentiation during embryogenesis. Mutations in Smoothened (Smo) a critical protein in the signal receptionsystem results in human diseases such as basal cell carcinoma and medulloblastoma. Investigation of how Ptcinhibits Smo in the absence of Hh and how Hh stimulation alleviates this inhibition will provide insights intodevelopmental problems and create novel concepts of Hh signaling in cancer and neurodegenerative diseases.


application_id: 11010392
project_number: 5R00AR081367-04
project_title: Contribution of ribosome specialization to the pathophysiology of muscular dystrophy
administering_ic: NIAMS
award_notice_date: 2024-11-08
opportunity_number: PA-20-188
application_type: 5
activity_code: R00
ic: AR
serial_number: 081367
program_official: LINDHURST, MARJORIE JEAN
project_start_date: 2023-11-01
project_end_date: 2026-10-31
study_section: NSS
contact_pi_person_id: 12197125
contact_pi: WEN, YUAN
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractStriated muscle tissue contains the highest mitochondrial content and the largest known proteinswhich present unique challenges to the translational machinery. Muscle tissue specifically expressesa paralogous ribosomal protein RLP3L that is roughly 80% similar to the ubiquitous RPL3 and isessential to the formation of the large subunit of the ribosome. In muscle RPL3L substitutes for RPL3in the ribosome but how this alters ribosome function remains unknown. Furthermore these twoparalogs demonstrate an inverse relationship under conditions of muscle adaptation stress andpathology. In dystrophic muscle RPL3L is lost in favor of RPL3 in the ribosome but the effects onmuscle functional decline are not understood. Recent evidence suggests that ribosomes canspecialize in order to selectively translate certain genes into proteins. Additionally translation controlhas emerged as a novel layer of regulation for mitochondrial function which declines early in thepathology of muscular dystrophy prior to an overt phenotype. Taken together I hypothesize that theloss of RPL3L in dystrophic muscle impairs ribosome specialization thus contributing to an imbalancebetween mitochondrial and sarcomeric protein synthesis exacerbating dystrophic diseaseprogression. Rescue of the muscle specific ribosomal protein in muscular dystrophy will provide thefirst evidence for a role of ribosome specialization in muscle functional decline and help guide thedesign of new therapeutics. The proposed studies will also for the first time investigate the impact ofglucocorticoids (a common therapy for dystrophy) on muscle ribosome specialization andtranslational selectivity. Successful completion of the proposed studies will reveal new therapeutictargets as well novel mechanisms underlying the pathophysiology of chronic debilitating diseases.

project_terms:
ATP Synthesis Pathway;Address;Adult;Biological Assay;Cells;Chronic;Contractile Proteins;Cytoplasm;Data;Disease;Disease Progression;Dose;Drops;Duchenne muscular dystrophy;Equilibrium;Exercise;Failure;Functional disorder;Generations;Genes;Genetic Diseases;Genetic Transcription;Glucocorticoid Receptor;Glucocorticoids;Growth;Hindlimb;Image;Impairment;In Vitro;Knock-out;Knockout Mice;Learning;Maintenance;Measurement;Measures;Mechanics;Mediating;Mentors;Mentorship;Mitochondria;Mitochondrial Proteins;Modeling;Morphology;Muscle;Muscle Proteins;Muscle function;Muscular Atrophy;Muscular Dystrophies;Oxygen Consumption;Pathogenesis;Pathology;Patients;Performance;Phase;Phenotype;Production;Protein Biosynthesis;Proteins;Regulation;Respiratory Diaphragm;Ribosomal Proteins;Ribosomes;Role;Running;Skeletal Muscle;Specificity;Steroid therapy;Steroids;Stress;Striated Muscles;System;Techniques;Testing;Time;Tissues;Training;Transcript;Translating;Translations;Upregulation;Ventilator;Yeasts;career;design;effective therapy;exercise training;functional decline;functional loss;improved;in vivo;mdx mouse;mitochondrial dysfunction;mouse model;muscle strength;new therapeutic target;novel;novel therapeutics;paralogous gene;postnatal development;protein expression;restoration;standard of care;transcriptome sequencing

public_health_relevance:
Project NarrativeMuscular dystrophy is a debilitating genetic disorder characterized by progressive loss of muscle function.There is currently no cure and the only effective therapy to delay functional loss is glucocorticoid steroidtherapy. The proposed project will investigate a novel mechanism of ribosome specialization as a contributor tothe pathogenesis of muscular dystrophy with the aim of developing additional therapies for the disease.


application_id: 11007744
project_number: 1R44CA295373-01
administering_ic: NCI
award_notice_date: 2024-08-23
opportunity_number: PA-23-230
application_type: 1
activity_code: R44
ic: CA
serial_number: 295373
program_official: ZHAO, MING
project_start_date: 2024-09-01
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1 ISB-Z (10)]
contact_pi_person_id: 10810394
contact_pi: MOLLOY, JANELLE ARLENE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 093718777
primary_uei: L8D1CH5FK9X3
duns_number: 093718777
uei: L8D1CH5FK9X3
fips: US
organization_id: 10052089
organization_name: WILD DOG PHYSICS, LLC
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403568039
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-09-01
project_title:
Improving allocation of scarce medical physics resources through a novel comprehensive quality assurance device.

project_abstract:
Healthcare disparities in the US result in large segments of the population without access to radiationtherapy (RT). This manifests itself in Eastern Kentucky and Appalachia wherein the impact is exacerbated bythe high incidence of smoking-related cancers. RT is an effective component of the treatment strategy forthese patients. Advanced techniques such as intensity modulated radiation therapy (IMRT) image-guided RT(IGRT) stereotactic body RT (SBRT) and stereotactic radiosurgery (SRS) improve outcomes and are deliveredusing medical linear accelerators (i.e. linacs). SBRT is especially appealing in these settings given that theprecise treatments are delivered in 1-5 daily treatment fractions as opposed to the 20-40 fractions required forconventional techniques. Providing SBRT in rural settings can improve access by administering these preciseabbreviated treatments to patients who have difficulty traveling to large regional medical centers. The quality assurance (QA) that medical physicists provide is critical for safe treatments yet there is ashortage of qualified medical physicists (QMPs) both in the US and globally. At the same time more centersare introducing modern techniques that are more precise but intrinsically have more risk due the high dosesand geometric precision required. There is widespread noncompliance with industry standard QA protocols inthe US and internationally. Existing QA devices have not evolved sufficiently to provide the precision versatilityand efficiency that is needed for high precision RT. Given these exacerbated safety risks the market needs aparadigm shift in how QA is performed in modern RT. Wild Dog Physics (WDP) proposes to design and test a new-generation QA device that addresses theseunmet medical needs. We have trademarked this device the RetrieverTM. When complete it will be moreprecise efficient and comprehensive than any QA solution currently on the market. The proposed projectseeks to develop a clinical prototype to be tested in the Radiation Therapy clinic at the University of Kentuckyas well as partner organizations located in rural underserved areas. Having proven feasibility in our feasibility study we seek to advance this innovation to commercialviability in Phase 2 through three specific aims: 1) hardware refinement to allow measurement of machineperformance metrics to within 0.5 mm and 1% relative does; 2) software development to allow real-time dataanalysis real-time compliance assessment and analytical tools that can monitor long-term trends abrupt shiftsand inter-machine and inter-institutional comparisons and; 3) clinical testing to validate the sensitivity andspecificity of the Retriever to shifts in machine characteristics. We will work with key academic and clinicalpartners in the design and testing phases including Qualified Medical Physicists (QMPs) serving in sparselypopulated low resource settings in the US. When successful this important innovation will help to bringaccurate state-of-the-art radiation therapy treatments to patients who might otherwise not receive them.

project_terms:
Abbreviations;Address;Adoption;Advocate;Appalachian Region;Assessment tool;Benchmarking;Canis familiaris;Characteristics;Clinic;Clinical;Collection;Computer software;Coupled;Data;Data Analyses;Dependence;Devices;Dose;Elderly;Feasibility Studies;Funding;Future;Generations;Geography;Image;Improve Access;Incidence;Industry Standard;Intensity-Modulated Radiotherapy;International;Kentucky;Linear Accelerator Radiotherapy Systems;Longitudinal trends;Marketing;Measurement;Mechanics;Medical;Medical center;Methods;Modernization;Monitor;Optics;Patients;Peer Review;Performance;Persons;Phase;Physics;Population;Positioning Attribute;Process;Protocols documentation;Qualifying;Quality Control;Radiation;Radiation therapy;Radiosurgery;Resource-limited setting;Resources;Risk;Rural;Safety;Sensitivity and Specificity;Series;Services;Specific qualifier value;System;Techniques;Technology;Testing;Time;Trademark;Travel;Universities;Validation;Visible Radiation;Vulnerable Populations;Work;analytical tool;commercialization;cost;design;dosimetry;health care disparity;human old age (65+);image guided radiation therapy;imaging system;improved;improved outcome;innovation;inter-institutional;low and middle-income countries;machine vision;manufacture;non-compliance;nonmetropolitan area;novel;peer support;product development;prototype;quality assurance;research clinical testing;rural setting;smoking-related cancer;software development;transmission process;treatment strategy;underserved area

public_health_relevance:
Healthcare disparities in the US result in large segments of the population without access to radiation therapyRT. We proposes to design and test a new-generation QA device that addresses these unmet medical needs.When successful this important innovation will help to bring accurate state-of-the-art radiation therapytreatments to patients who might otherwise not receive them.


application_id: 11007237
project_number: 5R01AI175220-03
project_title: Chlamydia type III effectors affecting the host actin-based cytoskeleton
administering_ic: NIAID
award_notice_date: 2025-01-22
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AI
serial_number: 175220
program_official: VINCENT, LEAH REBECCA
project_start_date: 2023-02-06
project_end_date: 2028-01-31
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
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:
Grant title: Chlamydia type III effectors affecting the host actin-based cytoskeletonAbstract:Chlamydia trachomatis is a significant concern for human health world-wide due to its prevalence andthe combined health and socioeconomic impact of acute and chronic disease. Chlamydiae are obligateintracellular pathogens that possess the ability to modulate host-cell biology while sequestered within amembrane-bound parasitophorous vacuole. Accumulating evidence indicates that a type III secretionsystem (T3SS) represents a significant mechanism employed by chlamydiae to manipulate thesecritical host cell functions. The host actin cytoskeleton and vesicular transport machinery representmajor targets for Chlamydia-mediated alterations. We have identified a novel pathway by whichintracellular chlamydiae redirect host cell vesicular trafficking. This mechanism requires the branchedactin network and at least two type III secretion effectors designated TmeA and TmeB. We propose toaddress the hypothesis that these effectors differentially modulate branched actin networks toaccomplish trafficking of host-cell resources to the mature inclusion by imposing an axis of host Arp2/3activation. We propose to elucidate molecular details by which the combined activities of C. trachomatisTmeA and TmeB affect host cells to promote intracellular development and evasion of cell-intrinsic hostdefenses. Corresponding C. muridarum mutant strains will be employed to elucidate the contributionsof these effectors to pathogenesis in an animal model. A balanced combination of genetic biochemicalcell-biology and animal-based studies are proposed that will define the overall role of these effectors inestablishing and maintaining infectivity that culminates in Chlamydia-mediated disease. Completion ofthis work will lead to an enhanced understanding of the molecular mechanisms employed by Chlamydiato impact host-pathogen interactions governing disease.

project_terms:
Actins;Acute Disease;Address;Affect;Animal Model;Animals;Binding;Biochemical;Biological;Biology;Cell Physiology;Cell membrane;Cells;Cellular biology;Chlamydia;Chlamydia Infections;Chlamydia muridarum;Chlamydia trachomatis;Chronic Disease;Communities;Cytoskeleton;Data;Detection;Development;Disease;Disease Progression;Epithelial Cells;Event;Genetic;Grant;Growth;Health;Host Defense;Human;Immune;In Vitro;Infection;Invaded;Link;Lipids;Mediating;Membrane;Microbiology;Modeling;Modification;Molecular;Mus;Mutation;Organelles;Outcome;Pathogenesis;Pathology;Pathway interactions;Polymers;Prevalence;Process;Proteins;Resources;Role;Science;Sexually Transmitted Agents;Sexually Transmitted Diseases;Source;Testing;Time;Type III Secretion System Pathway;Vacuole;Virulence;Work;comparative;design;economic impact;health economics;human pathogen;immunopathology;in vivo;member;mutant;novel;obligate intracellular parasite;parasitism;pathogen;polymerization;reproductive tract;socioeconomics;trafficking;vesicle transport

public_health_relevance:
Chlamydia trachomatis an agent of sexually transmitted disease relies on a specializedsecretion mechanism to deploy proteins exerting anti-host activities essential to pathogenesis.This proposal contains work designed to determine their specific contributions to chlamydialdisease.


application_id: 11007082
project_number: 1R43AT013038-01
administering_ic: NCCIH
award_notice_date: 2024-09-17
opportunity_number: PA-23-230
application_type: 1
activity_code: R43
ic: AT
serial_number: 013038
program_official: HORGUSLUOGLU, EMRIN U
project_start_date: 2024-09-17
project_end_date: 2026-09-14
study_section: Special Emphasis Panel[ZRG1 CCHI-J (10)]
contact_pi_person_id: 78083865
contact_pi: HOAGLAND, RICHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 080967428
primary_uei: WWN3NEW2K2Z7
duns_number: 080967428
uei: WWN3NEW2K2Z7
fips: US
organization_id: 10064272
organization_name: RALPHVR INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40507
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-09-17
project_title:
Virtual PARTNER (Provide Activate Restore Track iNspire Educate Rehabilitate): Multi-component virtual reality application to target a reduction in delirium in the intensive care unit.

project_abstract:
Project SummaryDelirium commonly plagues patients in the hospital. Patients in the intensive care unit (ICU) have the highestrisks for delirium estimated to be between 70% to 80%. The effects of delirium are profound with higher 12-month mortality rates following discharge significant increases in ICU length of stay duration of mechanicalventilation risk of long-term cognitive impairments and reduced quality of life after discharge. Delirium alsoleads to challenges for ICU staff including agitation and combative behavior. There are severe financial costsfrom delirium as well with higher healthcare costs per patient and an additional burden on the Americanhealthcare system of up to $152 billion each year. These statistics illustrate that an innovative and effectiveintervention strategy to prevent delirium in the ICU is highly significant and immediately clinicallyimpactful. Non-pharmacological multicomponent interventions (which may include patient mobilizationcognitive stimulation sleep optimization and more) have been shown to reduce the odds of incident delirium inhospitalized non-critically ill patients by approximately half. However such multicomponent interventions placean additional burden on the already constrained resources of nursing staff. Technology-based interventions maybe effective intervention delivery mechanisms but these technology interventions must be multicomponent andnot overburden staff. Crucially an intervention must be multicomponent can be tailored to specific patientcharacteristics targets the physical cognitive emotional and social needs of the patient and does notoverburden nursing staff. RalphVR is applying to this Phase I SBIR to achieve three Specific Aims. Aim 1:Employ focus groups comprised of staff involved in the treatment of delirium in the ICU (N=12) and former ICUpatients (N=12) for expert stakeholder and patient feedback and insight to inform development. Aim 2: Developa framework for three innovations and develop three mind body intervention (MBI) components then combinethese software systems into a single VR application (the Virtual PARTNER prototype). Aim 3: Run a feasibilitystudy targeting patients in the ICU (N=22). Three long-term objectives must be met to bring Virtual PARTNERto market: 1) determine the safety and feasibility of Virtual PARTNER to be delivered to patients in the ICU 2)determine Virtual PARTNERSs efficacy to promote target outcomes through successful delivery of MBIs and3) determine the efficacy of Virtual PARTNER as an intervention to reduce the occurrence of and treat delirium.Successfully completing the long-term goals and aims will result in a clinically validated intervention to treatdelirium in the ICU. The proposal addresses a gap in current clinical practice and responds to the National Centerfor Complementary and Integrative Health (NCCIH) program priority area of health promotion diseaseprevention health restoration and resilience. The proposed VR platform for patients in the ICU directlyaddresses multiple NCCIH research priority areas most notably development and testing of innovativetechnologies for multisensory delivery of an MBI.

project_terms:
Address;Adherence;Admission activity;Adopted;Affect;Agitation;Algorithmic Software;American;Area;Behavior;COVID-19 patient;Characteristics;Clinical;Cognitive;Complementary Medicine;Complementary and alternative medicine;Computer software;Data;Data Collection;Data Security;Death Rate;Delirium;Development;Devices;Economics;Effectiveness;Emotional;Ensure;Esthetics;Failure;Feasibility Studies;Feedback;Financial cost;Focus Groups;Foundations;Goals;Health;Health Care Costs;Health Promotion;Healthcare Systems;Hospitalization;Hospitals;Hour;Impaired cognition;Intensive Care Units;Intervention;Interview;Kentucky;Knowledge;Length of Stay;Marketing;Mechanical ventilation;Mechanics;Mind-Body Intervention;Mindfulness Training;Modality;Monitor;Music;National Center for Complementary and Integrative Health;Nonpharmacologic Therapy;Nursing Staff;Outcome;Patient Preferences;Patients;Phase;Pilot Projects;Quality of life;Randomized Controlled Trials;Readiness;Recommendation;Reporting;Research Priority;Resources;Risk;Running;Severities;Sleep;Small Business Innovation Research Grant;Socialization;Structure;System;Technology;Testing;Time;Translating;Universities;Voice;brain dysfunction;clinical efficacy;clinical practice;cost;design;digital technology;disorder prevention;effective intervention;efficacy evaluation;experience;feasibility testing;health definition;high risk;improved;innovation;innovative technologies;insight;intervention delivery;mind/body;mixed reality;mortality;multi-component intervention;multisensory;patient oriented;prevent;programs;prototype;resilience;restoration;safety and feasibility;social;software systems;statistics;success;technology intervention;therapeutically effective;tool;treatment strategy;usability;virtual;virtual delivery;virtual reality;virtual reality intervention

public_health_relevance:
Project NarrativeThis project will contribute to knowledge on delivery of mind and body interventions (MBIs) and specifically tothe delivery of MBIs through digital technology including virtual and mixed reality. Furthermore application ofthis knowledge will provide a treatment for delirium in the intensive care unit (ICU) which will contribute toenhanced health and decreased mortality both during and after admission to an ICU as well as improve qualityof life during an ICU stay.


application_id: 11006274
project_number: 5K01DK128022-04
project_title: Elucidating Molecular Mechanisms Linking Fructose to Cholesterol Metabolism
administering_ic: NIDDK
award_notice_date: 2024-12-20
opportunity_number: PA-20-190
application_type: 5
activity_code: K01
ic: DK
serial_number: 128022
program_official: SASLOWSKY, DAVID E
project_start_date: 2022-01-01
project_end_date: 2026-12-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 11480537
contact_pi: HELSLEY, ROBERT NATHANIEL
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYFructose consumption is not only a major risk factor for development of non-alcoholic fatty liver disease (NAFLD)but also promotes hypercholesterolemia and atherosclerosis in humans and rodents. Identification of themechanisms linking NAFLD to cardiovascular disease (CVD) remains poorly understand. This proposal focuseson identifying the influence dietary fructose has on synthesis and metabolism of cholesterol. Using a mousemodel of sugar-sweetened beverage consumption the candidate shows that fructose metabolism increasescitrate acetyl-CoA and hepatic cholesterol levels. In addition the candidate demonstrates fructose decreasesthe protein expression of carnitine palmitoyltransferase 1a (Cpt1a) a mitochondrial fatty acid transport protein.Moreover conditional CPT1a knockout mice exhibit similar lipid perturbations as mice fed fructose. Thereforeaim 1 utilizes dual stable isotope techniques coupled with NMR and mass spectrometry to quantify cholesterolsynthesis and fructose-derived carbon enrichment into the cholesterol biosynthetic pathway in male and femalemice. Livers from the mice will be used for acetyl-proteomics to delineate potential mechanisms linking fructoseto cholesterol biosynthesis. Aim 2 determines how transcriptional regulation of Cpt1a alters fructose-inducedsuppression of fatty acid oxidation and enhanced cholesterol synthesis using both in-vitro and in-vivoapproaches. The purpose of this aim is to uncover a previous unrecognized role of Cpt1a in coordinating theregulation of both lipid-signaling pathways (fatty acid oxidation and cholesterol synthesis) in response to fructose.Completion of these aims will yield mechanistic insight linking dietary sugar metabolism to hypercholesterolemia.The novelty of the proposed research is the comprehensive dual-stable isotope approach in conjunction withanalytical techniques to measure cholesterol synthesis and fructose-derived carbon enrichment into the sterolsynthesis pathway in the same cohort of animals. In addition the proposed research reveals several innovativemechanisms that have yet to be explored including acetylation of cholesterol synthesis enzymes and regulationof Cpt1a through transcriptional mechanisms. Strong collaborations among the Metabolomics Core at theUniversity of Kentucky Mass Spectrometry Core at the Buck Institute for Research on Aging and scientificadvisory committee members ensure successful completion of the proposed research by the candidate. Thisresearch is complimented by a career development plan in which the candidate will learn new experimentalmethodology in stable isotope metabolomics broaden his scientific network through attending workshops andconferences and develop his communication skills so that he is poised to become an independent investigator.This K01 award will allow him to reach his long-term goals of establishing a well-funded laboratory studyingdietary mechanisms in cardiometabolic disease.

project_terms:
Acetyl Coenzyme A;Acetylation;Advisory Committees;Affect;Aging;Animals;Atherosclerosis;Biological Assay;Biopsy;Carbon;Cardiometabolic Disease;Cardiovascular Diseases;Carnitine Palmitoyltransferase I;Catabolism;Cells;Cholesterol;Cholesterol Homeostasis;Citrates;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Committee Members;Communication;Consumption;Coupled;Data;Development;Development Plans;Dietary Sugars;Dyslipidemias;Educational workshop;Ensure;Enzymes;Epigenetic Process;Exhibits;Fat-Restricted Diet;Female;Food;Fructose;Funding;Genes;Genetic Transcription;Goals;Hepatic;Hepatocyte;Human;Image;Impairment;In Vitro;Isotope Labeling;Kentucky;Ketohexokinase;Knock-out;Knockout Mice;Laboratory Study;Learning;Link;Lipids;Liver;LoxP-flanked allele;Lysine;Mass Spectrum Analysis;Measures;Mediating;Mentored Research Scientist Development Award;Mentors;Messenger RNA;Metabolic;Metabolic Diseases;Metabolism;Methodology;Mitochondria;Modification;Molecular;Monosaccharides;Mus;Mutagenesis;Non-Insulin-Dependent Diabetes Mellitus;Nuclear;Obesity;Obesity associated liver disease;Observational Study;PPAR alpha;Pathway interactions;Patients;Persons;Phenotype;Phosphorylation;Prevalence;Process;Production;Proteins;Proteomics;Radiolabeled;Reducing diet;Regulation;Reporter;Research;Research Institute;Research Personnel;Risk Factors;Rodent;Role;SRE-2 binding protein;Serum;Signal Pathway;Signal Transduction;Small Interfering RNA;Stable Isotope Labeling;Sterols;Techniques;Testing;Tracer;Training;Transcriptional Regulation;Triglycerides;Universities;Water;Woman;acylcarnitine;cardiometabolic risk;cardiovascular disorder risk;career development;cholesterol biosynthesis;cohort;dietary;fast protein liquid chromatography;fatty acid oxidation;fatty acid-transport protein;feeding;genetic variant;hypercholesterolemia;in vivo;innovation;insight;knock-down;lipid biosynthesis;liquid chromatography mass spectrometry;male;men;metabolomics;mortality;mouse model;non-alcoholic fatty liver disease;novel therapeutics;nutrient metabolism;overexpression;protein expression;response;skills;stable isotope;sugar;sweetened beverage;symposium

public_health_relevance:
PROJECT NARRATIVECardiovascular disease (CVD) the number one killer in men and women is associated with the prevalence ofnonalcoholic fatty liver disease (NAFLD). Consumption of fructose primarily found in sugar-sweetenedbeverages and processed foods is a major risk factor for development of both NAFLD and CVD. The primarygoal of this proposal is to determine the mechanisms by which fructose increases cholesterol levels which willyield insight into novel therapeutic options for NAFLD and associated CVD risk.


application_id: 11003999
project_number: 3R35GM142679-04S1
project_title: The role of muscle contraction in gene activation and tissue regeneration
administering_ic: NIGMS
award_notice_date: 2024-07-30
opportunity_number: PA-23-189
application_type: 3
activity_code: R35
ic: GM
serial_number: 142679
suffix: S1
program_official: PHILLIPS, ANDRE W
project_start_date: 2021-09-01
project_end_date: 2025-06-30
study_section: Special Emphasis Panel[ZRG1(55)-R]
contact_pi_person_id: 10461818
contact_pi: DUNCAN, ELIZABETH MARIE
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
SUMMARY OF PARENT GRANT:Regeneration is a remarkable phenomenon that is both ubiquitous and mysterious; although many differentanimals are capable of replacing damaged and/or lost structures it is unclear how these regenerative speciesmaintain both the cellular stability required for tissue integrity and the cellular plasticity needed to reactivatetissue development upon injury. Moreover as regeneration is often induced by spontaneous and imprecisetissue damage how do cells translate broad and sudden signals into cell-type-specific transcriptional changes? Genomic regulators such as transcription factors and chromatin-modifying enzymes work together toinstruct cell fate during developmental processes. Although there is substantial data describing how thesefactors orchestrate embryogenesis much less is known about how they are activated to induce regeneration.My central hypothesis is that chromatin serves as a mediator between the signaling events that are triggeredby significant tissue loss and the cellular changes they induce to activate regeneration. To uncover thefundamental molecular mechanisms underlying this process my laboratory studies the planarian model ofanimal regeneration. Planarians are free-living flatworms with incredible regenerative capacities. They are alsoamenable to genetic perturbation through RNAi easily dissociated for single cell analyses and encodechromatin modifying proteins with strong homology to those in other organisms. We are particularly interestedin how some planarian cell types respond to injury by activating specific essential regeneration genes whileothers activate an entirely different set of loci in response to the same injury. My lab uses multiple customizedmethods to isolate specific planarian cell types both differentiated and stem cells in order to characterize thechromatin state of these cell types before and after injury. We also leverage data showing that RNAi depletionof the MLL1/2 chromatin enzyme in the planarian Schmidtea mediterranea leads to loss of cilia on its outerepithelium. In addition we have recently isolated and characterized a new planarian species that has a uniquecilia pattern on its outer epithelium providing an exciting opportunity to use comparative genomic approachesto identify specific genes that are linked to this particular trait. Combining all these approaches we aim todissect the functional role and molecular signaling cues contributed by specific cell types during regeneration. The outer epithelium and other differentiated tissues are essential for planarian regeneration in large partbecause they signal to a population of heterogeneous multi and pluripotent stem cells that are maintained inadult planarians. Because these stem cells must differentiate into all needed cell types in response to missingtissue signals it is not surprising that they are highly plastic and transcriptionally heterogeneous. Yet it isunknown how they create and maintain this heterogeneity in vivo. We will test the hypothesis that a conservedchromatin signature regulates this critical feature. These studies will uncover important mechanisms underlyingboth regeneration and other biological processes that require dynamic gene regulation across complex tissues.SUMMARY OF PROPOSED RESEARCH FOR CANDIDATE:A growing body of research in the planarian field supports the hypothesis that longitudinal muscle fiberssecrete signaling proteins that are required for the regeneration of new tissues. However these papers largelydo not address the role of muscle contraction in this process. Nonetheless it is known that muscle contractionis induced immediately after injury and required for wound closure. In my lab we are interested in howsignaling events triggered by injury lead to changes in gene expression that are required for regeneration. Wehypothesize that the muscle contraction triggered by a significant injury induces the activation of essentialtissue patterning genes. We are using chemical inhibitors RNA interference and physiological measurementsto test our hypothesis. This project has been the focus of a talented undergraduate student in my laboratory Easter Kabuyawho graduated with a Bachelor of Science degree in Biology in December 2023. We are requesting funds tosupport her as a post-baccalaureate researcher in the laboratory so that she can complete her ongoing projectassemble it into a first author publication and enhance her competitiveness as an applicant to M.D./Ph.D.programs as well as future fellowships and grants. The completion of this project will not only further the careerof this candidate but also the objectives of the parent grant by connecting injury-induced changes in a specifictissue type with functional changes in gene expression during regeneration.

project_terms:
Address;Adult;Animal Model;Animals;Binding;Biochemical;Biological;Biological Process;Biology;Cells;Chemicals;Chromatin;Cilia;Competence;Complex;Cues;DNA;Data;Development;Developmental Process;Dissociation;Doctor of Medicine;Doctor of Philosophy;Embryonic Development;Enzymes;Epithelium;Essential Genes;Event;Fellowship;Functional Regeneration;Funding;Future;Gene Activation;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Genome;Genomic approach;Genomics;Goals;Grant;Heterogeneity;Injury;Knowledge;Laboratories;Laboratory Study;Lead;Link;MLL gene;Measurement;Mediator;Methods;Molecular;Multipotent Stem Cells;Mus;Muscle;Muscle Contraction;Muscle Fibers;Natural regeneration;Neurons;Organism;Paper;Pattern;Pharmaceutical Preparations;Physiological;Planarians;Platyhelminths;Play;Pluripotent Stem Cells;Population Heterogeneity;Postbaccalaureate;Principal Investigator;Process;Proteins;Proteomics;Publications;RNA Interference;Recreation;Regenerative Medicine;Regenerative capacity;Regulation;Research;Research Personnel;Retina;Role;Science;Signal Induction;Signal Transduction;Signaling Protein;Somatic Cell;Structure;Talents;Testing;Tissue Differentiation;Tissues;Translating;Width;Work;career;cell fate specification;cell type;comparative genomics;genomic locus;in vivo;inhibitor;injured;insight;interest;overexpression;parent grant;programs;regenerative;regenerative tissue;replacement tissue;response;single cell analysis;stem cell population;stem cells;tissue regeneration;tool;trait;transcription factor;undergraduate student;wound closure

public_health_relevance:
Research in my lab leverages the experimental tractability and remarkable regenerative abilitiesof planarian flatworms to uncover fundamental molecular mechanisms that link injury-inducedsignals to functional changes in gene expression. An undergraduate student in my laboratoryhas generated preliminary data suggesting that contraction of the planarian body wall musclemay be critical for the activation of key regeneration genes a finding that has broad implicationsfor regenerative medicine. As post-baccalaureate researcher she will test her hypothesis usingmultiple orthogonal approaches.


application_id: 11003568
project_number: 1UG3DA061620-01
administering_ic: NIDA
award_notice_date: 2024-07-02
opportunity_number: PAR-22-200
application_type: 1
activity_code: UG3
ic: DA
serial_number: 061620
program_official: SEYMOUR, KAREN ELIZABETH
project_start_date: 2024-07-15
project_end_date: 2025-06-30
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 79542818
contact_pi: SCHMIDT, LEE
other_pis: MASSEY, VERONICA LYNCH
congressional_district: 03
department: Unavailable
primary_duns: 117542566
primary_uei: NLTVUPB2NJL5
duns_number: 117542566
uei: NLTVUPB2NJL5
fips: US
organization_id: 10061427
organization_name: USWM, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402411086
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-07-15
project_title:
Registration Development Program for LUCEMYRA (Lofexidine) Label Expansion for Opioid Withdrawal Treatment in Adolescents

project_abstract:
PROJECT SUMMARY:An alarming increase in the rate of opioid abuse among the general population has resulted in a public healthemergency since 2017. The striking rise in opioid use disorder has affected Americans broadly including steadyincreases in adolescent deaths due to opioid overdose. However a number of barriers exist for adolescents togain access to treatment; and current approaches to pharmacotherapy rely on the off-label use of opioids andother agents used in adults with OUD.Through a successful collaboration with NIDA USWM developed lofexidine for the mitigation of opioid withdrawalsymptoms in adults. The Food and Drug Administration (FDA) approved lofexidine tablets (LUCEMYRA) forthis indication in May 2018. Due to the anticipated utility of lofexidine for the treatment of opioid withdrawal inchildren USWM has completed all nonclinical prerequisites necessary to initiate studies in adolescents andengaged with FDA to confirm the approach to registration.The goal of this project is to further NIDA-USWM collaboration to complete FDA development requirements forthe approval of Lucemyra in adolescents. The use of an approved medication for opioid withdrawal will provideneeded safe and effective treatment options for this underserved patient population to optimize opportunities forinitial engagement in treatment and transition to longer term maintenance treatment options includingbuprenorphine and extended-release naltrexone recommended in current guidelines. The proposed researchleverages an efficient regulatory pathway using a full extrapolation approach wherein pharmacokinetic (PK)modeling can bridge established adult efficacy to adolescents through lofexidine exposure matching. Theapproach requires a PK study in adolescents experiencing acute opioid withdrawal to identify Lucemyra dosesproducing exposures associated with efficacy in adults and an open label safety study to provide adequatesafety data in support of registration requirements. Key components of the program include: i) completion of aPhase 1 PK in adolescents to complete efficacy requirements through exposure matching pediatric extrapolationprinciples (UG3 Aims 1 2) and completion of a formal FDA meeting to confirm the remaining scope of thedevelopment program (UG3 Key go/no go Milestone) and ii) completion of a Phase 2 open label safety studywhich together with the initial Phase 1 study can be integrated to satisfy the safety package requirements for asupplemental new drug application (UG3 Aim 3 UH3 Aims 1 & 3).

project_terms:
Acceleration;Acute;Adolescent;Adolescent Development;Adrenergic Agonists;Adult;Adverse event;Affect;Age;American;Benefits and Risks;Biological Assay;Blood;Blood Pressure;Body Weight;Buprenorphine;Cessation of life;Child;Childhood;Clinical;Collaborations;Data;Data Analyses;Data Pooling;Databases;Development;Development Plans;Diagnosis;Dose;Drug Kinetics;Electrocardiogram;Exposure to;Face;General Population;Goals;Guidelines;Health Services Accessibility;Heart Rate;Intervention;Label;Maintenance;Measures;Modeling;Naltrexone;National Institute of Drug Abuse;Opiate Addiction;Opioid;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase;Plasma;Population;Program Development;Recommendation;Reference Values;Regulatory Pathway;Research;Risk Assessment;Safety;Sampling;Severities;Suicide;Tablets;United States Food and Drug Administration;Visit;Withdrawal Symptom;Work;adolescent patient;aged;design;effective therapy;effectiveness evaluation;effectiveness measure;experience;follow-up;lofexidine;medication for opioid use disorder;meetings;novel therapeutics;off-label use;open label;opioid abuse;opioid epidemic;opioid misuse;opioid mortality;opioid overdose;opioid use disorder;opioid withdrawal;participant enrollment;patient engagement;patient population;pharmacokinetic model;phase 1 study;programs;public health emergency;respiratory;safety assessment;safety study;treatment guidelines;treatment response;treatment strategy;trend

public_health_relevance:
PROJECT NARRATIVE:The nations opioid epidemic has remained a public health emergency since 2017 with a steady increase inopioid misuse and deaths among Americans including adolescents a particularly underserved opioid usedisorder (OUD) population due in part to a lack of approved medications. The proposed research program willenable submission of a supplemental new drug application for Lucemyra (lofexidine) currently FDA approvedfor opioid withdrawal in adults to expand approval to adolescents and presenting a treatment option to facilitatepatient engagement in therapy and transition to longer term maintenance treatments such as buprenorphine orextended-release naltrexone as recommended by current adolescent treatment guidelines. Extrapolation ofadult efficacy to the adolescent population permits an efficient regulatory path for this work with two studiesplanned to complete registration requirements: i) a pharmacokinetic study in adolescents to identify dosesproducing lofexidine blood concentrations associated with efficacy in adults and ii) an open label safety study tocomplete an adequate safety package for approval in adolescents.


application_id: 11003314
project_number: 5K01HL149984-05
project_title: Pharmacological Mechanistic Insights into Thoracic Aortic Aneurysm
administering_ic: NHLBI
award_notice_date: 2024-11-29
opportunity_number: RFA-HL-19-026
application_type: 5
activity_code: K01
ic: HL
serial_number: 149984
program_official: HUANG, LI-SHIN
project_start_date: 2020-12-18
project_end_date: 2025-11-30
study_section: 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
arra_indicator: N
project_abstract:
Project SummaryThe applicant for this NIH Diversity K01 (RFA-HL-19-026) application is Dr. Mary Sheppard an AssistantProfessor at the University of Kentucky College of Medicine. Dr. Sheppards area of research interest isMarfan syndrome and she has established an Aortic Clinic in the Department of Surgery. Her long term careergoal is to develop new therapeutics for thoracic aortic aneurysm. This decision was influenced by her personalchallenges with this diagnosis. Desiring more treatment options Dr. Sheppard has decided to embark onadditional training in basic science research. Her short term goals which form the basis for the research planare: (1) to develop preclinical research skills that will enable her to identify new therapeutic targets to treatvascular diseases; (2) to establish herself as an expert in aneurysm research; and (3) to submit an R01funding application upon this projects completion. Dr. Sheppard has assembled an impressive mentoring teamcomposed of Drs. Daugherty Cassis Graf and Milewicz. Her primary mentor Dr. Daugherty has extensiveexpertise in animal models of aneurysm formation and he has been a successfully funded NIH investigator forseveral decades. Co-mentor Dr. Lisa Cassis is an expert in the renin-angiotensin system and sexualdimorphism of aortic aneurysms. Co-mentor Dr. Greg Graf is an expert in cholesterol metabolism and statinpharmacology. Dr. Dianna Milewicz an expert in medical genetics has a career in translational studiesfocused on genetic predisposition to vascular diseases. All mentors are senior scientists with a track record ofsuccessfully mentoring new faculty to independent NIH funding. This mentor team will assist Dr. Sheppard inlearning laboratory techniques which include advanced microscopy subcellular fractionationimmunohistochemistry and fluorescence activated cell sorting. The proposed research will examine themechanisms by which statins attenuate thoracic aortic aneurysm growth in a mouse model of Marfansyndrome. The impact of Ras farnesylation on aneurysm growth Raf/ERK expression matrixmetalloproteinase activity elastin fragmentation and leukocyte accumulation will be evaluated in Aim 1. Theimpact of statin combined with -adrenoceptor antagonist or angiotensin receptor blocker in thoracic aorticaneurysm will be investigated in Aim 2. The findings of these studies will form the preliminary data for an R01research application which will transition Dr. Sheppard from trainee status to independent physician-scientist.

project_terms:
3-hydroxy-3-methylglutaryl-coenzyme A;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;Cholesterol;Cholesterol Homeostasis;Clinic;Clinical Research;Confocal Microscopy;Cultured Cells;Data;Diagnosis;Disease;Dissection;Elasticity;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;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;Oxidoreductase;Patients;Persons;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Physicians;Plasma;Pravastatin;Production;Proteins;Publications;RAS inhibition;Regimen;Renin-Angiotensin System;Research;Research Personnel;Research Project Grants;Retrospective Studies;Risk;Scientist;Senior Scientist;Signal Transduction;Signaling Molecule;Smooth Muscle Myocytes;Techniques;Testing;Therapeutic Uses;Thoracic Aortic Aneurysm;Thoracic aorta;Tissues;Training;Transforming Growth Factor beta;United States National Institutes of Health;Universities;Vascular Diseases;Vascular Smooth Muscle;Work;antagonist;ascending aorta;career;clinically relevant;college;experimental study;farnesyl pyrophosphate;farnesylation;in vivo;insight;interest;mouse model;new therapeutic target;novel therapeutics;pharmacologic;pre-clinical research;prevent;professor;repaired;sexual dimorphism;skills;standard of care;translational study;ultra high resolution;ultrasound

public_health_relevance:
Project NarrativeMarfan syndrome is a genetic condition that causes thoracic aortic aneurysm a life-threatening dilation of thelargest blood vessel in the body. This research project will examine how statin medicines prevent thoracicaortic aneurysm growth and whether they add benefit to the medicines currently used to treat thoracic aorticaneurysm in Marfan syndrome.


application_id: 11002727
project_number: 5P20GM121327-09
project_title: Targeting Glutamine Uptake via ASCT2 Inhibition in MYCN-amplified Neuroblastomas
administering_ic: NIGMS
award_notice_date: 2024-12-23
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3
subproject_number: 6479
contact_pi_person_id: 12051773
contact_pi: RELLINGER, ERIC JAMES
other_pis: ST CLAIR, DARET K
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:
Neuroblastoma (NB) is the most common extracranial solid tumor in children. MYCN-amplification is present in ~25% of NBs and nearly half of all high-risk NBs. N-MYC is a proto-oncogene that drives cancer cell growth angiogenesis and metabolism. Aberrant glutamine metabolism is a hallmark of MYC-driven cancers. N-MYC enhances expression of the glutamine transporter ASCT2. ASCT2 has been shown to be critical for MYCN-amplified NB cell survival in vitro and in subcutaneous xenograft formation in vivo. Our central hypothesis is that aberrant glutamine uptake via ASCT2 is critical for MYCN-amplified NB primary tumor growth and metastasis. We will define the critical role of ASCT2 in NB utilizing CRISPR-Cas9 knockout and V-9302 a small molecule ASCT2 inhibitor in 3-D organoid and patient-derived orthotopic xenograft (PDOX) models of MYCN-amplified NB. Stable-isotope resolved metabolomics will be used to define aberrant metabolic pathways activated to sustain NB survival in the presence of ASCT2 blockade. We will also seek to define metabolic vulnerabilities uncovered by ASCT2 inhibition utilizing an unbiased CRISPR-Cas9 lineage dropout screen to assess for dual synthetic lethality in MYCN-amplified NB cells.

project_terms:
3-Dimensional;CRISPR/Cas technology;Cancer Cell Growth;Cancer Center;Cell Survival;Cephalic;Dropout;Glutamine;In Vitro;Kentucky;Knock-out;MYCN gene;Malignant Neoplasms;Metabolic;Metabolic Pathway;Metabolism;Neoplasm Metastasis;Neuroblastoma;Organoids;Patients;Pediatric Neoplasm;Primary Neoplasm;Proto-Oncogenes;Role;Solid Neoplasm;Universities;Xenograft Model;Xenograft procedure;angiogenesis;high risk;in vivo;inhibitor;metabolomics;neuroblastoma cell;small molecule;stable isotope;subcutaneous;synthetic lethal interaction;tumor growth;tumor metabolism;uptake


application_id: 11002725
project_number: 5P20GM121327-09
administering_ic: NIGMS
award_notice_date: 2024-12-23
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3
subproject_number: 6478
contact_pi_person_id: 11597020
contact_pi: FONG, KA-WING
other_pis: ST CLAIR, DARET K
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: 2025-01-01
project_title:
TRIM28 fuels prostate cancer growth through SETDB1-mediated epigenetic silencing of androgen metabolic genes UGT2B15 and UGT2B17

project_abstract:
Prostate cancer (PCa) is the second-leading cause of cancer-related death in men. The mainstay treatment for metastatic PCa is androgen deprivation therapy (ADT). However the disease will inevitably return in an incurable form termed castration-resistant prostate cancer (CRPC). Importantly aberrant androgen receptor (AR) activation in the milieu of low androgen is the main driver of CRPC. Molecular characterization of CRPC paves the way for discovery of novel therapeutic targets and my previous studies showed that TRIM28 is aberrantly upregulated in advanced PCa. High TRIM28 levels are associated with worse clinical outcomes which suggests that TRIM28 could serve as a promising target for PCa therapy. It is known that TRIM28 in a complex with trimethyl-histone H3 lysine 9 (H3K9me3)-specific methyltransferase (SETDB1) possesses transcriptional co-repressor activity but its genomic targets remain largely unexplored in PCa. Moreover the TRIM28 downstream oncogenic pathway has not been comprehensively investigated in PCa. By molecular gene signature analysis I found that the steroid hormone metabolic pathway is regulated by TRIM28. In particular I found that the androgen eliminating enzymes UGT2B15 and UGT2B17 are the key TRIM28-repressed genes. It is known that genomic targeting of the TRIM28 complex is facilitated by transcription factors that bind to specific DNA recognition motifs. My data revealed that TRIM28 interacts with AR. In addition my preliminary results indicated there is co-occupancy of TRIM28 AR and H3K9me3 deposition at UGT2B15 and UGT2B17 gene loci. Based on these findings I hypothesize that TRIM28 acts together with AR to epigenetically silence the expression of androgen metabolic enzymes through SETDB1-mediated H3K9me3. I propose to test this hypothesis in Aim1. UGT2B15 and UGT2B17 are known to inactivate androgen through glucuronidation using UDPGlucA as the sugar-donor. Given that the overexpression of UGT2B15 and UGT2B17 correlate to more UDP-GlucA consumption I hypothesize that levels of UDP-GlucA will decrease in TRIM28 knockdown cells or with treatment of the SETDB1 inhibitor Mit in CRPC cells. I propose to test this hypothesis in Aim2. The results from this proposal will not only reveal a novel epigenetic mechanism for regulating androgen glucuronidation but also have significant implications for the development of SETDB1-targeted therapy for CRPC treatment.

project_terms:
Androgen Receptor;Androgens;Binding;Cancer Center;Cancer Etiology;Cells;Cessation of life;Clinical;Complex;Consumption;DNA;Data;Deposition;Development;Disease;Enzymes;Epigenetic Process;Genes;Genetic Transcription;Genomics;Growth;Histone H3;Kentucky;Lysine;Malignant neoplasm of prostate;Mediating;Metabolic;Metabolic Pathway;Metastatic Prostate Cancer;Methyltransferase;Molecular;Oncogenic;Outcome;Pathway interactions;Prostate Cancer therapy;Receptor Activation;SETDB1 gene;Testing;Universities;advanced prostate cancer;androgen deprivation therapy;androgen independent prostate cancer;epigenetic silencing;gene repression;genetic corepressor;genetic signature;genomic locus;inhibitor;knock-down;men;new therapeutic target;novel;overexpression;prostate cancer cell;steroid hormone;sugar;targeted treatment;transcription factor;tumor metabolism


application_id: 11002707
project_number: 5P20GM121327-09
project_title: Imaging Core
administering_ic: NIGMS
award_notice_date: 2024-12-23
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3
subproject_number: 6635
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
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 SUMMARYThe Imaging Core of the Center for Cancer and Metabolism (CCM) is the technical service and support corefor CCM project research laboratories and pilot project recipients. The integrated services of the Core rangefrom the imaging capabilities of simple microscopes to imaging analysis by sophisticated and advancedimaging methodologies. The Imaging Core personnel assist users to operate the instruments and analyzeimaging data. The Core provides advice for the current PIs in this Center of Biomedical Research Excellence(COBRE) application to use the Imaging Core for their specific studies. The Imaging Core has providedtremendous help to the projects in Phase I of COBRE support and will continue to make its services readilyavailable and easily accessible to all COBRE laboratories in order to generate high quality data. Toward thegoals of providing efficient and high-quality imaging services and of establishing a robust imaging infrastructurewithin the CCM we have added new features and new imaging systems to the Core. Our specific aims are: 1)to provide project-specific training and consultation for COBRE investigators; 2) to develop and adapt state-of-the art imaging techniques to enhance the research of early-stage and pilot project investigators; and 3) todevelop and implement new methods to enhance CCM imaging services and make such services available toCOBRE and non-COBRE users. This Core will provide an easily accessible facility where investigators canevaluate their tissue and/or cellular samples using various types of imaging systems. Dr. Jianhang Jia theDirector of the Imaging Core is a highly productive investigator who has successfully obtained substantialextramural research support including an NIGMS Maximizing Investigators' Research Award (MIRA) (R35)award for established investigators that relies extensively on sophisticated imaging capabilities. He has workedclosely with all graduated COBRE PIs making significant contributions to their successes in obtainingindependent research support. Dr. Jia has guided the development of the four CCM research projects in thisPhase II application and he will continue to advise CCM investigators on the design of experiments that useimaging modalities.

project_terms:
Advanced Malignant Neoplasm;Aging;Animal Disease Models;Area;Award;Bioinformatics;Bioluminescence;Biomedical Research;Biometry;Cancer Center;Centers of Research Excellence;Clinical;Complex;Computer software;Consult;Consultations;Data;Dedications;Development;Disease Progression;Distant;Equipment;Evaluation;Experimental Designs;Extramural Activities;Faculty;Floor;Fluorescence;Goals;Human Resources;Image;Imaging Device;Imaging Techniques;Individual;Infrastructure;Kentucky;Laboratories;Laboratory Research;Link;Malignant Neoplasms;Medicine;Metabolic;Metabolism;Methodology;Methods;Microscope;Mission;Monitor;Mus;National Institute of General Medical Sciences;Neoplasm Metastasis;Organ;Pathology;Phase;Pilot Projects;Positioning Attribute;Productivity;Proteins;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Role;Sampling;Scientist;Services;Site;Slide;System;Tissues;Training;Transfection;Universities;Work;advanced analytics;analytical tool;animal facility;anti-cancer research;cancer therapy;cell motility;cost effective;design;digital;flexibility;imaging capabilities;imaging modality;imaging study;imaging system;in vivo;in vivo imaging;in vivo imaging system;instrument;metabolomics;multidisciplinary;novel;optical imaging;programs;skills;success;treatment response;tumor initiation;tumor metabolism;tumorigenesis


application_id: 11002700
project_number: 5P20GM121327-09
project_title: Metabolism Core
administering_ic: NIGMS
award_notice_date: 2024-12-23
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3
subproject_number: 6634
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
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 SUMMARYMetabolomics largely consists of metabolic profiling which is the process of identification and quantification ofa large number of metabolites of many different biochemical classes from diverse biological samples includingcells culture media tissue and biofluids. However to understand the metabolic underpinning of diseases suchas cancer biochemical mechanism(s) must be elucidated in which case it is necessary to introduce appropriatestable isotope tracers. Although this greatly increases the number of analytes to be quantified it also enablesthe retrieval of much more biologically relevant information. This Stable Isotope Resolved Metabolomics (SIRM)approach is a unique specialty of the Metabolism Core led by PIs with over 40 years of combined expertise inSIRM. The goals of the Metabolism Core are to provide services for a wide coverage of the metabolome withisotopomer and isotopologue analysis and high throughput protein analysis. To achieve this we make use offour major analytical platforms namely (1) high resolution nuclear magnetic resonance (NMR) (2) ultra-highresolution Fourier-transform mass spectrometry (UHR-FTMS) with or without chromatography (3) ultra-traceelemental analyses by inductively-coupled plasma MS (ICPMS) and (4) Reverse Phase Protein Arrays (RPPA).The Metabolism Core personnel will advise on analytical methods and SIRM-based experimental design withdevelopment of additional techniques to address specific issues of identification and quantification and biologicalinterpretation relevant to the COBRE Projects. Because experimental design and sample preparation are integralto the data acquisition and interpretation the Metabolism Core provides expertise in these and informaticsrelevant to the SIRM approach. These goals will be achieved according to the following Specific Aims. SpecificAim 1. To provide access and expertise across a wide range of NMR MS and RPPA technologies toinvestigators. Specific Aim 2. To provide experimental design sample processing and support to theinvestigators for data reduction metabolic pathway and biochemical mechanism analyses. Specific Aim3. To develop and implement new methods to enhance metabolic capabilities relevant to the COBREProjects. This Core will support the young investigators by providing advanced analytical technologies andexpertise in the metabolic requirements for cancer development and behavior.

project_terms:
Address;Algorithms;Behavior;Biochemical;Biochemistry;Bioinformatics Shared Resource;Biological;Biology;Biomass;Biometry;Cancer Center;Carbon;Cells;Centers of Research Excellence;Chromatography;Classification;Collaborations;Consult;Culture Media;Data;Data Analyses;Databases;Development;Dinucleoside Phosphates;Disease;Electrophoresis;Experimental Designs;Fourier Transform;Genomics;Goals;Human Resources;Inductively Coupled Plasma Mass Spectrometry;Informatics;Infusion procedures;Isotope Labeling;Isotopes;Kentucky;Liquid Chromatography;Literature;Logistic Regressions;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic;Metabolic Pathway;Metabolism;Methods;Mus;Nuclear Magnetic Resonance;Operative Surgical Procedures;Organism;Output;Oxidation-Reduction;Pathway Analysis;Phase;Preparation;Principal Investigator;Procedures;Process;Protein Analysis;Protein Array;Proteins;Research Personnel;Resolution;Retrieval;Sampling;Schedule;Services;Source;Standardization;Statistical Data Interpretation;System;Techniques;Technology;Time;Tissue Harvesting;Tissues;Trace Elements;Tracer;Universities;Update;Validation;advanced analytics;analytical method;cell growth;data acquisition;data reduction;high throughput analysis;medical specialties;metabolic abnormality assessment;metabolome;metabolomics;stable isotope;tumor metabolism;ultra high resolution;web site


application_id: 11002696
project_number: 5P20GM121327-09
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2024-12-23
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3
subproject_number: 6633
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
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 The University of Kentucky (UK) Center for Cancer and Metabolism (CCM) is a unique multidisciplinary Center of Biomedical Research Excellence (COBRE) embedding a strategically developed sustainable center infrastructure that cultivates cutting-edge research focused on the role of metabolic dysregulation in cancer development and progression. The Administrative Core provides critical scientific and administrative leadership to advance the goals of the CCM: to develop and sustain a thematically focused multidisciplinary center infrastructure dedicated to defining the role of altered metabolism in the development and treatment of cancer and to use this innovative center structure to develop promising early-stage investigators with enhanced cancer research skills. The goal of the Administrative Core is to increase the scientific productivity of the centers faculty by delivering efficient administrative services across scientific projects and cores as well as pilot projects through an organizational / leadership framework that supports flexible team-based mentoring and provides for clear accountability. The Administrative Core is the central coordinating hub responsible for integrating highly complementary disciplinary strengths at UK in cancer metabolism and informatics and leveraging sophisticated metabolomics tools and advanced cancer imaging capabilities in support of data-intensive research focused on cancer metabolism. The core has primary responsibility for facilitating the CCMs scientific vision operating on principles grounded in transformational leadership and shared administrative oversight. Administrative Core functions are operationalized through the following 3 specific aims: 1) to provide overall operational management of the center; 2) to facilitate research training mentoring and career development activities to develop early- stage investigators in cancer and metabolism and expand research in this area through pilot projects; and 3) to conduct overall planning and evaluation of CCM activities and resources. The core implements all administrative activities of the CCM: oversees daily center activities; manages program communications fiscal processes meeting organization and advisory committee input; facilitates and expedites interactions among projects and cores; manages the pilot project program; and leads program and project evaluation efforts. The core oversees a total of 4 projects 2 scientific cores a biostatistics and bioinformatics support component that is integrated into each project and 4 pilot projects each year. In addition the core ensures highly effective well-planned team- based mentorship including basic and clinical perspectives and external expertise for early-stage investigators. The core supports CCM investigators through their career development milestones including tenure and promotion stages. In implementing these activities effectively the Administrative Core contributes substantially to development of a sustainable biomedical research infrastructure dedicated to advancing a cancer metabolism multidisciplinary theme.

project_terms:
Accountability;Address;Administrative Efficiency;Administrator;Advanced Malignant Neoplasm;Advisory Committees;Area;Biochemistry;Bioinformatics;Biomedical Research;Biometry;Cancer Center;Cardiovascular Diseases;Centers of Research Excellence;Clinical;Clinical Sciences;Communication;Communication Programs;Coupled;Data;Data Science;Death Rate;Dedications;Development;Disparate;Effectiveness;Ensure;Evaluation;Faculty;Fostering;Goals;Health;Incidence;Informatics;Infrastructure;Kentucky;Knowledge;Leadership;Malignant Neoplasms;Mediator;Mentors;Mentorship;Metabolic;Metabolism;Molecular Medicine;Monitor;National Cancer Institute;Obesity;Oncogenic;Pharmacologic Substance;Pilot Projects;Play;Process;Productivity;Program Evaluation;Research;Research Infrastructure;Research Personnel;Research Training;Resource Sharing;Resources;Role;Scientist;Seasons;Senior Scientist;Services;Structure;System;Translational Research;Universities;Vision;anti-cancer research;biomedical informatics;cancer therapy;career development;clinical center;flexibility;imaging capabilities;improved;innovation;meetings;metabolomics;multidisciplinary;next generation;novel;programs;skills;success;synergism;therapeutic target;tool;tumor metabolism


application_id: 11002695
project_number: 5P20GM121327-09
project_title: University of Kentucky Center for Cancer Metabolism
administering_ic: NIGMS
award_notice_date: 2024-12-23
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: REVILLEZA, MARIA JAMELA R
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3(C2)
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe University of Kentucky (UK) Center of Biomedical Research Excellence on Cancer and Metabolism (CCM)was established in March 2017 by a multidisciplinary team of basic and clinical scientists engaged in cutting-edge research on metabolic dysregulations in cancer an emerging hallmark of disease responsible for tumordevelopment drug resistance and distant metastasis. The overarching goal of the Phase II CCM is to continueefforts to expand a thematically focused multidisciplinary infrastructure dedicated to defining the contribution ofmetabolism in the development and treatment of cancer and to use this novel multidisciplinary platform todevelop promising project leaders with enhanced skills in an exciting new area of cancer research. With adedicated team of mentors combining basic and clinical expertise in redox biology cancer cell signalingepigenetics systems biochemistry and clinical trials as well as core strengths in advanced metabolomics andsophisticated cancer imaging we will accomplish this overall goal by conducting high-quality basic andtranslational research addressing metabolic reprogramming governing tumor initiation metastasis drugresistance and recurrence. This objective will be met by achieving 2 Specific Aims. Specific Aim 1 is to expandthe critical mass of investigators conducting CCM thematic research. We will recruit coach and solidify thecommitment of a cadre of promising project leaders to conduct cancer and metabolism research utilizing a highlyeffective mentoring system and provide these scientists with cutting-edge research core facilities and services.Proposed new synergies will be developed through 4 well-crafted research projects; an Administrative Core;innovative research cores in metabolism and imaging; strong biostatistics and bioinformatics support; andcollaborations with other UK research centers to facilitate the translation of basic findings in cancer metabolisminto early therapeutic and/or intervention approaches. Specific Aim 2 is to advance an independent sustainablemultidisciplinary thematic biomedical infrastructure and research program on cancer and metabolism bystrengthening key scientific cores. We propose to expand the scope and capacity of these vital cores by acquiringand installing new state-of-the-art equipment introducing new technologies and service as well as providingtraining sessions workshops and symposiums. Kentucky ranks highest in rates of overall cancer incidence andmortality [1]. In Phase I the CCM had a transformative impact in career research and retention of the nextgeneration of scientists who address metabolic dysregulations underpinning the causal links between metabolicdisorders and cancer development a major health threat in the nation. Importantly the Phase II application willbuild upon these accomplishments to propel CCM to a nationally recognized center in cancer and metabolismresearch that will also address the regions critical needs.

project_terms:
Address;Applications Grants;Area;Basic Science;Biochemistry;Bioinformatics;Biology;Biometry;Cancer Center;Cell Survival;Centers of Research Excellence;Clinical;Clinical Trials;Collaborations;Core Facility;Coupled;Data;Dedications;Development;Disease;Distant Metastasis;Drug resistance;Early Diagnosis;Educational workshop;Environment;Epigenetic Process;Equipment;Extramural Activities;Faculty;Fees;Fostering;Foundations;Funding;Goals;Grant;Growth;Health;Image;Incidence;Infrastructure;Institution;Interdisciplinary Study;Intervention;Kentucky;Link;Malignant Neoplasms;Mediator;Mentors;Metabolic;Metabolic Diseases;Metabolism;Methodology;Neoplasm Metastasis;Obesity;Outcome;Oxidation-Reduction;Phase;Pilot Projects;Positioning Attribute;Productivity;Protein Array;Quality of life;Recurrence;Research;Research Personnel;Research Project Grants;Research Support;Role;Scientist;Services;Signal Transduction;System;Therapeutic;Training;Translational Research;Translations;United States National Institutes of Health;Universities;Vital capacity;animal imaging;anti-cancer research;base;biomarker identification;cancer cell;cancer imaging;cancer initiation;cancer prevention;cancer therapy;career;defined contribution;editorial;improved;in vivo;innovation;metabolomics;mortality;multidisciplinary;new technology;next generation;novel;prevent;programs;recruit;skills;success;symposium;synergism;therapeutic target;therapy resistant;tool;tumor;tumor initiation;tumor metabolism;tumorigenesis

public_health_relevance:
PROJECT NARRATIVEKentucky ranks highest in rates of overall cancer incidence and mortality [1]. To address this major health issuethe University of Kentucky Center of Biomedical Research Excellence on Cancer and Metabolism will sustain arobust infrastructure to continue to conduct basic and translational research to better define the metabolicdysregulations governing tumor development metastasis drug resistance and recurrence. This will be achievedthrough the cultivation and expansion of a cadre of promising project leaders by providing research supportmentoring and access to state-of-the-art metabolic and imaging core facilities.


application_id: 11002684
project_number: 5G08LM014412-02
administering_ic: NLM
award_notice_date: 2024-12-11
opportunity_number: PAR-20-283
application_type: 5
activity_code: G08
ic: LM
serial_number: 014412
program_official: HUANG, ZOE E
project_start_date: 2024-01-01
project_end_date: 2026-12-31
study_section: ZLM1-ZH-G(01)
contact_pi_person_id: 11808630
contact_pi: WHITE, BRANDI MICHELLE
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-01-01
project_title:
DASH-ing to Heart Health: Supporting Low-Income African American Women with an Interactive "Meals that Heal" Resource Book

project_abstract:
Although the DASH diet [Dietary Approaches to Stop Hypertension] has been shown tosignificantly reduce the risk of hypertension and other cardiovascular disease risk factors thereis a lack of available health information on how to follow a feasible DASH diet for low-incomeAfrican American women who may be at the most risk for hypertension because of poor socialdeterminants of health. The long-term goal of this project is to increase the accessibility andacceptability of culturally- and economically-responsive dietary approaches to reducehypertension risk for low-income African American women. The overall goal of this project is tocreate a useful and usable interactive resource book that increases awareness/knowledge ofhypertension and improves ease of following a DASH diet by providing culturally relevant andlow-cost DASH recipes that low-income African American women can utilize when making hearthealthy food choices. The specific aims are to: (1) evaluate how currently available DASHrecipes perform in terms of cultural relevance and economic feasibility; (2) describe what factorsinfluence adherence to the DASH diet; and (3) determine how effective an interactive resourcebook is at increasing DASH knowledge and the likelihood of using DASH recipes. The first aimwill use an integrative review to synthesize related literature. The second aim will explorebarriers and facilitators to DASH adherence including dietary preferences and food budgetarydecision making. The third aim will evaluate the effectiveness of the resource throughcommunity-based food demonstration workshops. This proposed project is innovative becauseit focuses on adherence to DASH diet and low-income African American women a group that isdisproportionately impacted by hypertension. The proposed project is significant becausefindings will increase the availability of accessible and usable evidence-based health informationfor health disparity populations. This knowledge has the potential to increase the adherence tothe DASH diet and overall effectiveness of existing interventions which is critical to reducinghypertension disparities.

project_terms:
Adherence;Adopted;Adult;Affect;African American;African American Women;African American population;American;Asian Women;Awareness;Behavioral;Books;Budgets;Cardiac health;Cardiovascular Diseases;Communities;Complex;DASH diet;Decision Making;Diastolic blood pressure;Diet;Diet Modification;Disease Management;Disparity;Eating;Economics;Educational workshop;Effectiveness;Family;Family member;Financial Hardship;Food;Food Preferences;Goals;Government;Health;Health Care Costs;Health Food;Healthy Eating;Heart;Hispanic Women;Hypertension;Information Resources;Intervention;Interview;Knowledge;Literature;Low Income Population;Low income;Marketing;Outcome;Pathway interactions;Peer Review;Persons;Primary Prevention;Professional Organizations;Psychosocial Stress;Public Housing;Publications;Recipe;Research;Research Project Grants;Resources;Risk;Risk Factors;Risk Reduction;Social Environment;Social support;Subgroup;United States National Library of Medicine;Woman;adherence rate;blood pressure reduction;built environment;cardiovascular disorder risk;community-centered;cost;dietary;dietary adherence;dietary approach;disorder prevention;economic disparity;effectiveness evaluation;evidence base;food insecurity;food quality;good diet;healing;health disparity populations;high risk;hypertension control;hypertension prevention;improved;informant;innovation;lifestyle intervention;prevent;racial discrimination;social health determinants;socioeconomics;usability

public_health_relevance:
The "Meals that Heal" project will develop disseminate and evaluate a useful and usableinteractive health information resource for low-income African American women and othereconomically-disadvantaged African Americans. The interactive resource book will providetailored health information about hypertension risk reduction and the DASH diet [DietaryApproaches to Stop Hypertension] including culturally relevant and low-cost DASH recipesfor hypertension disease prevention or management. The resource book will be marketed toa broader audience through existing community-based partnerships and networks.


application_id: 11002332
project_number: 5K08DK124566-05
project_title: Muscle bone interaction and its role in diabetic bone disease of Type I diabetes
administering_ic: NIDDK
award_notice_date: 2024-12-20
opportunity_number: PA-19-117
application_type: 5
activity_code: K08
ic: DK
serial_number: 124566
program_official: MALOZOWSKI, SAUL N
project_start_date: 2021-03-01
project_end_date: 2026-06-30
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
arra_indicator: N
project_abstract:
Summary Bone fracture incidence observed in individuals with Type 1 diabetes (T1D) is much higher compared tothe general population. The burden of diabetic bone disease is partially due to lack of evidence to supporttargeted prevention and interventions to reduce fractures in this population. Furthermore those with T1Dexhibit skeletal muscle dysfunction associated with decreased muscle strength and muscle mass. Skeletalmuscle and bone communication is a potential modifiable factor that may contribute to development of diabeticmusculoskeletal disease. More specifically the candidate proposes that a myokine called myostatin is directlyinvolved in development of diabetic bone disease and may associate with skeletal muscle dysfunction. Therole of myostatin in T1D and how it affects the musculoskeletal system in this disease are gaps in knowledgethat will be addressed with this proposal. Specifically the three aims of this proposal are: 1. Quantify therelationship between myostatin levels in serum and skeletal muscle and bone parameters of humans with andwithout T1D; 2. Quantify the relationship between myostatin levels in serum and muscle and the bonephenotype of mice with insulin-deficient diabetes; 3. Evaluate whether inhibition of myostatin is beneficial forprevention of DBD in insulin-deficient diabetes; and lastly 4: Determine the mechanism of action of myostatinon osteoblastic bone cells under normoglycemic and hyperglycemic conditions. Myostatin which is thought tonegatively affect both bone and skeletal muscle may serve both as a marker of musculoskeletal function andsurrogate for risk for fracture in those with T1D. Additionally it may offer an opportunity for targetedintervention to prevent or improve musculoskeletal dysfunction associated with T1D. The knowledge gainedfrom these studies will set the ground for future studies in musculoskeletal health in diabetes and will offer thecandidate an opportunity to transition towards an independent career in the abovementioned field. This proposal presents a five-year research career development program focused on the study ofmuscle and bone interactions in Type 1 diabetes; and specifically how muscle derived molecules calledmyokines contribute to diabetic bone disease a serious and emerging complication of Type 1 diabetes. Thecandidate currently holds a position as an Assistant Professor of Pediatrics in the Division of PediatricEndocrinology at the University of Kentucky. She has 75% protected time for research independent officespace laboratory space and access to all equipment and resources offered by the Barnstable Brown DiabetesCenter. The candidate is strongly committed to an academic career in the field of musculoskeletal research indiabetes and is supported by her mentors and her department. The proposed study and the complementarydidactic work will provide the candidate with research skills in basic translational and clinical research therebyenabling to transition to an independent clinician scientist.

project_terms:
20 year old;Activin Receptor;Address;Affect;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;Functional disorder;Future;GDF8 gene;Gene Expression;Gene Proteins;General Population;Genes;Health;Hip Fractures;Hip region structure;Human;Hyperglycemia;Impairment;In Vitro;Incidence;Incidental Findings;Individual;Insulin deficiency;Insulin-Dependent Diabetes Mellitus;Intervention;Kentucky;Knowledge;Laboratories;Life;MAP Kinase Gene;Measures;Mechanics;Mediating;Mediator;Mentors;Mus;Muscle;Muscle function;Musculoskeletal;Musculoskeletal Diseases;Musculoskeletal System;Nurses' Health Study;Osteoblasts;Osteocalcin;Osteocytes;Osteogenesis;Outcome;Pathway interactions;Pediatrics;Pharmacotherapy;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 fracture repair;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;novel;osteoblast differentiation;paracrine;pharmacologic;prevent;professor;prospective;receptor;reduced muscle mass;reduced muscle strength;skills;young adult;younger age

public_health_relevance:
Project NarrativeIndividuals with Type 1 diabetes have higher fracture rates and smaller and weaker muscles compared tothose without diabetes even in young ages. With this project we will try to identify whether a molecule thatcomes from skeletal muscle called myostatin is involved in the increased risk of fractures and the poor qualityof skeletal muscle in young individuals with Type 1 diabetes.


application_id: 11001991
project_number: 5R00AA030627-04
project_title: Restoration and preservation of hepatic cardiolipin levels promotes liver regeneration in AH
administering_ic: NIAAA
award_notice_date: 2024-11-21
opportunity_number: PAR-21-271
application_type: 5
activity_code: R00
ic: AA
serial_number: 030627
program_official: LIN, LI
project_start_date: 2022-09-21
project_end_date: 2026-11-30
study_section: NSS
contact_pi_person_id: 14169641
contact_pi: HARDESTY, JOSIAH E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract:Alcohol-associated hepatitis (AH) is a clinical manifestation of alcohol-associated liver disease (ALD) that has avery poor prognosis. Current treatments are ineffective and liver transplantation is the only long-term solution.The liver has the unique ability to regenerate post-injury but in ALD/AH this process becomes compromised.Mitochondria dysfunction is a hallmark of ALD and AH that can contribute to compromised liver regeneration.Mitochondria enriched with cardiolipin maintain the energy requirements (e.g. ATP) necessary for hepatocyteproliferation and liver regeneration. Preliminary data demonstrate that hepatic cardiolipin synthesis iscompromised in clinical AH and experimental AH. Cardiolipin is required to maintain mitochondrial bioenergeticsand undergoes oxidation and depletion in ALD compromising liver regeneration. However treatment withcardiolipin or elamipretide (drug that prevents cardiolipin oxidation) can restore hepatocyte mitochondrial functionand proliferation. The aim of this study is to determine if cardiolipin supplementation and preservation willpromote liver regeneration via maintenance of ATP synthesis and prevention of hepatocyte apoptosis alleviatinghepatic insufficiency in AH. This study uses pre-clinical animal models and human in vitro models of AH toassess the treatment efficacy of cardiolipin supplementation and preservation. Aim 1 will determine if mice withcardiolipin deficient hepatocytes have compromised liver regeneration due to loss of mitochondrial ATPsynthesis in a model of AH. Aim 2 will test whether treatment with cardiolipin and elamipretide will enhancehepatic mitochondrial function liver regeneration and proliferating hepatocyte populations in an experimentalanimal model of AH. Aim 3 will identify cardiolipin species in human AH liver and plasma and assess their effecton hepatocyte proliferation and inflammatory responses in immune cells. The K99-phase (Aim 1) will providetraining in assaying liver regeneration and mitochondrial function sc-RNASeq analysis and use of a mousedeficient in hepatocyte cardiolipin. This MOSAIC K99/R00 proposal will provide the training necessary (K99) tobuild a solid research foundation providing a pathway to independence as an independent researcher in the fieldof ALD and liver regeneration (R00). Findings from this study will identify a therapeutic strategy to treat AH viaenhanced liver regeneration which could replace the only long-term treatment alternative liver transplantation.

project_terms:
ATP Synthesis Pathway;Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic liver damage;Alcohols;Animal Model;Animals;Apoptosis;Binding;Bioenergetics;Biogenesis;Biological Assay;Biological Markers;Cardiolipins;Cells;Cessation of life;Clinical;Clinical Trials;Culture Media;Data;Death Rate;Dextrins;Dose;Enzymes;Ethanol;Euthanasia;Evaluation;Experimental Animal Model;Foundations;Galactosamine;Genes;Genus Hippocampus;Hepatic;Hepatic Insufficiency;Hepatitis;Hepatocyte;Human;Immune;Impairment;In Vitro;Inflammation;Inflammatory Response;Injections;Injury;Lead;Lipids;Liver;Liver Mitochondria;Liver Regeneration;Liver diseases;LoxP-flanked allele;Maintenance;Maltose;Measurement;Mediating;Mitochondria;Mitochondrial Myopathies;Modeling;Mus;Natural regeneration;Oxidative Phosphorylation;Partial Hepatectomy;Pathway interactions;Patients;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phase;Phospholipids;Plasma;Population;Preclinical data;Prevention;Process;Prognosis;Proliferating;Proliferation Marker;Proteins;Regimen;Research;Research Personnel;Respiratory Chain;Rodent;Role;Safety;Sampling;Solid;Sorting;Structure;Supplementation;TNF gene;Tail;Testing;Therapeutic;Training;Translations;Treatment Efficacy;Veins;Vesicle;Viral;Viral Genome;alternative treatment;chronic liver disease;cytochrome c;cytokine;disorder control;feeding;hepatocyte injury;improved;in vitro Model;ineffective therapies;lipidomics;liver cell proliferation;liver function;liver transplantation;male;mitochondrial dysfunction;mitochondrial membrane;novel;oxidation;particle;patient prognosis;pharmacologic;pre-clinical;preclinical study;preservation;prevent;problem drinker;response;restoration;single-cell RNA sequencing;therapeutically effective;treatment arm;treatment strategy

public_health_relevance:
Project Narrative:This study will aim to exploit the livers ability to regenerate in order to reverse alcohol-induced liver damagecommon in alcoholic-associated liver disease (ALD) and alcohol-associated hepatitis (AH). Specifically the studywill determine whether preservation and/or supplementation of hepatic cardiolipin promotes liver regeneration inALD/AH via multiple models (animal in vitro and human samples). Findings from this pre-clinical study will leadto the evaluation of the safety dose tolerance and efficacy of cardiolipin lipid vesicles and elamipretide as atreatment strategy for ALD/AH in clinical trials.


application_id: 11001949
project_number: 5R01NS129987-03
project_title: The role of SOCE in microglia and secondary degeneration after SCI
administering_ic: NINDS
award_notice_date: 2025-01-15
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: NS
serial_number: 129987
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2023-02-01
project_end_date: 2027-12-31
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: Neurological outcome after spinal cord injury (SCI) is dependent on the extent of primary injury andthe delayed secondary degeneration of spared white matter (WM) and grey matter. Although Ca2+ overload isestablished as a key mediator of secondary injury therapeutically targeting external sources of Ca2+ to datehave failed to improve neurological recovery in pre-clinical studies and following human SCI. This proposal willassess the role of store-operated Ca2+ entry (SOCE) directly in spinal cord neurons and microglia after SCIusing cell type specific knockout of key SOCE mediators. Although SOCE plays a vital role in maintaining Ca2+homeostasis and is necessary to sustain intracellular Ca2+ at critical levels for immune cell function wepropose that aberrant and excessive SOCE causes secondary degeneration of WM. The role of SOCE in WMinjury microglial activation and function remains poorly understood. Furthermore the precise role of theessential SOCE components including stromal interaction molecule (stim 1 and -2) and Orai 1-3 (form theCa2+ channel pore) in microglial function and neuronal injury remains unclear. Our preliminary data support animportant role for SOCE in mediating secondary degeneration microglial activation and proinflammatorycytokine release and worsening neurological recovery. We hypothesize that dysregulation of SOCE mediatesbystander secondary axonal degeneration following SCI by increasing Ca2+ permeability through Stim and/orOrai channels causing Ca2+ overload in axons. In addition we hypothesize that SOCE regulates microglialactivation and release of proinflammatory factors that negatively impacts neurological recovery after SCI. Ourspecific Aims are to 1. Determine the role of SOCE in secondary degeneration and neurological recoveryfollowing SCI. 2. Determine the role of microglial SOCE in secondary degeneration wound healing andneurological recovery after SCI. To accomplish these aims we will use two photon excitation intravital imagingto visualize the dynamic response of spinal cord axons and microglia after SCI in real time. We will use bothpharmacological SOCE inhibitors and cell type specific knockout of key SOCE mediators directly in spinalneurons and microglia. The most efficacious approach will then be assessed using behavioral testing amountof spared WM and grey matter and wound healing. The technology and approach may help advance the fieldas live imaging of axons over time allows unequivocal determination of the fate of injured axons and whetherthey can be rescued in real-time with treatment. Furthermore it allows direct visualization of microgliasimultaneously with axons and their interactions as these events are unfolding in the injured spinal cord. Thisproposal is innovative and uses advanced imaging techniques to explore overlooked areas of SCI research.The approach taken may also unveil novel drug targets and repurpose FDA approved drugs found to inhibitSOCE (e.g. teriflunomide). The underlying mechanisms of WM injury may also be relevant to otherneurological diseases of the nervous system such as multiple sclerosis stroke and TBI.

project_terms:
Acute;Afferent Neurons;Anti-Inflammatory Agents;Area;Axon;Biological Process;Blood;Breeding;Calcium;Cell Physiology;Chronic;Cicatrix;Data;Drug Targeting;Environment;Event;FDA approved;Growth;Growth Factor;Histology;Homeostasis;Human;Image;Imaging Techniques;Immune;Inflammation Mediators;Inflammatory;Injury;Knock-out;Knockout Mice;LoxP-flanked allele;Mediating;Mediator;Microglia;Molecular;Mouse Strains;Multiple Sclerosis;Mus;Myelogenous;Myeloid Cells;Nerve Degeneration;Nervous System;Nervous System Disorder;Neurodegenerative Disorders;Neurologic Deficit;Neurological outcome;Neuronal Injury;Neurons;Nitrogen;Outcome;Oxygen;Pain;Pathologic;Pathway interactions;Patients;Permeability;Pharmaceutical Preparations;Phenotype;Physiological;Play;Process;Production;Recovery;Recovery of Function;Reporter;Reporting;Research;Role;STIM1 gene;Secondary to;Signal Transduction;Site;Source;Spinal;Spinal Cord;Spinal cord injury;Stroke;Technology;Time;Tissue Preservation;Tissues;Visualization;Wallerian Degeneration;axon injury;axonal degeneration;behavior test;cell type;cytokine;cytotoxic;drug repurposing;effective therapy;experimental study;functional improvement;functional outcomes;glial activation;gray matter;improved;in vivo;inhibitor;innovation;intravital imaging;intravital microscopy;neuroinflammation;neurological recovery;neuroprotection;new therapeutic target;novel;pharmacologic;preclinical study;prevent;recruit;response;therapeutic target;two-photon;white matter;white matter injury;wound healing

public_health_relevance:
Project NarrativePatients often suffer from permanent neurological deficits due to secondary degeneration of axons after spinalcord injury and there are no effective therapies to treat these problems. The molecular mechanisms that causesecondary bystander axonal loss following spinal cord injury remain poorly understood; however growingscientific evidence suggests a key role of calcium overload and neuroinflammation in this process. We willexplore the role of aberrant store-operated calcium entry (SOCE) as mediating direct secondary bystanderdegeneration and indirectly by targeting SOCE in microglia.


application_id: 11001939
project_number: 5R01NS116068-05
project_title: Macrophage Depletion Therapy for Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2024-11-13
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: NS
serial_number: 116068
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2021-03-15
project_end_date: 2025-11-30
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8201969
contact_pi: GENSEL, JOHN C
other_pis: ALILAIN, WARREN JOSEPH
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT. Spinal cord injury (SCI) is a devastating lifelong affliction that impairs anumber of functions including locomotion breathing autonomic regulation and sensation/pain. Unfortunatelythere is no current FDA approved therapy for SCI. Therefore there is a critical need to translate basic sciencediscoveries developed in the laboratory with promising effects after experimental SCI towards humanapplication. SCI elicits an intraspinal inflammatory response comprised of resident glia and infiltrating bloodleukocytes. Although subsets of resident and recruited immune cells have been implicated in CNS repair morethan 20 years of experimental data in different animal models of SCI indicate that acute monocyte depletion(MD) is consistently neuroprotective. Further there are clinically viable drugs such as clodronate that caneffectively deplete monocytes after SCI. However a number of fundamental questions must be answeredbefore successful translation including understanding the extent to which injury level impacts therapeuticefficacy as well as understanding the long-term consequences of MD on functional recovery and monocyterepopulation and fate. Therefore the goals of this proposal are to examine chronic and level-specific functionalchanges after acute MD using clinically relevant outcomes including pain autonomic dysreflexia respirationand forelimb/hand function. We will study the effects of acute liposome encapsulated clodronate treatment forup to one year in rodent models of cervical and thoracic SCI. Specifically this grant seeks to: Aim 1: evaluatethe dose-response effects of acute MD on myelopoiesis biodistribution and toxicity; Aim 2: determine theefficacy of acute MD on recovery of locomotor sensory and autonomic function in chronic SCI rats. Aim 3:determine the effects of acute MD on recovery of respiratory motor and forelimb function after cervical SCI.The combined approach of examining the effects of MD after both cervical and thoracic SCI will provideunprecedented preclinical data regarding the effects of monocyte function on sensory autonomic pain andrespiratory outcomes. The feasibility of clodronate (aka disodium dichloromethylene diphosphonate) treatmentin SCI individuals was reported almost 40 years ago therefore our proposal is significant as data from ourstudies could be adapted to treat human SCI and is expected to be of critical translational impact.

project_terms:
Acute;Affect;American;Animal Model;Animals;Anti-Inflammatory Agents;Applications Grants;Autonomic Dysreflexia;Basic Science;Biodistribution;Biological Assay;Bone Marrow;Breathing;Caring;Cell Death;Cells;Cervical;Cervical spinal cord injury;Cervical spinal cord structure;Chronic;Clinical;Clinical Trials;Contusions;Data;Dichloromethylene Diphosphonate;Distal;Dose;Encapsulated;Esthesia;FDA approved;Flow Cytometry;Forelimb;Frustration;Functional impairment;Funding;Goals;Grant;Hand functions;Hindlimb;Hour;Human;Immune;Immune Targeting;Immunologic Deficiency Syndromes;Impairment;Individual;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Injury;Laboratories;Lesion;Leukocytes;Liposomes;Liver;Locomotion;Locomotor Recovery;Macrophage;Mediating;Minocycline;Modeling;Modification;Motor;Multiple Trauma;Myelopoiesis;Neuroglia;Organ;Outcome;Outcome Measure;Output;Pain;Pathology;Persons;Pharmaceutical Preparations;Pharmacotherapy;Phenotype;Population;Preclinical data;Production;Publishing;Rattus;Recovery;Recovery of Function;Regulation;Reporting;Research;Research Personnel;Respiration;Rodent;Rodent Model;Sensory;Site;Spinal Cord;Spinal Cord Contusions;Spinal Cord Plasticity;Spinal Injuries;Spinal cord injury;Spleen;Steroids;Testing;Therapeutic;Thoracic spinal cord structure;Time;Tissues;Toxic effect;Translating;Translations;Treatment Efficacy;United States;United States National Institutes of Health;Voice;arm;axonal sprouting;central pattern generator;clinically relevant;efficacy evaluation;functional outcomes;improved;improved outcome;indexing;innovation;meeting reports;meetings;monocyte;neuroprotection;novel therapeutic intervention;pre-clinical;preclinical evaluation;quality of life improvement;recruit;repaired;respiratory;response;side effect;synaptogenesis;tissue repair;translational impact;translational therapeutics

public_health_relevance:
PROJECT NARRATIVE. There are near 290000 people in the United States of America that have a spinalcord injury (SCI) (with at least 18000 new cases each year) many with functional impairment. The mainobjective of this grant proposal is to investigate a novel therapeutic strategy which modifies the inflammatoryresponse and can potentially lead to protection of the spinal cord after injury as well as functional recovery.This dose-response experimental approach will be studied in multiple injury levels and functional outcomes aswell as tracked over time and collectively these studies will lead to better understanding of the impact ofinflammatory modification after injury and can potentially lead to improvement in human care and outcomes.


application_id: 11001472
project_number: 5K99AG084892-02
project_title: Gabapentin prescription and health-related outcomes in older adults
administering_ic: NIA
award_notice_date: 2024-11-27
opportunity_number: PA-20-188
application_type: 5
activity_code: K99
ic: AG
serial_number: 084892
program_official: MARTIN, DAMALI
project_start_date: 2023-12-15
project_end_date: 2026-11-30
study_section: Career Development Facilitating The Transition to Independence Study Section[AGCD-1]
contact_pi_person_id: 78323710
contact_pi: OH, GYEON
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: 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 DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractGabapentin currently approved to treat partial seizures and postherpetic neuralgia wasthe 6th most commonly prescribed medication in the US in 2018. Notably close to 95% of gabapentinprescriptions are for off-label indications such as neuropathic pain migraines substance use disorder andpsychiatric symptoms. Gabapentin's widespread use may be driven by a belief that it is a safer drug thanopioids and antipsychotics. However there is an increasing concern about the safety of gabapentin use andseveral studies have reported that gabapentin has the potential for misuse and abuse. In particular althoughgabapentin prescription has dramatically increased in older adults our understanding of gabapentin use in thispopulation is limited. Due to gabapentin's known binding site alpha-2-delta-1 which has a relationship withcalcium channel NMDA receptor and thrombospondin it is possible that gabapentin could affect older adults'cognition and motor functions. To fill in the research gap this study proposes to assess longitudinal patterns ofgabapentin use in older adults and to estimate the risk of health-related outcomes associated with gabapentinprescriptions using Medicare claims data and linked Rush Alzheimer Disease Center-Medicare data. Aim 1 willdetermine the distinct patterns (e.g. duration of use concurrent medications history of medication prior togabapentin initiation) of gabapentin use and examine the factors including demographics and medical historyassociated with each pattern. This aim will provide clinically relevant characteristics of gabapentin users tofurther investigate. Aim 2 will examine the association of gabapentin use with health-related outcomesincluding falls fractures neurocognitive changes hospitalizations emergency department visits and mortality.These associations will be estimated marginal structural models by considering time-varying exposure patternsand time-varying confounders including concurrent use of other medications and medical history. Thisproposal fits into the National Institute on Aging's special interest of research on pain pain management andopioids in aging. Through completing this project Dr. Oh will gain experience in real-world evidence studies and expandher toolbox to serve her professional future as a neuro-pharmacoepidemiologist. Since medication use and itseffects is highly influenced by policy this project will build Dr. Oh's knowledge of the process of translatingresearch into policy. Lastly Dr. Oh will sharpen essential professional skills such as grant writing networkingand mentoring. She will be guided by a strong interdisciplinary mentoring team with collective expertise inneuroepidemiology pharmacoepidemiology health-related outcomes policy and biomedical informatics.Findings from this study will help healthcare providers and policymakers better understand the risks andbenefits of prescribing gabapentin to older adults and will provide the baseline knowledge for furtherinvestigation into establishing the causal relationship between gabapentin and health-related outcomes.

project_terms:
Adult;Affect;Aging;Alzheimer's Disease;Alzheimer's disease related dementia;Analgesics;Antipsychotic Agents;Autopsy;Behavior;Belief;Benefits and Risks;Benzodiazepines;Binding Sites;Breathing;Calcium Channel;Central Nervous System;Central Nervous System Depressants;Characteristics;Clinical;Cognition;Cognitive;Data;Data Coordinating Center;Data Reporting;Data Set;Dementia;Diagnosis;Drug Prescriptions;Drug usage;Emergency department visit;Enrollment;Ensure;Focal Seizure;Fracture;Future;Goals;Grant;Health;Health Care;Health Expenditures;Health Personnel;Hospitalization;Impaired cognition;Investigation;Knowledge;Label;Link;Manuscripts;Measures;Medical History;Medicare;Medicare claim;Medicine;Mentors;Methods;Migraine;Motor;N-Methyl-D-Aspartate Receptors;National Institute on Aging;Neurocognitive;Neuroepidemiology;Nursing Homes;Opioid;Oral;Outcome;Pain;Pain management;Patient-Focused Outcomes;Pattern;Pharmaceutical Preparations;Pharmacoepidemiology;Policies;Policy Maker;Population;Postherpetic neuralgia;Preparation;Process;Psychiatric therapeutic procedure;Recording of previous events;Reporting;Research;Risk Estimate;Role;Safety;Sample Size;Selection Bias;Structural Models;Substance Use Disorder;Surveys;Thrombospondins;Time;Translating;United States Centers for Medicare and Medicaid Services;United States Food and Drug Administration;Writing;anti-depressive agents;behavior change;beneficiary;biomedical informatics;career;clinically relevant;demographics;evidence base;experience;fall risk;falls;functional decline;gabapentin;improved;interest;mortality;motor behavior;neuropathology;off-label use;older adult;painful neuropathy;psychiatric symptom;real world evidence;skills;treatment risk;trend

public_health_relevance:
Project NarrativeAlthough gabapentin has been increasingly prescribed in the older adults as off-label indication the potentialhealth effects of gabapentin use on older adults are not well studied. This proposal will investigate the patternsof gabapentin use in older adults and the healthcare-related outcomes associated with gabapentin use. Thisstudy will provide healthcare providers and policymakers with a better understanding of the use and potentialhealth outcomes associated with gabapentin use in older adults.


application_id: 11001468
project_number: 5R01DA053070-05
project_title: Functional and Genomic Signatures of Escalated Fentanyl Use
administering_ic: NIDA
award_notice_date: 2024-12-19
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DA
serial_number: 053070
program_official: POLLOCK, JONATHAN D
project_start_date: 2021-03-15
project_end_date: 2026-12-31
study_section: Molecular Neuropharmacology and Signaling Study Section[MNPS]
contact_pi_person_id: 10484112
contact_pi: TURNER, JILL R.
other_pis: BARDO, MICHAEL T;ORTINSKI, PAVEL IVANOVICH
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractMisuse of opioids represents a substantial public and economic burden in the US and worldwide. The existingpharmacological approaches to treatment of opioid use disorder (OUD) are most efficacious when coupled withbehavioral therapies that target individual triggers to reduce or eliminate excessive drug consumption. Whileindividual variability in opioid use have been acknowledged repeatedly in animal behavioral models thegenomic markers linked to neurobiological adaptations underlying such variability are not well understood. Weargue that understanding the molecular background of individual differences in behavioral vulnerability toopioid use is critical for development of personalized pharmacogenomic approaches for OUD that mayreplicate clinical success of personalized cancer treatments. In line with this argument we hypothesize thatindividual behavioral variability in escalation of fentanyl use is linked to systems level variability ofgenomic and functional networks within in the nucleus accumbens and prefrontal cortex. Escalation ofdrug intake is a central component of OUD diagnosis that can be modeled in animals trained to self-administeropioids under extended access conditions. Based on the published literature and preliminary data we proposethree complementary Aims to monitor development of escalated intake at behavioral functionalcellular/network and genomic levels of analysis. Our Aim 1 hypothesizes that escalation of fentanyl intakeemerges on the background of individual differences in sensitivity to non-drug (sucrose) reward. Findingevidence to support this aim has the potential to identify vulnerable individuals prior to initiation of opioid use.Aim 2 examines neuronal outcomes associated with escalated fentanyl intake. Specifically we will evaluatewhether individual profiles of escalated intake reflect altered regulation of cell excitability by four potassiumchannel families and the impact on neuronal output at single cell and network levels. The data collected as partof this aim will establish functional neuronal drivers of vulnerability to escalated intake. Finally Aim 3compares the genomic landscape underlying variable fentanyl escalation in laboratory animals (rats) to humanopioid use databases. In this aim we take advantage of cell-type specific RNA sequencing to evaluate bothneuronal and non-neuronal mechanisms of escalated intake in the nucleus accumbens and prefrontal cortex.This aim is expected to identify novel molecular pathways linked to fentanyl escalation and test thetranslational relevance of our preclinical findings to a human sample. To characterize interactions at thebehavioral functional and genomic levels of analysis a unifying statistical framework is developed based onlinear mixed models to examine the strength of bi-directional relationships between behavioral escalation ofintake and molecular outcomes.

project_terms:
Acceleration;Animal Behavior;Animal Model;Animals;Astrocytes;Awareness;Behavior;Behavior Therapy;Behavioral;Behavioral Model;Biology;Biometry;Brain;Calcium;Calcium Signaling;Cells;Cessation of life;Chronic;Clinical;Clinical Research;Consumption;Coupled;Data;Databases;Dependence;Development;Diagnosis;Drug Targeting;Drug usage;Economic Burden;Electrophysiology (science);Evaluation;Family;Fentanyl;Genetic Databases;Genetic Markers;Genomics;Goals;Heroin;Human;Individual;Individual Differences;Intake;Joints;Laboratory Animals;Life;Link;Literature;Maintenance;Microglia;Modeling;Modernization;Molecular;Molecular Profiling;Monitor;Morphine;Motivation;Neurobiology;Neurons;Nucleus Accumbens;Opiate Addiction;Opioid;Opioid Receptor;Outcome;Output;Patch-Clamp Techniques;Pathway interactions;Pattern;Permeability;Persons;Pharmaceutical Preparations;Pharmacogenomics;Phenotype;Play;Policies;Population;Potassium;Potassium Channel;Preclinical data;Prefrontal Cortex;Prevention;Probability;Protein Family;Publishing;Rattus;Regulation;Relapse;Rewards;Role;Sampling;Self Administration;Shapes;Source;Statistical Models;Structure;Substance Use Disorder;Sucrose;System;Testing;Therapeutic;Training;United States National Center for Health Statistics;Vulnerable Populations;antagonist;behavioral pharmacology;behavioral phenotyping;big-data science;cancer therapy;cell type;drug abstinence;fentanyl abuse;fentanyl seeking;fentanyl self-administration;fentanyl use;gene product;genomic biomarker;genomic profiles;genomic signature;imaging approach;individual variation;interdisciplinary approach;medication-assisted treatment;neural circuit;non-drug;novel;novel therapeutics;opioid misuse;opioid mortality;opioid overdose;opioid use;opioid use disorder;opioid user;personalized approach;personalized cancer therapy;pharmacologic;reinforcer;success;synthetic opioid;targeted treatment;transcriptome sequencing;transcriptomics;whole genome

public_health_relevance:
PROJECT NARRATIVEAccording to 2018 data collected by the CDC 128 people die per day from opioid overdose (CDC/NCHS). Thisnumber represents the culmination of a 40% increase in deaths attributed to opioid overdose since 2015despite aggressive public messaging campaigns policies to curb availability of non-prescription opioids andwide-spread awareness of the dangers associated with opioid misuse. This proposal aims to understand howindividual variability for non-drug rewards relates to escalation of fentanyl-seeking and define the neurocircuitryand genomic contributors to these relationships.


application_id: 11001224
project_number: 5R01AG082142-03
administering_ic: NIA
award_notice_date: 2024-12-06
opportunity_number: RFA-AG-23-010
application_type: 5
activity_code: R01
ic: AG
serial_number: 082142
program_official: YAO, ALISON Q
project_start_date: 2023-04-15
project_end_date: 2027-12-31
study_section: ZAG1-ZIJ-G(J1)
contact_pi_person_id: 12467458
contact_pi: WANG, WANG-XIA
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-01-01
project_title:
MicroRNA lipid-nanoparticle based therapy targets neuroinflammation and ApoE dysregulation in Alzheimers disease

project_abstract:
Project Title: MicroRNA lipid-nanoparticle based therapy targets neuroinflammation and ApoE dysregulationin Alzheimers diseaseAbstractMicroRNAs (miRNA) are small non-coding regulatory RNA that have large impacts in health and disease.While prior studies have implicated miRNA in Alzheimers disease and associated dementias (ADRD) theyhave not been used yet in a successful therapeutic strategy. We discovered that microRNA-223 (miR-223) amiRNA residing on the X-chromosome which is enriched in microglia/macrophage cells regulates a sexuallydimorphic ApoE pathway via targeting CCAAT-enhancer-binding protein beta (CEBP). CEBP is an importantregulator of neuroinflammatory response and acts as a transcription factor mediating ApoE expression. Our recent data showed that deficiency of miR-223 resulted in a substantial female-biased elevation ofCEBP ApoE and a heightened inflammatory state in macrophages and in aged mouse brain following abrain injury. Thus miR-223 appears to regulate a sexually dimorphic microglia/macrophages-dependentincrease in inflammation and ApoE as brain cells become activated in parallel with age injury and/orAlzheimers disease-related pathology. We further demonstrated that miR-223 can be targeted using a novelmiRNA-liposome delivery system. Based on these exciting preliminary results the main goals of this proposalare to test the miR-223-CEBP pathway in regulating inflammation-triggered ApoE dysregulation in thebiological context of age sex and Alzheimers disease-relevant brain injury event; and to test the efficacy of anovel liposome-miRNA delivery method as a potential therapeutic strategy. To complete these objectives we will 1) confirm that miR-223 directly targets the CEBP-ApoE pathway inmyeloid cells and test whether liposome-miR-223 delivery affects this pathway; 2) test the miR-223-CEBP-ApoE pathway using a brain injury mouse model and target the pathway using the liposome miRNA deliverysystem in a novel miR-223 knockout mouse; 3) evaluate the miR-223-CEBP-ApoE pathway in human cells inparallel with neuropathological changes of Alzheimers disease. These studies will include assessments ofbrain tissue from the world-class University of Kentucky Alzheimers Disease Center biobank. Completion of the funded studies will extend our understanding of mechanisms regulatinginflammation/ApoE pathways in the context of sex aging and brain injury ultimately advancing treatments forAlzheimers disease. Filling these knowledge gaps could have a lasting impact on public health. Moreover ourinnovative miRNA-based therapeutic strategy targeting miR-223 provides a proof of efficacy for a new drugtarget particularly in females who are vulnerable for diseases associated with neuroinflammation and ApoEdysregulation including Alzheimers disease and other brain injury.

project_terms:
Acute;Affect;Age;Aging;Alleles;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease risk;Apolipoprotein E;Behavioral Assay;Biochemical;Biological;Bone Marrow;Brain;Brain Injuries;CCAAT-Enhancer-Binding Protein-beta;Cell Separation;Cells;Data;Dementia;Disease;Disproportionately impacts women;Event;Female;Funding;Genotype;Goals;Health;Histologic;Human;Human X Chromosome;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Injury;Intravenous;Kentucky;Knockout Mice;Knowledge;Late Onset Alzheimer Disease;Link;Liposomes;Macrophage;Mediating;Methods;MicroRNAs;Microglia;Modeling;Molecular;Mus;Myeloid Cells;Nerve Degeneration;Nervous System Physiology;Pathology;Pathway interactions;Proteins;Public Health;RNA;Regulation;Role;Sampling;Senile Plaques;Signal Transduction;System;Testing;Therapeutic;Therapeutically Targetable;Universities;Untranslated RNA;X Chromosome;aged;biobank;brain cell;brain tissue;efficacy testing;improved;in vivo;innovation;lipid nanoparticle;liposomal delivery;male;microRNA delivery;mouse model;neuroinflammation;neuropathology;new therapeutic target;novel;novel therapeutics;old mice;protein biomarkers;response;sex;sexual dimorphism;systemic inflammatory response;targeted treatment;therapeutic miRNA;transcription factor

public_health_relevance:
Project NarrativeThis project will reveal a novel mechanism regulating a female-biased neuroinflammation-trigged ApoEdysregulation pathway in the context of sex aging and brain injury. Furthermore this study will provide a proofof efficacy for a new drug target particularly in females who are vulnerable for diseases associated withneuroinflammation and ApoE dysregulation including Alzheimers disease and brain injury.


application_id: 11001192
project_number: 5R01HL171763-02
project_title: Cardiopulmonary Toxicity of Electronic Nicotine Delivery Systems
administering_ic: NHLBI
award_notice_date: 2024-12-05
opportunity_number: RFA-OD-21-002
application_type: 5
activity_code: R01
ic: HL
serial_number: 171763
program_official: POSTOW, LISA
project_start_date: 2023-12-14
project_end_date: 2028-11-30
study_section: Special Emphasis Panel[ZRG1-ICN-E(56)R]
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Cardiopulmonary Toxicity of Electronic Nicotine Delivery SystemsAlthough electronic nicotine delivery systems (ENDS) are widely used by youth and young adults the toxicityand the health effects of these products remain unclear. Many types of devices with varying constituents havebeen introduced into the market making it difficult to ascribe toxicity to a specific class of products or to studytheir long-term health effects. ENDS produce volatile organic compounds (VOCs) such as formaldehyde andacrolein which are generated by the thermal degradation of e-liquids containing propylene glycol:vegetableglycerin (PG:VG) and may lead to adverse health effects. Nevertheless the dependence of VOC generation one-liquid composition and constituents nicotine and other ingredients has not been studied and the contributionsof different constituents to the potential harmful effects of e-cigarettes remain unclear. Therefore within theframework of a regulatory context we plan to study the cardiovascular and pulmonary toxicity of e-cigaretteaerosols over a wide range of operating conditions and use patterns to provide rigorous and comprehensive datapertinent to the regulation of new and emerging devices by the US Food and Drug Administration (FDA). Basedon our previous work we propose that device-specific cardiovascular and pulmonary effects of e-cigarettes arein large part mediated by the extent of VOCs generation and toxicity which are modified by co-exposure tonicotine and other e-liquid ingredients as well as individual use patterns.

project_terms:
Acrolein;Address;Aerosols;Affect;Animal Model;Biological Markers;Carbon Monoxide;Cardiac;Cardiopulmonary;Cardiovascular Physiology;Cardiovascular system;Characteristics;Data;Dependence;Development;Devices;Electronic Nicotine Delivery Systems;Electronic cigarette;Evaluation;Exposure to;Flavoring;Formaldehyde;Generations;Health;Individual;Link;Marketing;Measures;Mediating;Metals;Modeling;Mus;Nicotine;Pattern;Policies;Production;Propylene Glycols;Protocols documentation;Public Health;Regulation;Risk;Role;Solvents;Tars;Technology;Testing;Toxic effect;United States Food and Drug Administration;Urine;Work;Youth;biomarker identification;combustible cigarette;design;disorder risk;e-cigarette aerosols;electronic cigarette use;electronic liquid;evidence base;hemodynamics;manufacture;nicotine exposure;novel;pod mods;pollutant;pulmonary;pulmonary function;tobacco advertising;tobacco products;vegetable glycerin;volatile organic compound;young adult

public_health_relevance:
Cardiopulmonary Toxicity of Electronic Nicotine Delivery SystemsIn the proposed studies we will investigate the cardiovascular and pulmonary toxicity of ENDS using animalmodels and state-of-the-art exposure technology protocols and biomarkers of exposure and of harm. As suchwe will directly address the Scientific Domain of Toxicity and thus will provide the FDA/CTP with rigorous andvalidated data to support policies regulating the design manufacturing and marketing of e-cigarette devices inorder to protect public health.


application_id: 11001167
project_number: 5R01AG070830-05
project_title: Contributions of astrocyte RelA signaling in aging-related neurodegenerative sequelae following TBI
administering_ic: NIA
award_notice_date: 2024-12-19
opportunity_number: PAR-19-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 070830
program_official: OPANASHUK, LISA A
project_start_date: 2021-01-15
project_end_date: 2026-12-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG-R]
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_abstract:
ABSTRACTTraumatic brain injury (TBI) is significantly correlated with increased risk for developing severalneurodegenerative disorders including Alzheimers Disease (AD) and AD-related dementia (ADRD)representing one of the most powerful environmental risk factors for AD/ADRD. Compounding these correlatesis that aging is a substantial factor in the incidence and vulnerability to TBI. Owing to the complexities surroundingTBI as a progressive neurodegenerative disorder leading to AD/ADRD the cellular mechanisms potentiallyunderlying the aging brains susceptibility to acquire degenerative responses remains elusive. To date the bulkof published findings related to TBI-related Alzheimers-like impairments have been examined using young adultand predominantly male rodents which does not accurately model the greatest at-risk population in humans.However our aging TBI model recapitulates several correlates of Alzheimers like impairments including chronicmemory impairment exacerbated neuroinflammation gliosis phosphorylated tau as well as microglialphenotypes previously documented in both humans and mouse models of Alzheimers disease. Guided bypreliminary findings our overarching hypothesis is that in the aging brain following TBI RelA drives exacerbatedastrocyte responses underlying the aging brains susceptibility for persistent decremental outcomes related tohomeostatic astrocyte susceptibility neuroinflammation and neural network dysfunction. We believe thesealtered responses initiated by TBI in the aging brain ultimately manifest in correlates characteristic of progressiveneurodegeneration associated with AD/ADRD. We will pursue three aims to test this hypothesis using novelgenetic models for targeting astrocytes in young and aged mice to determine 1.) The susceptibility of agedastrocytes to lose critical homeostatic features following TBI 2.) The ability of astrocytes to regulate theconversion of microglia towards decremental AD-associated inflammatory phenotypes following TBI and 3.) Therole of astrocytes in the vulnerability of synaptic circuitry and impaired memory a critical hallmark associatedwith TBI/ADRD. Cumulatively these studies will help to elucidate both the cellular and molecular substratesthrough which the aging brains response to TBI facilitates progressive neurodegenerative sequelae that caneventually lead to AD/ADRD. Our salient findings will ultimately determine the extent to which RelA is a criticalmediator in these AD-associated sequelae with the potential to elucidate new therapeutic targets toward theirprevention.

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;Inflammation;Inflammatory;Inflammatory Response;Ischemia;Knockout Mice;Lead;Link;Mediator;Memory impairment;Methods;Microglia;Modality;Modeling;Molecular;Multiple Sclerosis;NF-kappa B;Nerve Degeneration;Neurodegenerative Disorders;Neuroglia;Neurons;Neurophysiology - biologic function;Outcome;Pathway interactions;Persons;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;aging population;aging related;astrogliosis;cerebrovascular;conditional knockout;knockout animal;knowledgebase;loss of function;male;mouse model;network dysfunction;neural;neural circuit;neural network;neuroinflammation;new therapeutic target;novel;old mice;progressive neurodegeneration;protein profiling;response;response to injury;restoration;single-cell RNA sequencing;spatial transcriptomics;tau-1;transcription factor;transcriptome sequencing;transcriptomics;young adult

public_health_relevance:
Project NarrativeTraumatic brain injury (TBI) is a complex and progressive neurodegenerative disorder affectingmillions of people each year in the US as well as being a known environmental risk factor forthe development of Alzheimers disease-related dementia. However the mechanisms underlyingthe increased risk to develop Alzheimers disease-related dementia following TBI remainunclear. The salient findings from this project will significantly contribute to fundamentalknowledge-base of the role of inflammatory response of astrocytes in the aging brain asdeterminants of outcome following TBI.


application_id: 11001166
project_number: 5R01HL166225-03
project_title: Targeting smooth muscle cell BMAL1 as a new therapeutic strategy against restenosis
administering_ic: NHLBI
award_notice_date: 2024-12-09
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 166225
program_official: FLEG, JEROME L
project_start_date: 2023-01-01
project_end_date: 2026-12-31
study_section: Integrative Vascular Physiology and Pathology Study Section[IVPP]
contact_pi_person_id: 8664760
contact_pi: GUO, ZHENHENG
other_pis: GONG, MING C
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractCoronary heart disease (CHD) is the single leading cause of death in the United States. Coronaryrevascularization including coronary artery bypass graft and percutaneous coronary intervention is the mostcommon modality in patients with CHD. However it is often associated with a high incidence of restenosis.Although the rate of restenosis is reduced significantly by using bare-metal stent (BMS) and particularly withdrug-eluting stent (DES) a persistently high rate of restenosis after BMS and an increased risk of in-stentthrombosis with DES has been encountered as a major significant gap in the field. The current applicationproposes to bridge this gap and specifically investigates the role of the smooth muscle cell (SMC) BMAL1 inneointimal hyperplasia in mouse models of arterial injury. BMAL1 is a core molecular component of thecircadian clock. It has long been believed that loss of function of BMAL1 is detrimental to well-being. Howeverthis dogma was challenged by our recent report that genetic deletion of Bmal1 in SMCs (SM-Bmal1-KO)protects mice from aldosterone or angiotensin II-induced abdominal aortic aneurysm. Consistent with thisfinding our preliminary demonstrate that SMC-specific Bmal1 deletion also protects mice femoral artery wireinjury- or carotid artery ligation-induced neointimal hyperplasia. While the underlying mechanism remainselusive our preliminary data reveal arachidonic acid metabolism is most significantly affected by SMC-specificBmal1 deletion. Interestingly among enzymes implicated in arachidonic acid metabolism cytosolicphospholipase A2 alpha (cPLA2) is most downregulated by SMC-specific Bmal1 deletion. Mechanistically ourpreliminary data illustrate that BMAL1 binds to the mouse cPLA2 promoter and SMC BMAL1 is required forvascular injury-induced cPLA2 upregulation in neointima. Given the potential role of cPLA2 in VSMCproliferation and neointimal hyperplasia we hypothesize that upregulation of BMAL1 in SMCs by vascularinjury promotes cPLA2 expression thus mediating the initiation and progression of neointimal hyperplasia andsignificantly contributing to the development of restenosis after coronary revascularization. Aim 1 will test thehypothesis that upregulation of SMC BMAL1 by vascular injury is critical for the onset and progression ofneointimal hyperplasia. Aim 2 will define the mechanism by which SMC BMAL1 regulates cPLA2 and therebymediates vascular injury-induced neointimal hyperplasia. To achieve the goals SM-Bmal1-KO SM-cPLA2-KO and SM-Bmal1/cPLA2-KO mice will be subjected to femoral artery wire injury or carotid artery ligation toinduce neointimal hyperplasia and to determine the mechanism by which SMC BMAL1 and cPLA2 mediatevascular injury-induced neointimal hyperplasia. Results from the proposed studies will provide new mechanisticinsight on how SMC BMAL1 mediates vascular injury-induced neointimal hyperplasia via cPLA2. Moreoverresults from the proposed studies will provide preclinical evidence that inhibiting the BMAL1/cPLA2 signalingat the lesion site is a new therapeutic strategy against restenosis after coronary revascularization.

project_terms:
ARNTL gene;Abdominal Aortic Aneurysm;Adopted;Affect;Aging;Aldosterone;Alzheimer's Disease;American;Angiotensin II;Arachidonic Acids;Arterial Injury;Atherosclerosis;Binding;Biological Assay;Carotid Arteries;Cause of Death;Cell Proliferation;Cells;Clinical Research;Coronary;Coronary Artery Bypass;Coronary artery;Coronary heart disease;Cytosolic Phospholipase A2;Data;Development;Diabetes Mellitus;Endothelial Cells;Enzymes;Female;Genetic;Genetic Transcription;Goals;Hyperplasia;Hypertension;Immune response;Incidence;Injury;Knockout Mice;Lesion;Ligation;Malignant Neoplasms;Mediating;Messenger RNA;Metabolism;Metals;Modality;Molecular;Mus;Pathway Analysis;Patients;Personal Satisfaction;Pharmaceutical Preparations;Platelet-Derived Growth Factor;Proliferating;Reporting;Risk;Role;Scheme;Signal Transduction;Site;Sleep;Smooth Muscle Myocytes;Stents;Testing;Thrombosis;Time;United States;Upregulation;Vascular Smooth Muscle;Vascular remodeling;Woman;chromatin immunoprecipitation;circadian pacemaker;cost;femoral artery;insight;loss of function;male;men;mouse model;new therapeutic target;novel therapeutic intervention;novel therapeutics;overexpression;percutaneous coronary intervention;pleiotropism;pre-clinical;promoter;restenosis;revascularization;stent thrombosis;transcription factor;transcriptome sequencing;vascular inflammation;vascular injury

public_health_relevance:
Project narrativeCoronary revascularization (i.e. stent placement) has been adopted worldwide and is the most commonmodality in patients with coronary heart diseases in the United States. However it is also among the mostcostly and is often associated with a high incidence of restenosis (repeat narrowing of a coronary artery). Thisapplication aims to elucidate the mechanisms responsible for restenosis and thus identify new therapeutictargets to develop new drugs to treat restenosis after coronary revascularization.


application_id: 11000857
project_number: 5R21EY034674-02
project_title: Detailed Molecular Structures of Tear Film Lipid Layer for Improved Treatment of Dry Eye Syndrome
administering_ic: NEI
award_notice_date: 2024-11-21
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: EY
serial_number: 034674
program_official: MCKIE, GEORGE ANN
project_start_date: 2023-12-01
project_end_date: 2026-11-30
study_section: Special Emphasis Panel[ZRG1-NV-P(81)S]
contact_pi_person_id: 16225396
contact_pi: JAEGER, VANCE W
other_pis: BORCHMAN, DOUGLAS
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYDry eye syndrome (DES) afflicts over 7 million Americans. DES can cause chronic and severe symptoms leadingto visual disturbances. DES is caused by instability of the precorneal tear film (PCTF) at the surface of the eye.While it is known that the stability of the PCTF plays a central role in DES there is rigorous debate about whatcauses PCTF instability. The tear film lipid layer (TFLL) is central to the stability of tear films. The TFLL is anextremely thin layer of ordered lipid molecules separating the PCTF from the air. Researchers have proposedseveral functions for the TFLL including but not limited to reducing tear preventing the collapse of the tear layerand providing a layer of defense against pathogens. However it is unclear how changes in TFLL compositionthickness and arrangement induce PCTF instability and thinning. Several competing hypotheses naturally leadto different strategies for treating DES. Stimulation of tear production modulation of glandular function andsupplementation with externally applied lipid solutions are all possible treatment routes. However questionsabout the causes of DES are difficult to answer because of lack of a detailed molecular structure of the TFLL.Because of the TFLLs dynamic nature common experimental techniques are incapable of providing high-resolution structural detail about how molecules arrange in the TFLL at the air-lipid and lipid-water interfaces.Instead researchers use lower resolution methods to probe composition and structure sometimes indirectlythrough model chemical compounds. However these low-resolution techniques provide ambiguous resultsbecause multiple related molecular arrangements can produce the same signal. Thus there is not a one-to-onecorrelation between experimental results and molecular structures. In this study we will generate and validate aphysiochemical computational model of the TFLL which considers the energetics of the system and which willbe used to rationalize experimental observations about TFLL structure function and properties. Recentdevelopments in computational power allow researchers to simulate the motion of up to millions of atoms overtimescales long enough to allow the prediction of physical properties with a method called molecular dynamics.The model begins with a description of the inter- and intramolecular forces acting on the TFLLs components. Avirtual box of atoms is generated with a hypothetical molecular arrangement. Using classical physics forcesbetween molecules are translated into motion of all atoms and simulated snapshots of atomic positions arecollected. Analysis of these snapshots and associated energies allows the calculation of theoretical propertiesthat can be matched to experimental data. A successful model will match experimentally observed behavior andprovide a well-supported hypothetical TFLL structure for researchers to use for further studies. If successful themodel developed in this work can help provide evidence for or against prevailing and competing hypothesesabout the function of the TFLL and the underlying causes of DES. Ultimately the knowledge gained in this studycan be applied to improved design of treatments and therapeutics for DES.

project_terms:
3-Dimensional;Affect;Age Years;Air;Algorithms;American;Behavior;Binding;Biological;Chemical Models;Chemicals;Chronic;Compensation;Computer Models;Consensus;Cornea;Data;Development;Diffusion;Dry Eye Syndromes;Elasticity;Environment;Etiology;Eye;Film;Generations;Goals;Knowledge;Lacrimation;Lateral;Lead;Lipids;Measures;Methods;Modeling;Molecular;Molecular Conformation;Molecular Structure;Motion;NMR Spectroscopy;Nature;Nuclear Magnetic Resonance;Oils;Physics;Play;Population;Positioning Attribute;Probability;Property;Publishing;Rationalization;Research Personnel;Resolution;Role;Route;Sampling;Signal Transduction;Spectrum Analysis;Structural Models;Structure;Supplementation;Surface;Surface Tension;Symptoms;System;Techniques;Testing;Therapeutic;Thermodynamics;Thick;Thinness;Translating;Visual;Water;Work;chemical property;density;enthalpy;evaporation;experimental study;eye dryness;fluidity;human old age (65+);improved;macromolecule;meibomian gland;molecular dynamics;molecular modeling;pathogen;physical property;prevent;restraint;simulation;theories;therapy design;virtual

public_health_relevance:
PROJECT NARRATIVEThis project aims to provide a high-resolution description of the tear film lipid layer which is a thin layer of oil-likemolecules that separate tears on the surface of the eye from the ambient air. Physical and chemical propertiesof the tear film lipid layer have been implicated in the development of dry eye syndrome which affects 7 millionAmericans. With an improved high-resolution description of the tear film lipid layer researchers can testcompeting hypotheses about structure properties and function of the lipid layer and its relationship to thedevelopment of dry eye syndrome.


application_id: 11000516
project_number: 3P30CA177558-12S1
project_title: University of Kentucky Markey Cancer Center Support Grant ECIA Supplement
administering_ic: NCI
award_notice_date: 2024-08-22
opportunity_number: PA-20-272
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S1
program_official: ROBERSON, SONYA
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: ZCA1(M1)
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACT The Markey Cancer Center (MCC) is a university-based matrix cancer center at the University of Kentucky(UK) with a mission to reduce the cancer burden with a focus on Kentucky and its most vulnerable populationsthrough research prevention treatment education and community engagement. As the only National CancerInstitute (NCI)-designated Cancer Center in the state the MCC is vital to Kentucky the U.S. leader for highestall-site cancer incidence and mortality. Notably recognition of the extraordinary disease burden in Kentuckysvulnerable populations as a significant underpinning of that national ranking shapes the MCC vision and goalsand drives its unique focus on prevalent cancers and cancer risk factors in the catchment population. Over$569M in state institutional and philanthropic investment since 2009 has supported significant research andresource expansion propelling new faculty recruitment program development clinical and shared resourcespace renovations new state-of-the art instrumentation and statewide education and community outreach.MCCs 159 members align with one of three MCC Research Programs: Cancer Prevention and ControlMolecular and Cellular Oncology and Translational Oncology and are supported by seven Shared ResourceFacilities that facilitate cutting-edge research via robust infrastructure specialized expertise and advancedmethods: Biospecimen Procurement and Translational Pathology Biostatistics and Bioinformatics CancerResearch Informatics Flow Cytometry and Immune Monitoring Oncogenomics Patient-Oriented andPopulation Sciences and Redox Metabolism. Significant achievements in this funding period include anincreased research depth and breadth as indicated by increased total cancer-relevant funding (41%) peer-reviewed funding (35%) and NCI funding (55%). Expanded transdisciplinary collaborations driven in partthrough a strategic focus on precision medicine and a more streamlined translational pipeline resulted in 26new therapeutic trials 8 concepts or devices in Phase I or II clinical trials 10 agents or devices undergoing invivo validation 43 patent applications and 17 patents during the current funding periodall based on MCCscience. In collaboration with other U.S. and international cancer centers the number of U- and P-series grantsawarded to the MCC increased by 80%. The number of member publications increased by 28% (total of 1093)with 62% of the publications with cancer investigators at other institutions. Expanded education and traininginitiatives include a new NCI T32 focused on rural cancer health disparities a new NCI R25 Youth EnjoyScience award to engage Appalachian students in cancer research and two new training programsemphasizing diversity equity and inclusion. With unique research strengths and integrated statewidecommunity outreach and engagement MCCs programs provide robust capacity to deliver transformativeinterventional research to Kentuckys underserved populations thereby contributing to national efforts toconquer cancer through discovery and clinical translation cancer prevention and community outreach.

project_terms:
Acceleration;Achievement;Address;Appalachian Region;Award;Basic Science;Behavioral;Bioinformatics;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Catchment Area;Centers of Research Excellence;Climate;Clinical;Clinical Research;Clinical Trials;Clinical Trials Network;Collaborations;Community Outreach;Comprehensive Cancer Center;Death Rate;Development;Devices;Education;Education and Outreach;Epigenetic Process;Faculty Recruitment;Flow Cytometry;Foundations;Funding;Genetic;Geography;Goals;Grant;Immunologic Monitoring;Incidence;Informatics;Infrastructure;Institution;International;Intervention;Intervention Studies;Intervention Trial;Investigational Therapies;Investments;Kentucky;Leadership;Legal patent;Link;Malignant Neoplasms;Mediator;Mentors;Metabolic;Metabolism;Methods;Mission;Molecular;NCI Center for Cancer Research;National Cancer Institute;Needs Assessment;Oncology;Outcome;Oxidation-Reduction;Paper;Participant;Pathology;Patients;Peer Review;Phase;Policies;Population;Population Sciences;Positioning Attribute;Preclinical Testing;Prevalence;Prevention;Program Development;Publications;Publishing;Quality of life;Research;Research Personnel;Resource Sharing;Resources;Risk Factors;Rural;Rural Appalachia;SEER Program;Science;Scientist;Series;Services;Shapes;Signal Transduction;Strategic Planning;Students;Textiles;Therapeutic Clinical Trial;Therapeutic Trials;Training;Training Programs;Training and Education;Translating;Translational Research;Underserved Population;Universities;Validation;Vision;Vulnerable Populations;Work;Workforce Development;Youth;acronyms;anti-cancer research;burden of illness;cancer care;cancer education;cancer genomics;cancer health disparity;cancer prevention;cancer risk;cancer site;cancer survival;career;cellular oncology;clinical practice;clinical translation;community engagement;community organizations;equity diversity and inclusion;expectation;health disparity;health equity;improved;in vivo;innovation;instrumentation;interdisciplinary collaboration;investigator-initiated trial;member;molecular oncology;mortality;neoplasm registry;next generation;novel therapeutics;patient oriented;personalized diagnostics;personalized therapeutic;precision medicine;programs;recruit;social;translational impact;translational oncology;translational pipeline;treatment response;tumor

public_health_relevance:
PROJECT NARRATIVE As the only NCI-designated Cancer Center in Kentucky the University of Kentucky Markey Cancer Center serves a statewide catchment area with a population of 4.4 million residents and extraordinary cancer prevalence. In its mission to reduce cancer incidence and mortality with a focus on Kentucky through research prevention treatment education and community engagement the center has made and will continue to make significant strides in advancing access to quality cancer care; implementing bold transformational research spanning basic translational and population science including clinical trials to address Kentuckys unique cancer rates; and introducing innovative population-level interventions to accelerate translational impact and significantly impact patients in the state and the nation.


application_id: 11000315
project_number: 5R01GM144349-04
administering_ic: NIGMS
award_notice_date: 2024-12-16
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: GM
serial_number: 144349
program_official: CHO, THOMAS Y
project_start_date: 2022-01-01
project_end_date: 2026-12-31
study_section: Macromolecular Structure and Function A Study Section[MSFA]
contact_pi_person_id: 15235905
contact_pi: SABO, THOMAS MICHAEL
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: 2025-01-01
project_title:
Linking the conformational landscape to enzymatic function through functional site distant mutations

project_abstract:
An ongoing debate concerns the role conformational motions often termed dynamics play in biomolceularfuntion. For enzymes it so happens that the timescales for large-scale domain motions are similar to theapparent "$$). catalytic rate (!"# This observation is where the major point of contention has developed: do "$$. In this context the proposed studiesconformational motions directly impact the true rate of catalysis (!"#) or !"#will further explore how the modulation of the conformational landscape can indeed fine-tune "$$ without!"#impacting !"# and the ground state structure. The genesis of this proposal arises from our work with humanguanylate kinase (hGMPK) a potential therapeutic target for treating cancer and perhaps even SARS-CoV-2which motivated us to solve the first structure of hGMPK with nuclear magnetic resonance (NMR) spectroscopy(PDB: 6NUI). While solving the hGMPK structure we expressed a series of seven functional site distant (FSD) "$$ when compared to the wild-non-synonymous single nucleotide variants (nsSNVs) of hGMPK that enhance !"#type (wt). Intriguingly the 2D [1H15N]-HSQC NMR spectra of the wt hGMPK and its nsSNVs suggest that the ) for GMP binding toFSD mutations minimally impact hGMPKs backbone fold yet the apparent off-rates (wt and the FSD mutant V91M differ by ~3000 s-1. We hypothesize that hGMPKs activity can be modulated withFSD mutants by reshaping the conformational landscape. Utilizing NMR spectroscopy and isothermalcalorimetry we will test this hypothesis in the following two Specific Aims. In Aim 1 we will quantify the impactof the FSD mutations on the conformational landscape from kinetic and thermodynamic perspectives. The resultsfrom this Aim will provide a comprehensive picture as to where within the hGMPK catalytic and binding schemesthe FSD mutations have the largest impact on function. For Aim 2 we will deconvolute the contribution transientstructures within the conformational landscape play in enzymatic catalysis through experimentally drivenensemble generation. Our protocol will select hGMPK structures from unbiased molecular dynamics (MD)simulations based on residual dipolar couplings and cross-correlated relaxation rates measured with NMR. Theensembles will aid in the identification of the functionally important transient conformations and an assessmentof the impact the FSD mutations have on backbone dihedral correlated motions. To our knowledge this proposalprovides the first examples 1.) of experimentally driven ensemble generation for an enzyme spanningphysiologically relevant timescales and 2.) of determining thermodynamic and kinetic parameters with ligandbinding to the same exact site on a series of enzyme variants. The impact of this proposal is the direct linkageof the conformational landscape to enzymatic function. Immediate applications for these results include drugdiscovery where targeting structures within the conformational landscape rather than the ground state structurewill lead to better outcomes and biomolecular design where FSD mutations can be implemented to adjustfunction through manipulation of the conformational landscape.

project_terms:
2019-nCoV;Active Sites;Affect;Antineoplastic Agents;Architecture;Binding;Calorimetry;Catalysis;Cyclic GMP;DNA;Data;Development;Dissociation;Distant;Enzymes;Equilibrium;Future;Generations;Grant;Guanosine Triphosphate;Guanylate kinase;Human;Kinetics;Laboratories;Ligand Binding;Ligands;Link;Malignant Neoplasms;Measurable;Measures;Methods;Molecular Conformation;Motion;Muramidase;Mutation;NMR Spectroscopy;Nuclear Magnetic Resonance;Nucleosides;Nucleotides;Outcome;Phosphorylation;Phosphotransferases;Physiological;Play;Probability;Prodrugs;Production;Proteins;Protocols documentation;RNA;Rationalization;Regulation;Relaxation;Research Personnel;Residual state;Role;SARS coronavirus;Sampling;Scheme;Series;Shapes;Site;Structural Biologist;Structure;Testing;Therapeutic;Thermodynamics;Titrations;Ubiquitin;Variant;Vertebral column;Viral;Work;cancer cell;conformational conversion;design;drug discovery;enthalpy;inhibitor;molecular dynamics;mutant;nonsynonymous mutation;small molecule inhibitor;therapeutic target;tool

public_health_relevance:
Human guanylate kinase (hGMPK) is an essential enzyme in the production of DNA and RNA making it apotential therapeutic target for cancer and SARS-CoV-2. We have shown that active site distant mutations arisingfrom non-synonymous single nucleotide variants of hGMPK enhance enzymatic catalysis without a perceptiblechange in the kinases backbone structure an apparent contradiction to the structure-function paradigm. Thisproposal investigates what is responsible for this catalytic enhancement from a rigorous kinetic andthermodynamic perspective the results of which will impact future approaches toward drug discovery andbiomolecular regulation through the direct linkage of enzymatic function to the conformational landscape.


application_id: 10998144
project_number: 4R00DA056288-03
administering_ic: NIDA
award_notice_date: 2024-03-20
opportunity_number: PA-20-188
application_type: 4
activity_code: R00
ic: DA
serial_number: 056288
program_official: LIN, YU
project_start_date: 2022-04-01
project_end_date: 2027-03-31
study_section: ZDA1-SKM-D(02)S
contact_pi_person_id: 14132436
contact_pi: MCLAURIN, KRISTEN ADDIE
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-04-01
project_title:
Neurocognitive Impairments Resulting from Adolescent Prescription Opioid Use Disorder: Longitudinal Impact Neural Mechanisms and Comorbidities

project_abstract:
PROJECT SUMMARY/ABSTRACTThe goals of the proposed K99 career training plan include: 1) gaining expertise and research experience insubstance use disorders (SUD) addictive processes and opioid pharmacology; 2) mastering stereotaxic sur-geries adeno-associated virus gene delivery and in vivo fiber photometry; and 3) mastering and applying ana-lytical skills for the evaluation of third variable effects. The proposed research affords a venue to achieve thegoals of the training plan and address key challenges in the prescription opioid epidemic. Adolescence andyoung adulthood (i.e. 12-25 years of age) are critical developmental periods associated with substance useinitiation and brain circuit maturation with the former having key potential impacts on the latter. To date howeverthe critical role of adolescent prescription opioid use disorder (APOUD) on neurocognitive development andassociated neural mechanisms has yet to be fully elucidated. The role of biological sex and comorbidities (i.e.HIV-1) will be integral to the experimental design. We will causally test the guiding hypothesis that alterationsin the mesocortical dopamine (DA) system mechanistically underlie the differential progression of neurocognitivedevelopment in experimental (oxycodone (OXY) dependent) vs. control animals; and that unique neural mech-anisms will be engaged by comorbid APOUD and HIV-1. The hypothesis will be addressed via two building blockaims (K99 phase) and formally tested in my independent laboratory (R00 phase). Key aspects of human APOUDwill be modeled using a preclinical voluntary oral OXY self-administration experimental paradigm. In SpecificAim #1 (K99 phase) the dose-dependency of OXY self-administration for neurocognitive development (e.g.preattentive processes long-term episodic memory sustained attention) will be established using a longitudinalexperimental design. In Specific Aim #2 (K99 phase) dopaminergic alterations in the mesocortical DA systemfollowing OXY self-administration during assessments of higher-order cognitive processes will be determinedusing novel G protein-coupled receptor based biosensors and in vivo fiber photometry. Specific Aim #3 (R00phase) affords a causal test of the neural mechanism underlying neurocognitive impairments resulting fromAPOUD and/or comorbid HIV-1; the fundamental goal of my independent laboratory. Specifically the mesocor-tical DA system will be stimulated using designer receptors exclusively activated by designer drugs duringassessments of higher-order cognitive processes (e.g. sustained attention). Training (K99 phase) will be con-ducted at the University of South Carolina an outstanding environment under the tutelage of an internationallyrecognized mentoring team including Dr. R.M. Booze (mentor) Dr. E.M. Unterwald (co-mentor) and Dr. A.J.Fairchild (co-mentor). Additionally a Professional Development Advisory Committee including highly-regardedfaculty from multiple institutions (Dr. S. Letendre Dr. T.D. Langford and Dr. S. Fitting) is integral to the careertraining plan. Successful completion of the proposed training career development activities and research willprovide a strong foundation for the candidates transition to an independent scientist.

project_terms:
Address;Adolescence;Adolescent;Adolescent and Young Adult;Adult;Advisory Committees;Age Years;Agonist;Biosensor;Brain;Cells;Chronic;Clinical;Communicable Diseases;Control Animal;Dependence;Dependovirus;Development;Developmental Process;Dopamine;Dose;Environment;Episodic memory;Evaluation;Experimental Designs;Exposure to;Faculty;Female;Fiber;Foundations;Functional disorder;G-Protein-Coupled Receptors;Gene Delivery;Goals;HIV;HIV-1;Hour;Human;Infection;Institution;Intake;International;Laboratories;Mentors;Modeling;Muscarinics;National Institute of Drug Abuse;Neurocognitive;Neurocognitive Deficit;Operative Surgical Procedures;Opioid;Oral;Overdose;Oxycodone;Pharmacology;Phase;Photometry;Prefrontal Cortex;Process;Public Health;Rattus;Research;Role;Saline;Scientist;South Carolina;Strategic Planning;Substance Use Disorder;Synapses;System;Testing;Training;United States Substance Abuse and Mental Health Services Administration;Universities;Ventral Tegmental Area;Viral Proteins;Water;biological sex;biological systems;career;career development;cognitive process;comorbidity;critical developmental period;designer receptors exclusively activated by designer drugs;dopamine system;experience;experimental study;exposure route;high risk population;in vivo;male;neuromechanism;new therapeutic target;novel;opioid abuse;opioid epidemic;opioid use disorder;oxycodone self-administration;postnatal;pre-clinical;prescription opioid;skills;substance use;sustained attention;therapeutic target;young adult

public_health_relevance:
PROJECT NARRATIVEThe prescription opioid epidemic is a public health crisis with devastating consequences including inadvertentoverdose spread of infectious disease and neurocognitive impairments. Adolescents and young adults areuniquely vulnerable to substance use initiation given ongoing brain maturation. Discovering the neuralmechanisms underlying neurocognitive impairments resulting from adolescent prescription opioid use disorderaffords a critical opportunity to develop novel therapeutic targets; targets which may be unique under conditionsof comorbid opiate abuse and HIV-1.


application_id: 10995913
project_number: 1F31MD019997-01
administering_ic: NIMHD
award_notice_date: 2024-09-03
opportunity_number: PA-23-272
application_type: 1
activity_code: F31
ic: MD
serial_number: 019997
program_official: STINSON, NATHANIEL
project_start_date: 2024-09-03
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1 F16-T (21)]
contact_pi_person_id: 79490153
contact_pi: ROBERTS, MICHELLE KATHLEEN
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: 2024-09-03
project_title:
From Survival to Living Well: A Socioecological Approach to Understand Acquired Disability and Advance Health Equity in Rural Appalachia

project_abstract:
ABSTRACTPeople with disabilities are significantly more likely to experience chronic conditions and are at risk of dying up to 20 years earlier than people without disabilities due to physical social psychological and financial challenges. Appalachian Kentucky a rural area with limited healthcare access has twice the U.S. rate of disability22.7% compared with 12.6% nationally. Rates of new or acquired disability are escalating as medical advances allow more people to survive hospitalization and live with disability yet we lack the knowledge to help people live well post-hospitalization. Specifically while formal medical care plays an invaluable role in saving the lives of people who experience an acute health event these survivors and their families are often left to manage the enduring challenges of living with acquired disability on their own. I propose a mixed methods ethnographic investigation to understand the nature of acquired disability including subsequent care throughout the life course in the rural communities of Appalachian Kentucky. Ethnographic studies enable a holisticpersonal environmental sociocultural and politicalperspective to understand individuals lived experiences and identify opportunities to reduce adverse health outcomes. Long-term health is intimately intertwined with broader cultural and structural factors that contribute to significant health challenges for rural disabled populations including informal (family and social relations) formal (health and human services) and institutional (policy and programs) forms of care. Consistent with the socioecological model I will identify multilevel factors impacting quality of life and long-term health and identify strategies to reduce stressors. Obtaining grounded insights on how disability amplifies existing challenges is necessary to inform health policy and structural interventions to improve quality of life and long-term health for people with disabilities. I propose two related aims: (1) to ethnographically investigate and describe experiences of acquired disability among those with disabilities family caregivers health and human service providers and policymakers and (2) to develop and verify a shared cultural model of disability describing the range of barriers facilitators and opportunities to help rural Appalachians live well with disability. To achieve these aims I will obtain rigorous training in rapid ethnographic assessment concept mapping culturally adapted interventions and grant writing to support my growth as an independent health equity researcher. A robust understanding of disability based on grounded experiences will inform future culturally adapted interventions to mitigate health challenges and improve the lives of people with disabilities and their families.

project_terms:
Acquired disability;Acute;Address;Affect;Appalachian Region;Caring;Chronic;Chronic Disease;Chronic Obstructive Pulmonary Disease;Communities;Complex;Death Rate;Development;Diabetes Mellitus;Disabilities experience;Disability outcome;Disabled Persons;Equipment;Ethnography;Event;Face;Family;Family Caregiver;Focus Groups;Formal caregiver;Future;Goals;Grant;Growth;Health;Healthcare;Healthcare Systems;Heart Diseases;Hospitalization;Human;Individual;Inequality;Injury;Institution;Insurance;Intervention;Interview;Investigation;Kentucky;Knowledge;Left;Legal;Life Cycle Stages;Lived experience;Malignant Neoplasms;Medical;Mental Health;Methods;Modeling;Morbidity - disease rate;Nature;Outcome;Participant;Personal Satisfaction;Persons;Pharmaceutical Preparations;Play;Policies;Policy Maker;Politics;Premature Mortality;Prevalence;Preventive service;Quality of life;Reduce health disparities;Research;Research Methodology;Research Personnel;Resources;Risk;Risk Factors;Role;Rural;Rural Appalachia;Rural Community;Rural Population;Services;Social Change;Sorting;Stroke;Structure;Survivors;Training;Transportation;Underserved Population;Unemployment;United States National Institutes of Health;Writing;concept mapping;culturally appropriate intervention;disability;disabled;ethnographic method;experience;family management;follow-up;health care quality;health disparity populations;health equity;health inequalities;implementation intervention;improved;informal caregiver;informal caregiving;insight;low socioeconomic status;participant observation;physical conditioning;premature;programs;psychosocial;rural dwellers;rural health disparities;rural setting;service providers;social;social culture;structural determinants;underserved area;underserved rural area

public_health_relevance:
Public Health Relevance SectionPeople living in rural areas such as Appalachia are more likely to experience disability morbidity and premature mortality; despite the increasing prevalence of newly acquired disabilities and their negative impact on the well-being of rural residents we currently lack grounded perspectives on barriers and facilitators to optimal quality of life and health outcomes for people with disabilities. The proposed research will investigate diverse factors and circumstances that contributing to health challenges for rural disabled populations. This mixed methods research will expand knowledge of disability in Appalachia; identify gaps in health and human services; illuminate strategies to address individual interpersonal and community and policy-level challenges; and inform the future development and implementation of interventions across the socioecological model to improve the lives of people with disabilities and their families.


application_id: 10994999
project_number: 1F31EY036691-01
project_title: The Influence of the Pretectum on the Pulvinar Nucleus
administering_ic: NEI
award_notice_date: 2024-08-29
opportunity_number: PA-23-272
application_type: 1
activity_code: F31
ic: EY
serial_number: 036691
program_official: FORTRESS, ASHLEY
project_start_date: 2025-01-01
project_end_date: 2027-12-31
study_section: Special Emphasis Panel[ZRG1 F02B-Y (20)]
contact_pi_person_id: 77801873
contact_pi: BOONE, HOWARD CHASE
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 SummaryTo accurately code and react to the visual environment signals from the retina must integrate with the spatialand temporal aspects of eye and body movements. Projections from the pretectum (PT) to the pulvinarnucleus (PUL) may serve in modifying visual signals in the context of eye and/or body movements. Howeverthe specific role of the PT in active vision has not been tested using precise circuity manipulation methods. Inthe mouse projections from the PT innervate rostral regions of the PUL that are reciprocally connected tothe primary visual cortex (V1). However little is currently known regarding PT and rostral PUL circuits orhow manipulation of the PT modifies rostral PUL activity. I propose to address these gaps in knowledge viathe following specific aims. Aim 1) Determine the ultrastructure synaptic properties and convergencepatterns of layer 5 V1 and PT inputs to rostral PUL neurons using viral tracing electron microscopy in vitrorecording and optogenetics. Aim 2) Characterize the morphology and response properties of retinal ganglioncells that innervate PT-PUL neurons using combinations of herpes simplex virus retrograde tracingmonosynaptic rabies virus tracing and in vitro two-photon fluorescence imaging of calcium signals. Aim 3)Determine the response properties of PT neurons and how they affect the visual response properties ofrostral PUL neurons by combining in vivo recordings from the PT and PUL of awake head-fixed mice withoptogenetic inhibition of PT neurons. The goal of this project is to test the overarching hypothesis that the PTmodulates PUL visual signals in the context of animal movement.

project_terms:
Address;Affect;Amblyopia;Animals;Brain;Calcium Signaling;Cell Nucleus;Cells;Code;Darkness;Dendrites;Diagnosis;Disease;Dyslexia;Electron Microscopy;Enterobacteria phage P1 Cre recombinase;Environment;Exhibits;Eye Movements;Felis catus;Fiber Optics;Fluorescence;Frequencies;Glutamates;Goals;Head;Image;In Vitro;Individual;Injections;Knowledge;Lasers;Light;Link;Medical;Methods;Modeling;Morphology;Motion;Movement;Mus;Neurons;Nose;Ocular Motility Disorders;Opsin;Parvalbumins;Pathologic Nystagmus;Pathway interactions;Pattern;Photic Stimulation;Physiologic pulse;Presynaptic Terminals;Probability;Property;Protocols documentation;Pulvinar structure;RBP4 gene;Reaction;Reflex action;Reporter;Research;Retina;Retinal Ganglion Cells;Role;Running;Saccades;Schizophrenia;Shapes;Signal Transduction;Simplexvirus;Source;Speed;Stimulus;Strabismus;Structure;Synapses;Testing;Thalamic structure;Viral;Virus;Vision;Visual;Visual Fields;Visual Motion;Whole-Cell Recordings;active vision;area striata;awake;cell type;fluorescence imaging;gaze;in vivo;insight;optogenetics;preference;rabies viral tracing;response;tool;two-photon;visual stimulus;visual tracking

public_health_relevance:
The proposed research will inves1gate brain circuits involved in ac1ve vision (circuits that link visualmo1on percep1on and gaze shi:s). This research should provide informa1on relevant to the treatmentof disorders in which visual mo1on processing is compromised such as dyslexia and schizophrenia andmay provide insight into the use of eye tracking as a tool for medical diagnoses and/or eye movementdisorders such as nystagmus strabismus and amblyopia.


application_id: 10994636
project_number: 5R21NS135089-02
project_title: Cannabidiol (CBD) as a Potential Therapeutic for Experimental Subarachnoid Hemorrhage
administering_ic: NINDS
award_notice_date: 2024-11-15
opportunity_number: PA-21-219
application_type: 5
activity_code: R21
ic: NS
serial_number: 135089
program_official: HEYBURN, LANIER ADRYENNE
project_start_date: 2023-12-05
project_end_date: 2026-05-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 11256608
contact_pi: ROBERTS, JILL MARIE
other_pis: Not Applicable
congressional_district: 06
department: NEUROSURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTSubarachnoid hemorrhage (SAH) commonly caused by a ruptured aneurysm carries a high rate of disabilityand death. Preclinical studies demonstrate SAH induces dysregulation of the cerebrovasculature which con-tributes to early brain injury and delayed cerebral ischemia. Few treatment options currently exist for SAHpatients making it imperative to identify novel therapies to improve outcomes following SAH. Cannabidiol(CBD) has gained attention for its potential therapeutic properties and widespread mechanistic actions. Firstutilized for the treatment of pain preclinical studies demonstrate CBD has anti-inflammatory neuroprotectiveand vascular stabilization properties in experimental models of injury. However understanding of the effectsof CBD on blood vessels in the brain is limited and no studies have directly investigated CBD as a treatmentfor SAH representing critical gaps in knowledge. The overall objectives of this application are to determinethe therapeutic potential of CBD for SAH injury and identify processes by which CBD improves vascularhealth. The central hypothesis is that daily CBD treatment improves vascular integrity to increase cerebralblood flow (CBF) and prevent DCI thereby improving functional outcomes and mortality following SAH. Therationale for this project is that determination of CBDs therapeutic efficacy in SAH will generate a strongscientific framework from which new strategies for SAH therapy can be developed. The central hypothesiswill be tested by pursuing two specific aims: 1) Determine CBDs efficacy to improve functional outcomes andmortality following SAH and 2) Identify the impact of CBD therapy on cerebral microvessel pathology follow-ing SAH. Under the first aim multiple doses of CBD will be tested in mice following SAH injury (endovascularperforation) to determine the most effective dose that improves sensory/motor function and cognitive out-comes and reduces mortality. For the second aim the efficacy of CBD to reduce the development of vaso-spasm and blood-brain barrier leakage will be investigated utilizing intravital microscopy and ex vivo micro-Computed Tomography imaging. The research proposed in this application is innovative because it proposesthe use of a compound with a wide variety of molecular targets capable of ameliorating multiple aspects ofSAH pathology. The proposed research is significant because it is expected to provide scientific justificationfor the continued mechanistic investigation of CBD as a much-needed novel therapeutic for SAH patientsadvancing the field of stroke research.

project_terms:
Address;Adult;Affect;Age;Aneurysmal Subarachnoid Hemorrhages;Anti-Inflammatory Agents;Arteries;Attention;Blood - brain barrier anatomy;Blood Vessels;Blood brain barrier dysfunction;Blood-Retinal Barrier;Brain;Brain Injuries;Cannabidiol;Cerebral Ischemia;Cerebrovascular Circulation;Cerebrovascular Spasm;Cerebrovascular system;Cessation of life;Cognitive;Data;Death Rate;Development;Dose;Experimental Models;Extravasation;Feedback;Female;Functional disorder;Future;Health;Hemorrhage;Image;In Vitro;Incidence;Injury;Investigation;Iron Overload;Knowledge;Light;Marketing;Mediating;Medical;Mission;Molecular Target;Motor;Mus;Outcome;Pain management;Pathology;Patients;Perforation;Peripheral;Permeability;Policies;Preclinical data;Process;Productivity;Property;Public Health;Quality of life;Relaxation;Reporting;Research;Retina;Risk;Ruptured Aneurysm;Safety;Science;Sensory;Severities;Stroke;Subarachnoid Hemorrhage;Testing;Therapeutic;Treatment Efficacy;United States National Institutes of Health;Vasospasm;Work;blood-brain barrier permeabilization;cerebral microvasculature;cerebrovascular;cost;disability;functional improvement;functional outcomes;immune cell infiltrate;improved;improved outcome;innovation;intravital microscopy;male;microCT;mortality;neuroprotection;novel therapeutics;preclinical study;prevent;repaired;therapeutically effective

public_health_relevance:
NARRATIVEThe proposed research is relevant to public health because subarachnoid hemorrhage is a worldwide problemwith a high rate of disability and death in working age adults leading to high costs and loss in productivity.This project is focused on developing cannabidiol as an effective therapeutic for subarachnoid hemorrhageto improve vascular health and functional outcomes. Thus the proposed research is relevant to the NIH mis-sion to reduce illness and enhance quality of life.


application_id: 10992623
project_number: 5R01AG080589-03
project_title: APOE Allele Switching as a Therapeutic Approach for Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2024-11-22
opportunity_number: PAR-22-093
application_type: 5
activity_code: R01
ic: AG
serial_number: 080589
program_official: DIBATTISTA, AMANDA
project_start_date: 2022-12-01
project_end_date: 2027-11-30
study_section: Special Emphasis Panel[ZRG1-BDCN-A(55)R]
contact_pi_person_id: 11146000
contact_pi: JOHNSON, LANCE ALLEN
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:
AbstractIn comparison to the highly protective E2 allele of Apolipoprotein E (APOE) the E4 allele hasbeen associated with a host of detrimental effects including but not limited to increasedamyloid deposition more severe tau pathology heightened neuroinflammation cerebrovasculardysfunction and various metabolic deficits. With its strong risk profile and varied biologicalmechanisms APOE itself has emerged as an attractive candidate for gene therapy. In additionto providing a much-needed preclinical model for ongoing and future trials exploration of E4 toE2 allele switching has the potential to help answer several fundamental and longstandingbiological questions in the field. For example which ApoE-synthesizing cell-type(s) drive ADpathogenesis in E4 carriers and which are most protective in those with E2? Are E4-associateddeficits set in stone at birth (developmentally) or is later-life APOE editing a feasible approachto mitigate AD neuropathology and cognitive dysfunction? To this end we have generated aseries of novel APOE switch (4s2) mouse models that allow for temporal and cell-specific alleleswitching from E4 to E2. Our preliminary data confirms that these 4s2 mice synthesize a full-length human ApoE4 at baseline and importantly when crossed to various inducible CreERT2strains the switch successfully leads to efficient recombination and expression of human ApoE2in cell types of interest. Given the remarkable protective effects of E2 carriage and the variousroles of ApoE at differing steps of AD pathogenesis we hypothesize that astrocyte-specificallelic switching to E2 will simultaneously rescue multiple metabolic immune andneuropathological deficits associated with E4. We propose to leverage these unique mousemodels to determine the therapeutic window for CNS-specific E4 to E2 allele switching tosimultaneously mitigate metabolic deficits neuroinflammation cerebrovascular dysfunctionamyloid pathology and cognitive dysfunction. If successful this proposal will provide anessential preclinical model for ongoing and future clinical trials and will provide critical newinformation regarding ideal cell- region- and temporally-specific opportunities for therapeuticApoE modulation.

project_terms:
Affect;Alleles;Alzheimer's Disease;Alzheimer's disease pathology;Amyloid;Amyloid beta-Protein;Amyloid deposition;Amyloidosis;Apolipoprotein E;Astrocytes;Automobile Driving;Biological;Birth;Brain;Candidate Disease Gene;Cells;Cerebrovascular Disorders;Cerebrum;Clinical Trials;Cognitive deficits;Cre lox recombination system;Data;Development;Functional disorder;Future;Gene Expression Profile;Genes;Genetic;Genetic Recombination;Genotype;Homozygote;Human;Hyperlipidemia;Image;Immune;Impaired cognition;Individual;Inflammation;Knockout Mice;Late Onset Alzheimer Disease;Length;Life;Link;Measures;Metabolic;Metabolism;Modeling;Mouse Strains;Mus;Myelin;Nature;Nerve Degeneration;Neurons;Odds Ratio;Outcome;Pathogenesis;Pathologic;Pathway interactions;Peripheral;Phagocytosis;Physiological;Play;Pre-Clinical Model;Risk;Role;Series;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Supplementation;Synapses;Tauopathies;Testing;Therapeutic;amyloid pathology;apolipoprotein E-4;brain dysfunction;cell type;cerebrovascular;efficacy testing;gene therapy;genetic risk factor;in vivo;induced pluripotent stem cell;interest;late life;life span;lipidomics;loss of function;metabolomics;mouse model;neuroinflammation;neuropathology;novel;overexpression;protective effect;single-cell RNA sequencing;spatial transcriptomics;stable isotope

public_health_relevance:
PROJECT NARRATIVEThe strongest genetic risk factor for developing late-onset Alzheimers disease is the gene Apolipoprotein E(APOE) where the E4 allele dramatically increases risk while the E2 allele is strongly protective. In thisproject we will determine whether allelic switching from E4 to E2 will simultaneously rescue multipleneuropathological deficits associated with E4. If successful this proposal will provide an essential preclinicalmodel for ongoing and future clinical trials and will provide critical new information regarding opportunitiesfor therapeutic ApoE modulation.


application_id: 10991392
project_number: 5R21AI180274-02
project_title: Molecular mechanisms of Helicobacter pylori trans-kingdom DNA conjugation
administering_ic: NIAID
award_notice_date: 2024-11-27
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AI
serial_number: 180274
program_official: ZEITUNI, AMIR E
project_start_date: 2023-12-01
project_end_date: 2026-10-31
study_section: Bacterial-Host Interactions Study Section [BHI]
contact_pi_person_id: 11309989
contact_pi: SHAFFER, CARRIE
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYOf the recognized infection-associated malignancies the most significant carcinogenic microbe is the gastricbacterium Helicobacter pylori which chronically colonizes the stomach of over half of the global population andcontributes to the development of more than one million new cases of cancer per year. Despite many decadesof research we do not fully understand how H. pylori balances interactions with the human host to stimulate thedevelopment of gastric disease. The cancer-associated H. pylori cag type IV secretion system (cag T4SS) hasemerged as a paradigm for understanding how a single molecular device transports diverse immunostimulatorycargo into target eukaryotic cells. Whereas some T4SSs have the capacity to secrete multiple protein effectorsthe ability to translocate a pro-inflammatory bacterial oncoprotein and a repertoire of DNA and polysaccharidesubstrates distinguishes the cag T4SS from other nanomachines. In exciting new studies we discovered thatcag T4SS-dependent trans-kingdom DNA conjugation stimulates cytosolic nucleic acid reconnaissance systemsto provoke the production of multifarious interferons and inflammatory cytokines that orchestrate diverse immuneresponses. Our long-term objective is to mechanistically characterize how the dynamic cag T4SS transportscarcinogenic molecular cargo into gastric cells. Towards our objective we aim to define the kinetics andbiogeography of cag T4SS-dependent DNA translocation in vivo and delineate the mechanism by whichchromosomal DNA cargo is excised and coupled to the cag T4SS apparatus. Our studies will employ rodentinfection models high-resolution microscopy biochemical approaches and immunological assays to addresslongstanding knowledge gaps in gastric cancer biology and uncover microbial mechanisms that are involved inthe development of pre-malignant lesions. Collectively these investigations will advance our understanding ofimportant host-pathogen conflicts that engage nucleic acid surveillance pathways to regulate host immunity andtrigger microbial carcinogenesis. Furthermore our studies will provide the foundational framework for developingnew treatment and intervention strategies to reduce the incidence and severity of malignancies that arise as aconsequence of infection-induced chronic inflammation.

project_terms:
Address;Bacteria;Biochemical;Biological;Biological Assay;Biology;Cancer Biology;Carcinogens;Cells;Chronic;Coupled;DNA;DNA delivery;DNA relaxase;Data;Development;Devices;Disease Outcome;Eukaryotic Cell;Future;Gastritis;Goals;Helicobacter Infections;Helicobacter pylori;Human;Immune response;Immune signaling;Immunity;Immunologic Surveillance;Immunology procedure;Incidence;Infection;Inflammation;Inflammatory;Interferons;Intervention Strategies;Investigation;Isomerism;Kinetics;Knowledge;Lesion;Malignant Neoplasms;Mediating;Microbe;Microscopy;Modeling;Molecular;Nucleic Acids;Oncogenic;Oncoproteins;Orthologous Gene;Outcome;Pathway interactions;Polysaccharides;Population;Production;Proteins;Reporter;Research;Resolution;Risk Factors;Rodent;Role;Severities;Signal Transduction;Stomach;Stomach Diseases;System;Type IV Secretion System Pathway;Virus;Work;carcinogenesis;carcinogenicity;cytokine;endonuclease;in vivo;infection related cancer;innovation;malignant stomach neoplasm;microbial;mouse model;nanomachine;novel therapeutic intervention;pathogen;premalignant;secretion process;segregation;translational study;transposon/insertion element;tumorigenesis

public_health_relevance:
PROJECT NARRATIVEHelicobacter pylori chronically colonizes the stomach of more than half of the global population and is thestrongest known risk factor for the development of gastric cancer. The proposed studies will explore themechanisms by which H. pylori delivers microbial DNA into gastric cells trigger innate immune signaling. Theseinvestigations will advance our understanding of how an important bacterial carcinogen regulates host immunityto promote chronic inflammation and stimulate the development of stomach malignancies.


application_id: 10990721
project_number: 1R01HL170193-01A1
project_title: Targeting Lung Fibrosis Using Epigenetic Therapy
administering_ic: NHLBI
award_notice_date: 2024-08-09
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 170193
suffix: A1
program_official: VUGA, LOUIS J
project_start_date: 2024-08-15
project_end_date: 2028-07-31
study_section: Lung Injury, Repair, and Remodeling Study Section[LIRR]
contact_pi_person_id: 10317047
contact_pi: BRAINSON, CHRISTINE FILLMORE
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 Pulmonary fibrosis is a complex disease that limits lung function through development of collagen-richscar tissue. Although there are currently two FDA-approved therapies for fibrosis patients these drugs arecapable of extending life only months and do not reverse the progression of the disease. The research describedin this proposal would build upon evidence that reprogramming cellular fate through modulation of theepigenetic enzyme EZH2 can ameliorate several phenotypes of pulmonary fibrosis including aberrantalveolar cell fate and pro-fibrotic cytokine signaling. Specifically the aims will test if the FDA-approved EZH2inhibitor tazemetostat will allow for prevention or reversion of these cellular phenotypes. The model systems tobe used include both human and mouse organotypic cell cultures and two established in vivo models ofpulmonary fibrosis namely lung instillation of the chemotherapy bleomycin or adeno-associated virus (AAV)expressing TGF. For Aim 1 we will quantify the extent of aberrant basaloid/alveolar transition cells in lungepithelial cultures that are depleted for EZH2 activity genetically or pharmacologically and assess rescue of thisphenotype by deletion of the transcription factor FOXP2. FOXP2 deletion and knock-down will also be used tounderstand this important transcription factors role alveolar cell fate. We will also assess the down-regulation ofIL1 by EZH2 inhibition and its effects on both murine and human epithelial and fibroblast cells. The influenceof TGF on fibroblasts and epithelial cells in the presence of EZH2 inhibitor will be tested. In Aim 2 in vivo lunginjury models will be used to examine both prevention and treatment of lung fibrosis and to characterize specificchanges to the epithelial fibroblast and myeloid cell populations driven by EZH2 inhibition. Lung functiontesting histology scRNA-seq and flow cytometry will be used to characterize the lung phenotypes. Patienttissues will be used to understand if EZH2 activity is high and FOXP2 expression is low in aberrantbasaloid/alveolar transition cells in vivo. We expect that this research could validate the use of EZH2 inhibitionas a treatment for pulmonary fibrosis and will expand our knowledge in the field of lung epigenetics and stemcell biology.

project_terms:
Alveolar;Alveolar Cell;Attenuated;Biological Availability;Biological Models;Bleomycin;Cell Culture Techniques;Cell Lineage;Cell Reprogramming;Cells;ChIP-seq;Chromatin;Cicatrix;Collagen;Complex;Cytokine Signaling;DNA Sequence Alteration;Data;Dependovirus;Development;Disease;Disease Progression;Down-Regulation;EZH2 gene;Enzymes;Epigenetic Process;Epithelial Cells;Epithelium;FDA approved;FOXP2 gene;Fibroblasts;Fibrosis;Flow Cytometry;Gene Expression;Genes;Genetic Transcription;Harvest;Histologic;Histology;Histone H3;Human;Immune;Infection;Inflammatory;Injury;Interleukin-1 beta;Intervention;Knowledge;Laboratories;Life;LoxP-flanked allele;Lung;Lung Diseases;Lysine;Medicine;Mesenchymal;Methylation;Modeling;Mus;Myeloid Cells;Oral;Organoids;Patients;Persons;Pharmaceutical Preparations;Phenotype;Polycomb;Population;Prevention;Pulmonary Fibrosis;Pulmonary function tests;Radiation;Repression;Research;Role;Sampling;Signal Transduction;Silicon Dioxide;Stains;Supporting Cell;System;Testing;Therapeutic;Tissues;Transforming Growth Factor beta;Up-Regulation;Viral;Western Blotting;allergic airway disease;cell type;chemotherapy;cytokine;derepression;epigenetic therapy;histone methyltransferase;improved;in vivo;in vivo Model;inhibitor;insight;knock-down;lung injury;lung repair;novel therapeutic intervention;overexpression;pharmacologic;prevent;profibrotic cytokine;promoter;pulmonary function;response;single-cell RNA sequencing;small molecule;stem cell biology;transcription factor;transcriptome sequencing

public_health_relevance:
PROJECT NARRATIVELung fibrosis is a progressive incurable disease with few treatment options. This proposal aims to define iftargeting the epigenetic enzyme EZH2 using an FDA-approved drug would be a viable therapeutic option forlung fibrosis patients. The proposed research will expand our knowledge about how epi-drugs can influenceimportant phenotypes of lung disease.


application_id: 10990146
project_number: 1F99CA294265-01
administering_ic: NCI
award_notice_date: 2024-08-19
opportunity_number: RFA-CA-23-042
application_type: 1
activity_code: F99
ic: CA
serial_number: 294265
program_official: ODEH, HANA M
project_start_date: 2024-09-01
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZCA1 RTRB-U (M1)]
contact_pi_person_id: 79493459
contact_pi: OZA, VIRAL
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-09-01
project_title:
Harnessing Extracellular Vesicles to Overcome Radiation Resistance in Pediatric Diffuse Midline Glioma

project_abstract:
PROJECT SUMMARY Diffuse midline gliomas with H3K27M alteration (DMG-H3K27M) are the leading cause of pediatricbrain tumor-associated deaths. All DMG-H3K27M becomes resistant to radiation the standard of care andmost children succumb to their disease within two years of diagnosis. New treatment options are urgentlyneeded. The applicant's long-term goal is to combine engineering and cancer cell biology to lead a researchgroup that advances extracellular vesicle (EV)-based drug delivery for central nervous system diseases likeDMG-H3K27M. EVs are potent signaling vehicles in the tumor microenvironment and are understudied inDMG-H3K27M. The overall objectives are to define how DMG-H3K27M derived EVs contribute to radiationresistance within a heterogenous tumor and to develop EVs as a delivery vehicle for brain-penetrantradiosensitizers while equipping the applicant with the skills to become a strong independent cancerresearcher. Preliminary data show that some subclones within DMG-H3K27M are inherently radiation resistantand can release EVs readily taken up by radiosensitive cells in a receptor-mediated manner. These EVsprotect the recipient tumor cells from radiation-induced cell death. Therefore the central hypothesis is that thecargo of DMG-H3K27M extracellular vesicles particularly microRNAs drives radiation resistance within thesetumors and that targeting these factors can sensitize DMG-H3K27M cells to radiotherapy. Additionally theselective uptake of EVs by DMG-H3K27M cells suggests that EVs can be exploited as a drug delivery tool. Therationale is that this research will provide novel insights into mechanisms of radioresistance in DMG-H3K27Mand may result in new approaches to target this cancer. The hypothesis will be tested by pursuing two specificaims: 1) Determine the mechanism of EV-mediated radioresistance in DMG-H3K27M and 2) Engineerextracellular vesicles to selectively target brain tumor cells and deliver radiosensitizers. The first aim will becarried out as part of the dissertation research and will use patient-derived DMG-H3K27M cells proteomicsapproaches and chemical inhibitors to define the mechanism of EV uptake. miRNA mimics and antagomirs willalso be used to overexpress and silence miRNAs found in EV cargo released from radioresistant cells toidentify miRNAs that confer enhanced radioresistance in DMG-H3K27M. Targets will be validated usingzebrafish xenograft models. The second aim will encompass the post-doctoral research and focus on usingsingle-cell microfluidic methods to engineer non-tumor extracellular vesicles for specificity towards brain tumorcells and assessing their capability to cross the blood-brain barrier to deliver radiosensitizers. The researchproposed in this application is significant because it will provide new insights into the role of tumorheterogeneity in driving therapy resistance. This project will also identify new mechanisms of DMG-H3K27Mradioresistance and develop an innovative strategy for drug delivery to optimize the therapeutic efficacy ofradiosensitizers in the brain potentially improving treatment outcomes for children with DMG-H3K27M.

project_terms:
Address;Affect;Automobile Driving;Biodistribution;Biology;Brain;Brain Neoplasms;Cancer Biology;Cancer Model;Cell Death Induction;Cells;Cellular biology;Central Nervous System Diseases;Cessation of life;Chemicals;Child;Childhood;Childhood Brain Neoplasm;Clinic;Clinical;Communication;Communities;Creativeness;DNA Repair;Data;Development;Diagnosis;Diffuse intrinsic pontine glioma;Disease;Drug Delivery Systems;Drug Targeting;Electroporation;Engineering;Ensure;Fostering;Fractionated radiotherapy;Gene Expression;Genes;Genetic;Glioma;Goals;Health;Histones;Human;In Vitro;Individual;Investigation;Knowledge;Label;Link;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Methods;MicroRNAs;Microfluidic Microchips;Microfluidics;Mission;Modeling;Mutation;Outcome;Pathway interactions;Patients;Penetrance;Pharmaceutical Preparations;Phase;Population;Postdoctoral Fellow;Process;Proteomics;Public Health;Radiation;Radiation Tolerance;Radiation therapy;Radiation-Sensitizing Agents;Research;Research Personnel;Research Project Grants;Research Training;Resistance;Role;Scientist;Signal Transduction;Specificity;Surface;Testing;Therapeutic;Training;Treatment Efficacy;Treatment outcome;Tumor-Derived;Xenograft Model;Xenograft procedure;Zebrafish;antagonist;blood-brain barrier crossing;blood-brain barrier penetration;cancer cell;cancer therapy;cell type;combinatorial;delivery vehicle;diffuse midline glioma;extracellular vesicles;improved;inhibitor;innovation;insight;knock-down;machine learning model;multidisciplinary;neoplastic cell;new therapeutic target;next generation;novel;novel strategies;novel therapeutic intervention;overexpression;radiation resistance;radioresistant;receptor;skills;standard of care;success;therapy resistant;tool;treatment strategy;tumor;tumor heterogeneity;tumor microenvironment;tumor progression;uptake;vesicular release

public_health_relevance:
PROJECT NARRATIVEThe investigation of Diffuse Midline Glioma-derived extracellular vesicles and their impact on tumorradioresistance is relevant to public health as it addresses the leading cause of pediatric brain tumor-relateddeaths and seeks to provide new insights into overcoming treatment resistance. By focusing on the functionaleffects of extracellular vesicles and their potential as drug-delivery agents this research is relevant to NCIsmission of understanding cancer mechanisms and developing innovative treatment strategies.


application_id: 10989902
project_number: 5R01HL163003-03
project_title: Mechanisms Contributing to Pregnancy-induced Cardiac Remodeling
administering_ic: NHLBI
award_notice_date: 2024-12-23
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 163003
program_official: POIZAT, CORALIE ISABELLE
project_start_date: 2022-12-15
project_end_date: 2027-11-30
study_section: Basic Biology of Blood, Heart and Vasculature Study Section [BBHV]
contact_pi_person_id: 11677367
contact_pi: COLLINS, HELEN E
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Maternal healthcare in the US continues to rank poorly in comparison to other developed countries. Maternalmortality rates in US have been increasing yearly accounting for 23.8 deaths per 100000 live births in 2020.Cardiovascular complications are the leading cause of death in pregnant and postpartum women; however littleis known regarding the underlying factors leading to this increase which has been hindered by the lack ofknowledge of how the heart responds to normal pregnancy. Despite this it is known that during pregnancy theheart adapts to meet the increased metabolic demands of maternal organs and the growing fetus. Thisadaptation is characterized by reversible cardiac growth and ventricular remodeling which sustain high cardiacoutput during the final trimester of pregnancy. Yet the molecular programs that support the coordinatedremodeling of the maternal heart during and after pregnancy remain unknown. Coordinated changes inmetabolism could be critical to pregnancy-induced cardiac remodeling as suggested by their importance in othercontexts. For example increased cardiac ketone body (KB) metabolism prevents cardiac dysfunction andremodeling in heart failure and changes in glucose metabolism regulate exercise-induced cardiac growth.Nevertheless surprisingly little is known in the context of pregnancy. This knowledge is important because itcould be leveraged to support maternal cardiac health. There is rationale to expect a link between KB metabolismand cardiac remodeling. To wit circulating fatty acids and triglycerides are higher during pregnancy; they supplyenergy to highly metabolic tissues and they are used for liver ketogenesis. Indeed circulating KBs increaseduring late pregnancy in humans and are thought to provide alternative fuel sources for the heart. Furthermoreour data indicate that the KB metabolism enzyme -hydroxybutyrate dehydrogenase 1 (Bdh1) is upregulatedin the heart early in pregnancy followed in late pregnancy by higher levels of circulating KBs and reduced cardiacglucose catabolism. These findings suggest that KB availability and the capacity of the maternal heart to oxidizeKBs are increased during pregnancy. We hypothesize that higher cardiac KB oxidation during pregnancy mayspare glucose-derived carbon for anabolic pathways to increase the abundance of glucose-derived metabolitesthat facilitate cardiac growth. In support of this idea our preliminary studies show increased glucose-derivedcarbon allocation to nucleotides glycerophospholipids and amino acids during pregnancy. In this study we willtest three aims: in Aim 1 we will determine the extent to which KB availability influences cardiac structure andfunction during pregnancy; in Aim 2 we will evaluate the impact of cardiac KB utilization on structural andmetabolic remodeling in the maternal heart; and in Aim 3 we will delineate the influence of KB metabolism onthe reversal of pregnancy-induced cardiac remodeling. Knowledge of how cardiac metabolism contributes topregnancy-induced cardiac growth will provide a framework for developing interventions to support maternalcardiac health.

project_terms:
Accounting;Affect;Amino Acids;Biochemical;Birth;Carbon;Cardiac;Cardiac Myocytes;Cardiac health;Cardiovascular system;Catabolism;Cause of Death;Cessation of life;Contrast Echocardiography;Data;Death Rate;Developed Countries;Echocardiography;Energy Supply;Ensure;Enzymes;Exercise;Extracellular Matrix;Fatty Acids;Fetus;Genetic Transcription;Glucose;Glycerophospholipids;Goals;Growth;Heart;Heart failure;High Cardiac Output;Histologic;Histological Techniques;Human;Hypertrophy;Intervention;Ketone Bodies;Knowledge;Lactation;Late pregnancy;Link;Literature;Live Birth;Liver;Maternal Health Services;Maternal Mortality;Measures;Mechanics;Metabolic;Metabolism;Molecular;Mus;Myocardial;Myocardial dysfunction;Nucleotides;Nutrient;Organ;Oxidoreductase;Oxygen;Pathology;Pathway interactions;Perfusion;Physiological;Physiology;Postpartum Period;Postpartum Women;Pregnancy;Pregnancy Trimesters;Pregnant Women;Radiolabeled;Signal Transduction;Source;Structure;Testing;Tissues;Tracer;Triglycerides;Ventricular;Ventricular Remodeling;Western Blotting;Wit;angiogenesis;beta-Hydroxybutyrate;early pregnancy;glucose metabolism;heart dimension/size;heart function;heart metabolism;hemodynamics;in vivo;indexing;ketogenesis;metabolic phenotype;osmotic minipump;overexpression;oxidation;post pregnancy;pregnancy induced changes;prevent;programs;stable isotope;transcriptome sequencing

public_health_relevance:
Project NarrativePregnancy promotes remarkable changes in maternal metabolism and physiology. To ensure appropriatedelivery of oxygen and nutrients to the fetus and maternal organs the maternal heart undergoes a physiologicalform of hypertrophy; however the mechanisms that contribute to this adaptive remodeling are unknown. Thisproject will examine how the maternal heart adapts to the demands of pregnancy with the goal of understandinghow changes in cardiac metabolism influence pregnancy-induced cardiac growth as well as reversal of cardiacgrowth following pregnancy.


application_id: 10989895
project_number: 5R01HL168198-02
project_title: Role of the PEP cycle in cardiac fibrosis
administering_ic: NHLBI
award_notice_date: 2024-11-29
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 168198
program_official: ADHIKARI, BISHOW B
project_start_date: 2023-12-01
project_end_date: 2027-11-30
study_section: Integrative Myocardial Physiology/Pathophysiology B Study Section[MPPB]
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
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 SummaryAfter myocardial infarction (MI) fibroblasts differentiate to a hypersecretory phenotype. Attesting to the scale oftheir extracellular matrix (ECM)-manufacturing capacity a single fibroblast can produce >500000 procollagenchains per hour. Such large demands for collagen production must be met by changes in the metabolic networkto drive carbon for glycine and proline synthesis which constitute a large proportion of collagen. Previous studieshave shown that this demand is met by de novo amino acid synthesis which requires metabolic remodeling tocoordinate substrate utilization with biosynthetic pathway activity. Understanding mechanisms that facilitatemetabolic changes to promote fibroblast-mediated ECM deposition could provide actionable targets to improvecardiac remodeling after injury. Previous studies indicate that metabolism plays critical roles in fibroblast functionwith glycolysis and glutaminolysis playing important roles in fibroblast activation and collagen secretion. We findthat fibrogenic stimuli upregulate enzymes known to participate in a unique metabolic cycle that could upholdrapid and voluminous collagen synthesis after MI. Fibroblasts isolated from infarcted hearts as well as navefibroblasts treated with TGF- upregulate pyruvate kinase M2 (Pkm2) and phosphoenolpyruvate carboxykinase2 (Pck2) which play essential roles in the phosphoenolpyruvate (PEP) cycle. In our working model Pkm acts asa rheostat in the PEP cycle: catalytically slower Pkm2 promotes a PEPSLOW cycle that functions to augmentbiosynthesis while catalytically faster Pkm1 promotes a futile PEPFAST cycle that diminishes biosynthetic pathwayactivity and collagen production. The PEP cycle is completed via Pck2 which utilizes additional carbon fromanaplerosis to form non-glycolytic PEP which provides additional triose precursors for glycine and collagensynthesis. Thus we hypothesize that fibroblast collagen secretion is amplified by an extant PEPSLOW cycle whichfunctions to accelerate glycine synthesis and can be targeted to diminish fibrotic burden. Consistent with a roleof the PEP cycle in fibrosis our data suggest that induction of a PEPFAST cycle via fibroblast-specificPkm2Pkm1 splice variant switching improves cardiac remodeling and diminishes collagen deposition after MI.Our preliminary data also suggest that promoting Pkm1-like activity by pharmacologically activating Pkm2decreases collagen abundance in isolated fibroblasts. Similarly deletion of Pck2 influences fibroblast phenotypeand could play a major role in regulating collagen synthesis. Thus in this project we will thoroughly examine therole of the PEP cycle in cardiac fibroblasts and assess the mechanisms by which it influences cardiac fibrosis.To test our general hypothesis we will: (1) elucidate the role of Pkm alternative splicing on cardiac fibroblastmetabolism and cardiac fibrosis; and (2) delineate how the PEP cycle influences cardiac fibrosis after MI. Resultsof these studies will delineate the mechanisms by which the PEP cycle influences ECM synthesis and modulatesthe response of the heart to MI. This project could lead to the development of actionable therapies to diminishcollagen biosynthesis and cardiac fibrosis for which there are no currently approved therapies.

project_terms:
Acceleration;Alternative Splicing;Amino Acids;Anabolism;Biochemical Pathway;Carbon;Cardiac;Cicatrix;Citric Acid Cycle;Collagen;Data;Deposition;Development;Enzymes;Extracellular Matrix;Fibroblasts;Fibrosis;Glutamine;Glycine;Glycolysis;Heart;Heart Injuries;Hour;In Vitro;Injury;Mediating;Metabolic;Metabolic Pathway;Metabolism;Modeling;Myocardial Infarction;Myofibroblast;Pathway interactions;Phenotype;Phosphoenolpyruvate;Phosphoenolpyruvate Carboxylase;Play;Process;Procollagen;Production;Proline;Protein Isoforms;Pyruvate Kinase;RNA Splicing;Role;Serine;Stimulus;Structure;Testing;Transforming Growth Factor beta;Variant;coronary fibrosis;improved;in vivo;manufacturing capabilities;pharmacologic;response;translational potential

public_health_relevance:
Project NarrativeThe mechanisms that influence fibrosis in the heart after injury are poorly understood. This project will assesshow changes in metabolism in fibroblasts influence the response of the heart to myocardial infarction.


application_id: 10988641
project_number: 1R03HD113906-01A1
project_title: Role of Long Non-coding RNAs in the Ovulatory Process
administering_ic: NICHD
award_notice_date: 2024-08-16
opportunity_number: PA-20-200
application_type: 1
activity_code: R03
ic: HD
serial_number: 113906
suffix: A1
program_official: TAYMANS, SUSAN
project_start_date: 2024-08-16
project_end_date: 2026-07-31
study_section: Reproduction, Andrology, and Gynecology Study Section[CHHD-R]
contact_pi_person_id: 78617977
contact_pi: SHRESTHA, KETAN
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
TITLE: Role of Long non-coding RNAs in the Ovulatory Process.ABSTRACT Womens reproductive health plays a pivotal role in regulating overall well-being. Unfortunately about 12%of reproductive-age women experience infertility. One of the most common causes of infertility is anovulation oroligo-ovulation supporting the paramount role of the ovulatory process in female reproductive success. Althougha few key ovulatory mediators induced by LH have been established new and innovative research techniquescontinue to discover new players in the ovulatory process. Using RNA sequencing we have identified severallong non-coding RNAs (lncRNAs transcripts >200 nucleotides) that are regulated during the periovulatory periodin mouse granulosa cells. In past these lncRNAs were considered as junk DNA and believed to be transcriptionalnoise and functionless. But in recent years evidence has accumulated showing that lncRNAs are widelyexpressed are tissue-specific and have key roles in gene regulation by interacting with DNA RNA and proteins.However the role of lncRNAs in the ovary and specifically the ovulatory process has not been well explored.From our novel RNA sequencing data we have found 10 lncRNAs transcripts that are increased in granulosacells collected at 4h and 12h after human chorionic gonadotropin (hCG: LH analog) administration. Amongstthese 10 lncRNAs Gm12648 a 656-nucleotide lncRNA was the most highly induced by hCG (160-fold).Although very little is known about Gm12648 it is located directly upstream of cyclin dependent kinase inhibitor2A which encodes the cell-cycle inhibitor p16 in the mouse. Moreover the RNA-RNA interactome shows thatGm12648 can interact with transcription factors (TFs) that are essential during the ovulatory process. Thus it ispossible that Gm12648 may exert some regulatory control of genes and TFs and thereby possibly contribute toovarian cell fate during the periovulatory period. Similarly other hCG upregulated lncRNAs could also exert theirregulatory role on adjacent protein-coding genes. Thus our goal is to identify the top 5 most highly LH/hCG-regulated candidate lncRNAs and investigate the function of these lncRNAs in the ovary specifically their rolein the ovulatory process. To achieve our goal mouse ovaries granulosa cells and COCs collected across theperiovulatory period will be utilized to characterize the expression of lncRNAs that were discovered in ourpreliminary study (Aim 1) determine the target genes of Gm12648 in the granulosa cells using a RNA-seq andRNA-RNA interaction assay approach after knocking down the expression of Gm12648 (Aim 2) and begin toelucidate the function of Gm12648 by characterizing the proteins coded by the target genes and identify post-translational modifications such as phosphorylation acetylation methylation and ubiquitination (Aim 3) in theovulation process. We will use a high-impact translational mouse model in this study. The proposed project willlay a foundation for future studies examining lncRNA function in the human ovary. These discoveries will furtherimprove our understanding of the ovulatory process which provides a fundamental platform to improve infertilitytreatments and/or to develop the contraceptive measures that specifically target ovulation inhibition.

project_terms:
Acetylation;Affect;Age;Anovulation;Apoptosis;Biological Assay;Candidate Disease Gene;Cell Cycle;Cell Physiology;Cells;Code;Collecting Cell;Collection;Complex;Contraceptive Agents;Contraceptive methods;Cyclin-Dependent Kinase Inhibitor 2A;DNA;Data;Defect;Female;Female infertility;Fertility;Foundations;Future;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Goals;Human;Human Chorionic Gonadotropin;Infertility;Junk DNA;Knock-out;Liver;Luteinizing Hormone;Measures;Mediator;Methylation;Mus;Noise;Nucleotides;Oocytes;Ovarian;Ovary;Ovulation;Ovulation Inhibition;Pathway interactions;Personal Satisfaction;Phosphorylation;Play;Polycystic Ovary Syndrome;Post-Translational Protein Processing;Premature Ovarian Failure;Process;Proteins;RNA;RNA Sequences;Regulation;Reporting;Research Technics;Residual state;Role;Rupture;Small Interfering RNA;Sterility;Structure;Techniques;Testing;Time;Tissues;Transcript;Ubiquitination;Untranslated RNA;Woman;differential expression;experience;female fertility;granulosa cell;hormone analog;improved;improved outcome;infertility treatment;inhibitor;innovation;knock-down;mouse model;novel;oligo ovulation;reproductive;reproductive success;transcription factor;transcriptome sequencing;women's diagnosis;women's reproductive health

public_health_relevance:
NARRATIVE The present study explores the role of long non-coding RNAs (lncRNAs) in the ovulatory process. We havediscovered a number of lncRNA transcripts that were highly regulated by hCG (LH-analog) prior to ovulation inmice however nothing is known about their function in the ovulatory process. Hence the proposed studies willinvestigate the role of the most highly LH/hCG-regulated ovarian lncRNAs associated with the processes offollicular rupture and oocyte release which will aid in the understanding of the regulation of human fertility.


application_id: 10988277
project_number: 5R01AG066724-05
administering_ic: NIA
award_notice_date: 2024-11-28
opportunity_number: PA-17-088
application_type: 5
activity_code: R01
ic: AG
serial_number: 066724
program_official: GAO, HONGWEI
project_start_date: 2021-01-01
project_end_date: 2026-02-28
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
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
budget_start_date: 2024-12-01
project_title:
Novel gastrocnemius muscle characteristics in peripheral artery disease patients associated with impaired functional performance

project_abstract:
Lower extremity peripheral artery disease (PAD) significantly affects aging populations and results in functionalimpairment. Although the clinical importance of finding efficacious interventions for PAD is well-recognized fewmedical therapies are currently available. PAD is diagnosed using the ankle brachial index (ABI) a measure ofblood flow to the lower extremities. Lower ABI is associated with worse function; however low ABI alonecannot fully explain functional impairments in PAD. Small studies have reported oxidative stress mitochondrialdysfunction and/or fiber damage in gastrocnemius muscle biopsies from PAD patients suggesting skeletalmuscle perturbations may contribute to functional decline. We reported highly variable fiber type compositionand fiber type grouping in a small cohort of PAD patients and observed lack of intermyofibrillar mitochondria(IMFM-) in oxidative myosin heavy chain (MyHC) type I fibers. We have provocative new preliminary datasuggesting variability in response to ongoing denervation and in fiber type and mitochondrial adaptations withPAD. The purpose of this study is to define specific characteristics of muscle in PAD associated with impairedwalking performance through detailed immunohistochemical analyses of 400 baseline gastrocnemius musclebiopsies stored in the Northwestern biorepository collected from 9 different clinical trials. This biorepository ofmuscle from PAD patients is one-of-a-kind and is associated with detailed clinical and functional characteristicsof the donors. We hypothesize that variability in fiber size fiber type and mitochondrial adaptations in responseto ischemia-reperfusion damage and denervation in individuals with PAD will have value in predicting walkingimpairment. In Aim 1 we will quantify the proportion of IMFM- areas in type I fibers with normal type I MyHCabundance or accumulation of type IIX MyHC and/or LC3 a marker of autophagy and determine associationswith fiber type composition and fiber size as well as relationships of muscle features to walking performance inPAD. We hypothesize that LC3 will co-localize with IIX MyHC in IMFM- areas suggesting both incompleteautophagic clearance of IIX MyHC and mitochondrial biogenesis during fiber transition from type IIX to type Ias a result of denervation and reinnervation. In Aim 2 we will quantify denervated NCAM+ fibers and fiberswith elevated oxidative damage markers by fiber type. We hypothesize that denervation in PAD willpreferentially affect fibers expressing IIX MyHC and that only IMFM- areas that accumulate IIX MyHC will beNCAM+. In Aim 3 we will perform predictive modeling of PAD disease severity and functional impairment usingmorphological characteristics of muscle quantified in Aims 1 and 2 as biomarkers in conjunction withsupervised classification approaches. In Aim 4 we will test the hypothesis that baseline muscle characteristicswill predict longitudinal functional outcomes at 6-month follow up. This model will provide a powerful tool toaide in identifying biologic processes for targeted interventions and to assess the mechanism of action andeffectiveness of current pharmacological and exercise interventions in ongoing PAD clinical trials.

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;Disability prevention;Disease;Disease Progression;Effectiveness;Fiber;Foundations;Functional impairment;Future;Gait abnormality;Gastrocnemius Muscle;Goals;Grouping;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;Persons;Pharmacotherapy;Phase;Population;Property;Proteins;Recycling;Reperfusion Injury;Reperfusion Therapy;Reporting;Sampling;Severity of illness;Skeletal Muscle;Testing;Theoretical model;Training;Walking;biobank;cohort;coping;efficacious intervention;exercise intervention;follow-up;functional decline;functional improvement;functional outcomes;improved;indexing;mitochondrial autophagy;mitochondrial dysfunction;novel;oxidative damage;predictive modeling;preservation;reinnervation;response;tool;walking performance

public_health_relevance:
Peripheral artery disease (PAD) significantly affects aging populations and results in functional impairment andmobility loss. Few medical therapies are currently available to treat PAD because the underlying pathology incalf muscle is not understood. The goal of this study is identify aberrant properties of muscle to aide in thedevelopment of new targeted interventions to improve walking ability in individuals with PAD.


application_id: 10987454
project_number: 1R61DA061365-01
administering_ic: NIDA
award_notice_date: 2024-09-19
opportunity_number: RFA-DA-23-053
application_type: 1
activity_code: R61
ic: DA
serial_number: 061365
program_official: HIGHSMITH, KEISHER S
project_start_date: 2024-09-30
project_end_date: 2025-09-29
study_section: Special Emphasis Panel[ZDA1 SKP-E (M2)]
contact_pi_person_id: 14909213
contact_pi: STATON, MICHELE
other_pis: KNIGHT, KEVIN
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-09-30
project_title:
An innovative trauma-informed approach for reducing overdose risk among women re-entering the community from prison

project_abstract:
Overdose continues to ravage US communities with deaths at an all-time high and women aredisproportionately affected. Overdose deaths among women rose nearly 500% in the past two decades a rate considerably higher than men. Yet overdose prevention approaches that target the unique risks of women particularly those involved in the criminal legal system (CLS) are limited. Considering the complex histories of substance use and violence among justice-involved women there is a need to adapt and implement innovative and targeted intervention strategies that address violent victimization and related problems as part of the substance use disorder (SUD) treatment continuum including the need to target risks prior to prison release andduring community re-entry. This application is submitted in response to RFA-DA-053 with the overall aim of accelerating the translation of research to practice addressing overdose risk for justice-involved women during community re-entry through the adaptation and testing of an innovative trauma-informed relational intervention approach which also closely aligns with NIDAs funding priority area NOT-DA-23-007 to improve substance use outcomes for individuals with a history of violence. Guided by the ADAPT-ITT framework and previous research the R61 phase will focus on achieving 2 specific aims: 1) Adapt TBRI by focusing on two interventioncomponents: prison group sessions and re-entry recovery support. A focus group process will be used that engages key stakeholders (N=30) including administrators practitioners and women with lived experience target alignment with the unique treatment needs of the women and establish intervention feasibility; 2) Pilot test the adapted TBRI-Womens Reentry Approach (TBRI-WRA) intervention components in one group of women in KY (n=8). Final adaptations will be made to TBRI-WRA for the R33 implementation and testing across four sites. The R33 will use a Hybrid Type 1 effectiveness implementation design to achieve the following aims: Aim 3) Examine effectiveness of TBRI-WRA to reduce overdose risk among women (N=264) being released from four in-prison SUD treatment program sites using random assignment of sites to start date. Comparisons will examine (1) Treatment as Usual (TAU standard in-prison SUD treatment n=88) (2) In-prison TBRI (TAU +TBRI prison-based sessions only; n=88) and (3) TBRI + Re-entry Recovery Support (TAU + prison-based TBRI sessions + Re-entry Recovery Support; n=88). The primary outcome is overdose risk defined as any illicit substance use (self-reported and urine drug screen results; excluding alcohol and marijuana) during the 6 months after release from prison; secondary outcomes include trauma-related symptoms and connection(recovery supports emotional regulation and healthy coping) during the 6 months post-release. Aim 4) Examine implementation factors associated with study preparation launch and sustainability guided by the EPIS framework. This study and resulting adapted intervention have the potential for significant impact on overdose risk reduction among justice-involved women re-entering the community with a history of violence exposure.This study is part of the NIHs Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction.

project_terms:
Acceleration;Address;Administrator;Adolescent;Adult women;Alcohols;Area;Cessation of life;Collaborations;Communities;Complex;Coping Skills;Data;Death Rate;Disproportionately impacts women;Drug Screening;Effectiveness of Interventions;Exclusion;Focus Groups;Funding;Gender;General Population;Group Processes;Helping to End Addiction Long-term;High Risk Woman;Hybrids;Imprisonment;Individual;Intervention;Justice;Kentucky;Legal system;Lived experience;Marijuana;National Institute of Drug Abuse;Opiate Addiction;Opioid;Outcome;Overdose;Overdose reduction;Patient Self-Report;Pharmaceutical Preparations;Phase;Preparation;Prevention approach;Prisons;Public Health;Randomized;Recording of previous events;Recovery;Recovery Support;Reporting;Research;Research Personnel;Risk;Risk Reduction;Screening Result;Site;Speed;Substance Use Disorder;Symptoms;Testing;Texas;Time;Translational Research;Trauma;Trust;United States National Institutes of Health;United States Substance Abuse and Mental Health Services Administration;Universities;Urine;Victimization;Violence;Woman;Women's Group;Women's mortality;Youth;community reentry;coping;early life adversity;effectiveness evaluation;effectiveness/implementation design;emotion regulation;experience;feasibility testing;implementation determinants;improved;improved outcome;individualized medicine;innovation;men;opioid misuse;overdose death;overdose prevention;overdose risk;pilot test;primary outcome;research to practice;response;secondary outcome;substance use;support network;therapy design;treatment as usual;treatment program;violence exposure;women versus men

public_health_relevance:
PROJECT NARRATIVEThis application is submitted in response to RFA-DA-053 with the overall aim of accelerating the translation ofresearch to practice reduce overdose risk for women during community re-entry following release from prisonthrough the adaptation and testing of an innovative trauma-informed relational intervention approach. Theproposed study closely aligns with NIDAs funding priority area NOT-DA-23-007 to improve substance useoutcomes for individuals with a history of violence.


application_id: 10986484
project_number: 1R01MH134859-01A1
project_title: Neural Mechanisms of Menstrual Cycle Effects on ADHD and Cognition
administering_ic: NIMH
award_notice_date: 2024-08-12
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: MH
serial_number: 134859
suffix: A1
program_official: PACHECO, JENNIFER LYNN
project_start_date: 2024-08-15
project_end_date: 2029-04-30
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 8204810
contact_pi: MARTEL, MICHELLE M
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACTAttention-Deficit/Hyperactivity Disorder (ADHD) is increasingly recognized as a serious and debilitatingproblem in adolescent and adult females with impairment and comorbidity in female patients with ADHDincreasing dramatically around puberty. Given the deleterious consequences of ADHD and substantialcomorbidities in this group there is an urgent need to understand sex-specific factors contributing to symptomexpression in this understudied population. One promising but understudied factor is ovarian hormones whichbecome activated around puberty and fluctuate monthly in adulthood. To date no study outside of our lab hasexamined the effects of estrogen and progesterone changes on ADHD symptoms in female patients but basicscience data from animal studies provide a strong scientific premise for this work. These studies date back 20years and suggest that withdrawal fromand lower levels ofestradiol the predominant estrogen causecognitive and attention problems based on experimental work with ovariectomized rats. In fact we have pilotdata establishing the basic scientific premise and feasibility of this study design showing declines in estrogenpredict worsening response inhibition and working memory and increases in ADHD symptoms in a clinicalsample of female patients with ADHD. Yet it remains unclear what accounts for these effects at theneurobiological level in humans despite animal work showing estrogen effects on dopamine and human workin female heavy drinkers showing estrogen effects on insular brain activation patterns during responseinhibition tasks. The current project aims to use an innovative quasi-experimental and intensive longitudinalmenstrual cycle study design to elucidate the neurobiological mechanisms of estrogen effects on neuralmechanisms of cognition and ADHD symptoms in a clinical sample of 120 young adult female patients ages 18to 25 with ADHD. The project will evaluate whether menstrual cycle phase and hormonal effects on the neuralcircuitry involved in response inhibition and working memory predict short-term longitudinal change in ADHDsymptoms and medication response in young adult females with ADHD. This work is a critical extension of ourpreliminary data which found cycle phase and hormonal effects on ADHD and response inhibition and workingmemory but did not evaluate neural mechanisms or hormonal effects on treatment response. The long-termgoal of this project is to test whether medication titration or hormone stabilization across menstrual cycle phaseor reproductive phase improves ADHD symptoms and normalizes underlying neurocognitive and biologicalmechanisms in females. Such information is critical to advancing neurobiological theory of ADHD andsuggesting new avenues for personalized sex-specific assessment and psychopharmacological treatment ofADHD which may need to be targeted to cycle or reproductive phase hormonal profiles and impactedneurofunctional regions in pharmacotherapies.

project_terms:
Adolescence;Adolescent;Adult;Adult women;Age;Alcoholic beverage heavy drinker;Animals;Attention;Attention deficit hyperactivity disorder;Back;Basic Science;Biological;Brain;Childhood;Clinical;Cognition;Cognitive;Data;Dopamine;Estradiol;Estrogen decline;Estrogens;Feasibility Studies;Female;Goals;Gonadal Steroid Hormones;Hormonal;Hormones;Human;Impairment;Inferior;Link;Longitudinal Studies;Mediating;Menstrual cycle;Neurobiology;Neurocognitive;Neurophysiology - biologic function;Ovarian hormone;Ovariectomy;Participant;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Phase;Population;Prevalence;Progesterone;Puberty;Quasi-experiment;Rattus;Research Design;Risk;Risk Factors;Sampling;Short-Term Memory;Symptoms;Testing;Titrations;Translating;Withdrawal;Work;animal data;caudate nucleus;cognitive task;comorbidity;design;hypothalamic pituitary gonadal axis;improved;innovation;male;neural circuit;neurobiological mechanism;neuromechanism;perimenstrual;phase change;psychopharmacologic;psychostimulant;reproductive;response;sex;symptom treatment;theories;treatment response;women patients;young adult

public_health_relevance:
NarrativeThe current project will evaluate the neural mechanisms underlying menstrual cycle phase and hormonaleffects on response inhibition and working memory in females with ADHD. In addition the project willdetermine whether and how well cycle phase and hormonal effects on neural function during cognitive taskspredict ADHD symptoms and treatment response.


application_id: 10986264
project_number: 1R21AT013164-01
administering_ic: NCCIH
award_notice_date: 2024-09-17
opportunity_number: PAR-22-098
application_type: 1
activity_code: R21
ic: AT
serial_number: 013164
program_official: STILL, PATRICK COLBY
project_start_date: 2024-09-17
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1 CN-L (55)]
contact_pi_person_id: 8077002
contact_pi: TIDGEWELL, KEVIN JOSEPH
other_pis: KOLBER, BENEDICT J;NGUELEFACK, TELESPHORE BENOIT
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-09-17
project_title:
From traditional medicine to innovation: Discovering novel analgesics targeting calcium modulation from Cameroonian phytochemicals

project_abstract:
PROJECT SUMMARY/ABSTRACT There is a pressing need to identify and validate new targets for chronic pain and new sources for novelcompounds. This proposal will use novel extracts and pure compounds from multiple Cameroonian plantsnamely Paullinia pinnata Petersianthus macrocarpus and Acacia sieberiana to probe the biology and therapeuticpotential of an exciting non-opioid target for pain focusing on calcium homeostasis especially through sigma 2(-2) (aka transmembrane protein 97 (TMEM97)). Agonists for -2/TMEM97 reduce neuropathic andinflammatory pain in mice. Our primary research goal is to use a focused interdisciplinary approach to isolatebioactive compounds from traditional medicine and utilize these new tools in Cameroon to address research andeducation disparities that contribute to poor pain outcomes in Central Africa. This goal will be pursued with aunique collaboration that we have developed between researchers at the University of Dschang (Cameroon; Dr.Nguelefack) the University of Texas at Dallas (USA; Dr. Kolber) and the University of Kentucky (USA; Dr.Tidgewell). Preliminarily the Nguelefack lab has shown that crude extracts of P. Pinnata P. macrocarpus andA. sieberiana significantly decrease inflammatory and neuropathic pain in rats. The Tidgewell/Kolber groupshave shown that the methanol extracts of P. pinnata show in vitro binding affinity to -2/TMEM97 and modulateprimary sensory neurons. This proposal will utilize our interdisciplinary and international approach with in vitroevaluation of plant extracts followed by fractionation in vitro testing of -2/TMEM97 binding and additional invitro validation at UT Dallas and Dschang with pure compounds. In addition to the research focus on Ca2+homeostasis this proposal aims to build research and clinical capacity for the study of pain in Cameroon andsurrounding countries. This will be accomplished using a mixture of capacity building initiatives including thetraining of Cameroon trainees in the US and Cameroon the building of Dschang University as a center for painresearch in central Africa and the hosting of local workshops at Dschang to support the spread of researchknowledge in Cameroon and surrounding countries.

project_terms:
Acacia;Address;Afferent Neurons;Affinity;African;African Traditional Medicine;Agonist;Analgesics;Animals;Area;Binding;Biological Assay;Biology;Blinded;Calcium;Cameroon;Cells;Central Africa;Chemistry;Clinical;Collaborations;Computing Methodologies;Country;Crude Extracts;Development;Disparity;Education;Educational workshop;Elements;Europe;Evaluation;Fluorescence;Fractionation;Functional disorder;Goals;Homeostasis;Human;Human Resources;Image;In Vitro;Integral Membrane Protein;International;Kentucky;Knowledge;Mediating;Medicinal Plants;Membrane;Methanol;Microscopy;Modernization;Molecular;Mus;Natural Products;Neurons;Neurosciences;Neurosciences Research;New Agents;Outcome;Pain;Pain Clinics;Pain Research;Paullinia pinnata;Peripheral;Peripheral Nervous System;Physiology;Phytochemical;Plant Extracts;Plants;Poison;Process;Psychotropic Drugs;Rattus;Research;Research Infrastructure;Research Personnel;Resources;Rodent;Sensory;Site;Source;Spinal Ganglia;Surface;Testing;Texas;Therapeutic;Traditional Medicine;Training;Triage;Universities;Validation;Work;calcium metabolism;chronic neuropathic pain;chronic pain;cytotoxicity;drug development;drug discovery;experimental study;improved;in vitro Assay;in vitro testing;inflammatory pain;innovation;interdisciplinary approach;interest;new therapeutic target;non-opioid analgesic;novel;pain inhibition;pain model;pain outcome;pain reduction;painful neuropathy;pharmacologic;receptor;reduce symptoms;screening;screening program;targeted agent;therapy outcome;tool;training opportunity

public_health_relevance:
PROJECT NARRATIVE Chronic pain is a serious problem in the USA and worldwide and this international collaboration focuses onthe use of interdisciplinary approaches to identify and validate novel drug targets and build pain researchcapacity in Cameroon and Central Africa. The scientific focus of the proposal is on identifying the compoundsfrom analgesic medicinal plants that modulate neurons through calcium metabolism. This includesinvestigating Cameroonian plants used in traditional medicine like Paullinia pinnata that show analgesiceffects in models of pain have affinity for the calcium modulator sigma-2 (-2)/Transmembrane Protein 97(TMEM97) receptor in vitro and are capable of regulating primary sensory neurons.


application_id: 10985020
project_number: 4U24NS133945-02
project_title: Federated digital pathology platform for AD/ADRD research and diagnostics
administering_ic: NINDS
award_notice_date: 2025-09-13
opportunity_number: RFA-NS-22-062
application_type: 4
activity_code: U24
ic: NS
serial_number: 133945
program_official: UMOH, NSINI ALEASE
project_start_date: 2023-09-20
project_end_date: 2028-08-31
study_section: ZNS1-SRB-O(23)
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: BUMGARDNER, CODY ;FLANAGAN, MARGARET E
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract We will connect multiple Alzheimers disease and related dementias (AD/ADRD) research centers for optimized and standardized whole slide image (WSI) advanced analytics. We propose these Specific Aims:  Specific Aim 1: Generate a federated platform for data sharing and analysis of human digital neuropathological (DNP) slides. Specific Aim 1a: Develop an open-source platform to aggregate data distributed across multiple repositories into a central registry portal. This subaim will follow federated data curation harmonization annotation and standardization employing FAIR (findable accessible interoperable and reusable) principles. Specific Aim 1b: Develop a federated data curation and management system. This subaim provides methods to curate physical data such as digital images across federated sites. WSI data and metadata will be shared with private repositories and high-performance clusters.  Specific Aim 2: Develop and demonstrate a platform for federated machine learning/artificial intelligence (ML/AI) result evaluation and central project information constituting a management hub for AD/ADRD studies. Specific Aim 2a: Develop a federated data annotation and automated AI/ML processing system. This subaim provides methods for users to prepare AI-ready multimodal (WSIs metadata demographics etc.) datasets from distributed sources and conduct multi-site data transfer and federated training. Services and tools developed in Aim 1 will be used to programmatically generate and populate user-defined AI/ML pipelines. Specific Aim 2b: Develop an open-source platform for the generation and review of datasets and associated models. This subaim will provide a project evaluation portal integrating cohort dataset and model training results in a unified interface. A public-facing model hub will provide project data specifications and model data to support data sharing and analysis requirements. To optimize and demonstrate the strengths of the novel federated network five integrated projects are proposed. These will span a diverse sampling of human populations and diseases to leverage the unique strengths of DNP.  The following sites will contribute resources expertise experimental study design data and analyses: University of Kentucky (PIs Nelson and Bumgardner Co-Is Cheung and Fardo). Generate standardized SOPs useful for DNP diagnoses and research along with ML/AI expertise for a federated network. Northwestern/Nun Study and UTSA Universities (PI Flanagan). A focus on TDP-43 proteinopathy in community-based cohorts and ethno-racially diverse populations. Universityof So Paulo and UCSF (Co-I Suemoto and OSC Grinberg). Evaluate ADNC from the brains of individuals with African and non-African ancestries. University of Toronto (Co-I Kovacs): Use ML to study white matter tau pathologic changes for novel insights into multiple tauopathies. University of Washington (Co-I Keene): Study tau pathologies across ages and environmental exposures with a focus on traumatic brain injuries.

project_terms:
African;African ancestry;Age;Alzheimer's disease related dementia;Area;Artificial Intelligence;Autopsy;Benchmarking;Brain;Classification;Clinical;Collection;Communities;Computer software;Correlation Studies;Data;Data Aggregation;Data Analyses;Data Element;Data Management Resources;Data Set;Diagnosis;Diagnostic;Disease;Environmental Exposure;Evaluation;FAIR principles;Generations;Hand;Human;Image;Image Analysis;Individual;Institution;Kentucky;Machine Learning;Metadata;Methods;Modeling;Pathologic;Pathology;Performance;Population;Population Heterogeneity;Privatization;Procedures;Process;Recording of previous events;Registries;Reproducibility;Research;Research Design;Research Personnel;Resources;Sampling;Scanning;Secure;Services;Site;Slide;Source;Specific qualifier value;Standardization;System;TDP43 proteinopathy;Tauopathies;Training;Traumatic Brain Injury;Universities;Washington;Work;Workload;advanced analytics;annotation  system;cohort;data curation;data exchange;data harmonization;data modeling;data platform;data sharing;demographics;digital;digital data;digital imaging;digital pathology;distributed data;experimental study;federated data;imaging Segmentation;insight;machine learning pipeline;multimodal data;multimodality;neuropathology;novel;open source;protein TDP-43;racial diversity;repository;synthetic data;tau mutation;tool;white matter;whole slide imaging

public_health_relevance:
Project NarrativeTo optimize and standardize procedures for digital neuropathology studies in Alzheimers disease and related dementia (AD/ADRD) we will connect multiple research centers for integrated whole slide image (WSI) advanced analytics. Using thousands of WSIs from diverse subjects and methods cross-validated with benchmark standards we will develop a novel platform that can be meaningfully expanded for research diagnostic and didactic applications. A key strength of this proposal is clinical-pathological correlation studies from content experts to be used as models for leveraging WSI analyses in AD/ADRD research.


application_id: 10984962
project_number: 5R01HL160927-04
project_title: Fibroblast growth factor 1 prevents hyperlipidemia and atherosclerosis
administering_ic: NHLBI
award_notice_date: 2024-11-20
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 160927
program_official: LIU, LIJUAN
project_start_date: 2021-12-01
project_end_date: 2026-11-30
study_section: Special Emphasis Panel[ZRG1-TDPS-R(01)]
contact_pi_person_id: 12101586
contact_pi: TAN, YI
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
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:
Atherosclerosis is a narrowing of arteries caused by plaque buildup. Dyslipidemia especially elevated low-density lipoprotein cholesterol is a major risk factor for atherosclerotic plaque formation. Current therapies foratherosclerosis focus on lowering cholesterol. However conventional lipid lowering therapies (such as statins)are associated with obvious side effects. Developing more specific and efficient treatments are needed.Fibroblast growth factor 1 (FGF1) has been widely studied for its therapeutic benefits in cardiovascular disordersprimary utilization of its mitogenic functions. Recently FGF1 was shown to exert an unexpected metabolic activityby regulating adipose remodeling and glucose homeostasis demonstrating a potential for treatment of metabolicsyndrome. However wild-type FGF1 (FGF1WT) induced hyperproliferation can lead to increased tumorigenic risk;this becomes the primary obstacle for its widespread application. To reduce this risk we recently engineered apartial FGF1 agonist carrying triple mutations of the heparin-binding sites (FGF1HBS) which abolishedproliferative potential but maintains full FGF1WT metabolic activity. Notably chronic treatment of db/db mice withFGF1HBS almost completely reversed diabetes-associated NAFLD. These findings suggest that FGF1HBS is apotentially safe and efficient therapeutic approach for treatment of metabolic syndrome.Although characterization of the metabolic functions of FGF1 is ongoing little is known about its roles inatherosclerosis. A small case observation found an increased FGF1 expression in neovascularized andmacrophage-rich regions of plaque implying a potential pathological role of FGF1 in human atherogenesis.However whether and how FGF1 plays beneficial or detrimental roles in atherogenesis remain unexplored. Werecently examined the impact of FGF1 administration on the pathogenesis of atherosclerosis in ApoE-KO miceand found that FGF1HBS markedly ameliorated atherosclerotic phenotypes without significant proliferativepotential in liver. Furthermore FGF1 treatment reduced cholesterol levels in the blood liver and intestine butincreased cholesterol contents in feces. These preliminary data indicate that FGF1 regulation of cholesterolhomeostasis in both liver and intestine is responsible for its protection from atherosclerosis. The liver is a majorsite for cholesterol biosynthesis while the intestine maintains cholesterol homeostasis by mediating intestinalabsorption of dietary and biliary cholesterol. Therefore we hypothesize that non-mitogenic variant FGF1HBSprevents atherosclerosis by inhibiting hepatic cholesterol synthesis and suppressing intestinalcholesterol absorption without risks of hyperproliferation. We will test the hypothesis in three specific aims:1) Determine the roles of FGF1 in the development of atherosclerosis; 2) Determine the effects and mechanismof FGF1 on hepatic cholesterol biosynthesis; 3) Determine the effects and mechanism of FGF1 on intestinalcholesterol absorption. This project will provide fundamental evidence for FGF1HBS acting at the hepatocytesand intestinal enterocytes as a novel approach for the prevention of atherosclerosis in future clinical studies.

project_terms:
Adipose tissue;Agonist;Animal Model;Apolipoprotein E;Arterial Fatty Streak;Arteries;Atherogenicity;Atherosclerosis;Attenuated;Biliary;Binding Sites;Blood;Breeding;Cardiovascular Diseases;Cell Proliferation;Cells;Cholesterol;Cholesterol Homeostasis;Chronic;Clinical Research;Coagulation Process;Data;Development;Diabetes Mellitus;Dose;Dyslipidemias;Engineering;Enterocytes;FGF1 gene;Feces;Fluorescein;Future;Genetic Transcription;Heparin Binding;Hepatic;Hepatocyte;Human;Hyperlipidemia;Intestinal Absorption;Intestines;Knockout Mice;LDL Cholesterol Lipoproteins;Label;Life Style;Lipids;Liver;Macrophage;Mediating;Mediator;Metabolic;Metabolic syndrome;Mutation;Non-Insulin-Dependent Diabetes Mellitus;Nuclear Translocation;Operative Surgical Procedures;Organ;Organoids;Pathogenesis;Pathologic;Patients;Phenotype;Play;Prevention approach;Radioisotopes;Recombinants;Regulation;Risk;Risk Factors;Role;Site;Testing;Therapeutic;Upregulation;Variant;angiogenesis;atherogenesis;blood glucose regulation;cholesterol absorption;cholesterol biosynthesis;clinical practice;clinical translation;db/db mouse;dietary;insight;neovascularization;non-alcoholic fatty liver disease;novel;novel strategies;novel therapeutic intervention;overexpression;prevent;proliferation potential;side effect;transcription factor;translational potential;tumorigenic

public_health_relevance:
The objective of this study is to define how FGF1 protects against atherosclerosis and whether there is aclinical translational potential of the novel non-mitogenic variant FGF1HBS for preventing atherosclerosis byinhibiting hepatic cholesterol biosynthesis and suppressing intestinal cholesterol absorption without risk ofhyperproliferation. We will first optimize the doses of FGF1 protection against atherosclerosis in two distinctatherogenic animal models and determine the roles of endogenous FGF1 in the development ofatherosclerosis. Next we will determine the effects and mechanism of FGF1 on hepatic cholesterolbiosynthesis and intestinal cholesterol absorption. This project will reveal new insight into the underlyingmechanism behind FGF1 protection against atherosclerosis as well as provide fundamental evidencesupporting the non-mitogenic variant FGF1HBS as a novel therapeutic approach for prevention ofatherosclerosis in future clinical practice.


application_id: 10984199
project_number: 1R21AI178108-01A1
project_title: Role of putative cytotoxins in Chlamydia infection
administering_ic: NIAID
award_notice_date: 2024-08-21
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AI
serial_number: 178108
suffix: A1
program_official: VINCENT, LEAH REBECCA
project_start_date: 2024-08-21
project_end_date: 2026-06-30
study_section: Bacterial Virulence Study Section [BV]
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
project_abstract:
ABSTRACT Chlamydia species are important pathogens that represent a paradigm for understandingsuccessful obligate intracellular parasitism. C. trachomatis is a prevalent human pathogenswhereas C. muridarum is a murine-specific pathogen often used to study chlamydial disease ina small animal model. Species-specific variability in coding capacity within the so-calledplasticity zone of the chlamydial chromosome is thought to be one source dictating differencesin infection biology. The presence/absence of genes encoding glycosyltransferases designatedas putative cytotoxins represents an intriguing example of this diversity. C. muridarum expressmultiple homologous proteins that also show similarity to a family of larger cytotoxins. Theplasticity zone of common urogenital C. trachomatis serovars express a truncated protein whileocular serovars of members of the lymphogranuloma venereum (LGV) biovar lack the toxingenes completely. These cytotoxins have been proposed to mediate immediate toxicity in highlyinfected epithelial cells by interfering with actin polymerization. Lack of tractable genetics in Cmuridarum and urogenital C. trachomatis in particular has previously confounded definitivestudies leading to a paucity in details regarding molecular mechanisms of infection. We haveovercome this barrier by deletion of putative cytotoxin genes in C. muridarum. Our dataindicated that these proteins were dispensable for immediate toxicity. Combined with analysis ofC. trachomatis CT166 our data implicate an alternative function for these proteins. We proposeto apply genetic and biochemical approaches to delineate molecular function(s) of theseputative glycosyltransferases and address their contribution(s) to species-specific infectionbiology.

project_terms:
Actins;Address;Affect;Animal Model;Antibodies;Applied Genetics;Biochemical;Biological Assay;Biology;Caspase;Cell Culture Techniques;Cells;Cellular biology;Chlamydia;Chlamydia Infections;Chlamydia muridarum;Chlamydia trachomatis;Chlamydiaceae;Chlamydiales;Chlamydophila pneumoniae;Chromosomes;Chronic;Code;Cytoskeleton;Cytotoxin;Data;Disease;Engineering;Epithelial Cells;Eukaryotic Cell;Exhibits;Family;Family member;Foundations;Gene Order;Genes;Genetic;Genitourinary system;Goals;Guanosine Triphosphate Phosphohydrolases;Homologous Protein;Human;Infection;Inflammation;Invaded;Longitudinal Studies;Lymphogranuloma Venereum;Mediating;Modeling;Molecular;Mucous Membrane;Mus;Outcome;Pathogenesis;Pathology;Pathway interactions;Polymers;Protein Truncation;Proteins;Reproducibility;Research Design;Role;Source;Surface;Testing;Time;Toxic effect;Toxin;Virulence;Work;cell type;comparative;design;experience;genital infection;glycosyltransferase;human disease;human pathogen;in vivo;intracellular parasitism;member;mouse model;mutant;obligate intracellular parasite;pathogen;polymerization;protein function;reproductive tract;respiratory pathogen;rho;success;tissue tropism

public_health_relevance:
Chlamydia species infect a wide range of mammalian hosts and deploy an array of anti-hostproteins to promote the ability to cause disease. While many of these proteins are conservedacross species some have diverged and are likely to contribute to species-specific differencesin infection. This proposal contains work designed to characterize a group of those variableproteins and elucidate specific contributions to chlamydial disease.


application_id: 10983878
project_number: 1P20GM155899-01
project_title: Community Engagement and Outreach (CEO) Core
administering_ic: NIGMS
award_notice_date: 2024-07-09
opportunity_number: PAR-23-257
application_type: 1
activity_code: P20
ic: GM
serial_number: 155899
project_start_date: 2024-07-10
project_end_date: 2029-06-30
study_section: Special Emphasis Panel[ZGM1 RCB-3 (CD)]
subproject_number: 9136
contact_pi_person_id: 79485266
contact_pi: DUNN, KELLI MATHESON BULLARD
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 vision of the Community Engagement and Outreach (CEO) Core is to develop and sustain crucialcommunity- academic research partnerships that enhance population health by addressing critical gaps inhealth care resources and understanding the diverse needs of Kentucky residents. Despite existing communityoutreach engagement and research efforts KY lags significantly in all national health metrics especiallyamong diverse and under-resourced residents. A critical need for multi-directional efforts exists to promoteawareness of and sensitivity to local health issues while ensuring community-participatory interventionsand research addresses the needs of a diverse underserved and under- resourced community. Theoverarching goals of this core are to improve the overall health and well-being of Kentuckians by raisingawareness of community health research needs and improving access to relevant research studies and datawhile addressing the needs of at-risk subgroups including health education health literacy and trust. Toaccomplish these goals the proposed project will build community trust and health literacy through healthintervention and research partnerships using community-to-bedside prevention modalities innovativecommunity-participatory research healthcare partners and medical advances. Our multifaceted approachincludes multi-directional information sharing in many formats including Community Knowledge ExchangeSessions (CKES) Stakeholder Advisory Boards (SAB) collaborative activities with other Louisville Clinical andTranslational Research Center (LCTRC) Cores and discussions among citizen scientists clinical investigatorshealth clinics partners research coordinators and physician/community liaisons. We will work to integratecultural respect and sensitivity throughout the design implementation and dissemination of community-participatory research. These activities will provide a base for strategic partnerships and study participants forclinical and translational (C&T) research geared toward mitigating health disparities. We will leverage ourteams breadth and depth of experience in community outreach and engagement and C&T research to addressthe following Aims:Specific Aim 1: Promote understanding of community health/research needs and disseminateknowledge health research education and share C&T research and resources with target communities.Specific Aim 2: Develop and support community-led and clinical investigator-initiated community-basedparticipatory research.Impact: The CEO Core in concert with stakeholders will invest in both community-led and community-participatory C&T research to prevent manage and treat chronic diseases using multi-directional inputs that aresensitive to the culture and needs of our underserved target audience.

project_terms:
Address;Awareness;Cardiometabolic Disease;Cardiovascular system;Center for Translational Science Activities;Chronic Disease;Clinic;Clinical;Clinical Investigator;Clinical Research;Communities;Community Health;Community Outreach;Data;Ensure;Goals;Health;Health behavior;Health education;Healthcare;Household;Improve Access;Intervention;Investments;Kentucky;Knowledge;Lung;Malignant Neoplasms;Medical;Metabolic;Modality;Obesity;Outcome;Participant;Personal Satisfaction;Physicians;Poverty;Prevention;Reduce health disparities;Research;Research Methodology;Research Project Grants;Resources;Risk;Rural;Smoking;Subgroup;Training;Translating;Translational Research;Trust;Universities;Vision;Work;base;citizen science;combat;community academic partnership;community based participatory research;community building;community engagement;community involvement;community partners;cultural competence;design;education research;experience;health literacy;improved;innovation;population health;prevent;programs;research study;socioeconomics


application_id: 10983877
project_number: 1P20GM155899-01
project_title: Health Resources (HR) Core
administering_ic: NIGMS
award_notice_date: 2024-07-09
opportunity_number: PAR-23-257
application_type: 1
activity_code: P20
ic: GM
serial_number: 155899
project_start_date: 2024-07-10
project_end_date: 2029-06-30
study_section: Special Emphasis Panel[ZGM1 RCB-3 (CD)]
subproject_number: 9135
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG 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 Health Resources (HR) Core will manage all research supported by the LCTRC supporting two types ofprojects to increase the Clinical and Translational (C&T) workforce and strengthen investigator- initiated C&Tresearch. We will support two types of seed grantspilots and developmental grants. We will purposefully beinclusive of historically underrepresented groups. The HR Core is responsible for soliciting reviewingselecting and administering these projects. We prioritize community-engaged research research on healthdisparities and research studying diseases that affect LCTRC populations or involve collaborations of basicclinical and translational researchers. The HR Core will ensure that research subjects involved in HR Core-supported projects are representative of the populations we serve and that our investigators likewiserepresent those groups. The HR Core will work closely with the PD Core to identify relevant topics delivertraining and find/develop mentors to prepare investigators to conduct C&T research. We will work with theCEO Core to ensure that a portion of the grants supported in the HR Core are community engaged researchand that research recommendations from the community are incorporated into pilot and developmentalprojects. We will work with the RDCD Core to ensure that all HR Core supported projects are well designedexecuted and analyzed. We will work with the Administrative Core to evaluate progress to ensure that theoverall goals of the LCTRC are achieved in a fiscally and ethically responsible fashion and with the CTU in theAC in order to assure regulatory compliance. Our objective is to provide new clinical and translationalinvestigators with the necessary resources to increase their competitiveness to secure extramural funding andto create the next generation of innovations to improve the quality of life of Kentuckians and beyond. We willachieve our goal through the following Aims: Specific Aim 1: Solicit review and select new Pilot Projectswith the potential to develop independent applications such as NIH career development (K-series) ordevelopmental research project awards (e.g. R21). Specific Aim 2: Solicit review and select newDevelopmental Projects for two years of support for independent investigators with the requisitebackground and scientific expertise. Specific Aim 3: Pair project leads of HR Core projects that involveclinical trials with experienced clinician scientists who serve as mentors and make necessary coreresources available to investigators. Specific Aim 4: Monitor HR Core projects to ensure studyparticipant safety and that all federal state local and organizational regulatory requirements are met.We will also monitor projects for abstract paper grant application and external funding productivity.Impact: The research supported in this core will result in a critical increase in clinical and translational researchat UofL and its partners and will develop our next generation of clinical and translational scientists.

project_terms:
Affect;Applications Grants;Award;Center for Translational Science Activities;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Clinical Trials Unit;Collaborations;Communities;Community Outreach;Development;Disease;Ensure;Ethics;Extramural Activities;Funding;Future;Goals;Grant;Grant Review Process;Health Priorities;Health Resources;Institution;Investigation;Link;Mentors;Monitor;Paper;Persons;Pilot Projects;Population;Productivity;Quality of life;Recommendation;Reduce health disparities;Research;Research Design;Research Personnel;Research Project Grants;Research Subjects;Research Support;Resources;Scientist;Secure;Series;Testing;Training;Translational Research;Underrepresented Populations;United States National Institutes of Health;Universities;Work;career development;community engaged research;community engagement;data management;design;experience;health disparity;improved;innovation;investigator training;next generation;participant safety;programs;research study;translational scientist;virtual


application_id: 10983876
project_number: 1P20GM155899-01
project_title: Research Design Compliance and Data Management (RDCD)
administering_ic: NIGMS
award_notice_date: 2024-07-09
opportunity_number: PAR-23-257
application_type: 1
activity_code: P20
ic: GM
serial_number: 155899
project_start_date: 2024-07-10
project_end_date: 2029-06-30
study_section: Special Emphasis Panel[ZGM1 RCB-3 (CD)]
subproject_number: 9134
contact_pi_person_id: 9599235
contact_pi: KONG, MAIYING
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 Research Design Compliance and Data Management (RDCD) Core envisions itself as an unwaveringbeacon dedicated to supporting LCTRC investigators with timely and robust statistical assistance onexperimental design and data analysis access to Electronic Health Records (EHR) databases to conduct C&Tresearch facilitation of clinical trials and creation of research databases and guidance and resources on riskmanagement federal regulatory and reporting compliance on human subjects research.The UofL RDCD Core is under the leadership of Dr. Maiying Kong who is a professor in the UofL Departmentof Bioinformatics and Biostatistics (DBB) holds the Wendell Cherry Chair in Clinical Trial Research and is theDirector of Biostatistics Core at the UofL Brown Cancer Center (BCC). She has formed a talented team thatincludes four faculty members from the DBB the UofL Health (ULH) Chief Medical Information Officer (Dr. SunitaKasliwal) and her staff and the Chief Director of the UofL Clinical Trial Unit (Rachel Sheppard) and her staff.The RDCD Core aims to foster close collaboration between these accomplished DBB members and the C&Tresearchers. While ULH possesses valuable access to two extensive EHR databases Epic Cosmos and theCerner Learning Health Network (LHN) availability of these databases to UofL C&T researchers has beenrestricted. The RDCD Core is taking proactive steps to establish a partnership with ULH to make these EHRdatabases accessible to UofL C&T researchers. In conclusion the RDCD Core will harness a wealth of expertiseand resources to bring its vision to fruition through the following Specific Aims:Specific Aim 1: Provide state-of-the-art statistical support in design analysis and dissemination offindings across a spectrum of basic science translational clinical and population health studies.Specific Aim 2: Facilitate and provide guidance on the use of EHR and other large clinical datasets toensure compliance with NIH and institutional data management policies to safeguard protected healthinformation.Specific Aim 3: Provide guidance resources and training to enhance the competency of LCTRCresearchers in conducting human subjects research.Impact: RDCD Core is an essential piece of a successful UofL CTR-D program. The successful execution of thiscore will establish a centralized resource and coordination hub to provide LCTRC investigators with essentialsupport in research design data analysis compliance and data management. Furthermore through ourpartnership with ULH we will make both national Epic Cosmos and the Cerner LHN EHR databases and localEDW databases accessible which will enable LCTRC investigators to conduct C&T research with heightenedefficiency precision and put a direct focus on improving patient care.

project_terms:
Area;Basic Science;Bioinformatics;Biometry;Biostatistics Core;Cancer Center;Center for Translational Science Activities;Clinical;Clinical Data;Clinical Research;Clinical Trials;Clinical Trials Unit;Collaborations;Community Outreach;Competence;Consultations;Data Analyses;Data Set;Databases;Dedications;Development;Educational workshop;Electronic Health Record;Ensure;Experimental Designs;Faculty;Fostering;Funding;Grant;Health;Health Resources;Health protection;Human Subject Research;Individual;Institution;Journals;Leadership;Learning;Medical;Mentorship;Methodology;Patient Care;Policies;Population Study;Publications;Records;Reporting;Research;Research Design;Research Infrastructure;Research Personnel;Resources;Risk Management;Talents;Training;Training Activity;Translational Research;United States National Institutes of Health;Universities;Vision;Work;clinical database;community engagement;data management;data warehouse;design;electronic data;improved;interdisciplinary collaboration;member;population health;professor;programs;translational scientist


application_id: 10983875
project_number: 1P20GM155899-01
project_title: Professional Development (PD) Core
administering_ic: NIGMS
award_notice_date: 2024-07-09
opportunity_number: PAR-23-257
application_type: 1
activity_code: P20
ic: GM
serial_number: 155899
project_start_date: 2024-07-10
project_end_date: 2029-06-30
study_section: Special Emphasis Panel[ZGM1 RCB-3 (CD)]
subproject_number: 9133
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Louisville Clinical and Translational Research Center (LCTRC) Professional Development (PD) Core shallpromote a diversity of training experiences to build a knowledgeable and thriving collaborative cross-disciplinarycommunity of Clinical and Translational Researchers at the University of Louisville (UofL). The PD Core aims toaddress a lack of critical mass of investigators proficient in the core competencies required to create and translateour innovations successfully. Through coordination with the Health Research (HR) Community Engagement andOutreach (CEO) and Research Design Compliance and Data Management(RDCD) Cores and with oversight from the Administrative Core (AC) the PD Core will build an innovativeeducational program and mentoring program with the following aims:Specific Aim 1: Develop a core of well-trained and supported early-stage clinician-investigators capableof securing grant funding to sustain UofL's commitment to research and translation to practice.Specific Aim 2: Build interdisciplinary teams and networks of investigators to promote innovation in C&TResearch.Specific Aim 3: Nurture our pipeline of clinician scientists by developing C&T research skills andcompetencies in our clinical professional students.Specific Aim 4: Train clinical research coordinators and research nurses in best practices and policiesand mentoring practices to better support UofLs clinical research enterprise. We will train and retain aclinical research coordinator workforce to support anticipated increases in C&T research provide 24/7 coveragefor acute care studies and support community-engaged research in the LTCRC. Regular interactions with theCEO Core shall promote and facilitate engagement in research by diverse members of the local community.Impact. Success will lead to a sustained base of well-trained clinician-scientists and mentors representing thediverse backgrounds of our target communities in South/West Louisville and Owensboro as they conductinvestigator-initiated C&T research in interdisciplinary teams in our LTCRC and improved healthcare outcomesfor the communities within Kentucky and beyond.

project_terms:
Address;Award;Center for Translational Science Activities;Clinical;Clinical Research;Clinical Trials;Collaborations;Communities;Community Outreach;Competence;Credentialing;Degree program;Dental Students;Development;Discipline;Doctor of Philosophy;Education;Educational workshop;Engineering;Faculty;Funding;Future;Grant;Growth;Health;Investigation;K-Series Research Career Programs;Kentucky;Medical Students;Mentors;Mentorship;Nursing Research;Outcome;Physicians;Policies;Productivity;Research;Research Design;Research Personnel;Research Project Grants;Scholars Program;Science;Scientist;Secure;Students;Time;Training;Training Programs;Translating;Translational Research;Translations;United States National Institutes of Health;Universities;acute care;base;care outcomes;career development;community building;community engaged research;community engagement;data management;design;experience;improved;innovation;member;professional students;programs;skill acquisition;skills;success;translational scientist;web site


application_id: 10983874
project_number: 1P20GM155899-01
project_title: Administrative Core (AC)
administering_ic: NIGMS
award_notice_date: 2024-07-09
opportunity_number: PAR-23-257
application_type: 1
activity_code: P20
ic: GM
serial_number: 155899
project_start_date: 2024-07-10
project_end_date: 2029-06-30
study_section: Special Emphasis Panel[ZGM1 RCB-3 (CD)]
subproject_number: 9132
contact_pi_person_id: 2105319
contact_pi: KLEIN, JON
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 goal of this Administrative Core (AC) is to create the Louisville Clinical and Translational Research Center(LCTRC) that provides a programmatic approach to C&T research that expands and fully integrates efforts andconnects them directly with existing IDeA COBREs and the INBRE programs at UofL. The AC will lead andmanage the cores supporting a single point of access for C&T research for UofL students faculty andcommunity members.The AC will provide governance needs assessment evaluation and ensure the cores work togethercohesively and in a coordinated manner through the following Specific Aims:Specific Aim 1: Create a formal management and governance structure.Specific Aim 2: Administer resources to increase clinical trial capacity and capabilities.Specific Aim 3: Increase LCTRC and UofL IDeA COBREs and INBRE interaction and synergy.Specific Aim 4: Create and optimize a Tracking and Evaluation program.Impact. Achieving these aims will create a flexible and accountable management structure for increased C&Tresearch; enlarge the C&T research infrastructure and add novel capabilities that will allow us to perform moreC&T investigations in the urban and rural populations. The LCTRC will serve as a single point of contact forC&T research infrastructure training funding and community engagement which will ultimately lead to noveltherapeutics decreased health disparities and improved public health.

project_terms:
Accidents;Accountability;Achievement;Address;Admission activity;Award;Budgets;Cancer Center;Cardiac;Caring;Center for Translational Science Activities;Centers of Research Excellence;Chronic Disease;Chronic Obstructive Pulmonary Disease;Clinical;Clinical Research;Clinical Trials;Clinical Trials Unit;Collaborations;Communication;Communities;Diabetes Mellitus;Educational Curriculum;Ensure;Environmental Health;Evaluation;Faculty;Feedback;Funding;Goals;Health;Healthcare;Hospitals;Human Resources;Incidence;Individual;Infrastructure;Kentucky;Kidney Diseases;Lead;Malignant Neoplasms;Measures;Medical center;Mentorship;Metabolic Diseases;Methods;Monitor;Needs Assessment;Nervous System Disorder;Nervous System Trauma;Patients;Performance;Policies;Program Evaluation;Public Health;Reduce health disparities;Research;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Rural;Rural Health;Rural Population;Strategic Planning;Structure;Students;Technology;Time;Training;Translational Research;Transplantation;Universities;Urban Population;Work;cardiovascular health;chronic liver disease;citizen science;clinical center;clinical investigation;community engagement;conflict resolution;flexibility;health care availability;improved;innovation;member;metropolitan;novel;novel therapeutics;programs;rural area;synergism;translational research program;urban area;wearable sensor technology


application_id: 10983873
project_number: 1P20GM155899-01
project_title: Louisville Clinical And Translational Research Center (LCTRC)
administering_ic: NIGMS
award_notice_date: 2024-07-09
opportunity_number: PAR-23-257
application_type: 1
activity_code: P20
ic: GM
serial_number: 155899
program_official: RICHARDS, CRYSTAL LYNETTE
project_start_date: 2024-07-10
project_end_date: 2029-06-30
study_section: Special Emphasis Panel[ZGM1 RCB-3 (CD)]
contact_pi_person_id: 2105319
contact_pi: KLEIN, JON
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:
The vision of the Louisville Clinical and Translational Research Center (LCTRC) is to build an impactful Clinicaland Translational (C&T) research program at the University of Louisville (UofL) to improve the health of Kentucky(KY) communities. Kentucky is by any measure a poor and largely rural state with a single large metropolitancenter that suffers disproportionately from many chronic diseases. For example KY is ranked first in the U.S. incancer and COPD incidence. To address these problems the UofL in its research strategic planning processcreated Programs of Distinction in cardiovascular disease neuroscience cancer and metabolic disease. ThusUofL has been very deliberate about developing research programs to meet the states most pressing healthproblems. However UofL has approached C&T research of these health problems through underfunded andadmittedly uncoordinated efforts in clinical trials infrastructure research design research funding andmentorship. Also until 2019 UofL C&T research was performed almost exclusively at two facilities. In 2019UofL created UofL Healthcare (ULH) that has 11 hospitals a cancer center and multiple outpatient centers. ULHwith its larger footprint and patient volume has challenged the capacity of our C&T infrastructure but also createda major opportunity to increase the amount and quality of our C&T research. The long-term goal of the LCTRCis to build the needed workforce and expertise at UofL and our affiliated healthcare systems to conduct impactfuland community engaged C&T research. We will achieve this goal through these five Specific Aims:Specific Aim 1: Expand and fully integrate clinical and translational research at UofL ULH and otherhealthcare partners. (Administrative and Community Engagement and Outreach Cores).Specific Aim 2: Create and implement professional development for early-career clinician investigatorsstudents and C&T research staff (Professional Development Core).Specific Aim 3: Develop Pilot and Developmental projects to support community scientists traineesearly-career and established C&T investigators (Health Research Core).Specific Aim 4: Establish a centralized resource that provides LCTRC investigators with essentialsupport in research design data analysis compliance and data management (Research DesignCompliance and Data Management Core).Specific Aim 5: Invest in both community-led and community-participatory C&T research to improvepublic health using multi-directional inputs sensitive to the culture and needs of underservedpopulations. (Synergistic among all Cores). Successful implementation of the LCTRC will create a singlepoint of access program for C&T research that allows us to perform studies in urban and rural populations thatultimately improve public health.

project_terms:
Address;Admission activity;Award;Biomedical Research;Biometry;Cancer Center;Cardiac;Cardiovascular Diseases;Caring;Center for Translational Science Activities;Chronic Disease;Chronic Obstructive Pulmonary Disease;Clinical;Clinical Informatics;Clinical Investigator;Clinical Research;Clinical Trials;Collaborations;Communication;Communities;Community Outreach;Community Participation;Community Physician;Data Analyses;Databases;Development;Diabetes Mellitus;Discipline;Disease;Educational workshop;Ensure;Foundations;Funding;Goals;Growth;Health;Healthcare;Healthcare Systems;Heart Diseases;Home;Hospitals;Incidence;Industry;Inflammation;Infrastructure;Institution;Instruction;Investments;Kentucky;Lead;Malignant Neoplasms;Measures;Mentors;Mentorship;Metabolic Diseases;Monitor;Neurosciences;Nursing Research;Obesity;Outcome;Pathogenicity;Patients;Process;Program Development;Public Health;Rehabilitation Centers;Research;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Rural;Rural Community;Rural Population;Scientist;Strategic Planning;Stroke;Students;Testing;Toxicology;Training;Translational Research;Transplantation;Underserved Population;Universities;Urban Community;Urban Population;Vision;Workforce Development;biological research;career;community engagement;data management;design;follower of religion Jewish;improved;learning network;member;metropolitan;microbiome research;next generation;outpatient facility;participant safety;programs;recruit;translational health science;translational research program;translational scientist;workforce needs

public_health_relevance:
Our overall goal is to develop a program at the University of Louisville (UofL) its healthcarepartners and the urban and rural communities we serve to perform impactful collaborative clinicaland translational research. We will also leverage existing UofL IDeA programs to positively impactthe health outcomes of our populace (including the underserved) and to create an interactiveprofessional development program that will create a pipeline for the next generation of clinicaland translational investigators.


application_id: 10983752
project_number: 5R00DA049908-05
project_title: Executive function in opioid-exposed offspring and subsequent molecular signatures
administering_ic: NIDA
award_notice_date: 2024-10-30
opportunity_number: PA-19-130
application_type: 5
activity_code: R00
ic: DA
serial_number: 049908
program_official: LIN, YU
project_start_date: 2020-05-01
project_end_date: 2026-11-30
study_section: ZDA1-SXM-M(02)S
contact_pi_person_id: 11000796
contact_pi: SMITH, BRITTANY L
other_pis: Not Applicable
congressional_district: 04
department: PSYCHOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary My long-term career goal is to become a translational researcher who uses rodent models and humansamples to facilitate innovative interventions that readily adapt to the clinic. The current proposal represents animportant step in my transition to scientific independence and will significantly extend my training in behavioraland developmental neuroscience as well as provide new training in bioinformatics and translational research.These training activities will occur within the context of a timely public health crisis seen with the opioidepidemic. Children born to opioid-abusing mothers including mothers stabilized on medication-assistedtreatment (MAT) are at an increased risk for cognitive deficits that frequently display as problems withexecutive function (e.g. inattention impulsivity). Work in an animal model is necessary to 1) identify themechanisms underlying executive function deficits in order to develop treatment strategies and 2) control forunavoidable confounds seen in the clinic (e.g. polysubstance use). Currently there are no animal studies ofexecutive function after maternal opioid use and the present proposal seeks to fill this gap. Further tounderstand potential biological mechanisms we will use an unbiased hypothesis-driving bioinformaticsapproach to discover offspring molecular signatures of maternal opioid use. Overall the current proposal willtest the hypothesis that maternal opioid exposure including MAT causes executive function deficits inadulthood that are associated with transcriptional changes within the prefrontal cortex an area of the brainvulnerable to environmental exposures and important for executive function. Specific Aim 1 (mentored phase) will examine executive function in opioid-exposed offspring includingMAT using the 5 choice serial reaction time task. This training will extend my expertise in developmental andbehavioral neuroscience. Specific Aim 2 will test the hypothesis that maternal opioid exposure includingMAT creates gene expression signatures in the prefrontal cortex that relate to executive function deficits andwill include training (mentored phase; certificate program in Bioinformatics) and experiments (independentphase; RNA-seq of brains from Aim 1). I will use bioinformatics strategies to integrate RNA sequencing dataand complex executive function behavioral data. Specific Aim 3 (mentored phase) will test the hypothesis thatin humans maternal opioid exposure produces distinct epigenomic signatures that are detectable in humanDNA samples. This will take advantage of unique access to human samples from both opioid-exposed andnon-exposed children as well as access to their paired electronic health records. This will provide criticaltraining in working with clinical samples and is a key aspect of my training in translational research. My trainingwill be further supported by regular meetings with an expert Advisory Committee and completion of graduatecertificates in both Biomedical Informatics and Clinical & Translational Research.

project_terms:
Address;Adolescence;Adult;Advisory Committees;Affect;Animal Model;Animals;Area;Attention;Attention deficit hyperactivity disorder;Automobile Driving;Behavior;Behavior assessment;Behavioral;Bioinformatics;Biological;Blood;Blood specimen;Brain;Brain region;Buprenorphine;Child;Clinic;Clinical;Clinical Research;Cognition;Cognitive deficits;Complex;Complex Variables;DNA;Data;Development;Diagnosis;Electronic Health Record;Environment;Environmental Exposure;Epidemic;Epigenetic Process;Executive Dysfunction;Exposure to;Fetal Development;Foundations;Future;Future Generations;Gene Expression;Gene Expression Profile;Genetic Transcription;Goals;Government-Sponsored Programs;Hospital Charges;Hospitalization;Human;Impulsivity;Incidence;Infant;Intervention;Investigation;Life;Mentors;Methadone;Methylation;Molecular;Molecular Profiling;Mothers;Mus;Neonatal Abstinence Syndrome;Neurosciences;Newborn Infant;Opiate Addiction;Opioid;Outcome;Pattern;Peripheral;Pharmaceutical Preparations;Phase;Placenta;Population;Prefrontal Cortex;Pregnancy;Pregnant Women;Problem behavior;Prognosis;Public Health;Reaction Time;Recording of previous events;Reporting;Research;Resources;Risk;Rodent;Rodent Model;Sampling;Self-control as a personality trait;Severities;Short-Term Memory;Survival Rate;Swab;Testing;Therapeutic Intervention;Time;Training;Training Activity;Translational Research;Whole Blood;Woman;Work;biomedical informatics;career;certificate program;epigenomics;executive function;experimental study;genome-wide;health care resources;help-seeking behavior;human DNA;human data;improved;improved outcome;in utero;inattention;innovation;maternal opioid use;medication-assisted treatment;meetings;mouse model;neonate;offspring;opioid abuse;opioid epidemic;opioid exposure;opioid use;polysubstance use;pre-clinical;prenatal;programs;response;standard of care;therapeutically effective;transcriptome sequencing;translational scientist;translational study;treatment strategy

public_health_relevance:
Project Narrative Children exposed to opioids in utero either through the mothers opioid use/abuse or via medication-assisted treatment for opioid addiction (MAT methadone or buprenorphine) are at an increased risk forcognitive deficits particularly those related to attention and impulse control. No study has addressed this in ananimal model so the goal of this proposal is to test how maternal opioid use including MAT affects offspringbrain development and behavior in a mouse model. These studies will establish a foundation for futureinvestigations into potential interventions to improve outcomes in opioid-exposed children.


application_id: 10983732
project_number: 5F31AI178999-02
project_title: Defining the impact of Extracellular Vesicles on inflammation during pneumonic plague
administering_ic: NIAID
award_notice_date: 2024-07-30
opportunity_number: PA-21-052
application_type: 5
activity_code: F31
ic: AI
serial_number: 178999
program_official: MOITRA, KAROBI
project_start_date: 2023-08-01
project_end_date: 2026-07-31
study_section: Special Emphasis Panel[ZRG1-F07A-B(20)L]
contact_pi_person_id: 77802022
contact_pi: SHENEMAN, KATELYN RENEE
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTDuring infection immune cells rely on communication to productively target and eliminate invading pathogens.Extracellular vesicles (EVs) are one key mediator of intercellular communication between immune cells. Thesemembrane-bound vesicles contain proteins lipids and nucleic acids that represent the inflammatory state of agiven cell. Upon release these EVs can fuse with other immune cells establishing biochemical communicationbetween cells and amplifying the inflammatory response to augment pathogen clearance. Yersinia pestis is theetiologic agent of the human disease known as plague. A hallmark of this disease is the sophisticatedsuppression of the host immune system in a biphasic manner. During acute infection Y. pestis utilizes its type 3secretion system (T3SS) to inject effector proteins into host cells which disrupt signaling pathways essential forbacterial clearance. Thus acute infection is hallmarked by the maintenance of a non-inflammatory environmentin which the bacteria can proliferate without host intervention. The second stage of infection the pro-inflammatory phase begins 36-48 hours post-infection in which the host begins to successfully mount animmune response against the pathogen. However the bacterial load ultimately overwhelms the host delayedresponses at which point the host may succumb to infection. Previous work has demonstrated that thegeneration of this non-inflammatory environment during acute infection is essential for Y. pestis virulence. Whilenumerous studies have highlighted the importance of suppressing phagocytosis exocytosis and otherantibacterial responses there is a gap in knowledge of how Y. pestis manipulates the EV response and how thisimpacts intercellular communication. Preliminary studies suggest that Y. pestis can manipulate the proteinspackaged into EVs by neutrophils in vitro. These data support the hypothesis that Y. pestis disrupts EVsproduction during infection to alter inflammation. The studies presented here will expand on our preliminary databy delineating the in vivo EV response during pneumonic plague (Aim 1) and defining the impact of EVs onimmune modulation (Aim 2). These studies will be the first to investigate the role of EV-mediated intracellularcommunication during plague. Therefore completion of these aims will significantly improve our understandingof how. Y. pestis exploits EV trafficking to manipulate the host immune response.

project_terms:
Antibacterial Response;Bacteria;Bacterial Infections;Binding;Biochemical;Cells;Communication;Data;Dependence;Development;Disease;Disease Progression;Endocytosis Inhibition;Environment;Etiology;Exocytosis;Generations;Goals;Hour;Human;Immune;Immune response;Immune system;In Vitro;Infection;Inflammation;Inflammatory;Inflammatory Response;Intervention;Invaded;Knowledge;Lipids;Lung;Lung infections;Maintenance;Mediating;Mediator;Membrane;Neutrophil Infiltration;Nucleic Acids;Organism;Outcome;Pathogenesis;Pathway interactions;Phagocytes;Phagocytosis;Phase;Plague;Play;Pneumonic Plague;Population;Production;Productivity;Proliferating;Protein Secretion;Proteins;Pulmonary Inflammation;Role;Signal Pathway;Testing;Time;Tissues;Type III Secretion System Pathway;Vesicle;Virulence;Work;Yersinia pestis;acute infection;antimicrobial;cell type;cytokine;extracellular vesicles;human disease;immunoregulation;improved;in vivo;in vivo evaluation;intercellular communication;mutant;neutrophil;new therapeutic target;pathogen;response;tool;trafficking

public_health_relevance:
PROJECT NARRATIVEYersinia pestis the etiologic agent of the plague has refined mechanisms to manipulate the host immuneresponse and suppress inflammation. This project will define the impact of disrupting extracellular vesicletrafficking and illustrate how this manipulation contributes to disease pathogenesis. Understanding thesemechanisms of immune subversion is essential for the development of novel targeted therapeutics.


application_id: 10982837
project_number: 3R34MH128213-03S1
administering_ic: NIMH
award_notice_date: 2023-11-30
opportunity_number: PA-21-071
application_type: 3
activity_code: R34
ic: MH
serial_number: 128213
suffix: S1
program_official: SWEENEY, MARY MARGARET
project_start_date: 2021-12-17
project_end_date: 2025-11-30
study_section: ZMH1-ERB-N(08)
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
project_title:
A Pilot Investigation of Network-Informed Personalized Treatment for Eating Disorders versus Enhanced Cognitive Behavioral Therapy and Dynamic Mechanisms of Change

project_abstract:
PROJECT SUMMARY/ABSTRACTEating disorders (EDs) are serious mental illness with the second highest mortality rate of anypsychiatric disorder and carry high societal personal and economic costs. Treatment responsefor EDs are suboptimal with only 50% of adults responding to evidence based treatments andno evidence-based treatment for anorexia nervosa (AN) or Other Specified Feeding or EatingDisorder (OSFED) in existence. Part of the reason EDs are so difficult to treat is the highheterogeneity in symptom presentation making it difficult to identify what to target in treatmentas two individuals even with the same diagnosis substantially vary. Personalized treatments forEDs are urgently needed that can improve treatment response and minimize the sufferingassociated with these illnesses. Our scientific premise developed from our past work is thattreatment personalized based on idiographic models (termed Network Informed PersonalizedTreatment; NA-PT) will outperform the current gold-standard treatment (Enhanced CognitiveBehavioral Therapy: CBT-E). Our study goals are to (1) develop and test the acceptabilityfeasibility and preliminary efficacy of a randomization of NA-PT versus CBT-E and (2) to test ifnetwork-identified precision targets are the mechanism of change. These goals will ultimatelylead to the very first personalized treatment for ED and can be extended to additionalpsychiatric illnesses. The proposed research uses highly innovative methods; intensivelongitudinal data collected with mobile technology is combined with state-of-the art idiographicmodeling methods to deliver a virtual personalized treatment. Specific aims are (1) To collectpreliminary data on the feasibility and acceptability of the randomization of NA-PT (n=40) forEDs versus CBT-E (n=40) (2) To test the initial clinical efficacy of NA-PT versus CBT-E onclinical outcomes (e.g. ED symptoms body mass index quality of life) and (3) To examine ifchanges in NA-identified precision targets as well as in dynamic network structure areassociated with change in clinical outcomes. The proposed research has clinical impact.Ultimately this proposal will lead directly to the creation and dissemination of an evidence-based personalized treatment for EDs as well as will serve as an exemplar for personalizedtreatment development across the entire field of psychiatry.

project_terms:
Address;Adult;Aftercare;Anorexia Nervosa;Behavior Disorders;Binge Eating;Binge eating disorder;Body mass index;Bulimia;Caring;Cellular Phone;Cessation of life;Clinical;Cognitive Therapy;Complex;Data;Death Rate;Development;Diagnosis;Diagnostic;Dropout;Eating Disorders;Evidence based treatment;Fright;Goals;Heterogeneity;Impairment;Individual;Intervention;Investigation;Judgment;Lead;Left;Mental disorders;Methodology;Methods;Modeling;Outcome;Participant;Pathology;Pathway Analysis;Pattern;Population;Precision therapeutics;Prediction of Response to Therapy;Psychiatry;Psychotherapy;Quality of life;Randomized;Research;Specific qualifier value;Structure;Symptoms;Testing;Time;Translating;Treatment outcome;United States National Institutes of Health;Visualization;Weight Gain;Work;acceptability and feasibility;clinical efficacy;cognitive enhancement;comorbidity;economic cost;evidence base;feeding;follow-up;improved;individualized medicine;innovation;long term recovery;mobile computing;novel;personalized medicine;prevent;public health relevance;response;severe mental illness;smartphone based assessment;societal costs;standard care;theories;therapy development;treatment optimization;treatment planning;treatment response;user friendly software;virtual

public_health_relevance:
PROJECT NARRATIVEThis project will collect data on the feasibility acceptability efficacy and target engagement of apersonalized treatment for eating disorders. The proposed research has significant public healthrelevance as it will directly lead to a highly accessible and deployable personalized treatmentthat can improve treatment response rates and decrease the high societal burden associatedwith eating disorders. The proposed research is relevant to NIHs strategic aim 3.3b as it willlead to the creation of a personalized treatment consistent with NIHs precision treatmentinitiative.


application_id: 10982089
project_number: 1R01HL163419-01A1
project_title: Role of carnosine in peripheral arterial disease
public_health_relevance: AbstractA food supplement carnosine can improve the walking ability of patients having legischemia.
administering_ic: NHLBI
award_notice_date: 2024-08-14
opportunity_number: PA-20-183
application_type: 1
activity_code: R01
ic: HL
serial_number: 163419
suffix: A1
program_official: REID, DIANE M
project_start_date: 2024-08-15
project_end_date: 2029-05-31
study_section: Clinical Integrative Cardiovascular and Hematological Sciences Study Section[CCHS]
contact_pi_person_id: 11110260
contact_pi: BABA, SHAHID P
other_pis: BHATNAGAR, ARUNI ;DWIVEDI, AMIT J
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
project_abstract:
AbstractPeripheral arterial disease is a serious manifestation of atherosclerosis in the lowerextremities. Current interventions approved by FDA are either ineffective or have amodest effect. Surgical revascularization is the only viable option for PAD subjects;however the stents can fail. Patients with PAD have marked defects in skeletal musclemetabolism where the aerobic and anaerobic metabolism are uncoupled increasedacidification of the skeletal muscle and decreased ATP synthesis. In glycolytically activetissue such as skeletal muscle there are present histidyl dipeptides such as carnosinewhich buffers intracellular pH under ischemic conditions and facilitate the utilization ofglucose during exercise and ischemia. Recent evidence from our laboratory shows thatin addition to buffering carnosine chelates first transition metals and improvesangiogenesis forms conjugates with reactive aldehydes derived from lipid peroxidationand regress atherosclerosis. Hence enhancing carnosine via supplementation whicheasily permeates through the ischemic muscle is easily could be a feasible therapeuticthat can target the underlying pathophysiological associated with PAD and increase limbfunction. To achieve this goal we will treat the PAD subjects with carnosine and examinewhether the carnosine supplementation improves the lower extremity function. Secondwe will perform extensive mechanistic studies to elucidate the mechanism by whichcarnosine improves the muscle function and finally we will follow these subjects anddetermine if carnosine has durable effects. Collectively our pilot clinical trial will help ustest the efficacy of carnosine as a low-cost therapeutic intervention for PAD patients andthe data generated will serve as a strong rationale to design large definitive Phase IIIclinical trial for carnosine.

project_terms:
ATP Synthesis Pathway;Aerobic;Affect;Aftercare;Aldehydes;American;Ankle;Arterial Fatty Streak;Arterial Occlusive Diseases;Arteries;Atherosclerosis;Attenuated;Binding;Biopsy;Blood flow;Buffers;Cardiac;Carnosine;Cell Therapy;Chronic;Clinical Management;Clinical Trials;Data;Defect;Dipeptides;Double-Blind Method;Effectiveness;Enrollment;Enzymes;Excision;Excretory function;Exercise;FDA approved;Female;Fibrosis;Food Supplements;Foundations;Functional disorder;Glucose;Goals;Growth;Hindlimb;Histidine;Impairment;Intermittent Claudication;Intervention;Ischemia;Isolated limb perfusion;Laboratories;Leg;Limb structure;Lipid Peroxidation;Lower Extremity;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Measures;Mediating;Medical;Metabolic;Metabolic dysfunction;Metabolism;Metals;Mitochondria;Morbidity - disease rate;Mus;Muscle;Muscle function;Obstruction;Operative Surgical Procedures;Outcome Study;Participant;Pathway interactions;Patients;Performance;Perfusion;Peripheral arterial disease;Persons;Pharmacotherapy;Phase III Clinical Trials;Placebos;Process;Property;Proteomics;Quality of life;Randomized;Reperfusion Injury;Rest;Risk Factors;Role;Secondary to;Skeletal Muscle;Stenosis;Stents;Supplementation;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;Transition Elements;Walking;angiogenesis;blood perfusion;cardiovascular disorder risk;chelation;claudication;clinical efficacy;cost;design;efficacy testing;exercise capacity;feeding;follow-up;hemodynamics;improved;indexing;limb loss;male;metabolomics;mortality;muscle physiology;novel;pre-clinical;prevent;primary outcome;protein expression;revascularization surgery;secondary outcome;skeletal muscle metabolism;standard of care;success;treadmill;urinary;walking performance;-Alanine


application_id: 10981630
project_number: 2R01ES029846-06A1
project_title: Urban Greenness and Cardiovascular Health
administering_ic: NIEHS
award_notice_date: 2024-08-09
opportunity_number: PA-20-185
application_type: 2
activity_code: R01
ic: ES
serial_number: 029846
suffix: A1
program_official: JOUBERT, BONNIE
project_start_date: 2018-07-01
project_end_date: 2029-05-31
study_section: Social and Environmental Determinants of Health Study Section[SEDH]
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
ABSTRACTAlthough the results of many studies suggest that urban greenspaces have conducive effects of health fromextant data it is difficult to isolate causal links or to identify the environmental and physiological processes thatcontribute to the health-promoting effect of greenery. A better understanding and assessment of the healtheffects of urban greenness is therefore needed to optimize its public health impact. To examine the effects ofgreenness directly we initiated the Green Heart Project which is a community based clinical trial to test thehypothesis that increasing neighborhood greenery diminishes the risk of cardiovascular disease (CVD) bydecreasing the levels of local air pollutants. In the first phase of the phase of the project we acquired baselinedata on neighborhood characteristics and community health from 8 control (C) and 8 adjacent target (T) clustersof neighborhoods in Louisville KY. We acquired aerial hyperspectral and LiDAR scans of the area and conductedstationary and mobile monitoring to develop high-resolution maps of local air pollution. We conducted in-personexams to acquire baseline physical and psychosocial data. After acquiring baseline data we planted mostlyevergreen mature trees and upon completion of planting we evaluated changes in pollution and reacquiredhealth data from in-person exams. We now plan to conduct follow-up studies to determine the long-term effectsof the greening intervention on the levels of air pollutants and the health of individuals living in the neighborhood.For this we assess CVD risk and psychosocial characteristics and collect biospecimens from the cohort every2 years for the next 4 years to quantify the impact of changes in greenery and greenness-related neighborhoodcharacteristics on differences in cardiovascular health. Using high-resolution hyperspectral and LiDAR imagerywe will determine the effects of the greening intervention on neighborhood greenery and measure changes inair pollution temperature and noise to evaluate whether the healthful effects of greenery are related to positivechanges in neighborhood characteristics. To ensure sustainability we will identify barriers and facilitatorsincluding how urban greenness is perceived used and maintained and estimate the ecosystem servicesprovided by the increase in greenery. Successful completion of the project will lead to a rigorous and directevaluation of the link between greenspaces and cardiovascular health. Findings of the project will help delineatethe contribution of environmental psychological social and physical factors to the beneficial effects of greeneryand guide the development of new strategies for increasing sustainable healthfulness of urban neighborhoods.By evaluating the impact of greenness on pollution and temperature the project could provide new insights intomitigating the effects of climate change. Lessons learned from implementation and sustainability and long-termcost-benefit analyses of the greening intervention could inform the development of large-scale environmentalinterventions to promote community health. Collectively these results could inform new public health policiesand facilitate evidence-based optimization of ongoing greening efforts worldwide.

project_terms:
Air Pollutants;Air Pollution;Ancillary Study;Area;Biological Markers;Biomass;Blood;Characteristics;Clinical Data;Clinical Trials;Communities;Community Health;Cost-Benefit Analysis;Data;Data Set;Databases;Development;Ecosystem;Ensure;Environment;Environmental Exposure;Environmental Impact;Evaluation;Exposure to;Follow-Up Studies;Green space;Hair;Health;Health Policy;Health Promotion;Heart;Human;Imagery;Immunity;Income;Individual;Interruption;Intervention;Link;Long-Term Effects;Longitudinal Studies;Maps;Measures;Monitor;Nature;Neighborhoods;Noise;Observational Study;Outcome;Ozone;Persons;Phase;Physiological Processes;Plants;Pollution;Population;Public Health;Questionnaires;Research Design;Resolution;Sampling;Scanning;Selection Criteria;Series;Services;Stress;Temperature;Testing;Time;Trees;Urine;Work;arterial stiffness;cardiovascular disorder risk;cardiovascular health;climate change;cohort;community engagement;criteria air pollutant;efficacy trial;environmental intervention;epidemiologic data;evidence base;follow-up;foot;health assessment;health data;implementation facilitators;insight;intervention effect;member;psychologic;psychosocial;racial diversity;secondary analysis;social;systemic inflammatory response;ultrafine particle;volatile organic compound

public_health_relevance:
NARRATIVEThis project is to assess the impact of urban greenspaces on community health. For this assessment weacquired health data from individuals living in a low-to-middle income neighborhoods in Louisville KY beforeand after planting a large number of mature trees and shrubs in the area. We have also acquired data on airpollution before and after the planting. We now plan to study the long-term impact of this intervention oncommunity health and the levels of air pollution in the neighborhoods.


application_id: 10980586
project_number: 2R01AR070313-06A1
project_title: Deciphering how tissue resident macrophages regulate musculoskeletal regeneration in spiny mice
administering_ic: NIAMS
award_notice_date: 2024-09-12
opportunity_number: PA-20-185
application_type: 2
activity_code: R01
ic: AR
serial_number: 070313
suffix: A1
program_official: BELKIN, ALEXEY
project_start_date: 2017-03-13
project_end_date: 2029-07-31
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
project_abstract:
One path towards generating new therapeutic avenues to induce regeneration is understanding fundamentaldifferences between a regenerative and scarring response to injury. When tissue regeneration in spiny mice(Acomys) is studied in parallel with rodent models of scarring (e.g. laboratory mice - Mus) this comparativeapproach can uncover fundamental cell states and molecular signals that explain how identical injuries followone healing trajectory instead of the other. At the outset of either healing type tissue trauma stimulates sterileinflammation that first protects and then resolves the injury. Inflammation is orchestrated by macrophageswhose phenotypic states can have diverse functions. While current data supports that macrophages arerequired for proper wound healing whether macrophages specifically regulate musculoskeletal regeneration ispoorly understood. The long-term goal of our research is to uncover key molecular signals and cell states thatdirect mammalian musculoskeletal injuries towards regenerative healing. The objective of this proposal is tounderstand how tissue resident macrophages (TR-MFs) and their secreted products specifically regulateregeneration in spiny mice and to manipulate the wound microenvironment in laboratory mice to enhanceregenerative healing. The central hypothesis we will test is that TR-MFs are required separately during thewound healing and tissue generation stages of regeneration to first regulate inflammatory magnitude andoxidative stress and then to facilitate cell proliferation. This hypothesis is based upon our published andpreliminary studies demonstrating that when spiny mouse TR-MFs are depleted prior to injury regeneration isinhibited and Acomys TR-MFs uniquely produce secreted molecules such as VEGFc and lactoferrin (LTF)that are important for regeneration. Guided by strong preliminary data this hypothesis will be tested bypursuing the following three specific aims: (1) Asses how TR-MFs separately regulate cellular inflammationand new tissue formation during regeneration by depleting TR-MFs in spiny mice and using establishedassays to assess re-epithelialization inflammation extracellular matrix production and proliferation. Single cellRNA-sequencing will also be deployed to analyze how loss of TR-MFs alters resident cell states and behavior.(2) Define the species-specific epigenetic and transcriptional landscape of TR-MFs during regeneration(Acomys) versus scar formation (Mus) to discover the genetic program controlling TR-MF identity in spiny miceand (3) functionally assess if exogenous lactoferrin delivered to Acomys injuries in the absence of TR-MFs cancontrol inflammation and permit cell proliferation and when delivered to mouse injuries enhance healing. Theapproach is innovative in the applicants opinion because it explicitly focuses on understanding how complextissue regeneration occurs naturally in an adult mammal. The proposed research is significant because it isexpected to provide new and fundamental insight into how TR-MFs regulate musculoskeletal healing andbecause our discoveries can inform novel clinical interventions to reduce fibrosis and stimulate regeneration.

project_terms:
Acomys;Adult;Behavior;Biological Assay;Cell Aging;Cell Cycle Progression;Cell Proliferation;Cells;Chromatin;Cicatrix;Clinical;Complement;Complex;Data;Dichloromethylene Diphosphonate;Drug or chemical Tissue Distribution;Ear;Epigenetic Process;Extracellular Matrix;Fibrosis;Gene Expression;Generations;Genetic;Genetic Transcription;Goals;Human;Infiltration;Inflammation;Inflammatory;Injury;Intervention;Laboratory mice;Lactoferrin;Leucocytic infiltrate;Liposomes;Macrophage;Mammals;Molecular;Mus;Musculoskeletal;Natural regeneration;Oxidative Stress;Phase;Phenotype;Production;Proliferating;Public Health;Publishing;Research;Resolution;Rodent;Rodent Model;Signal Transduction;Spatial Distribution;Sterility;Stress;Stromal Cells;Testing;Tissue atlas;Tissues;VEGFC gene;Work;cell type;comparative;cytokine;disability;external ear auricle;healing;improved;injured;innovation;insight;multiple omics;musculoskeletal injury;novel;novel therapeutics;programs;re-epithelialization;regenerative;regenerative healing;regenerative tissue;repaired;response;response to injury;single nucleus RNA-sequencing;single-cell RNA sequencing;tissue regeneration;tissue trauma;transcriptome sequencing;wound;wound healing

public_health_relevance:
PROJECT NARRATIVESpiny mice naturally regenerate complex musculoskeletal tissues whereas other mammals use scar tissue torepair identical injuries. Thus the proposed research is relevant to public health because discovering the celltypes and molecules that permit and direct this unique example of mammalian regeneration is expected togenerate novel clinical interventions to reduce fibrosis and enhance healing in humans. Stimulating tissueregeneration greatly improves the functionality of injured tissue and will help reduce the burden humandisability.


application_id: 10979839
project_number: 1R01HL171111-01A1
project_title: Functional Interactions Between Lipoproteins and Protease Inhibitors in Atherosclerosis
administering_ic: NHLBI
award_notice_date: 2024-07-05
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 171111
suffix: A1
program_official: LIU, LIJUAN
project_start_date: 2024-07-01
project_end_date: 2028-04-30
study_section: Atherosclerosis and Vascular Inflammation Study Section[AVI]
contact_pi_person_id: 14386534
contact_pi: GORDON, SCOTT M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project SummaryLipoproteins are dynamic complexes of lipid and protein in the circulation that are correlated withcardiovascular events. Lipoprotein particles can interact with over 100 different proteins in thecirculation. However except for a few core lipid-binding proteins (apolipoproteins) the functionalimplications of these protein-lipoprotein interactions are not known. We found that about 20% oflipoprotein-associated proteins are protease inhibitors. Proteases are enzymes that cleave otherproteins and they play important roles in many physiological pathways. In atherosclerosis their activityis often associated with inflammation and unstable lesions that may be more prone to rupture. Becauselipoproteins accumulate within atherosclerotic lesions and these particles are enriched with proteaseinhibitors we propose that lipoprotein-associated protease inhibitor activity may be a novel mechanismby which lipoproteins can suppress vascular inflammation and stabilize atherosclerotic lesions. Alpha-1-antitrypsin (AAT) is an abundant plasma serine protease inhibitor that is detected onboth low density and high-density lipoproteins (LDL and HDL respectively). AAT is an endogenousinhibitor of neutrophil elastase a protease generated by neutrophils and macrophages withinatherosclerotic lesions. Our central hypothesis is that lipoproteins can modulate AAT function and thiscontributes to lipoprotein-mediated effects on atherosclerosis by influencing vascular inflammation. Ourpreliminary data suggest a unique structural interaction between AAT and lipoproteins that results infunctional preservation of AAT activity. Aim 1 of our proposal will investigate this structure-functioninteraction in detail and will determine the mechanistic basis for this observation on LDL and HDL.These studies will utilize cross-liking mass spectrometry and detailed in vitro functional assays. Theliterature and our preliminary data support a potential role of AAT in various cardiovascular diseaseshowever the mechanistic contribution of AAT to vascular inflammation in atherosclerosis has not beenstudied. Aim 2 will determine the role of lipoprotein-associated elastase-inhibitor activity in vascularinflammation and atherosclerosis using in vivo mouse models of atherosclerosis. Furthermore we havedeveloped a novel lipoprotein-targeting elastase-inhibitor peptide for synthetic enhancement oflipoprotein-associated protease inhibitor activity. Aim 3 will utilize a newly generated AAT-deficientmouse model to examine the impact of AAT on hepatic lipid metabolism and atherosclerosis. Togetherthese studies will fill a significant knowledge gap in our understanding of how non-apolipoproteincomponents of lipoproteins can impact atherosclerosis risk by modulating the antiinflammatory potentialof lipoproteins. This work will also develop new tools for enhancement of lipoprotein function and dataon the potential of this approach for atherosclerosis prevention or stabilization of high-risk lesions.

project_terms:
Affect;Affinity;Anti-Inflammatory Agents;Apolipoproteins;Arterial Fatty Streak;Atherosclerosis;Binding;Binding Proteins;Biological Assay;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Circulation;Complex;Coronary Arteriosclerosis;Data;Dyslipidemias;Elastases;Elasticity;Endothelium;Enzymes;Event;Genes;Genetic Variation;Hepatic;High Density Lipoproteins;Human;In Vitro;Inflammation;Inflammatory;Infusion procedures;Investigation;Knowledge;Lesion;Lipid Binding;Lipids;Lipoprotein (a);Lipoprotein Binding;Lipoproteins;Literature;Low-Density Lipoproteins;Macrophage;Maps;Mass Spectrum Analysis;Measures;Mediating;Metabolism;Modeling;Morphology;Mus;Ontology;Paint;Pathway interactions;Peptide Hydrolases;Phenotype;Physiological;Plasma;Plasma Proteins;Play;Prevention;Protease Inhibitor;Protein Array;Protein C Inhibitor;Proteins;Proteomics;Risk;Role;Rupture;Serine Protease;Signal Transduction;Structure;Testing;Work;alpha 1-Antitrypsin;alpha 1-Antitrypsin Deficiency;atherogenesis;atheroprotective;atherosclerosis risk;biobank;cardiovascular risk factor;crosslink;density;elastase inhibitor;endothelial dysfunction;high risk;in vivo;lipid metabolism;lipid transport;mouse model;neutrophil;neutrophil elastase inhibitor;novel;particle;peptidomimetics;preservation;prevent;restoration;small molecule;synthetic peptide;tool;transcytosis;vascular inflammation;western diet

public_health_relevance:
Project NarrativeLipoproteins are dynamic complexes of lipid and protein in the circulation that are correlated withcardiovascular events. This project will examine a novel functional interaction between theantiinflammatory plasma protein alpha-1-antitrypsin and lipoproteins. These studies will test thehypothesis that lipoproteins influence the function of alpha-1-antitrypsin and this contributes toprotection against atherosclerotic cardiovascular disease by reducing vascular inflammation.


application_id: 10979373
project_number: 1R01ES034786-01A1
project_title: Mechanisms of Sex-specific Metabolic Disruption Caused by Organophosphate Flame Retardant Exposure
administering_ic: NIEHS
award_notice_date: 2024-07-01
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: ES
serial_number: 034786
suffix: A1
program_official: SCHUG, THADDEUS
project_start_date: 2024-07-01
project_end_date: 2029-06-30
study_section: Cell Signaling and Molecular Endocrinology Study Section[CSME]
contact_pi_person_id: 10299348
contact_pi: RASHID, CETEWAYO SAIF
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 Abstract: Tris(13-dichloro-2-propyl) phosphate (TDCPP) is an organophosphate flame retardant usedto meet federal and state flammability standards of various consumer products. Off-gassing causes TDCPP toaccumulate in dust and contaminate indoor spaces. TDCPP is stable in the environment but when it enters thebody which is most commonly via hand-to-mouth contact TDCPP is readily metabolized to bis(13-dichloro-2-propyl) phosphate (BDCPP). Ninety percent of Americans have detectable BDCPP in their urine indicatingubiquitous exposure. Studies utilizing data from the National Health and Nutrition Examination Survey found asignificant positive association between urinary BDCPP levels and metabolic syndrome with the componentscentral adiposity and hyperglycemia carrying the association. Interestingly the association with BDCPP andmetabolic syndrome was found only in men. We have developed a mouse model of TDCPP exposure thatreproduces male sex-specific metabolic disruption. TDCPP is incorporated into purified low phytoestrogen dietsto mimic the primary route of exposure in humans. When fed this diet male wild-type mice have increasedpercent body fat and insulin resistance. Euglycemic clamp showed insulin resistance was liver-specific. Wescreened TDCPP in vitro for agonist activity against 26 nuclear receptors and found that TDCPP activates onlyfarnesoid X and pregnane X receptors (PXR). However in livers of TDCPP-treated mice only PXR target geneswere differentially expressed. Building upon our preliminary findings our proposed studies will test the overallhypothesis that PXR activation mediates male sex-specific TDCPP-induced hepatic insulin resistance. Toincrease clinical translation of the proposed research we will use transgenic mice expressing the human PXR(hPXR) gene. Our preliminary studies show transgenic hPXR mice are at least 100x more sensitive to TDCPP-induced metabolic disruption than wild-type mice. We will interrogate insulin action and signaling in livers of maleand female hPXR mice. Using PXR deficient mice and dietary exposure to BDCPP which is not a PXR agonistwe will determine whether PXR activation is necessary to confer metabolic disruption. We will gonadectomizemale and female mice to determine whether TDCPP-induced metabolic disruption is sex hormone-dependent.Finally to further elucidate the mechanistic underpinnings of TDCPP's sex-specific metabolic disruption we willperform mRNA sequencing of livers from hPXR PXR deficient and castrated male and female mice exposed toTDCPP. The proposed preclinical studies fill a critical emergent knowledge gap regarding whether the ubiquitousenvironmental contaminant TDCPP promotes development of metabolic syndrome. Successful completion ofthe proposed studies will drive future knowledge toward interventions and screening strategies to identifymetabolically innocuous flame retardants; and furthermore progress our understanding of xenobiotic-mediatedsex differences which may be generalizable to many other endocrine disrupting chemicals.

project_terms:
Adipose tissue;Adverse effects;Agonist;American;Androgen Receptor;Body Composition;Body fat;C57BL/6 Mouse;Chemicals;Consumption;Data;Development;Diet;Dose;Dust;Endocrine Disruptors;Environment;Environmental Exposure;Environmental Pollutants;Epidemiology;Estrogen Receptors;Evaluation;Event;Exposure to;Fatty Liver;Fatty acid glycerol esters;Female;Flame Retardants;Frequencies;Future;Genes;Glucose Clamp;Gonadal Steroid Hormones;Hand;Hepatic;Human;Hyperglycemia;Hyperinsulinism;Impairment;In Vitro;Industrialization;Insulin;Insulin Resistance;Intervention;Knowledge;Liver;Male Castration;Mediating;Metabolic;Metabolic dysfunction;Metabolic syndrome;Metabolism;Modeling;Mus;Muscle;National Health and Nutrition Examination Survey;Non-Insulin-Dependent Diabetes Mellitus;Nuclear Receptors;Obesity;Oral cavity;Orchiectomy;Organophosphates;Overnutrition;Pathway interactions;Peripheral;Phosphorylation;Physiological;Phytoestrogens;Pre-Clinical Model;RNA Sequences;Receptor Activation;Receptor Gene;Research;Rodent;Role;Route;Saline;Sex Differences;Signal Transduction;Suggestion;Testing;Tracer;Transactivation;Transgenic Mice;Transgenic Organisms;Urine;Wild Type Mouse;Woman;Xenobiotics;blood glucose regulation;clinical translation;consumer product;dietary;differential expression;experimental study;exposed human population;exposure route;fasting plasma glucose;follow-up;glucose production;glucose tolerance;glucose uptake;human female;improved;inorganic phosphate;insulin signaling;lipid biosynthesis;liver inflammation;mRNA sequencing;male;men;mouse model;non-alcoholic fatty liver disease;novel;off-gassing;poor health outcome;preclinical study;pregnane X receptor;receptor;response;screening;sex;skeletal tissue;stable isotope;sugar;transcriptome;transcriptome sequencing;urinary

public_health_relevance:
Project Narrative: Over 90% of Americans are exposed to the flame-retardant chemical tris(13-dichloro-2-propyl) phosphate (TDCPP). TDCPP exposure is positively associated with metabolic syndrome in men butwomen are protected from its harmful effects. The proposed studies interrogate the role of nuclear receptors andsex hormones in conferring sex-specific metabolic disruption associated with TDCPP exposure which will driveour knowledge toward interventions and screening strategies for less harmful flame retardants.


application_id: 10979152
project_number: 5R01ES032396-05
project_title: A university-community partnership to reduce exposure to disinfection byproducts in Appalachia
administering_ic: NIEHS
award_notice_date: 2024-12-09
opportunity_number: RFA-ES-20-002
application_type: 5
activity_code: R01
ic: ES
serial_number: 032396
program_official: O'FALLON, LIAM
project_start_date: 2021-01-01
project_end_date: 2026-10-31
study_section: ZES1-ARL-K(R)
contact_pi_person_id: 14229942
contact_pi: UNRINE, JASON
other_pis: HOOVER, ANNA GOODMAN
congressional_district: 06
department: OTHER BASIC SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Appalachian Kentuckians in Martin and Letcher Counties are grappling with a health-threateningdrinking water crisis arising from exposures to disinfection by-products (DBPs) .. DBPs includetrihalomethanes (TH Ms) haloacetic acids (HAAs) chlorate and other compounds that have beenassociated with a variety of adverse health effects including increased risk of bladder cancer andcardiovascular birth defects. This study which builds on findings from two community-engagedNIEHS P30-funded pilot studies and one P30-funded community grant implements a multistakeholdermulti-method approach to raise understanding of characterize spatial and temporalvariations in and reduce exposure to DBPs in Martin and Letcher Counties. This research seeksto achieve the following aims: To accomplish these goals we will pursue three Specific Aims: 1)Enhance existing multisectoral partnerships via a formalized Stakeholder Consultation Core thatinforms and evaluates study components; strengthens multidirectional communication; increasesparticipants' EHL; and collaboratively builds partnerships and trust among community groupspublic officials and university researchers; 2) Examine the associations between home locationhome characteristics temporal variation and multi-route DBP exposure risks resulting from smalldrinking water systems. We hypothesize that exposure risks are generally greatest in autumn andsummer but are dynamically influenced by home characteristics and precise home location withinthe water distribution network; and 3) Apply emerging knowledge of source water chemistry andsystem operating conditions to develop validate and disseminate predictive models that cansupport small drinking water utilities in reducing DBP formation. Through collaboration amongcommunity partners a university-based and we will refine multi-stakeholder research processesand generate translational products that will be transferrable to other rural communities facingsimilar drinking water infrastructure challenges ultimately helping reduce DBP exposure.

project_terms:
Acids;Address;Appalachian Region;Businesses;Cardiovascular system;Characteristics;Chemicals;Chemistry;Chloramines;Chlorates;Chlorine;Coal;Collaborations;Communication;Communities;Congenital Abnormality;Consultations;County;Data;Disinfectants;Disinfection;Economics;Environmental Health;Exposure to;Funding;Goals;Grant;Halogens;Health;Home;Human;Infrastructure;Intervention;Kentucky;Knowledge;Laws;Location;Malignant neoplasm of urinary bladder;Methods;Modeling;National Institute of Environmental Health Sciences;Ozone;Participant;Persons;Pilot Projects;Population;Process;Public Health;Reaction;Regulation;Research;Research Personnel;Resources;Risk;Risk Reduction;Route;Rural Community;Sampling;Scientist;Source;Surface;System;Testing;Training and Infrastructure;Trihalomethanes;Trust;Ultraviolet Rays;United States;United States Environmental Protection Agency;Universities;Variant;Virginia;Water;West Virginia;citizen science;community academic partnership;community partners;drinking water;exposure route;ground water;health communication;health literacy;improved;indoor air;predictive modeling;public drinking;rural America;rural dwellers;social;spatiotemporal;water quality

public_health_relevance:
PROJECT NARRATIVEAppalachian Kentuckians in Martin and Letcher Counties are grappling with a health-threateningdrinking water crisis arising from exposures to disinfection by-products (DBPs). DBPs includecompounds that have been associated with a variety of adverse health effects includingincreased risk of bladder cancer and cardiovascular birth defects. This study which builds onfindings from two community-engaged NIEHS P30-funded pilot studies and one P30-fundedcommunity grant uses a multi-method approach stakeholder-engaged approach to reduce DBPexposures and improve public health in target counties.


application_id: 10979015
project_number: 1R01AG084688-01A1
project_title: Metabolic regulation of myocardial perfusion in the aging heart
administering_ic: NIA
award_notice_date: 2024-09-04
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AG
serial_number: 084688
suffix: A1
program_official: GAO, HONGWEI
project_start_date: 2024-09-15
project_end_date: 2025-08-31
study_section: Integrative Myocardial Physiology/Pathophysiology A Study Section [MPPA]
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
other_pis: NYSTORIAK, MATTHEW A
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARYAdvanced age is the leading risk factor for all chronic diseases. It is associated with a host of geneticimmunologic and physiologic changes that contribute to progressive tissue dysfunction and an increased risk ofmortality. Although many hallmarks of aging have been identified a key physiological feature of aging isdecreased tissue perfusion and an inability to match perfusion to the metabolic requirements of organ function.The impacts of such deficits in perfusion are more pronounced in tissues with high oxygen demand; hence dueto its high energy demand the heart is particularly vulnerable to perfusion deficits. Acute increases in myocardialdemand such as those due to increased physical activity are met by an increase in perfusion (i.e. hyperemia).This increase in myocardial perfusion is triggered by metabolic signals that evoke coronary vasodilation. Ourrecent work shows that increases in O2 demand in cardiomyocytes modify the pyridine nucleotide redox potential(i.e. elevates NADH:NAD) in coronary arterial smooth muscle cells which stimulates voltage-gated K+ (Kv)channel activity to promote vasodilation. Inhibition of this heterocellular signaling results in hypoperfusion andacute pump failure during stress. We propose that disruption to this signaling is the key mechanism underlyingthe progressive age-dependent loss of coupling between myocardial metabolism and coronary vascular tone.Moreover because cardiac output is essential for adequate perfusion and function of all peripheral tissuesdiminished cardiac function at high workloads (e.g. during exercise) likely contributes to widespread dysfunctionand could explain the pervasive deleterious effects of aging. Our preliminary data show that aged mice havereduced myocardial perfusion impaired diastolic and systolic function and lower exercise capacity comparedwith sex-matched young mice. Consistent with cardiac metabolic remodeling as an underlying cause of thesechanges recapitulating the metabolic profile of the aged significantly blunts work-dependent paracrine redoxsignals to the vasculature and suppresses the hyperemic response consistent with a loss of redox-dependentKv channel stimulation. Furthermore acute interventions that decrease cardiomyocyte carbohydrate metabolism(ketone body infusion) rescue myocardial perfusion in aged mice. Based on these preliminary data wehypothesize that age-dependent changes in myocardial metabolism suppress pyridine nucleotide redox-dependent K+ efflux in vascular smooth muscle leading to progressive uncoupling of coronary perfusion frommyocardial workload. Accordingly our specific aims are to: (1) delineate age-dependent changes in cardiacmetabolism myocardial perfusion and left ventricular function; (2) assess the impact of changes in myocardialglucose metabolism on redox-dependent myocardial hyperemia; and (3) determine the efficacy of myocardialmetabolic interventions to prevent age-dependent exercise intolerance and cardiac remodeling. This project willelucidate the mechanism underlying a key physiological defect associated with aging and provide new insightsinto how this defect could be attenuated to prolong cardiovascular health and function over the lifespan.

project_terms:
Acute;Affect;Aging;Atherosclerosis;Attenuated;Blood Vessels;Blood flow;Carbohydrates;Cardiac;Cardiac Myocytes;Cardiac Output;Cardiovascular Physiology;Catabolism;Chronic;Chronic Disease;Clinical;Contrast Echocardiography;Coronary;Coupling;Data;Defect;Dementia;Diabetes Mellitus;Elderly;Etiology;Exercise;Exercise Tolerance;Failure;Fatty Acids;Functional disorder;Genetic;Genetic Models;Glucose;Heart;Hyperemia;Immunologics;Impairment;In Vitro;Infusion procedures;Intervention;Ketone Bodies;Knowledge;Left Ventricular Function;Link;Longevity;Measures;Metabolic;Metabolism;Modeling;Mus;Myocardial;Myocardial perfusion;NADH;Organ;Oxidation-Reduction;Oxygen;Perfusion;Peripheral;Physical activity;Physiological;Play;Pump;Radiolabeled;Regulation;Risk Factors;Role;Signal Transduction;Smooth Muscle;Smooth Muscle Myocytes;Stress;Structure;Testing;Tissues;Vascular Smooth Muscle;Vasodilation;Work;Workload;active lifestyle;age effect;age related;age related changes;age related decline;age-related disease;aged;carbohydrate metabolism;cardiac aging;cardiovascular health;coronary perfusion;efficacy evaluation;exercise capacity;exercise intolerance;fatty acid metabolism;flexibility;glucose metabolism;hallmarks of aging;heart function;heart metabolism;hypoperfusion;improved;in vivo;insight;life span;metabolic profile;mortality risk;novel strategies;old mice;oxidation;paracrine;pathological aging;preservation;pressure;prevent;pyridine nucleotide;response;restoration;sex;stable isotope;voltage

public_health_relevance:
PROJECT NARRATIVEAdvanced age is the leading risk factor for all chronic diseases. Although many hallmarks of aging have beenidentified a key physiological feature of aging is decreased blood flow and an inability to match blood flow toorgan requirements. This project will elucidate the metabolic mechanisms by which aging impairs blood flow inthe heart and identify interventions to improve blood flow heart function and exercise tolerance over the lifespan.


application_id: 10977761
project_number: 4R00AR081367-03
project_title: Contribution of ribosome specialization to the pathophysiology of muscular dystrophy
administering_ic: NIAMS
award_notice_date: 2024-01-11
opportunity_number: PA-20-188
application_type: 4
activity_code: R00
ic: AR
serial_number: 081367
program_official: EISENSTEIN, JANA S
project_start_date: 2023-11-01
project_end_date: 2026-10-31
study_section: NSS
contact_pi_person_id: 12197125
contact_pi: WEN, YUAN
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractStriated muscle tissue contains the highest mitochondrial content and the largest known proteinswhich present unique challenges to the translational machinery. Muscle tissue specifically expressesa paralogous ribosomal protein RLP3L that is roughly 80% similar to the ubiquitous RPL3 and isessential to the formation of the large subunit of the ribosome. In muscle RPL3L substitutes for RPL3in the ribosome but how this alters ribosome function remains unknown. Furthermore these twoparalogs demonstrate an inverse relationship under conditions of muscle adaptation stress andpathology. In dystrophic muscle RPL3L is lost in favor of RPL3 in the ribosome but the effects onmuscle functional decline are not understood. Recent evidence suggests that ribosomes canspecialize in order to selectively translate certain genes into proteins. Additionally translation controlhas emerged as a novel layer of regulation for mitochondrial function which declines early in thepathology of muscular dystrophy prior to an overt phenotype. Taken together I hypothesize that theloss of RPL3L in dystrophic muscle impairs ribosome specialization thus contributing to an imbalancebetween mitochondrial and sarcomeric protein synthesis exacerbating dystrophic diseaseprogression. Rescue of the muscle specific ribosomal protein in muscular dystrophy will provide thefirst evidence for a role of ribosome specialization in muscle functional decline and help guide thedesign of new therapeutics. The proposed studies will also for the first time investigate the impact ofglucocorticoids (a common therapy for dystrophy) on muscle ribosome specialization andtranslational selectivity. Successful completion of the proposed studies will reveal new therapeutictargets as well novel mechanisms underlying the pathophysiology of chronic debilitating diseases.

project_terms:
ATP Synthesis Pathway;Address;Adult;Biological Assay;Cells;Chronic;Contractile Proteins;Cytoplasm;Data;Disease;Disease Progression;Dose;Drops;Duchenne muscular dystrophy;Equilibrium;Exercise;Failure;Functional disorder;Generations;Genes;Genetic Diseases;Genetic Transcription;Glucocorticoid Receptor;Glucocorticoids;Growth;Hindlimb;Image;Impairment;In Vitro;Knock-out;Knockout Mice;Learning;Maintenance;Measurement;Measures;Mechanics;Mediating;Mentors;Mentorship;Mitochondria;Mitochondrial Proteins;Modeling;Morphology;Muscle;Muscle Proteins;Muscle function;Muscular Atrophy;Muscular Dystrophies;Oxygen Consumption;Pathogenesis;Pathology;Patients;Performance;Phase;Phenotype;Production;Protein Biosynthesis;Proteins;Regulation;Respiratory Diaphragm;Ribosomal Proteins;Ribosomes;Role;Running;Skeletal Muscle;Specificity;Steroid therapy;Steroids;Stress;Striated Muscles;System;Techniques;Testing;Time;Tissues;Training;Transcript;Translating;Translations;Up-Regulation;Ventilator;Yeasts;career;design;effective therapy;exercise training;functional decline;functional loss;improved;in vivo;mdx mouse;mitochondrial dysfunction;mouse model;muscle strength;new therapeutic target;novel;novel therapeutics;paralogous gene;postnatal development;protein expression;restoration;standard of care;transcriptome sequencing

public_health_relevance:
Project NarrativeMuscular dystrophy is a debilitating genetic disorder characterized by progressive loss of muscle function.There is currently no cure and the only effective therapy to delay functional loss is glucocorticoid steroidtherapy. The proposed project will investigate a novel mechanism of ribosome specialization as a contributor tothe pathogenesis of muscular dystrophy with the aim of developing additional therapies for the disease.


application_id: 10977287
project_number: 3R01CA133429-17S1
project_title: The Role of PHLPP in Colon Cancer
administering_ic: NCI
award_notice_date: 2024-04-30
opportunity_number: PA-19-056
application_type: 3
activity_code: R01
ic: CA
serial_number: 133429
suffix: S1
program_official: SALNIKOW, KONSTANTIN
project_start_date: 2009-04-01
project_end_date: 2026-04-30
study_section: Molecular Oncogenesis Study Section[MONC]
contact_pi_person_id: 7353657
contact_pi: GAO, TIANYAN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately145000 new cases and 51000 deaths are predicted for the year 2019; and this mortality is predominantly dueto poor responses to available treatment options. A better understanding of the molecular events leading tocancer progression and chemoresistance is needed in order to improve the overall survival of cancer patients.My lab has been intensively focused on elucidating the role of a novel family of protein phosphatases PHLPP(PH domain Leucine-rich-repeats Protein Phosphatase) in inhibiting colon cancer initiation and progression. Wehave made substantial progress in understanding the functional importance of PHLPP as a tumor suppressor aswell as the molecular mechanism underlying PHLPP regulation. The overall objective of this study is to furtherdevelop a mechanistic understanding of PHLPP-mediated regulation of cellular stress response in supportingcell survival and tumorigenesis. In exciting recent findings we demonstrated that chemotherapy-induced ERstress promotes PHLPP degradation and PHLPP-loss provides a survival advantage by upregulatingeIF2/ATF4-mediated signaling. In addition we found that downregulation of PHLPP promotes mitochondrialfission by regulating Drp1 phosphorylation. Collectively the central hypothesis driving this proposed study isthat PHLPP serves an essential stress sensor in CRC in which cellular stress signals trigger PHLPP degradationto promote cell survival and tumorigenesis. The following specific aims are proposed: 1) to delineate themolecular mechanism underlying PHLPP-mediated regulation of eIF2/ATF4 signaling. We will determine ifdownregulation of PHLPP renders colon cancer cells resistant to chemotherapy drugs as a result of autophagyactivation; 2) to determine the functional importance of PHLPP-mediated regulation of mitochondrial dynamics.We will test the hypothesis that PHLPP plays an important role in regulating mitochondrial dynamics byenhancing Drp1 activity in order to cope with proinflammatory stress signals; and 3) to define the role ofmitochondrial dynamics in cooperating with PHLPP-loss to promote tumorigenesis in vivo. We will utilize Drp1and PHLPP knockout mice to determine the function interaction between PHLPP and Drp1 on regulating coloncancer tumorigenesis in vivo. Our proposed study centers on a novel hypothesis that that PHLPP-loss plays apivotal role in orchestrating multiple pro-survival responses downstream of cellular stress signals to promotetumorigenesis. Our study will fill an important knowledge gap on how altered mitochondrial dynamics contributesto tumor initiation and progression in colon cancer. Ultimately by providing mechanistic insights into PHLPP-dependent regulation of stress response our findings will help identify new treatment options and better predictthe effectiveness of chemotherapy agents based on PHLPP status in cancer patients.

project_terms:
Automobile Driving;Autophagocytosis;Cancer Etiology;Cancer Patient;Cell Death Induction;Cell Migration Inhibition function;Cell Proliferation;Cell Survival;Cells;Cellular Stress;Cessation of life;Chemoresistance;Collaborations;Colon Carcinoma;Colorectal Cancer;Development;Disease;Down-Regulation;EIF-2alpha;Effectiveness;Ensure;Epithelial Cells;Equilibrium;Event;Funding;Grant;HK2 gene;Inflammation;Inflammatory;Integrins;Intestines;Knockout Mice;Knowledge;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Metabolic;Metabolism;Mitochondria;Molecular;Oncogenic;Organism;PH Domain;Pathway interactions;Pharmaceutical Preparations;Phosphoric Monoester Hydrolases;Phosphorylation;Physiological;Play;Protein Dephosphorylation;Protein Family;Protein Kinase;Protein phosphatase;Proto-Oncogene Proteins c-akt;Regulation;Resistance;Role;Signal Pathway;Signal Transduction;Stress;Supporting Cell;Testing;Tumor Suppressor Proteins;United States;biological adaptation to stress;cancer cell;cancer initiation;cancer survival;cancer type;cell growth regulation;chemotherapy;colon tumorigenesis;coping;coping mechanism;endoplasmic reticulum stress;improved;in vivo;insight;leucine-rich repeat protein;mitochondrial autophagy;mortality;mouse model;multicatalytic endopeptidase complex;novel;protein expression;response;sensor;success;tumor initiation;tumor metabolism;tumor progression;tumorigenesis

public_health_relevance:
PROJECT NARRATIVE Colorectal cancer mortality is predominantly due to the development of disseminated disease and resistantto conventional chemotherapy. Our study focuses on developing a mechanistic understanding of PHLPP-mediated regulation of cellular stress signaling to circumvent chemoresistance. Results from our studies willhelp identify new treatment options and better predict the effectiveness of chemotherapy agents.


application_id: 10976839
project_number: 2R01DE011111-31
project_title: P. gingivalis interactions with gingival epithelial cells
administering_ic: NIDCR
award_notice_date: 2025-04-17
opportunity_number: PA-20-185
application_type: 2
activity_code: R01
ic: DE
serial_number: 011111
program_official: MCNEALY, TAMARA L
project_start_date: 1995-04-01
project_end_date: 2030-03-31
study_section: Special Emphasis Panel[ZRG1 MSOS-L (03)]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: BODDULURI, HARIBABU ;URIARTE, SILVIA M
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:
Porphyromonas gingivalis is considered a major pathogen in periodontal disease. Virulence however is onlyexpressed in the context of a polymicrobial community which contains both pathobionts and homeostaticcommensals and P. gingivalis is non-pathogenic in germ-free animal models of periodontal disease. Throughselective re-inoculations of germ-free mice we have established that a polymicrobial consortium (PMC)comprising Fusobacterium nucleatum Filifactor alocis Selenomoas sputigena and Streptococcus gordonii issynergistically pathogenic with P. gingivalis. Characterization of the virulence factors of P. gingivalis that areoperational in the community context along with the molecular and cellular basis of synergistic pathogenicity isthe goal of this proposal. We have found that a tyrosine phosphatase Ltp1 secreted by P. gingivalis is activewithin gingival epithelial cells (GECs) and is unaffected by the PMC. Ltp1 suppressed GEC production of IP-10a T-cell chemokine that at basal levels contributes to immune surveillance at the gingival barrier. Elevated levelsof IP-10 however increase mobilization of tissue-damaging Th1 and Th17 cells. A reduction in Th1 and Th17activity mediated by Ltp1 is consistent with the lack of pathogenicity of P. gingivalis as a monoinfection. Howeverdisruption of immune surveillance can be predicted to facilitate pathobiont outgrowth. In a model of pathobiontovergrowth we found that prolonged action of the PMC on GECs incites IFN- synthesis which reverses P.gingivalis-induced inhibition of IP-10. Our overall hypothesis therefore is that P. gingivalis Ltp1 induces atransient immune suppression by reducing basal levels of IP-10 at the gingival interface. While recruitment oftissue damaging T-cells is thus diminished the ensuing impaired immune surveillance facilitates expansion ofpathobionts in the microbial community. The pathobionts overwhelm immune suppression and the resultingincreased IP-10 levels recruit tissue damaging Th1 and Th17 cells leading to alveolar bone loss. The mechanismof action of Ltp1 is the focus of the first Aim. We shall examine Ltp1-dependent modulation of GEC signalingpathways focusing on the Ltp1-target STAT1 which control the transcriptional activity of IP-10. In the secondAim we shall molecularly dissect the IFN- dependent GEC pathway by which the PMC overcomes suppressionof IP-10. The third Aim will define the biological consequences of Ltp1-induced polymicrobial synergy throughthe characterization of pathobiont expansion together with T-cell and cytokine responses in the gingival tissueof germ-free mice. Collectively this proposal will define a novel tyrosine dephosphorylation-based mechanismby which P. gingivalis can re-program host cell signaling pathways to compromise immune surveillance at thegingival epithelial interface. We will further establish the basis of synergistic polymicrobial pathogenicity withregard to the dysbiotic host responses which are associated with tissue destruction in vivo. This work will achievea new level of integration of molecular virulence with polymicrobial community pathogenicity and the consequentdestructive inflammatory responses in periodontal tissues.

project_terms:
Alveolar Bone Loss;Animal Disease Models;Animal Model;Biological;CXCL10 gene;CXCR3 gene;Cells;Communities;Dangerousness;Data;Defense Mechanisms;Disease;Epithelial Cells;Epithelium;Etiology;Fusobacterium nucleatum;Germ-Free;Gingiva;Goals;Growth;Homeostasis;Immune;Immune response;Immunologic Surveillance;Immunosuppression;Impairment;Inflammatory;Inflammatory Response;Interferon-;Mediating;Microbe;Modeling;Molecular;Mus;Oral;Organism;Pathogenesis;Pathogenicity;Pathway interactions;Periodontal Diseases;Porphyromonas gingivalis;Production;Protein Dephosphorylation;Protein Tyrosine Phosphatase;Role;STAT1 gene;Selenomonas sputigena;Signal Pathway;Signal Transduction;Streptococcus gordonii;Surface;System;T-Lymphocyte;Th1 Cells;Tissues;Transcriptional Regulation;Tyrosine;Virulence;Virulence Factors;Work;chemokine;community partners;cytokine;dysbiosis;immune activation;in vivo;microbial community;mutant;novel;pathobiont;pathogen;prevent;programs;recruit;response;subgingival microbiome;synergism

public_health_relevance:
Periodontal (gum) diseases are caused by mixtures of microbes that are more destructive to our gum tissue incombination than singly. In this proposal we shall study how these communities of organisms become moredangerous and the effects that they have on immune defense mechanisms in cells on the surface of our gums.The work may allow us to identify targets for new periodontal disease treatments.


application_id: 10975136
project_number: 3R33DC019602-03S1
project_title: Hearing Healthcare Assessment in Rural Communities (HHARC)
administering_ic: NIDCD
award_notice_date: 2023-10-27
opportunity_number: RFA-DC-19-001
application_type: 3
activity_code: R33
ic: DC
serial_number: 019602
suffix: S1
program_official: KING, KELLY ANNE
project_start_date: 2021-08-04
project_end_date: 2026-07-31
study_section: ZDC1-SRB-R(39)
contact_pi_person_id: 11512687
contact_pi: BUSH, MATTHEW LEE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARYHearing loss in adults is the third most common chronic health condition in the United States with a prevalenceof over 20% in younger adults and over 40% in older adults. Untreated hearing loss causes a measurable impacton health and social occupational and emotional well-being of adults. Only 26% of adults have had a diagnostichearing test within the past 5 years and delayed hearing loss diagnosis and treatment may lead to communicationimpairment with profound effects on education employment and overall health. The prevalence of hearing lossis higher among adults living in rural communities compared with those in urban settings; furthermore ruraladults with hearing loss may never receive treatment or may be delayed in diagnosis and/or treatment comparedwith urban adults. Rural health clinics (RHCs) represent a federally designated health system care that providesprimary care within rural underserved communities; however hearing healthcare services have not been asignificant component of RHC care delivery. RHCs are ideally positioned to partner with rural communities todevelop an intervention that can help rural adults navigate different aspects of hearing healthcare such aseducation prevention screening diagnosis and treatment. The goal of this study is to assess the utilization ofhearing healthcare among rural adults through RHCs with the R21 phase of the program and then develop aculturally responsive RHC patient navigation program (PNP) to promote utilization of hearing healthcare. Toconduct this study we will partner with 10 high-need under-resourced RHCs within rural Appalachian countiesin Kentucky and utilize the PRECEDE-PROCEED model (PPM) to systematically assess the rural adult hearinghealth and healthcare priorities needs and resources to inform intervention development. During the R21 phasewe will 1) conduct a social and epidemiological assessment of rural adult hearing healthcare and 2) assess theorganizational and environmental factors influencing hearing healthcare utilization in RHCs. The milestones ofthe R21 include the determination of the prevalence of hearing loss and hearing healthcare utilization in ruraladults establishment of rural adult hearing healthcare priorities and development of a community advisory boardand a rural provider taskforce. During the R33 phase we will 1) develop of a community-based hearing healthcarepatient navigation program for RHCs and 2) pilot test the rural hearing healthcare navigation program. Themilestones of the R33 phase include the development of a PNP protocol assessment of the impact of thenavigator on rural adults obtaining diagnostic audiogram and evaluation of the PNP feasibility acceptability andappropriateness. This study is significant because it aims to reduce access to care barriers to timely diagnostichearing testing for rural adults to prevent negative consequences. This research is innovative in developmentand pilot testing of a novel intervention not previously assessed in adult hearing healthcare within an RHC setting.Our results will impact the field by partnering with communities to inform the development and delivery ofinnovative patient supportive interventions to improve rural hearing healthcare access.

project_terms:
Address;Administrator;Adult;Advisory Committees;Affect;Appalachian Region;Area;Certification;Chronic;Communication impairment;Communities;Community Health;Community Healthcare;Country;County;Depressed mood;Development;Diagnosis;Diagnostic;Disease;Education;Employment;Enabling Factors;Enrollment;Environmental Risk Factor;Epidemiology;Evaluation;Face;Geographic state;Goals;Health;Health Personnel;Health Resources;Health Services Accessibility;Healthcare;Healthcare Systems;Healthcare promotion;Hearing;Hearing Tests;Intervention;Kentucky;Life;Measurable;Medical;Medical Economics;Methods;Morbidity - disease rate;Occupational;Outcome;Patients;Phase;Population;Positioning Attribute;Precede-Proceed Model;Predisposing Factor;Prevalence;Prevention;Primary Care;Protocols documentation;Provider;Public Health;Reinforcing Factor;Research;Resources;Rural;Rural Appalachia;Rural Community;United States;Vulnerable Populations;Well in self;barrier to care;care delivery;community advisory board;experience;health assessment;health care availability;health care delivery;health care service;health care service utilization;hearing impairment;hearing loss treatment;improved;innovation;medical specialties;medically underserved;mortality;novel;older adult;patient navigation;pilot test;practice-based research network;preference;prevent;primary care practice;primary care services;programs;rural area;rural health clinic;rural healthcare;rural patients;rural underserved;screening;social;therapy development;treatment comparison;underserved community;urban setting;virtual;young adult

public_health_relevance:
PROJECT NARRATIVEHearing loss affects over 40 million adults in the United States and can negatively impact many areas of life foradults. The lack of access to diagnostic hearing tests prevents timely diagnosis and treatment of hearing lossespecially among adults who live in rural areas. This study will (1) evaluate the experiences and challenges inobtaining hearing tests among adults who live in rural areas and are patients at rural health clinics and (2)develop a program in partnership with rural patients and medical providers which can help rural adults geteasier access to hearing tests.


application_id: 10974071
project_number: 1R15AG085260-01A1
project_title: Metabolic regulation of the stem cell niche
administering_ic: NIA
award_notice_date: 2024-08-12
opportunity_number: PAR-21-155
application_type: 1
activity_code: R15
ic: AG
serial_number: 085260
suffix: A1
program_official: COGLIATI, TIZIANA PAOLA
project_start_date: 2024-08-15
project_end_date: 2027-07-31
study_section: Special Emphasis Panel[ZRG1 CDB-B (81)]
contact_pi_person_id: 12213212
contact_pi: DEMARCO, RAFAEL S
other_pis: Not Applicable
congressional_district: 03
department: 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 ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACTAdult stem cells constitute a group of progenitor cells capable of tissue regeneration during life through the abilityto both self-renewal and produce specialized cells upon division. In tissues stem cells reside inmicroenvironments called niches that integrate systemic cues and provide signals for stem cell maintenance.With age a decline in both stem and niche cell maintenance has been observed. Over the years the use of thestem cell systems present in Drosophila melanogaster has revealed mechanisms behind the loss of stem cellfunction in age. For instance aged flies have a smaller number of male germline stem cells as well as niche(hub) cells. Recent evidence however points to a strong conserved correlation between age-related changesin metabolism and stem cell dysfunction. Given the power of Drosophila genetics the readily accessiblemolecular tools the well-characterized stem and niche cell populations and the relatively short lifespan the flytestis niche is an ideal model for the intersectional study of metabolism aging and stem cell biology. Our long-term goal is to understand how changes in lipid metabolism affect stem cell niche homeostasis. The PIspublished works build a model where the ectopic accumulation of lipids in the fly testis niche is detrimental tostem cell function. Excess lipid accumulation in stem cells led to their loss through differentiation. Accordinglylipid accumulation has been shown to be detrimental to stem cell maintenance across species. The overallobjective of this proposal is to understand mechanistically how the stem cell niche is affected by the age-relatedectopic accumulation of lipids. Preliminary data in this proposal shows that lipid droplets accumulate specificallyin niche (hub) cells of the fly testis. Moreover we also describe the activation of pathways involved in lipidaccumulation (Target of Rapamycin TOR and Sterol regulatory element binding protein SREBP) in niche cells.Of note both environmental and genetic manipulations that result in the activation of SREBP led to niche cellloss through the unexpected conversion into stem cells. Hence our central hypothesis is that the age-relatedectopic activation of TOR and SREBP contribute to lipid accumulation and loss of niche cell maintenance andfunction. We will test this hypothesis through two specific aims: 1) testing if suppressing the age-related ectopicactivation of TOR and SREBP in niche (hub) cells is sufficient to prevent the decay in niche cell maintenanceand function; 2) characterizing the mechanism of SREBP-mediated hub cell loss. The merit of this study relieson its novelty  showing that changes in lipid metabolism can promote the conversion from a niche cell into astem cell  and on the generation of a useful paradigm for testing how age-related changes in metabolism yieldin loss of stem cell niches. The proposed studies will also strengthen the undergraduate student researchenvironment at the University of Louisville as the experiments are designed to be conducted by undergraduateresearch assistants in the laboratory.

project_terms:
Adult;Affect;Age;Aging;Anabolism;Binding Proteins;Biological Models;Catabolism;Cell Count;Cell Maintenance;Cell Physiology;Cells;Cues;Data;Development;Dietary Supplementation;Drosophila genus;Drosophila melanogaster;Elements;Environment;Equilibrium;Experimental Designs;Family;Fatty Acids;Functional disorder;Gene Expression;Generations;Genetic;Goals;Homeostasis;Homologous Gene;Laboratories;Levocarnitine;Life;Lipids;Maintenance;Mediating;Metabolic;Metabolism;Mitochondria;Modeling;Molecular;Older Population;Organ;Pathway interactions;Play;Population;Process;Publishing;Regulation;Regulatory Element;Research;Research Assistant;Role;Signal Transduction;Sirolimus;Snails;Sterols;Supporting Cell;System;Testing;Testis;Tissues;Universities;Work;adult stem cell;age related;age related changes;age related decline;aged;cancer cell;cell age;cell behavior;cell type;dietary;fly;genetic manipulation;germline stem cells;life span;lipid metabolism;loss of function;male;metabolic abnormality assessment;prevent;regenerative therapy;self-renewal;stem;stem cell biology;stem cell function;stem cell niche;stem cell population;stem cells;tissue regeneration;tool;transcription factor;undergraduate research;undergraduate student

public_health_relevance:
PROJECT NARRATIVEA model has emerged showing that ectopic lipid accumulation is associated with loss of stem cell maintenanceand tissue homeostasis with age. Elucidating mechanisms regulating ectopic lipid accumulation in stem cellniches will aid in the development of new strategies targeting stem cell-based regenerative therapies.


