# projects

application_id: 11132104
project_number: 1R01NS138333-01A1
administering_ic: NINDS
award_notice_date: 2025-05-07
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: NS
serial_number: 138333
suffix: A1
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2025-05-05
project_end_date: 2030-03-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 7612305
contact_pi: HETMAN, MICHAL
other_pis: SARASWAT, SUJATA OHRI
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_title:
Cell type-specific effects of the integrated stress response pathway after traumatic spinal cord injury

project_abstract:
After contusive spinal cord injury (SCI) primary loss of neural tissue is followed by secondary damage thatexacerbates functional deficits and can be targeted for neuroprotection. Functionally important components ofthe secondary injury include destruction of axons death of oligodendrocytes (OLs) and demyelination thatresult in white matter damage (WMD). WMD is further amplified by neurotoxic inflammation that is mediated bythe microglia (MG) and monocyte-derived macrophages (MDMs). After SCI MG/MDMs are activated bypattern recognition molecules (PRM) and lipid overload. The integrated stress response (ISR) is triggered byvarious stimuli including ER stress mitochondrial damage or PRM-associated cytosolic aggregation ofsignaling adapter proteins such as ASC. Those stimuli activate ISR kinases such as PERK and HRI thatphosphorylate the translation factor eIF2 at the Ser-51 residue (peIF2) leading to inhibition of general proteinsynthesis and upregulation of the transcription factors ATF4 and CHOP. Initially ISR activation attempts torestore cellular homeostasis. If that fails prolonged ISR follows and cell death may occur. In addition HRI-mediated ISR may facilitate pro-inflammatory signaling by PRMs. We and others have demonstrated that afterSCI the ISR is activated and global deletion of Chop protects OLs improves functional recovery and reducesneuroinflammation. Preliminary data show that global deficiency of HRI/EIF2AK1 reduces ISR activationpromotes OL survival suppresses neuroinflammation and improves functional recovery after SCI. Moreoverthe deleterious lipid overload phenotype is reduced in Hri-/- mice in vivo and in bone marrow derivedmacrophages (BMDM) in culture. Additional cell culture studies reveal partial protection of Hri-/- OLs and areduced inflammatory potential of Hri-/- MGs after PRM stimulation. These findings support the novelhypothesis that after contusive SCI the ISR kinase HRI is a major contributor to the secondary injury includingdeath of OLs and cytotoxic neuroinflammation. In OLs the HRI-mediated ISR promotes cell death downstreamof HRI-activating stimuli (mitochondrial/oxidative stress). In MG/MDMs HRI facilitates cytotoxicneuroinflammation by enhancing PRM signaling and/or foamy macrophage formation. Therefore aim 1 will testthe cell autonomous contributions of HRI to OL death after SCI. Aim 2 will define the role of the HRI as aregulator of the SCI-associated neuroinflammation. Aim 3 will examine whether pharmacological inhibition ofHRI improves SCI outcome. Mouse lines with OL- or MG/MDM-specific deletions of Hri or a specific CNSpermeable HRI inhibitor will be used with a moderate contusive T9 SCI in mice. Gene expression changes willbe analyzed using the Ribotag system. This proposal will evaluate HRI as a targetable pleiotropic mediator ofthe secondary injury after SCI. It will also probe regulation of SCI-associated neuroinflammation by HRI.Importantly HRI inhibition may become a new therapeutic target for small molecule drugs to promoteneuroprotection and/or reduce cytotoxic neuroinflammation following traumatic CNS injury.

project_terms:
Acute;Adaptor Signaling Protein;Adult;Axon;Bone Marrow;Cell Culture Techniques;Cell Death;Cells;Cessation of life;Clinical;Data;Demyelinations;Dose;EIF-2alpha;Exposure to;Flow Cytometry;Foamy Macrophage;Gene Expression;Genetic Recombination;Homeostasis;Immune;Inflammation;Inflammatory;Injury;Lipids;Macrophage;Mediating;Mediator;Microglia;Mitochondria;Mus;Myelogenous;Neonatal;Oligodendroglia;Outcome;Oxidative Stress;PRKR gene;Pathway interactions;Pattern Recognition;Permeability;Pharmaceutical Preparations;Phenotype;Phosphorylation;Phosphotransferases;Protein Biosynthesis;Recovery of Function;Regulation;Reporter;RiboTag;Role;Secondary to;Signal Transduction;Signaling Molecule;Spinal cord injury;Stimulus;System;Technology;Testing;Therapeutic;Tissues;Toxin;Transcript;Traumatic CNS injury;Upregulation;attenuation;biological adaptation to stress;cell type;cytotoxic;effective therapy;endoplasmic reticulum stress;improved;improved outcome;in vivo;inhibitor;monocyte;neural;neuroinflammation;neuroprotection;neurotoxic;new therapeutic target;novel;pharmacologic;programs;small molecule;small molecule inhibitor;therapeutic evaluation;transcription factor;transcription factor CHOP;translation factor;white matter;white matter damage

public_health_relevance:
Project narrativeCurrently there are no clinically effective treatments to improve outcome after traumatic spinal cord injury(SCI). This proposal will examine the role of a novel candidate regulator of secondary tissue damage followingSCI. Hence a new therapeutic target may be identified to enhance functional recovery after SCI.


application_id: 11131062
project_number: 5R01CA272483-03
project_title: Targeting the Plk1/Pdcd4/mTORC2 Signaling to Treat Castration-Resistant Prostate Cancer
administering_ic: NCI
award_notice_date: 2025-05-08
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 272483
program_official: GREENBERG, WILLIAM A
project_start_date: 2023-07-01
project_end_date: 2028-06-30
study_section: Mechanisms of Cancer Therapeutics B Study Section[MCTB]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: YANG, HSIN-SHENG
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Title: Targeting the Plk1/Pdcd4/mTORC2 signaling to treat castration-resistant prostate cancerAbstractAndrogen receptor (AR) signaling is essential for development of prostate cancer (PCa) including castration-resistant prostate cancer (CRPC). Consequently androgen signaling inhibitors (ASIs) such as abiraterone andenzalutamide are becoming the first line treatment for CRPC. However the limited success of ASIs makes iturgent to develop approaches to treat CRPC patients who are no longer responsive to ASIs. Programmed celldeath 4 (Pdcd4) is a tumor suppressor which has been demonstrated to inhibit tumor progression andchemoresistance. Furthermore Pdcd4 is an androgen-repressed protein that regulates PCa growth andcastration resistance. As such it will be of clinical significance to understand the regulation mechanism of Pdcd4as it will reveal novel approaches to overcome ASI resistance. Polo-like kinase 1 (Plk1) a critical regulator ofcell cycle-related events is a documented target for PCa treatment. Of note we previously demonstrated thatinhibition of Plk1 enhances the efficacy of ASIs. The long-term goals of this study are to identify druggablesignaling pathways that offer effective treatment options for patients with CPRC who are no longer responsiveto ASIs. The objective is to define the role of Plk1 in regulating Pdcd4 and to exploit these pathways as a noveltherapeutic target for CRPC. Our data show that 1) Pdcd4 enhances the sensitivity to enzalutamide due toinhibition of mTORC2 (the mammalian target of rapamycin complex 2) and AR expression; 2) Plk1phosphorylation of Pdcd4 results in its protein degradation; and 3) the dominant negative Pdcd4 peptide (TAT-RBD) overcomes ASI resistance in PCa. Based on these observations we aim to test the central hypothesis thatPlk1-associated phosphorylation of Pdcd4 results its degradation which causes subsequent activation of themTORC2 eventually contributing to activation of AR signaling and ASI resistance. Our hypothesis will be testedby pursuing three Specific Aims - (1) to demonstrate that loss of Pdcd4 to activate mTORC2 contributes to ASIresistance; (2) to dissect how Plk1 phosphorylation of Pdcd4 regulates its function as a tumor suppressor; and(3) to analyze clinical significance of Plk1 phosphorylation of Pdcd4. These complementary aims will beaccomplished using biochemical analyses of signaling intermediates and employing genetic strategies withculture systems inducible PCa mouse models patient-derived xenograft (PDX) and human PCa samples. Therationale for the research is that it will probe the importance of Plk1-associated activity to Pdcd4 and to examinewhether TAT-RBD peptide is a novel approach to treat ASI-resistant CRPC. This contribution is significantbecause if positive the results of the proposed study will support an immediate clinical trial for TAT-RBD peptideto treat CRPC that not respond to ASIs. The multiple-PI team consisted of complementary expertise on Plk1 (X.Liu) and Pdcd4 (Yang) as well as prostate cancer pathology (Allison) and biostatistics (Chen) will be able tofinish the proposed research in a timely manner.

project_terms:
Ablation;Agreement;Androgen Receptor;Androgens;Apoptosis;Binding;Biochemical;Biometry;Cancer Patient;Castration;Cell Cycle;Cells;Chemoresistance;Clinical Research;Clinical Trials;Complex;Creativeness;Data;Development;Disease;Dominant-Negative Mutation;Down-Regulation;Drug resistance;Event;FRAP1 gene;Fostering;Genetically Engineered Mouse;Goals;Growth;Health;Human;Investigation;Knock-out;Laboratories;Malignant Neoplasms;Malignant neoplasm of prostate;Mission;Operative Surgical Procedures;Outcome;PLK1 gene;Pathology;Pathway interactions;Patient-Focused Outcomes;Patients;Peptides;Pharmaceutical Preparations;Phosphorylation;Play;Prostate Cancer therapy;Proteins;Public Health;Receptor Signaling;Regulation;Reporting;Repression;Research;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Specimen;System;Tertiary Protein Structure;Testing;Therapeutic;Tumor Suppression;Tumor Suppressor Proteins;United States National Institutes of Health;Work;Xenograft procedure;abiraterone;androgen independent prostate cancer;clinically significant;design;docetaxel;effective therapy;enzalutamide;genetic approach;improved;in vivo;inhibitor;innovation;mouse model;new therapeutic target;novel;novel strategies;patient derived xenograft model;programmed cell death protein 1;prostate cancer cell;prostate cancer progression;protein degradation;receptor expression;success;tumor growth;tumor initiation;tumor progression

public_health_relevance:
NarrativeThe proposed research is relevant to public health because it focuses on discovery of novel signaling pathwaysthat drive castration-resistant prostate cancer. These studies will establish new avenues of investigation todevelop improved therapeutics to treat this deadly disease and to greatly improve patient outcome. Thus theproposed research is relevant to NIH's mission of fostering creative discoveries and innovativeresearch strategies for protecting and improving health and reducing the burdens associated with cancer.


application_id: 11130342
project_number: 1R01DK140148-01A1
project_title: Role of Hypothalamic Adgrl1 in Counteracting Hypoglycemia
administering_ic: NIDDK
award_notice_date: 2025-06-16
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: DK
serial_number: 140148
suffix: A1
program_official: COOKE, BRAD
project_start_date: 2025-06-17
project_end_date: 2030-03-31
study_section: Pathophysiology of Obesity and Metabolic Disease Study Section[POMD]
contact_pi_person_id: 10526655
contact_pi: CHHABRA, KAVALJIT H
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:
The hypothalamus is a hub for counteracting dangerously low blood glucose levels bystimulating the counterregulatory response (CRR) to subsequently restore normal blood glucoselevels. We recently identified hypothalamic Adhesion G-protein coupled receptor L 1 (Adgrl1) asa glucose receptor involved in energy and glucose balance. Adgrl1 is necessary in mediating aglucose-inhibited response in the ventromedial nucleus of the hypothalamus (VMH) neurons.Our preliminary findings show that Adgrl1 in the VMH is sufficient to restore the CRR tohypoglycemia in otherwise global Adgrl1 knockout mice. Moreover Adgrl1 deficiency specificallyin the VMH causes an impairment in the glutamate responses to hypoglycemia. RemarkablyAdgrl1 mRNA is decreased in the VMH in mouse models of diabetes a phenotype that mayexplain compromised CRR to hypoglycemia. Adgrl1-expressing neurons in the VMHdemonstrate impaired neuronal activity following recurrent hypoglycemia. Based on thesepreliminary data we hypothesize: Adgrl1 in the VMH is essential for eliciting thecounterregulatory response to hypoglycemia and the reduced function of VMH-Adgrl1contributes to hypoglycemia-associated autonomic failure including compromised glutamatergictone and impaired sympathoadrenal response. We will test the hypothesis with the followingAims: In Aim1 we will establish the contribution of VMH-Adgrl1 to eliciting the counterregulatoryresponse to hypoglycemia. In Aim2 we will determine the involvement of VMH-Adgrl1 inregulating glutamatergic tone and adrenal sympathetic nerve activity in response tohypoglycemia to explain mechanisms underlying hypoglycemia-associated autonomic failure.Altogether this project will likely establish the contribution of the novel glucoreceptor Adgrl1 tocounteracting hypoglycemia and attenuating hypoglycemia associated autonomic failure.

project_terms:
Adhesions;Adrenal Glands;Biological;Blood Glucose;Brain;Cell Nucleus;Chromaffin Cells;Closure by clamp;Continuous Glucose Monitor;Coupled;Dangerousness;Data;Deterioration;Development;Diabetes Mellitus;Diabetic mouse;Electrophysiology (science);Equilibrium;Failure;Fiber;G-Protein-Coupled Receptors;Glucose;Glucose Clamp;Glutamates;Homeostasis;Human;Hypoglycemia;Hypothalamic structure;Iatrogenesis;Impairment;Insulin;Insulin-Dependent Diabetes Mellitus;Knockout Mice;Measurement;Measures;Mediating;Messenger RNA;Methods;Modeling;Monitor;Mus;Mutation;Nerve;Neurons;Non obese;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pharmaceutical Preparations;Phenotype;Photometry;Procedures;Protocols documentation;Recurrence;Risk;Role;Streptozocin;Synapses;Synaptic Transmission;Testing;Time;blood glucose regulation;clinically relevant;defined contribution;glucose monitor;glucose receptor;improved;in vivo;mouse model;novel;prevent;real time monitoring;response;restoration;transmission process;vector

public_health_relevance:
We have identified Adgrl1 as a glucoreceptor in the brain which appears to be involvedin counteracting hypoglycemia (dangerously low blood glucose levels). Through thisstudy we will establish the contribution of Adgrl1 to glucose sensing in the brain and itsfunction in glucose homeostasis including counteracting hypoglycemia. Adgrl1 mayemerge as a new target for preventing hypoglycemia or associated autonomic failure indiabetes.


application_id: 11130333
project_number: 1R01DK139147-01A1
administering_ic: NIDDK
award_notice_date: 2025-09-04
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: DK
serial_number: 139147
suffix: A1
program_official: GARCIA, MARTHA
project_start_date: 2025-09-05
project_end_date: 2029-09-04
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 11480537
contact_pi: HELSLEY, ROBERT NATHANIEL
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Deciphering the Mechanisms by which Long Chain Fatty Acid Oxidation Influences Spatial Microvesicular Steatosis

project_abstract:
PROJECT SUMMARYMetabolic dysfunction-associated steatotic liver disease (MASLD) is associated with a 4-year decrease inlifespan and is expected to become the leading cause of liver related morbidity and mortality within the next 15years. A hallmark of MASLD is the accumulation of small (microvesicular steatosis) and large (macrovesicularsteatosis) lipid droplets in the liver. However mechanisms driving the size and zonal deposition (e.g.accumulation in periportal versus pericentral hepatocytes) of lipid droplets remains poorly understood. Thecarnitine palmitoyltransferase 1a (Cpt1a) enzyme facilitates long chain fatty acid oxidation but impairments inthis pathway have been associated with microvesicular steatosis and reductions in circulating polyunsaturatedfatty acids (PUFAs) in humans. Therefore this proposal aims to identify the mechanisms explaining theseassociations. Using a mouse model of impaired long chain fatty acid oxidation preliminary data shows a sexuallydimorphic response to liver-specific deletion of Cpt1a characterized by panlobular microvesicular steatosis infemale mice while only slight periportal steatosis in male mice. In addition female knockout mice developexacerbated inflammation which coincides with reductions in 3-PUFAs in the liver. Therefore Aim 1 utilizes in-vitro mechanistic approaches to quantify lipid droplet dynamics and peroxisomal oxidation of PUFAs in responseto Cpt1a-deletion in cultured hepatocytes. Aim 2 utilizes gain- and loss-of-function approaches to modulateCpt1a expression specifically in periportal and pericentral hepatocytes across male and female mice. To assessthe impact of zonal-specific Cpt1a deletion and overexpression on the progression from MASLD to metabolicdysfunction-associated steatohepatitis (MASH) livers will be used for dual spatial transcriptomics and lipidomicsand for flow cytometry to assess the immune cell profiles in the liver. Completion of these aims will yieldmechanistic insight linking mitochondrial and peroxisomal oxidation to spatial lipid deposition in the liver. Theproposed research reveals several innovative mechanisms that have yet to be explored including how Cpt1aalters PUFA oxidation and lipid droplet formation across the periportal-pericentral axis. In addition the proposedstudy uses innovative approaches including the use of zonal-specific gain- and loss-of-function mouse modelsin conjunction with next generation spatial lipidomic and transcriptomic technology to address the overallhypothesis. Strong collaborations among the University of Kentucky Arts and Sciences Imaging CenterOncogenomics Shared Resource Facility COCVD Analytical research Core Biostatistics and BioinformaticsShared Resource Facility and the Center for Advanced Biomolecule Research at the University of Florida ensuresuccessful completion of the proposed research by the candidate. This R01 will support the applicant in reachinghis ultimate goal of becoming an independent yet collaborative versatile PI leveraging his unique skill set in bothbasic and clinical research arenas to identify novel therapeutics to treat cardiometabolic disease.

project_terms:
Ablation;Address;Affect;Affinity;Animal Model;Arts;Automobile Driving;Basic Science;Binding;Biogenesis;Bioinformatics Shared Resource;Biometry;CYP1A2 gene;Caenorhabditis elegans;Cardiometabolic Disease;Carnitine Palmitoyltransferase I;Cells;Child;Cirrhosis;Citric Acid Cycle;Clinical Research;Collaborations;Data;Deposition;Diet;Disease Outcome;Docosahexaenoic Acids;Ensure;Enterobacteria phage P1 Cre recombinase;Enzymes;Exhibits;Fasting;Fatty Liver;Female;Fibrosis;Florida;Flow Cytometry;Gene Expression;Genes;Genomics;Genus Hippocampus;Glutaminase;Goals;Hepatocyte;Human;Hydrolysis;Immune;Impairment;In Vitro;Individual;Inflammation;Kentucky;Knockout Mice;Knowledge;Link;Lipids;Liver;Liver Failure;Liver diseases;Metabolic dysfunction;Mitochondria;Molecular;Monounsaturated Fatty Acids;Morbidity - disease rate;Mus;Oleates;Omega-3 Fatty Acids;Pathologic;Pathway interactions;Persons;Phospholipids;Polyunsaturated Fatty Acids;Publishing;Radioisotopes;Reporting;Research;Resolution;Resource Sharing;Science;Severity of illness;Sex Differences;Steatohepatitis;Techniques;Technology;Therapeutic;Triglycerides;United States;Universities;Variant;Western Blotting;Work;acylcarnitine;cancer genomics;cardiovascular disorder risk;experimental study;fatty acid metabolism;fatty acid oxidation;gain of function;imaging facilities;innovation;insight;life span;light scattering;lipidomics;liver injury;long chain fatty acid;loss of function;male;mortality;mouse model;next generation;non-alcoholic fatty liver disease;novel therapeutics;overexpression;oxidation;perilipin;peroxisome;prevent;response;sexual dimorphism;simple steatosis;skills;spatial transcriptomics;stable isotope;transcriptomics

public_health_relevance:
PROJECT NARRATIVEMetabolic dysfunction-associated steatotic liver disease (MASLD) affects 1 billion people worldwide andassociates with a 4-year decrease in lifespan and greater cardiovascular disease risk. Impairments in theoxidation of long chain fatty acids have been associated with reductions in polyunsaturated fatty acidsmicrovesicular steatosis and worsened liver injury. The primary goal of this proposal is to identify mechanismsexplaining these associations yielding further insight into novel therapeutic options for MASLD.


application_id: 11130108
project_number: 1R01AI185075-01A1
project_title: Comprehensively Defining the Novel Alphaviral Capsid Protein / IRAK1 Interaction
administering_ic: NIAID
award_notice_date: 2025-09-04
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AI
serial_number: 185075
suffix: A1
program_official: DUPUY, LESLEY CONRAD
project_start_date: 2025-09-04
project_end_date: 2029-08-31
study_section: Molecular and Cellular Biology of Virus Infection Study Section[MCV]
contact_pi_person_id: 10849785
contact_pi: SOKOLOSKI, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY / ABSTRACT Alphaviruses are mosquito-borne pathogens that are capable of causing significant outbreaks of severeclinical disease. Currently for many alphaviruses there are no approved antiviral therapies or safe and effectivevaccines. Therefore research which seeks to determine the mechanisms by which the alphaviruses evade ordysregulate the host innate immune response is essential and critically important to systematically definingalphaviral biology and the development of innovative antiviral strategies. The overarching research objective ofthis proposal is to comprehensively define the impact of a novel interaction between the alphaviral Capsid (CP)protein and the host IRAK1 protein. The rationale and scientific premises supporting this objective are based onthe importance of the IRAK1 protein to host innate immune and inflammatory signaling pathways and a robustbody of preliminary evidence that indicates that the CP/IRAK1 interaction is highly conserved amongst themembers of the genus Alphavirus crucial to limiting the induction of type-I interferon and essential to Sindbis(SINV) virus neuropathogenesis in vivo. Nonetheless the precise impacts of the CP/IRAK1 interaction onalphaviral infection and pathogenesis remain fully unrealized constituting a critical gap in the knowledgebase.Thus we propose the following specific aims- i) To delineate the impact of the CP/IRAK1 interaction onalphaviral pathogenesis in vivo; ii) To define the molecular impacts of the CP/IRAK1 interaction on host cellularbiology; and iii) to determine the impact and consequences of the CP/IRAK1 interaction on the alphaviral CPprotein. Over the course of the first aim we will utilize highly tractable mouse models of alphaviral infection andpathogenesis to specifically probe the role of the CP/IRAK1 interaction on the evasion of Toll-Like Receptor(TLR) signaling and induction of an innate immune response and the dysregulation of IL-1 family cytokinesignaling. The second aim uses robust cellular models to discern the mechanism by which the CP/IRAK1interaction negatively impacts signaling and to define the precise impacts of the CP/IRAK1 interaction on thehost response to IL-1 stimulation. Finally the third aim uses robust cellular models of alphaviral infection torigorously determine the molecular consequences of IRAK1-mediated phosphorylation of the CP protein. This proposed work is highly significant in that it will comprehensively assess the importance of the novelCP/IRAK1 interaction to alphaviral infection and pathogenesis. Moreover these efforts are conceptually andtechnically innovative as robust tried-and-true and state-of-the-art approaches techniques and models ofinfection will be used to rigorously define the biological and molecular importance of the CP/IRAK1 interaction.The successful completion of these efforts will serve to fundamentally expand the understanding of alphaviralbiology and lay the foundation for the development of meaningful therapeutic interventions.

project_terms:
Adult;Alpha Virus;Animal Model;Anti-viral Therapy;Arthritis;Attenuated;Biological;Biology;Capsid;Capsid Proteins;Cell model;Cells;Cellular biology;Cessation of life;Chikungunya virus;Child;Clinical;Communities;Cytokine Signaling;Data;Development;Disease;Disease Outbreaks;Elderly;Family;Foundations;Gene Expression;Genetic Transcription;Geographic Distribution;IRAK1 gene;Immune;Immune response;Immunologics;Infection;Inflammation;Inflammatory;Innate Immune Response;Interferon Type I;Interferons;Interleukin-1;Joints;Lead;Mass Spectrum Analysis;Mayaro virus;Mediating;Mediator;Modeling;Molecular;Neuropathogenesis;Pathogenesis;Pattern;Phosphorylation;Phosphotransferases;Population;Proteins;Public Health;Quality of life;Receptor Signaling;Research;Rest;Role;Ross river virus;Seasons;Severities;Signal Pathway;Signal Transduction;Sindbis Virus;South American;Techniques;Therapeutic Intervention;Toll-Like Receptor Pathway;Toll-like receptors;Vaccines;Veins;Viral;Viral Encephalitis;Viral Genes;Viral Pathogenesis;Virus Diseases;Virus Replication;Work;genetic approach;in vivo;innovation;knowledgebase;member;molecular modeling;mosquito-borne pathogen;mouse model;mutant;novel;pathogen;permissiveness;response;reverse genetics;vector mosquito

public_health_relevance:
PROJECT NARRATIVE Alphaviruses represent a significant threat to public health due to their broad host range and geographicdistribution. Infections of otherwise healthy adults children and the elderly may result in severe clinical diseaseincluding incapacitating multi-joint arthritis which may persist for several years or viral encephalitis / death. Thework proposed here characterizes the impact of a novel host / pathogen interaction on the evasion of the innateimmune response using state-of-the-art molecular cellular and animal models of infection.


application_id: 11129720
project_number: 5T32CA160003-13
project_title: Oncology Research Training for Surgeon-Scientists
project_terms: Oncology;Research Training;Scientist;Surgeon
administering_ic: NCI
award_notice_date: 2025-07-22
opportunity_number: PA-20-142
application_type: 5
activity_code: T32
ic: CA
serial_number: 160003
program_official: LIM, SUSAN E
project_start_date: 2011-07-01
project_end_date: 2028-06-30
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: HULL, PAMELA CARMEN;O'CONNOR, KATHLEEN L.
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:
This application is a competitive renewal of Translational Oncology Research Training for Surgeon Scientists a transformative training program at the University of Kentucky (UK) designed for qualified trainees in the surgical disciplines and with an interest in oncology research. The program addresses critical national declines in the number of surgeon scientists engaged in cancer research through a two-year period of intensive interdisciplinary mentored research training to prepare trainees to become independent scientists who are well prepared to incorporate state-of-the-art techniques learned during their training period into a successful academic research career. Trainees (2 each year) typically enter the program following completion of postgraduate year (PGY) 2 or 3 of their residency training or upon completion of the surgical residency and select either the basic science option (Track 1) or the healthcare delivery research option (Track 2). Opportunities in Track 1 span cell signaling tumor biology cancer progression and metastasis as well as evolving areas such metabolomics oncogenomics and epigenetics. Track 2 a proposed new program component provides training in prevalent cancer challenges implementation science and population-level enquiry. In addition to an intensive research experience trainees complete a Master of Science or PhD degree in clinical and translational sciences and supplement their coursework with further development through a combination of formal courses and professional skills development workshops and seminars in such areas as responsible conduct of research reproducibility and manuscript and proposal development. Through regularly scheduled seminars and lectures available through the Markey Cancer Center their departments and prominent UK centers including the Center for Clinical and Translational Science trainees engage in rich experiential and didactic learning that prepares them as active contributors to the types of multidisciplinary teams that are essential for the optimal treatment of the complex cancer patient. The requirement to successfully complete either a masters or PhD degree adds depth and breadth to this program of training broadening exposure to other UK scientists serving on thesis committees. The primary training faculty is composed of basic and population scientists and clinician-scientists all of whom work collaboratively across disciplines; each primary faculty mentor is a recognized expert in his or her field and has a long record of research productivity in the training of young investigators. A pipeline mentor development mechanism allows us to develop promising early-career faculty members as mentors within our team-based mentoring approach. This program which is committed to fostering an interdisciplinary community of surgeon scientists has been highly successful in achieving its goals to address alarming declines in the number of active surgeon-scientists conducting oncology research. As a training faculty we are passionate motivated and committed to the training of future academic surgeons.

public_health_relevance:
The number of clinician scientists and in particular surgeon scientists is decreasing at an alarming rate; this reduction negatively impacts the ability and rapidity to translate basic and clinical discoveries made in cancer research to the patient. Our training program representing a collaboration between the Markey Cancer Center and the academic clinical departments (Departments of Surgery Pathology and Laboratory Medicine and Otolaryngology-Head & Neck Surgery and the Division of Gynecologic Oncology) at the University of Kentucky is focused on the interdisciplinary training of future clinician scientists in the various surgical specialties and disciplines. The overall objective of this program is to train clinician scientists in the skills and expertise in Basic Science (Track 1) and Healthcare Delivery Research (Track 2) to compete in the academic arena and to be active participants in multidisciplinary cancer teams which are required for the care of the complex cancer patient.


application_id: 11129695
project_number: 5R01CA283929-03
administering_ic: NCI
award_notice_date: 2025-07-18
opportunity_number: RFA-CA-22-050
application_type: 5
activity_code: R01
ic: CA
serial_number: 283929
program_official: STRECK, BRENNAN PARMELEE
project_start_date: 2023-07-25
project_end_date: 2028-06-30
study_section: ZCA1-RPRB-6(M2)S
contact_pi_person_id: 11642450
contact_pi: MCLOUTH, LAURIE
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: 2025-07-01
project_title:
Pathways a Hope-Based Intervention to Support Personal Goal Pursuit Mental Health and Quality of Life during Advanced Lung Cancer Treatment

project_abstract:
ABSTRACTThe psychosocial care of patients with advanced lung cancer (ALC) has not kept pace with current medicaltreatments creating significant gaps in care. Treatments like immunotherapy have radically changed ALC careyielding less toxicity and unprecedented increases in 5-year survival. However mental health and quality of lifeconcerns persist which must be addressed to fully realize the survival benefits of these medicaladvancements. To meet the needs of patients in this new treatment context psychosocial and palliative carefor ALC must shift from a predominant end-of-life framework to one of survivorship. A hope-based interventionto support patients goal pursuits in their family social work and leisure lives is a promising approach tosupport mental health and quality of life in this current context. The long-term goal of this research is toimprove ALC patient mental health and quality of life during cancer treatment. The overall objective in thisapplication is to test the efficacy of a novel psychosocial intervention called Pathways to support personalgoal pursuit during ALC treatment. The central hypothesis is that Pathways will reduce goal disruption andthereby improve mental health and quality of life during ALC treatment. The rationale for this project is thatPathways a brief hope-based intervention delivered primarily at the point of ALC patient care by a range ofhealthcare providers (e.g. nurse occupational therapist social worker) has demonstrated feasibility andacceptability to ALC patients with encouraging preliminary effects on goal disruption mental health andquality of life outcomes. The central hypothesis will be tested through two specific aims: 1) Test the efficacy ofPathways against enhanced usual care; and 2) Evaluate goal interference and goal adjustment as mediators ofintervention effects. Because ALC disproportionately affects rural older underserved populations who havebeen underrepresented in psychosocial intervention trials Aim 3 will use mixed-methods to evaluate the reachand effectiveness of the Pathways intervention among these subgroups. To accomplish these aims 234patients undergoing treatment for ALC at the University of Kentucky Markey Cancer Center will be randomizedto Pathways or enhanced usual care with outcomes collected pre post and at follow-up. The researchproposed in this application is innovative because it is testing a novel intervention with respect to interventionfocus and intervention delivery at the point of ALC care. The proposed research is significant because it willdetermine the efficacy of an intervention that is responsive to patients needs in the current medical landscapefor ALC and has high potential for broad dissemination into routine ALC care in both high- and low-resourcedsettings. Once efficacy is demonstrated the effectiveness of the intervention will be tested in both academicand community oncology practices with other advanced cancer patient populations significantly advancingpsychosocial and palliative care in this new treatment era and ultimately having a large impact on the over600000 people living with advanced cancer in the U.S.

project_terms:
Address;Adult;Advanced Malignant Neoplasm;Affect;Age;Anxiety;Attention;Behavioral Sciences;Cancer Burden;Cancer Center;Cancer Patient;Cancer Survivorship;Caregivers;Caring;Clinical;Clinical Trials;Community Clinical Oncology Program;Data;Diagnosis;Distress;Effectiveness;Effectiveness of Interventions;Family;Feedback;Friends;Future;Goals;Health Care Costs;Health Personnel;Immunotherapy;Impairment;Incidence;Infusion procedures;Intervention;Intervention Trial;Kentucky;Leisures;Life;Malignant neoplasm of lung;Mediating;Mediator;Medical;Medical Oncology;Mental Health;Methods;Mind;Mission;National Cancer Institute;Normalcy;Nurses;Occupational Therapist;Outcome;Palliative Care;Pathway interactions;Patient Care;Patients;Performance Status;Persons;Population;Poverty;Premature Mortality;Psychology;Psychosocial Assessment and Care;Public Health;Quality of life;Randomized;Reporting;Research;Resource-limited setting;Role;Rural;Social Functioning;Social Workers;Subgroup;Telephone;Testing;Thinking;Toxic effect;Treatment Efficacy;Underserved Population;Universities;Update;Work;acceptability and feasibility;anxiety symptoms;cancer care;cancer therapy;care delivery;clinical practice;community setting;depressive symptoms;design;effectiveness trial;efficacy evaluation;efficacy testing;efficacy trial;end of life;evidence base;follow-up;health related quality of life;improved;innovation;intervention delivery;intervention effect;male;novel;palliative;patient population;primary outcome;psychological distress;psychosocial;psychosocial outcome;randomized trial;reduce symptoms;residence;response;routine care;satisfaction;sex;skills;social;socioeconomic disadvantage;survivorship;theories;therapy design;treatment as usual;treatment response

public_health_relevance:
PROJECT NARRATIVEThe proposed research is relevant to public health because it proposes to test a new psychosocial interventionthat addresses a critical intervention gap in current psychosocial care for patients living with advanced lungcancer the most common advanced cancer associated with high rates of psychological distress and poorquality of life and which disproportionately affects rural socioeconomically disadvantaged adults. Because theintervention was designed with patient needs and clinical practice in mind it could easily be implemented inroutine advanced cancer care in both academic and community oncology settings and could be exported foruse among the over 600000 people living with advanced cancer in the U.S. Thus the proposed research willsupport the National Cancer Institutes mission of reducing the burden of cancer through high quality cancercare.


application_id: 11129185
project_number: 7R03AG083363-02
project_title: Astrocytic exocytosis of ATP in amyloid pathology and Alzheimer's disease
administering_ic: NIA
award_notice_date: 2024-07-11
opportunity_number: PA-21-268
application_type: 7
activity_code: R03
ic: AG
serial_number: 083363
program_official: OPANASHUK, LISA A
project_start_date: 2023-09-01
project_end_date: 2026-08-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 11340283
contact_pi: CAI, WEIKANG
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:
Contact PD/PI: Cai WeikangProject Summary/Abstract:Alzheimers disease (AD) is a devastating neurodegenerative disease with no cure. It is characterized by -amyloid (A)-containing senile plaques and tau-containing neurofibrillary tangles in the brain. Among manymechanisms contributing to AD excessive deposition of toxic A peptides is considered to play a key role.Recent studies have demonstrated that A deposition in the brain triggers robust morphological andtranscriptomic changes in astrocytes. How these alterations of astrocyte functions may contribute to thedevelopment of AD remains unclear. The preliminary studies of the PIs research group show that A42induces ATP release in cultured astrocytes. Further loss of vesicular nucleotide transporter (Vnut) which isresponsible of loading cytosolic ATP into the excretory lysosomes in astrocytes dramatically reduces Aplaques by ~50% and improved cognitive function in 6-month-old female 5xFAD mice. These data stronglysuggest that elimination of ATP exocytosis in astrocytes blocks the accumulation of amyloid plaques andalleviates the cognitive decline. With the strong support of these exciting preliminary data the proposedresearch hypothesize that A deposition enhances astrocytic exocytosis of ATP and chronic elevation ofastrocyte-derived ATP further induces neuroinflammation impairs A production and clearance andexacerbates cognitive decline. The proposed research will address this central hypothesis in specific aims:Aim 1: To examine the dynamic interaction between astrocytic exocytosis of ATP and A deposition. Brieflymicrodialysis will be used to assess how extracellular ATP levels in the brain are altered when Vnut is deletedin astrocytes in response to A deposition. The reduced A deposition could be due to decreased productionor increased clearance. To this end the relative contents of APP products including soluble APP A40 andA42 will be quantified to assess the preference of A production. In addition A-associated astrocytes andmicroglia will be quantified as an indicator of glial-dependent A clearance. Aim 2: To assess the contributionsof the astrocytic exocytosis of ATP on neuroinflammation in mouse models of AD. Neuroinflammation in5xFAD mice without astrocytic Vnut will be examined using immunoblotting immunofluorescence qPCR andELISA and compared to appropriate control mice. In addition to explore additional contributing mechanismsthe transcriptomes of astrocytes of these mice will be analyzed using RNA Seq and bioinformatics.Throughout the project all the data on neuroinflammation the extracellular ATP levels and A deposition willbe correlated with the learning and memory of the same mice at 6 and 12 months of age. With a novel geneticmouse model the proposed research will provide valuable insight into the roles of astrocytes and purinergicsignaling in AD. This will help generate key preliminary data to support a more in-depth investigation in afuture R01 grant. In the long term this line of research may reveal new therapeutic approaches to treat ADand possibly other neurodegenerative diseases by targeting purinergic signaling.Project Summary/Abstract Page 6

public_health_relevance:
Project Narrative:Alzheimers disease (AD) is a devastating neurodegenerative disease with no cure. Recently glial cells likeastrocytes and microglia have emerged as critical players contributing to the progression of AD providingpotentially new avenues to develop AD treatment. The proposed research aims to understand the mechanismsby which astrocyte-derived purinergic signaling regulates amyloid deposition and neuroinflammation whichmay reveal new therapeutic strategies for AD by targeting purinergic system in the brain.


application_id: 11129121
project_number: 7R01MH125903-05
administering_ic: NIMH
award_notice_date: 2025-06-03
opportunity_number: PA-20-185
application_type: 7
activity_code: R01
ic: MH
serial_number: 125903
program_official: TONELLI, LEONARDO HERALDO
project_start_date: 2021-04-16
project_end_date: 2027-03-31
study_section: Pathophysiological Basis of Mental Disorders and Addictions Study Section[PMDA]
contact_pi_person_id: 11340283
contact_pi: CAI, WEIKANG
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: 2025-04-01
project_title:
Astrocyte-derived signals for neuronal and behavioral modulation and its implications in mental illness.

project_abstract:
Project Summary/Abstract:Major depressive disorder (MDD) is a common but serious mental illness that negatively affects emotioncognition physical activity and increases mortality. In general the manifestation of depression is thought to bedue to the imbalance of neurotransmitters in the brain. These neurotransmitters include glutamate GABA andespecially a class of monoamines such as serotonin dopamine and norepinephrine. Many recent studieshave demonstrated the importance of dopamine homeostasis and dynamics on reward and motivationespecially after exposure to chronic stress. Our previous studies have identified a novel astrocyte-dependentmodulatory mechanism for the dopamine system in which the hormone insulin regulates ATP release inastrocytes which in turn contributes to the modulation of dopamine release and depressive-like behavior inmice. These exciting findings provide a novel and potentially important molecular basis for the etiology ofdepressive disorders given the epidemiological link between diabetes and major depression. How insulinmediates astrocytic ATP release has yet to be elucidated although exocytosis from secretory lysosomes hasbeen suggested as a major route of ATP release by astrocytes. Therefore in the proposed research we aim tofurther investigate the molecular mechanism and functional relevance of the astrocytic insulin action and ATPrelease on dopaminergic signaling under chronic stress. We hypothesize that insulin regulates the exocytosisof ATP from secretory lysosomes in astrocytes to contribute to dopamine release and impairment of thisastrocyte-initiated pathway will negatively impact dopamine release and exacerbate deficits in reward in miceexposed to chronic stress. To test this central hypothesis we have developed a new genetic mouse model inwhich we can specifically delete astrocytic vesicular nucleotide transporters (VNUTs) that are required forloading ATP into secretory lysosomes. Consistent with our original findings preliminary analyses show thatastrocyte-specific VNUTKO mice display increased depressive-like behavior and decreased activation ofmedium spiny neurons in the nucleus accumbens indicating decreased dopamine signaling. Movingforward in Aim 1 we will continue to use astrocyte-specific VNUTKO mice to determine the role of ATPexocytosis by astrocyte on dopamine signaling and reward in these mice after exposure to both unpredictablechronic mild stress (CMS) and chronic social defeat stress (CSDS). In Aim 2 taking advantage of the highlysensitive luciferase-based ATP quantification and the super-resolution living imaging by Nanoimager S we willquantify the insulin-induced lysosomal trafficking and exocytosis of ATP in cultured astrocytes. Further in vitroand in vivo applications of pharmacological inhibitors and viral expression of mutations of key signalingmolecules will dissect the molecular mechanisms of insulin-stimulated ATP release by astrocytes. Togetherthe proposed research will expand our understanding of the etiology of depressive disorders from a novelperspective of insulin action in astrocytes and may reveal new therapeutic approaches for depression.

project_terms:
Address;Affect;Astrocytes;Autopsy;Beds;Behavior;Behavioral;Biological Assay;Brain;Chronic;Chronic stress;Cognition;Complex;Control Groups;Crowding;Data;Depressive disorder;Development;Diabetes Mellitus;Dopamine;Eating;Electrophysiology (science);Emotions;Epidemiology;Etiology;Exocytosis;Exposure to;Gene Silencing;Genetic;Glutamates;Homeostasis;Hormones;House mice;Housing;Image;Impairment;In Vitro;Individual;Injections;Insulin;Light;Link;Luciferases;Lysosomes;Major Depressive Disorder;Measures;Medial;Mediating;Mental Depression;Mental disorders;Metabolic;Microdialysis;Molecular;Moods;Morphology;Motivation;Mus;Mutation;Neurons;Neurotransmitters;Noise;Norepinephrine;Nucleotides;Nucleus Accumbens;Nutrient;Pathogenesis;Pathway interactions;Persons;Physical activity;Play;Prefrontal Cortex;Regulation;Research;Rewards;Role;Route;Serine;Serotonin;Signal Transduction;Signaling Molecule;Site;Sleep;Stress;Stressful Event;Sucrose;Synaptic plasticity;Testing;Tyrosine Phosphorylation;Viral;Virus;behavioral outcome;density;depressive symptoms;dopamine system;gamma-Aminobutyric Acid;in vivo;inhibitor;insight;insulin signaling;monoamine;mortality;mouse model;neural circuit;neural network;neurotransmission;neurotransmitter release;novel;novel therapeutic intervention;overexpression;pharmacologic;presynaptic;putamen;reward processing;risk variant;selective expression;severe mental illness;signal processing;social defeat;stressor;trafficking;ultra high resolution

public_health_relevance:
Project Narrative:The manifestation of depressive symptoms is contributed by the disturbance of complex neural networks including the dopaminergic neural circuit. Astrocytes have been shown to play an important role in the modulation of neuronal activity and synaptic plasticity and may be crucial for dopamine release during the development and progression of depressive symptoms. The proposed research aims to understand the mechanisms and contribution of insulin signaling-dependent exocytosis of ATP by astrocytes on the regulation of dopamine signaling and reward deficits under chronic stress exposure which will further expand our understanding of the etiology of depressive disorders and may reveal new therapeutic approaches for depressive disorders.


application_id: 11128730
project_number: 5R01ES034786-02
project_title: Mechanisms of Sex-specific Metabolic Disruption Caused by Organophosphate Flame Retardant Exposure
administering_ic: NIEHS
award_notice_date: 2025-07-28
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: ES
serial_number: 034786
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
arra_indicator: N
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;Female;Flame Retardants;Frequencies;Future;Genes;Glucose Clamp;Glucose tolerance test;Gonadal Steroid Hormones;Hand;Hepatic;Human;Hyperglycemia;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;high-fat/sugar diet;human female;improved;inorganic phosphate;insulin signaling;insulin tolerance test;lipid biosynthesis;liver inflammation;mRNA sequencing;male;male specific;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;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: 11128678
project_number: 5R35GM150599-04
project_title: Bacterial ribosome heterogeneity and gene expression
administering_ic: NIGMS
award_notice_date: 2025-07-22
opportunity_number: PAR-20-117
application_type: 5
activity_code: R35
ic: GM
serial_number: 150599
program_official: REDDY, MICHAEL K
project_start_date: 2023-08-15
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZRG1-MGG-J(55)R]
contact_pi_person_id: 10506803
contact_pi: RAMSEY, KATHRYN MARY
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 As antibiotic resistance increases globally there is an urgent need for new drugs tocombat bacterial infections. Approaches to developing new antimicrobials include inhibitingessential steps in gene expression and inhibiting virulence factor production. The overarchingfocus of the research program in my laboratory is to understand how bacterial cellsregulate gene expression to ultimately identify novel targets for antimicrobialdevelopment. The research funded by this award will leverage the Ramsey laboratorysexpertise in bacterial genetics and state of the art technologies to examine the impacts ofribosome heterogeneity in multiple bacterial species. The Ramsey laboratory identified aspecific homolog of the ribosomal protein bS21 that governs virulence gene expression in abacterial pathogen. These findings suggest that heterogeneity in ribosomes which are significantdrug targets can lead to changes in gene expression. The impacts of ribosome heterogeneity ontranslation gene expression and drug efficacy are generally not well understood and representkey gaps in our knowledge. Over the next five years we propose to continue our studies tounderstand the effects of ribosome heterogeneity on multiple bacterial species. The proposedwork is innovative because it takes a rigorous reductionist approach to examine one poorly-understood source of ribosome heterogeneity with species-specific impacts on translation toelucidate fundamental features of translation and inform the design of novel antimicrobials. Ourgoals include determining how multiple bS21 homologs function to govern gene expression whybS21 is essential in some cells and how bS21 contributes to antibiotic sensitivity. We expect ourwork will allow us to make clear connections between ribosome composition and functionaloutcomes as we will limit the complexity of ribosomal heterogeneity to changes in a singleribosomal protein bS21. Expected future work will include developing screens for novel specificribosome inhibitors and studying the function of bS21 or other independent sources of ribosomeheterogeneity in these and/or other organisms. Ultimately our studies will provide key insights intoribosome function gene expression and may identify novel targets for antimicrobial drugs.

project_terms:
Antibiotic Resistance;Antibiotics;Antimicrobial Resistance;Award;Bacterial Infections;Cells;Development;Drug Targeting;Funding;Future;Gene Expression;Goals;Heterogeneity;Homologous Gene;Knowledge;Laboratories;Organism;Production;Public Health;Research;Ribosomal Proteins;Ribosomes;Source;Technology;Translations;United States;Virulence Factors;Work;anti-microbial drug;antimicrobial;bacterial genetics;combat;design;drug efficacy;functional outcomes;improved;inhibitor;innovation;insight;novel;novel therapeutics;pathogenic bacteria;programs;virulence gene

public_health_relevance:
NARRATIVEAntimicrobial resistance is an increasing public health threat in the United States and there is anurgent need to develop novel antimicrobials. The work proposed here will improve ourfundamental knowledge of a key antibiotic target the ribosome and potentially reveal newavenues for antimicrobial development.


application_id: 11128028
project_number: 3U24DA058961-02S1
administering_ic: NIDA
award_notice_date: 2024-09-03
opportunity_number: PA-20-272
application_type: 3
activity_code: U24
ic: DA
serial_number: 058961
suffix: S1
program_official: ROMBERG, ALEXA RUTH
project_start_date: 2024-07-01
project_end_date: 2025-06-30
contact_pi_person_id: 10667839
contact_pi: STEVENS-WATKINS, DANELLE J
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-07-01
project_title:
The University of Kentucky Racial Equity Initiative Coordinating Center (UK-REI-CC)- Administrative Supplement

project_abstract:
SUMMARY The overarching goal of the University of Kentucky Racial Equity Initiative CoordinatingCenter (UK-REI-CC) is to focus on collectivism and elevate the resilience of People of Color andIndigenous (POCI) communities through supporting REI grantees to conduct culturally relevantbest practice community engaged substance use research. UK-REI-CC will draw from theRadical Healing in Communities of Color6 a strength-based framework to coordinate projectsfrom both Highly Resourced Institutions (HRIs) and Limited Resourced Institutions (LRIs). TheUK-REI-CC is led by a PI and faculty with established collaborations and extensive experiencefocused on community-engagement drug treatment HIV randomized controlled trialsimplementation science pharmacology and justice-involvement. In collaboration with the NIDASteering Committee and expert panel UK-REI-CC will complete the following aims: 1) Todevelop and support a learning community through networking & training among REI grantees.UK REI-CC will organize and convene a kick-off annual meetings and monthly meetings of REIgrantees. Using Pure network mapping system7 REI grantees and community partners willaccess investigators and their worldwide networks. UK-REI-CC will conduct a bi-annual needsassessment convene workgroups devise quarterly trainings develop a speaker series andhost networking events encouraging collectivism and highlighting assets among the REIinstitutions. 2) To enhance REI projects by providing research resources focused on communityengagement. UK REI-CC will provide technical assistance and consultations focused onelevating the voices of marginalized communities. The center will provide quarterly trainings toREI project sites and resources focused on building and strengthening academic-communitypartnerships. 3) To optimize data collection and analyses by the REI community. UsingTableau UK-REI-CC will host an interactive dashboard illustrating progress for REI projects.The center will provide consultation on devising research questions culturally appropriatemeasures recruitment and retention strategies qualitative and quantitative data analyses andincorporating community partners in data analyses. 4) To facilitate broad and accessiblecommunication and dissemination of REI project findings for end users. UK REI-CC will developonline resources to share press releases publications and research presentations. In additionthe UK-REI-CC will leverage our expertise in culturally tailoring messaging to ensureaccessibility for all communities participating in the research. Taken together these activitieswill enhance the capacity for REI projects to conduct impactful substance use research.

project_terms:
Acceleration;Administrative Supplement;Affect;Black American;Collaborations;Color;Communication;Communities;Community Participation;Consultations;Data;Data Analyses;Data Collection;Ensure;Ethnic Origin;Event;Faculty;Goals;HIV;Hospitals;Human Resources;Indigenous;Indigenous American;Inequity;Institution;Intervention;Justice;Kentucky;Limited English Proficiency;Maps;Measures;Modeling;National Institute of Drug Abuse;Needs Assessment;Pharmacology;Pharmacotherapy;Positioning Attribute;Press Releases;Publications;Qualifying;Race;Racial Equity;Randomized Controlled Trials;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Science;Series;Site;Substance Use Disorder;System;Testing;Training;Trauma;Universities;Voice;Work;community academic partnership;community engaged research;community engagement;community partners;cost;dashboard;diversity and inclusion;experience;forgetting;healing;implementation science;indigenous community;innovation;learning community;marginalized community;meetings;member;novel;online resource;overdose death;people of color;recruit;resilience;retention rate;rural setting;social media;structural determinants;substance use;synergism;tailored messaging;urban setting;webinar

public_health_relevance:
Project Narrative: The UK-REI-CC is an innovative coordinating center model centering collectivism andemphasizing the resilience of racial and ethnic marginalized communities. The UK-REI-CC will enhance andsupport the NIDA REI projects by providing resources for networking and training conducting community-engaged research data collection and analyses and communication and dissemination. An administrativesupplement is being requested to support unanticipated changes in personnel costs requiring multiplesubawards.


application_id: 11127639
project_number: 5R01CA196634-11
project_title: Improving chemotherapy of castration-resistant prostate cancer.
administering_ic: NCI
award_notice_date: 2025-06-12
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 196634
program_official: FORRY, SUZANNE L
project_start_date: 2016-08-10
project_end_date: 2026-06-30
study_section: Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Title: Improving chemotherapy of castration-resistant prostate cancerAbstractAndrogen receptor (AR) signaling is essential for prostate cancer (PCa) development and growth even incastration-resistant PCa (CRPC) the lethal stage of the disease. Docetaxel is the standard treatment for CRPCpatients due to a combination of mitotic catastrophe and inhibition of AR signaling. Androgen signaling inhibitors(ASI) are also used to treat CRPC post-docetaxel with limited success. Therefore it is urgent to identify newtargets and develop novel approaches to treat CRPC that are resistant to the existing therapies. Brd4 aconserved member of the bromodomain and extraterminal (BET) family of chromatin readers promotes genetranscription via interacting with core positive transcription elongation factor (P-TEFb) consisting of Cdk9 andcyclin T1. Significantly AR signaling-competent CRPC cells are preferentially sensitive to Brd4 inhibitor JQ1 asJQ1 treatment disrupts AR recruitment to target gene loci thus resulting in inhibition of AR signaling directly.Furthermore JQ1 enhances the efficacy of ASI in PCa. Loss-of-function mutations in E3 ubiquitin ligasesubstrate-binding adaptor speckle-type POZ protein (SPOP) cause stabilization of Brd4 and JQ1 resistance.Thus it will be of clinical significance to understand the regulation mechanism of Brd4 regulation and to developa new approach to cause Brd4 degradation even in the presence of SPOP mutations. The long-term goals ofthis study are to identify novel and druggable signaling pathways that offer more effective treatment options forpatients with therapy-resistant CRPC. The objective is to define the role of polo-like kinase 1 (Plk1) in regulatingBrd4 degradation and AR signaling and to exploit this unique mechanism to develop a novel approach fortreatment. Our preliminary data show that Plk1 phosphorylation of Brd4 leads to its protein degradation even inthe presence of SPOP mutations. The central hypothesis is that Plk1-associated phosphorylation of Brd4 resultsin its degradation thus docetaxel-associated Plk1 elevation is one approach to overcome resistance to Brd4inhibitors. This hypothesis will be tested by pursuing three Specific Aims - (1) to dissect how Plk1 phosphorylationof Brd4 regulates AR signaling; (2) to understand how Brd4 phosphorylation contributes to PCa cell proliferation;and (3) to analyze clinical significance of Plk1-associated Brd4 phosphorylation. These complementary aims willbe accomplished using biochemical analyses of signaling intermediates and employing genetic strategies withPCa mouse models culture systems and PCa xenograft methodologies. The rationale for the research is that itwill be the first to probe the importance of Plk1 to Brd4 and AR signaling and to examine whether a combinationof docetaxel and Brd4 inhibitor ABBV-744 is a novel approach to treat ASI-resistant CRPC. This contribution issignificant because it will (i) define the molecular mechanism by which Plk1 regulates Brd4 degradation andAR signaling; and (ii) validate docetaxel as a therapeutic agent to enhance the efficacy of Brd4 inhibitors.

project_terms:
Ablation;Acetylation;Affect;Androgen Receptor;Androgens;Binding;Biochemical;Bromodomain;Cancer Patient;Castration;Cell Cycle;Cell Cycle Progression;Cell Proliferation;Cells;Chemoresistance;Chromatin;Clinical Research;Creativeness;Data;Development;Disease;Docking;Epigenetic Process;Event;Family;Fostering;Genetic Transcription;Genetically Engineered Mouse;Goals;Growth and Development function;Health;Investigation;Lysine;Malignant Neoplasms;Malignant neoplasm of prostate;Methodology;Mission;Mitosis;Mitotic;Molecular;Mutation;Operative Surgical Procedures;Outcome;PLK1 gene;Paclitaxel;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phosphorylation;Phosphorylation Site;Phosphotransferases;Proteins;Public Health;Reader;Receptor Signaling;Regulation;Research;Resistance;Resistance development;Role;Signal Pathway;Signal Transduction;Site;Specimen;System;Testing;Therapeutic;Therapeutic Agents;Transcriptional Elongation Factors;United States National Institutes of Health;Work;Xenograft procedure;abiraterone;androgen independent prostate cancer;chemotherapy;clinically significant;cyclin T1;design;docetaxel;effective therapy;enzalutamide;genetic approach;genomic locus;improved;in vivo;inhibitor;innovation;loss of function mutation;member;mouse model;multicatalytic endopeptidase complex;novel;novel strategies;patient derived xenograft model;prostate cancer cell;prostate cancer progression;protein degradation;recruit;refractory cancer;standard care;success;therapy resistant;ubiquitin-protein ligase

public_health_relevance:
NarrativeThe proposed research is relevant to public health because it focuses on discovery of novel signalingpathways that drive castration-resistant prostate cancer. These studies will establish new avenues ofinvestigation to develop improved therapeutics to treat this deadly disease and to greatly improve patientoutcome. Thus the proposed research is relevant to NIH's mission of fostering creative discoveries andinnovative research strategies for protecting and improving health and reducing the burdens associated withcancer.


application_id: 11127470
project_number: 5T35EY026509-09
project_title: Summer Vision Sciences Training Program
administering_ic: NEI
award_notice_date: 2025-09-23
opportunity_number: PA-20-162
application_type: 5
activity_code: T35
ic: EY
serial_number: 026509
program_official: FORTRESS, ASHLEY
project_start_date: 2017-07-01
project_end_date: 2027-03-31
study_section: ZEY1-VSN(06)
contact_pi_person_id: 1925445
contact_pi: CERESA, BRIAN P.
other_pis: MCCALL, MAUREEN A
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 SectionThis is a renewal application for a T35 summer medical student training program in vision research with two Specific Aims: 1) To provide hands-on training in basic and clinical vision research to medical students in a structured mentored environment and 2) To provide an interactive educational experience that introduces medical students the fundamental skills necessary for basic translational and clinical research in vision biology. The co-directors of this program request support for 8 second-year medical students each summer in vision related research laboratories that focus on topics such as visual circuitry retinal degeneration corneal epithelial homeostasis uveitis ocular drug discovery and development of the visual system. Trainees will be selected from the first-year class at University of Louisville School of Medicine. Students will review research projects submitted by 18 faculty funded by the NEI or vision related foundations. Students will review the available projects and rank their 1st-5th choices allowing matching of trainees with mentors. Final decisions will be made based on interviews between mentors and Trainees. During the 10-week summer training students work with mentors on their research project in laboratory settings complete training in the Responsible Conduct of Research including topics such as fabrication and falsification of data plagiarism managing scientific data publication practices and responsible authorship mentorship stewardship and conflict of interest. Trainees will complete human subject IRB training and animal care and handling as required by their specific research projects. All Trainees will attend a 2-hour weekly Vision Sciences Research Training Seminar designed to introduce clinical/translational research in Ophthalmology led by mentors in this T35 program. The seminar series will culminate with each Trainee presenting his/her research project to peers and mentors. In addition trainees present the results of their research as posters with peers at a School of Medicine-wide week-long celebration of research (Research!Louisville) that includes nationally recognized physician-scientists as keynote speakers. Trainees will be encouraged to continue research as part of the Distinction in Research track that is an enrichment program focusing on providing meaningful and productive research experiences throughout second through fourth years of medical school with ongoing presentations by students with mentors and 4+ weeks of research time in the fourth year toward the goal of developing clinician-researchers. Trainees will be tracked to assess the impact of this T35 program on careers as physician-scientists.

project_terms:
Authorship;Basic Science;Biology;Clinical;Clinical Research;Conflict of Interest;Data;Education;Environment;Faculty;Foundations;Funding;Goals;Homeostasis;Hour;Institutional Review Boards;Interview;Laboratories;Laboratory Research;Medical Students;Mentors;Mentorship;Ophthalmology;Physicians;Plagiarism;Productivity;Publications;Research;Research Personnel;Research Project Grants;Research Training;Retinal Degeneration;Scientist;Series;Structure;Students;Systems Development;Time;Training;Training Programs;Translational Research;Universities;Uveitis;Vision;Vision research;Visual;Work;animal care;career;corneal epithelium;design;drug discovery;experience;fabrication;human subject;medical schools;peer;posters;programs;responsible research conduct;skills;vision development;vision science

public_health_relevance:
This NEI Short-Term Institutional Training Grant renewal application requests 5 years of support for 8 rising second year Medical Student trainees in our Vision Science laboratories for a 10-week research experience. The T35 training grant will be used to entice our medical students into our Distinction in Research Track a program that encourages students to participate in laboratory research in years 2-4 of medical school with an eye toward scholarly activities in academic medicine to continue to build a pipeline of translational clinician-researchers.


application_id: 11127432
project_number: 5T32NS077889-14
project_title: Neurobiology of CNS Injury and Repair
project_terms: Neurobiology;central nervous system injury;injury and repair
administering_ic: NINDS
award_notice_date: 2025-06-26
opportunity_number: PAR-21-149
application_type: 5
activity_code: T32
ic: NS
serial_number: 077889
program_official: SYPEK, ELIZABETH IRENE
project_start_date: 2012-07-01
project_end_date: 2027-06-30
study_section: ZNS1-SRB-D(05)
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
other_pis: ALILAIN, WARREN JOSEPH;GENSEL, JOHN C
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project SummaryThis is a renewal application requesting continued funding for a Neurobiology of CNS Injury and Repair T32Training Program to support 4 predoctoral fellows per year for a 2-year training period working toward theirPhD degrees in the fields of traumatic brain injury (TBI) spinal cord injury (SCI) or stroke. The overall goalcontinues to be to prepare highly motivated graduate students for careers in neurotrauma research-relatedfields by providing broad-based training in the pathophysiology of TBI SCI and stroke and the identification ofpotential disease-modifying molecular targets that can drive the discovery of pharmacological or gene-basedtherapeutic strategies. An Executive Committee will select trainees from a pool of qualified applicantsgenerally in their third year of PhD training. Trainees will receive intensive hands-on research mentoring withan emphasis on understanding and applying quantitative assessment tools in laboratories of Training Facultyappointed in the Depts. of Neuroscience Physiology Molecular and Cellular Biochemistry and PharmaceuticalSciences who regularly interact and collaborate through their affiliation with the University of Kentucky's (UK)Spinal Cord & Brain Injury Research Center and Center for Advanced Translational Stroke Science (CATSS).In addition to coursework trainees will engage in journal clubs responsible conduct of research trainingCenter and Departmental seminar series and a customized set of program-wide meetings in ProfessionalSkills and Quantitative Literacy-Experimental Design and Statistics (PSQL-EDS). The monthly PSQL-EDS willfacilitate active learning of concepts such as quantitative literacy statistical analysis and scientific rigor aswell as scientific writing and professional development. Of the students appointed to the T32 Program in theprevious 9 years 13 have completed their PhDs 2 will complete their PhDs in year 10 and 6 will continue theirPhD training. All those that completed their PhDs continued into science-related positions. Several arecontinuing their education (3 postdocs 1 resident) one is an AAAS science policy fellow at the NIH and themajority are pursuing careers in academia (3 Assistant Professors 1 instructor 1 researcher) and biomedicalindustry (2). The PhD completion and career placement success of the T32 Program is further highlighted byan outstanding record of recruiting and retaining diverse trainees: a large proportion of appointees are ofunderrepresented race or ethnicity have a disability or come from disadvantaged backgrounds. Theprogram's success and continued evolution will be guided by two groups: an Executive Committee comprisedof the Program Directors Training Faculty and senior UK faculty who bring expertise in administrationmentoring and inclusion research initiatives and an External Advisory Board of national leaders in TBI SCIand stroke research. Through the pairing of comprehensive research-intensive training with didactic andinteractive educational/career development activities delivered from diverse perspectives this T32 Program isuniquely positioned to fill a growing need for rigorously trained scientists who desire careers in neurotrauma.

public_health_relevance:
Project NarrativeAcute central nervous system (CNS) injuries such as spinal cord injury traumatic brain injury and stroke sharemany common cellular and molecular mechanisms of damage and repair. These mechanisms often differsubstantially from other genetic developmental or degenerative brain diseases necessitating specializededucation and research training for those who pursue careers in CNS injury research with the goal of lesseningthe health-related burden of CNS injury on survivors. The Neurobiology of CNS Injury and Repair T32 Programis designed to provide outstanding comprehensive educational and research-intensive training to predoctoralstudents and fully prepare them for their transition to independent careers.


application_id: 11127353
project_number: 5U60OH008483-20
project_title: Kentucky Occupational Safety and Health Surveillance Program
administering_ic: NIOSH
award_notice_date: 2025-07-18
opportunity_number: PAR-20-312
application_type: 5
activity_code: U60
ic: OH
serial_number: 008483
program_official: O'NEILL, EDUARDO
project_start_date: 2021-07-01
project_end_date: 2026-06-30
study_section: ZOH1-EHG(03)
contact_pi_person_id: 12619306
contact_pi: NORTHCUTT, CAITLIN A
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
From January 1 2021- August 3 2021 there were 16906 long-term care resident COVID-19cases and 12544 long-term care staff cases; deaths numbered 2222 resident deaths and 13staff member deaths with 408 facilities impacted(https://covidtracking.com/data/state/kentucky/long-term-care#-84.8703299177646536.6772134423337954.626992127286515). The Kentucky OccupationalSafety and Health Surveillance Program (KOSHS) is proposing to utilize the Vaccine TaskForce (VTF) supplement to identify vaccination rates and hesitancy among employees who carefor the most vulnerable population for COVID 19Long Term Care residents. In recentdiscussions with the Kentucky Department of Public Health it was suggested that the traditionalmethods of improving vaccination rates are not working in the long-term care facility employeegroup. This goal of this proposal is to adopt a mixed-methods approach to understand thehesitancy among this population and to develop appropriate strategies and materials to assist inincreasing vaccination rates.

public_health_relevance:
The Kentucky Occupational Safety and Health Surveillance Program (KOSHS) is proposing toutilize the Vaccine Task Force (VTF) supplement to identify vaccination rates and hesitancyamong employees who care for the most vulnerable population for COVID 19Long Term Careresidents.


application_id: 11126965
project_number: 4R00AG078286-02
project_title: Early Characterization of Cognitive Status and AD Risk in African American Men
administering_ic: NIA
award_notice_date: 2024-08-20
opportunity_number: PAR-21-220
application_type: 4
activity_code: R00
ic: AG
serial_number: 078286
program_official: LUO, YUAN
project_start_date: 2023-09-01
project_end_date: 2025-08-31
study_section: NSS
contact_pi_person_id: 78098700
contact_pi: ESIAKA, DARLINGTINA
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Although past studies done primarily on white Americans report that men have a higher risk of mildcognitive impairment (MCI) and more rapid progression from MCI to AD we do not know if this is also the casefor African American men. Early characterization of cognitive status and Alzheimers disease (AD) risk in olderAfrican American men is a critical unmet challenge. There have been notably few dementia studies that includedsubstantial numbers of older African American men. In particular there is a paucity of neuroimaging data onolder African American men in the years prior to and during cognitive decline to AD. We will utilize a cross-sectional study of older urban African American men to characterize genetic social and environmentalinfluences on the brain and neural markers indicative of cognitive status and AD risk. My training application willnot only advance our understanding of neural changes and brain activity in older African American menespecially those exposed to conditions that put them at high risk for AD but how their brain health relates tobehavioral genetic neural lifestyle social and environmental risk factors. Using observational study during theK99 phase I will capture brain and neural pathways to cognitive changes/decline in African Americans whileundergoing extensive training to gain mastery of neuroimaging tools and concepts proficiency in examining brainimage biomarkers neuropsychological assessments and task-based fMRI testing and analyses. In the R00phase we will examine the neural pathways through which social and environmental factors impact cognitionand identify individual variability that moderates their impact. Also we will explore if social and environmentalinfluences are mediated by their effect on the APOE 4 and ABCA7-80 genes to impact cognitive status and ADrisk in older African American men. Understanding the mechanisms involved in brain health and AD risk in olderAfrican American men will improve our knowledge of how AD affects men and which tailored interventions aremost effective for mitigating AD risk and improving cognitive function in African American men. The developmentof tailored interventions is increasingly urgent given the increase in the number of African American older adultsexperiencing AD and the AD-associated burdens to the individuals families and communities. At the end of theK99 I will have obtained intensive training experience in structural and functional neuroimaging analytictechniques and increased my knowledge of cognitive and genetic markers of AD. Further I will have gainedadditional expertise in aging-related chronic illness risk reduction in pre-clinical African American men. Theexpertise would serve as a basis for my R00 and future independent research where I would focus on social andenvironmental determinants of health to observe and document factors that impact brain health and preventAlzheimers disease in urban African American men.

project_terms:
Affect;African American;African American population;Age;Aging;Alzheimer's Disease;Alzheimer's disease diagnosis;Alzheimer's disease related dementia;Alzheimer's disease risk;Behavioral;Biological Markers;Brain;Brain imaging;Brain region;Chronic Disease;Cognition;Cognitive;Communities;Cross-Sectional Studies;Data;Dementia;Development;Diabetes Mellitus;Diagnosis;Diagnostic tests;Diet;Discrimination;Disease Progression;Early Diagnosis;Enrollment;Environmental Risk Factor;Exposure to;Family;Functional Magnetic Resonance Imaging;Future;Genes;Genetic;Genetic Markers;Genomics;Health;Hypertension;Impaired cognition;Individual;Intervention;Investigation;Knowledge;Life Style;Low income;Measures;Mediating;Mediator;Mentors;Moderate Activity;Neighborhoods;Neural Pathways;Neurologic Symptoms;Neuropsychology;Observational Study;Pathway interactions;Patient Self-Report;Phase;Physical activity;Prefrontal Cortex;Reporting;Research;Risk Marker;Risk Reduction;Smoking;Stress;Techniques;Testing;Training;Trauma;aging related;biomarker validation;brain health;brain pathway;caucasian American;cognitive change;cognitive function;cognitive neuroscience;cognitive training;comorbidity;coping;diagnostic accuracy;drinking;experience;health determinants;high risk;imaging biomarker;imaging study;improved;individual variation;insight;lifestyle factors;medial temporal lobe;men;mild cognitive impairment;neural;neuroimaging;older adult;pre-clinical;prevent;racism;risk variant;sleep quality;social;social factors;tool;urban dwelling;urban setting

public_health_relevance:
PROJECT NARRATIVEWe know little of the pathway to brain health in African American men mainly because therehave been notably few brain imaging studies that included substantial numbers of older AfricanAmerican men. My proposed research will examine cognition and AD risk markers testdiagnostic accuracy and characterize brain health in older cognitively healthy urban AfricanAmerican men. The results will provide insights toward identifying and validating markers ofbrain health and AD risk in African American mena necessary step to understanding how ADaffects men and which tailored interventions are most effective for mitigating AD.


application_id: 11126597
project_number: 5R01CA277946-03
project_title: Roles of mRNA Transfer in Cancer Cell-Platelet Communication
administering_ic: NCI
award_notice_date: 2025-06-24
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 277946
program_official: WATSON, JOANNA M
project_start_date: 2023-07-01
project_end_date: 2025-10-17
study_section: Tumor Evolution, Heterogeneity and Metastasis Study Section[TEHM]
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The interaction between cancer cells and platelets plays important roles in regulating cancer cell function.Understanding how platelets communicate with cancer cells to modulate cancer cell colonization at distantorgans may identify novel strategies to halt cancer spreading. We recently showed that recruitment of platelet tocancer cells is essential for the colonization of circulating tumor cells (CTCs) at the secondary organs. Howeverthe molecular mechanism by which platelets modulate cancer cell function to promote cancer cell colonizationremains to be determined. By analyzing RNA-seq data from CTCs and primary tumors we found that platelet-specific mRNA was significantly enriched in CTCs. RNAscope and Translating Ribosome Affinity Purification(TRAP) analyses showed the delivery of platelet mRNA and translation of platelet-derived mRNA in cancer cells.In vivo functional screening identified multiple platelet-derived mRNAs contribute to colonization of breast cancercell at distant organs. These results reveal the new role of platelet mRNA in mediating intercellularcommunication and in promoting cancer cell spreading. The overall objective of this proposal is to define themolecular mechanism by which platelet mRNA is delivered into breast cancer cells and determine roles of plateletmRNA as the signaling molecular in promoting cancer cell colonization at distant organs. We showed that CD9expression in CTCs correlated with the accumulation of platelet-specific mRNA. Silencing CD9 in breast cancercells significantly reduced platelet mRNA transferring and colonization of cancer cells. Platelet factor 4 (PF4) isa small cytokine belonging to the CXC chemokine family that is highly expressed in platelets. We showed thatthe transfer of PF4 mRNA from platelets to breast cancer cells enhanced stemness and colonization of cancercells. Based on these results the central hypothesis of this proposal is that the CD9-dependent mRNA transfermediates the platelet-cancer cell communication and promotes cancer cell stemness. We propose the followingtwo aims to test this hypothesis and achieve our objective. Aim 1. Elucidate the mechanism by which plateletmRNA is transferred into cancer cells. Aim 2. Determine how the transfer of platelet PF4 mRNA in cancer cellspromotes cancer metastasis.

project_terms:
Affinity Chromatography;Binding Proteins;Biological Assay;Biology;Blood Platelets;Breast Cancer Cell;CXC Chemokines;CXCR4 Receptors;CXCR4 gene;Cancer Patient;Cell Communication;Cell Physiology;Cell fusion;Cells;Co-Immunoprecipitations;Communication;Complex;Cytokine Activation;Data;Distant;Family;Galectin 3;Genes;Genetic Engineering;Hematogenous;Incidence;Knockout Mice;Knowledge;Malignant Breast Neoplasm;Malignant Neoplasms;Mediating;Membrane Fusion;Membrane Proteins;Messenger RNA;MicroRNAs;Microfluidic Microchips;Molecular;Neoplasm Circulating Cells;Neoplasm Metastasis;Organ;PF4 Gene;Pathway Analysis;Pathway interactions;Play;Population;Positioning Attribute;Primary Neoplasm;Proteins;Recurrence;Regulation;Research;Ribosomes;Role;Signal Transduction;Small RNA;Stromal Cell-Derived Factor 1;Testing;Tissues;Translating;Translations;breast cancer progression;cancer cell;cancer cell stemness;cancer genetics;carcinogenesis;chemokine;confocal imaging;cytokine;extracellular vesicles;gain of function;genetic signature;human data;in vivo;inhibitor;insight;intercellular communication;loss of function;mRNA delivery;mouse model;multidisciplinary;neoplastic cell;novel;novel strategies;protein complex;recruit;screening;small molecule;stemness;therapeutic target;tissue culture;transcriptome sequencing;tumor progression

public_health_relevance:
Defining how mRNA transferring mediates the platelet-cancer cell interaction will fill a critical gap in ourknowledge about the intercellular communication during cancer progression. Elucidating the mechanism bywhich CD9 regulates platelet mRNA transferring will significantly expand our understanding about cell fusion inthe platelet-cancer cell interaction and help to identify a potential therapeutic target to suppress the platelet-induced cancer progression and metastasis. The study of platelet PF4 mRNA in regulating cancer cell stemnesswill reveal a chemokine regulation pathway and new roles of PF4 in cancer cell colonization.


application_id: 11126090
project_number: 5P01AG078116-04
project_title: Project 4 - Astrocytic KATP channels in LATE+HS
administering_ic: NIA
award_notice_date: 2025-05-27
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7475
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT 4 SUMMARY/ABSTRACTAn astrocyte mechanism will be targeted with the goal of preventing a common subtype of dementia. Limbic-predominant age-related TDP-43 encephalopathy (LATE) and hippocampal sclerosis (HS) pathology arepresent at autopsy in approximately 25% of Alzheimers-type dementia cases. Notably a specific ABCC9gene variant is associated with increased risk of developing LATE+HS. ABCC9 encodes a protein that servesas a metabolic sensor linking brain hypoxia and stress to changes in intracellular calcium and blood flow.We hypothesize that dysregulation of ABCC9 in astrocytes causes or exacerbates LATE+HS via impairedcerebrovascular function hypometabolism (with ionic dyshomeostasis) and neuronal hyperexcitabilityaligning perfectly with themes of this P01. These astrocyte mechanisms can be targeted by a well-tolerateddrug (nicorandil) that has been shown to be clinically safe and effective with high potential public healthimpact. The research will be conducted with the following Specific Aims: Aim 1: Characterize ABCC9/SUR2transcripts and proteins in human astrocytes. We will test the hypothesis that the ABCC9 genetic variantassociated with LATE+HS risk is also associated with decreased ABCC9 expression in astrocytes. AstrocyteABCC9 transcripts are mostly unknown. In human samples we will evaluate the repertoire of mRNAtranscripts and splicing in astrocytes. We will characterize ABCC9 gene expression with RNA-Seq dataacross cell types. In genotyped human brains from Core C (LATE+HS and controls) we will evaluate ABCC9proteins immunohistochemically and we will explore Sur2 expression in mouse models. Aim 2: Test thehypothesis that modulation of astrocytic ABCC9//KATP leads to improved neurovascular and metabolicfunction in LATE+HS model mice. The novel (TetR-TDP) mouse an excellent animal model that has provenhippocampal cell loss astrocytosis TDP-43 proteinopathy and memory impairment will be used to test theimpact of astrocyte specific ABCC9 upregulation on neurovascular function (multiphoton to look atneurovascular coupling and vessel leakiness; MRI to look at cerebral blood flow and other endpoints). Theimpact of astrocyte specific upregulation of SUR2B on brain metabolism will also be tested (glutamate uptakein astrocytes; Ca2+ dynamics [GCaMP]; and MRS to characterize brain metabolites). Aim 3: Test thehypothesis that pharmacological modulation with nicorandil (a KATP channel agonist well-tolerated in oralpreparations) leads to improved neuronal and astrocyte function and neurobehavioral assessment outcomesin TetR-TDP mice. These outcomes will include readouts of neurobehavioral parameters (RAWM and Y-maze) and other endpoints including electrophysiological assessments in astrocytes. Follow-up assessmentswill include detailed neuropathology (astrocytosis HS TDP-43 proteinopathy and small vessel morphology).In summary while studying the mechanisms of astrocyte metabolic and neurovascular pathophysiology inLATE+HS we hope to test a novel therapeutic strategy.

project_terms:
Agonist;Alzheimer's Disease;Alzheimer's disease related dementia;Animal Model;Animals;Astrocytes;Astrocytosis;Automobile Driving;Autopsy;Binding;Blood Vessels;Blood flow;Brain;Brain Hypoxia;CRSP3 gene;Calcium;Cerebrovascular Circulation;Cerebrum;Clinical;Collaborations;Data;Dementia;Disease;Dose;EEF1A2 gene;Elderly;Electrophysiology (science);Evaluation;Functional disorder;Gene Expression;Genes;Genetic Variation;Genotype;Glutamates;Goals;Human;Image;Immunohistochemistry;Impairment;Ischemic Preconditioning;Knowledge;Link;Magnetic Resonance Imaging;Measures;Memory impairment;Messenger RNA;Metabolic;Methods;Microscopy;Modeling;Morphology;Mus;Nerve Degeneration;Neurons;Nicorandil;Oral;Outcome;Outcome Assessment;Pathologic;Pathology;Persons;Pharmaceutical Preparations;Physiology;Play;Potassium Channel;Preparation;Proteins;Public Health;RNA Splicing;Reporting;Research;Resources;Risk;Role;Sampling;Signal Transduction;Slice;Stress;TDP43 proteinopathy;Testing;Transcript;Upregulation;Western Blotting;biological adaptation to stress;brain metabolism;cell type;cerebrovascular;data management center;disorder control;drinking water;follow up assessment;genetic variant;gliovascular;hippocampal cell loss;hippocampal sclerosis;improved;in vivo;limbic-predominant age-related TDP-43 encephalopathy;member;mouse model;multi-photon;multidisciplinary;neurobehavioral;neurobehavioral test;neuropathology;neurovascular;neurovascular coupling;novel;novel therapeutic intervention;pharmacologic;prevent;sensor;single-cell RNA sequencing;skills;sulfonylurea receptor;transcriptome sequencing;two-photon;uptake


application_id: 11126088
project_number: 5P01AG078116-04
project_title: Project 3 - Astrocytic glutamate dysregulation in AD and VCID
administering_ic: NIA
award_notice_date: 2025-05-27
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7473
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT 3  ABSTRACT SUMMARYIn alignment with the overall P01Strategies for targeting Astrocyte Reactivity in AD and ADRD Project 3 willtarget the astrocyte glutamate transporter EAAT2/Glt-1 (gene name SLC1A2) and assess the impact oncerebrovascular function metabolism and neural network activity in Alzheimers disease (AD) and relateddementias (ADRD). We and other groups have shown that SLC1A2 levels are reduced in AD and ADRD achange that is recapitulated in many AD and ADRD mouse models. SLC1A2 is well known to guard againstexcitotoxic damage to synapses by minimizing synaptic glutamate spillover. This mechanism has been studiedin many different disease models. However much less is known about whether SLC1A2 similarly preventsglutamate from adversely affecting astrocyte endfeet and cerebrovessels which are widely known to undergodysfunction in AD and ADRD. SLC1A2 is also well known to drive the production of lactate a key componentof the astrocyte-neuron lactate shuttle. Nonetheless few studies have investigated the possibility that loss ofSLC1A2 in reactive astrocytes impairs lactate shuttling leading to hypometabolism (another well-characterizedpathology in AD and ADRD). We hypothesize that the loss of SLC1A2 is a key loss of function phenotypeof reactive astrocytes that underlies impaired cerebro-vascular function/integrity hypometabolism and disruptedneural network activity in AD and ADRD. We will test this hypothesis across three Aims using two astrocyte-targeting approaches: a restoration approach where we use AAV-Gfa2 to overexpress SLC1A2 in astrocytesof a comorbid A/vascular model (5xFAD mice with hyperhomocystenemia) and a knockdown approach wherewe will use AAV-GfaP-Cre to knock-down astrocytic SLC1A2 in FLOX-SLC1A2 mice. Aim 1 will determine theimpact of SLC1A2 modulation on astrocyte Ca2+ signaling endfeet and BBB integrity cerebral blood flow andneurovascular coupling using two photon (2P) imaging in awake mice and MRI (in anesthetized mice). Aim 2will determine the impact of SLC1A2 modulation on lactate and glucose signaling in awake mice usingmicroelectrode arrays. And Aim 3 will test the effects of SLC1A2 modulation on neuronal network fidelity andsynaptic function and plasticity using either 2P imaging of awake mice or electrophysiology on in situ brain slices.Points of interaction: All functional outcomes are assessed in our Animal Vascular-Metabolic-Neural Networkcore (Core B). Interrelationships between different astrocyte pathways (MMP9 modulation /Project 1 Insulinreceptor modulation/Project 2 and KATP modulation/Project 4) will be assessed as a function of AD and ADRDcomorbidities through the shared use of postmortem tissue across projects (cerebrovascular pathology/Project1 amyloid pathology/Project 2 amyloid+vascular pathology/Project 3 LATE + hippocampal sclerosispathology/Project 4). Similar interrelationships will be assessed across comorbidities in shared postmortemhuman biospecimens (Core C Human Consultation-Biosamples-Biomarkers). All data will flow into our DataManagement and Biostatistics Core (Core D) for analysis of endpoint measures both within and across projects.

project_terms:
Address;Affect;Alzheimer's Disease;Alzheimer's disease related dementia;Amyloid;Amyloid beta-Protein;Anesthesia procedures;Animals;Astrocytes;Attention;Autopsy;Biochemical;Biological Markers;Biostatistics Core;Blood Vessels;Blood flow;Brain;Cerebrovascular Circulation;Collaborations;Consultations;Data;Dementia;Electrophysiology (science);Endothelial Cells;Enterobacteria phage P1 Cre recombinase;Enzymes;Functional disorder;Genes;Glucose;Glucose Transporter;Glutamate Transporter;Glutamates;Human;Hyperhomocysteinemia;Image;Impairment;In Situ;Individual;Insulin Receptor;Intervention Strategies;Knowledge;Lactate Transporter;MMP9 gene;Magnetic Resonance Imaging;Measures;Metabolic;Metabolic dysfunction;Metabolism;Microelectrodes;Microvascular Dysfunction;Modeling;Mus;Names;Neurons;Outcome Assessment;Pathology;Pathway interactions;Phenotype;Production;Property;Proteins;Receptor Signaling;Rest;Role;Signal Transduction;Slice;Synapses;Synaptic plasticity;Testing;Tissues;Vibrissae;Work;amyloid pathology;awake;barrel cortex;calmodulin-dependent protein kinase II;cerebrovascular;cerebrovascular pathology;comorbidity;data management;disease model;excitotoxicity;extracellular;functional outcomes;hippocampal sclerosis;human tissue;knock-down;loss of function;mouse model;network dysfunction;neural network;neuroinflammation;neurotoxicity;neurovascular coupling;neurovascular unit;novel therapeutic intervention;overexpression;prevent;restoration;synaptic function;two-photon;vascular amyloidosis;vascular cognitive impairment and dementia;vascular contribution to Alzheimer's Disease;vector


application_id: 11126086
project_number: 5P01AG078116-04
project_title: Project 2 - Astrocytic insulin signaling and AD
administering_ic: NIA
award_notice_date: 2025-05-27
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7470
contact_pi_person_id: 8361727
contact_pi: THIBAULT, OLIVIER
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 2  ABSTRACT/SUMMARYIn alignment with the overall proposal and goal of this P01 Strategies for Targeting Astrocyte Reactivity in ADand ADRDwe believe astrocytes can be targeted to impact a multitude of functions known to be dysregulatedin Alzheimers disease (AD) and AD-related dementias (ADRD) because of their close physical proximity to othercell types and essential role in brain metabolism. It is our intention to use an astrocyte-centric approach todiscover new pathways and signals previously uncharacterized in vivo in order to better address future therapiestargeting the health of astrocytes in AD. Here we will test the hypothesis that elevating insulin signalingspecifically in astrocytes in mouse models of AD-like pathology will normalize cerebrovascular metabolicand neuronal Ca2+ network changes commonly associated with AD and ADRD. We will combine our expertiseusing intranasal insulin (INI) delivery in combination with two-photon (2P) microscopy in the 5xFAD mouse modelof AD-like pathology to investigate astrocyte-specific overexpression and knockdown of insulin receptors (IR) inthe brain and will characterize the impact of this manipulation on: (Aim 1) neurovascular unit (NVU) functionusing red blood cell flow measures; (Aim 2) astrocytic and neuronal bioenergetics using fluorescent measuresof ATP/ADP ratios glucose imaging using 2-NBDG and glucose and lactate levels using multi-electrode arrays(MEAs); and (Aim 3) neuronal/ astrocytic Ca2+ networks using GCaMP6 fluorescent measures of Ca2+. Resultsin 5xFAD males and females will be compared to age-matched WT littermates. All imaging experiments will beconducted in the somatosensory cortex (S1) at rest and during ambulation in head-fixed mice. We willcorroborate some of our results with hippocampal investigations using electrophysiology in the slice and alsomeasure spatial and memory processes using the radial arm water maze (RAWM). Our work will investigatenetworks of neurons astrocytes and blood vessels as targets of amyloidogenesis and vascular impairmentacross sex and will also test the hypothesis that astrocytes represent a target of INI in the brain and can helpregulate the onset of Ca2+ dysregulation. Together a conceptually novel and experimentally rich set of data willbe extracted in order to address new potential therapeutic targets in AD and ADRD and to elucidate howparticular elements of the NVU integrate to maintain function in health and disease. Under the leadership of CoreA our proposed collaborations with the other projects and cores sharing resources and expertise will provide aunique opportunity to share experimental protocols data results and interpretation across groups and will leadto a thorough and unprecedented characterization of astrocytic reactivity through the lens of experienced leadersin the field. This project within the context of the P01 could lead to a paradigm shift such that astrocyte healthand reactivity are considered along with other biological manifestations of AD in the clinic 1 perhaps switchingfrom the ATN classification (amyloid/tau/neuron degeneration) to the ATRAN (amyloid/tau/reactiveastrocytes/neuron degeneration) classification.

project_terms:
Address;Age;Aging;Alzheimer like pathology;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease model;Alzheimer's disease patient;Alzheimer's disease related dementia;Amyloid;Astrocytes;Attention;Autopsy;Behavior;Bioenergetics;Biological;Blood - brain barrier anatomy;Blood Vessels;Blood flow;Brain;Cells;Classification;Clinic;Clinical;Cognition;Collaborations;Coupled;Coupling;Data;Data Set;Disease;Electroencephalography;Electrophysiology (science);Elements;Environment;Erythrocytes;Female;Frequencies;Future;Gene Expression Regulation;Glial Fibrillary Acidic Protein;Glucose;Glucose Transporter;Goals;Head;Health;Hippocampus;Human;Image;Impairment;In Situ;Injections;Insulin;Insulin Receptor;Insulin deficiency;Intention;Investigation;Knockout Mice;Knowledge;Leadership;Learning;Magnetic Resonance Spectroscopy;Measures;Metabolic;Metabolism;Microscopy;Modeling;Mus;Nerve Degeneration;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Pathway interactions;Physiology;Play;Protocols documentation;Radial;Receptor Signaling;Reporting;Resolution;Resource Sharing;Rest;Rodent;Role;Sampling;Series;Signal Transduction;Site;Slice;Somatosensory Cortex;Specimen;Surface;Testing;Time;Translating;Work;adeno-associated viral vector;aged;amyloid pathology;amyloidogenesis;arm;brain dysfunction;brain metabolism;cell type;cellular targeting;cerebrovascular;cognitive function;data management center;density;experience;experimental study;glucose sensor;glucose uptake;in vivo;insulin signaling;knock-down;large datasets;lens;male;memory process;mouse model;multi-electrode arrays;neurovascular unit;novel;overexpression;promoter;rhodamine dextran;sex;targeted treatment;tau Proteins;therapeutic target;two-photon;vector;water maze


application_id: 11126084
project_number: 5P01AG078116-04
project_title: Project 1 - Astrocytic end-feet and VCID
administering_ic: NIA
award_notice_date: 2025-05-27
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7469
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT 1 ABSTRACT/SUMMARYVascular contributions to cognitive impairment and dementia (VCID) are a major cause of dementia both aloneand co-morbid with Alzheimers disease (AD) and AD Related Dementias (ADRD). Astrocytic end-feet arephysically anchored to the vascular basement membranes via dystroglycan complexes. At the end-feet arepotassium and water channels Kir4.1 and aquaporin 4 (AQP4) as well as monocarboxylic acid transporters(MCTs). AQP4 and Kir4.1 channels are polarized at the end-foot and are co-anchored via a -syntrophin-dystrophin 1 complex. We have found that cerebral small vessel disease (cSVD) induced byhyperhomocysteinemia (HHcy) resulted in degeneration and dissociation of the astrocytic end-feet and anassociated loss of AQP4 and Kir4.1 from the end-feet. This suggests that the end-feet are particularlysusceptible to vascular injury and as such may mediate neuronal dysfunction and neurodegenerationassociated with dementia. We have observed increased activity of matrix metalloproteinases (MMPs) inparticular MMP9 coincident with astrocytic end-foot degeneration. We therefore hypothesize that MMP9 isnecessary and sufficient for astrocytic end-foot degeneration and associated neurovascular couplingand metabolic and ionic dyshomeostasis.We will test our hypothesis in mice by manipulating MMP9 in our well-characterized HHcy mouse model of VCIDand our multi-modal multi-faceted outcome measures leverage the specific expertise of our Cores includingintravital MRI/MRS and electrophysiological measures provided by Core B and human tissue images andbiospecimens from Core C. We collaborate extensively with Projects 2-4 to determine relationships betweenend-foot disruption and glutamate transporters K+ATP channels and insulin transporters. All data will flowthrough Core D to quantitatively assess relationships between MMP9 and astrocytic and neuronal function withinthis Project and across all Projects in our P01Strategies for Targeting Astrocyte Reactivity in ADRD P01.To test our hypothesis we propose three distinct aims. Specific Aim 1: MMP9 mediated astrocytic end-foot degeneration will result in cerebrovascular dysfunction impaired neurovascular coupling. Specific Aim 2: MMP9 mediated astrocytic end-foot degeneration will result in metabolic and ionicdyshomeostasis. Specific Aim 3: Astrocytic end-foot degeneration results in profound changes in gene and protein expression and end-foot proteins can be used as biomarkers of end-foot degeneration.

project_terms:
Alzheimer's Disease;Alzheimer's disease related dementia;Astrocytes;Autopsy;Basement membrane;Biochemical;Biological Markers;Blood Vessels;Brain;Brain region;Cerebral small vessel disease;Cerebrovascular Disorders;Collaborations;Complex;Data;Dementia;Dissociation;Dystroglycan;Dystrophin;Electrophysiology (science);Euthanasia;Gene Expression;Gene Expression Profile;Glutamate Transporter;Harvest;Hemorrhage;Histologic;Human;Hyperhomocysteinemia;Image;Impaired cognition;Inflammatory;Insulin;Lasers;MMP9 gene;Magnetic Resonance Imaging;Matrix Metalloproteinases;Measurement;Measures;Mediating;Metabolic;Microelectrodes;Microscopy;Monocarboxylic Acid Transporters;Mus;Nerve Degeneration;Neuronal Dysfunction;Neurons;Outcome Measure;Pathology;Perfusion;Plasma;Potassium Channel;Predisposition;Proteins;Radial;Regulation;Slice;Testing;Time;Water;Wild Type Mouse;Work;aquaporin 4;arm;awake;candidate identification;candidate marker;cerebrovascular reactivity;comorbidity;cytokine;digital;human tissue;in vivo;mouse model;multimodality;neurovascular coupling;neurovascular pathology;novel;object recognition;overexpression;protein expression;syntrophin;two-photon;vascular cognitive impairment and dementia;vascular injury;water channel;water maze


application_id: 11126082
project_number: 5P01AG078116-04
project_title: Core D - Data Management and Statistics Core
administering_ic: NIA
award_notice_date: 2025-05-27
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7467
contact_pi_person_id: 12221415
contact_pi: KATSUMATA, YURIKO
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:
CORE D- ABSTRACT/SUMMARY The Data Management and Biostatistics (DMB) Core is an integral component of our team projectStrategies for Targeting Astrocyte Reactivity in Alzheimers Disease (AD) and AD related dementia (STAR-ADRD). The goal of the DMB Core is to provide a comprehensive multi-disciplinary resource for four STAR-ADRD projects by constructing and maintaining a centralized data repository and drawing biostatistical expertisefor the completion of their research. A unique aspect of this Core is the design and utilization of a StructuredQuery Language (SQL) server to store analytical data and metadata related to the four projects in a singlelocation for cross-project integration. The DMB Core will closely and regularly interact with other investigators toensure that all data are collected and deposited in alignment with the goal of generating rigorous andreproducible data repository. Given that interdisciplinary research requires researchers to use methods and datafrom a range of disciplines the role of the DMB Core is vital to the success of the STAR-ADRD team. The DMBCore will support these responsibilities through the following specific aims.Aim 1: Maintain and expand an integrated data warehouse and suite of Browser-based data collectionapplications and reporting platforms for the STAR-ADRD Cores and projects. Data management efforts will focuson collecting storing and sharing high quality data according to the standard operating procedures.Aim 2: Provide expertise on tailored and integrated statistical analyses. The DMB Core will provide statisticalanalyses individually tailored to the STAR-ADRD projects and Cores needs. The DMB Core will actively interactwith STAR-ADRD investigators examine their research hypotheses plan and suggest appropriate statisticalanalysis methods and models build tailored analysis pipelines interpret and discuss results create graphs andtables for presentations and manuscripts and write the statistical analysis section in manuscripts. Further theDMB Core will develop and apply statistical methodology on data harmonized and integrated across the fourSTAR-ADRD projects.Aim 3: Host training in data management practices for the research team. The DMB Core will offer in-person (orZoom) data quality and management workshops with the entire STAR-ADRD team. The materials developedand used for workshops will be documented and shared with STAR-ADRD team members. All four projects proposed in this P01 require data management and biostatistical expertise to ensure thatall data are reliable and statistically analytical. The DMB Core will play a key role in facilitating synergies acrossthe STAR-ADRD projects and Cores.

project_terms:
Alzheimer's Disease;Alzheimer's disease related dementia;Animals;Astrocytes;Binding;Bioinformatics;Biometry;Biostatistical Methods;Biostatistics Core;Communication;Complex;Computers;Data;Data Analyses;Data Collection;Data Security;Data Set;Data Storage and Retrieval;Database Management Systems;Deposition;Directories;Discipline;Educational workshop;Electrophysiology (science);Ensure;FAIR principles;Foundations;Goals;Graph;Human;Individual;Interdisciplinary Study;Language;Linux;Location;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Manuscripts;Metadata;Methodology;Methods;Microelectrodes;Mission;Modeling;Perception;Persons;Phase;Play;Practice Management;Procedures;Proteomics;Pythons;Quality Control;Reporting;Reproducibility;Research;Research Activity;Research Personnel;Research Support;Resource Sharing;Resources;Role;Secure;Series;Services;Standardization;Statistical Data Interpretation;Structure;System;Technology;Time;Training;Writing;analysis pipeline;biomedical imaging;data format;data harmonization;data integration;data integrity;data management;data quality;data repository;data reuse;data standards;data visualization;data warehouse;design;experimental study;large scale data;member;metabolomics;multi-photon;multidisciplinary;predictive modeling;statistics core;success;synergism;transcriptomics


application_id: 11126080
project_number: 5P01AG078116-04
project_title: Core C - Human Consultation-Biosamples-Biomarkers Core
administering_ic: NIA
award_notice_date: 2025-05-27
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7464
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
CORE C: HUMAN CONSULTATION BIOSAMPLES BIOMARKERS (CBB)ABSTRACTThe Human Consultation Biosamples Biomarkers (CBB) Core (Core C) will complement and integrate theProjects of the P01 Strategies for Targeting Reactive Astrocytes in AD and ADRD. It is critical to validatethe translational relevance of mechanistic mouse models and to extend those results toward further clinicalstudies. Yet there are challenges when it comes to addressing the complex pathobiology of the dementia clinicalsyndrome. Core C will bridge those critical gaps through the following Specific Aims: Aim 1: Optimizeclinically-relevant study design and manage ongoing data streams incorporating human biomarker andautopsy data. This Aim will foster integration organization coherence and documentation for Core C. Themultimodal data include molecular metabolic and network-wide domains in human endophenotypes andhuman preclinical and clinical endpoints. Aim 2: From existing autopsy material and data generate a setof human cases from the UK-ADRC that encompasses the AD/ADRD phenotypes studied in all 4Projects (AD VCID LATE+HS and controls) and provides a common basis for downstream biochemicaland neuropathological endpoint assessments relevant to the Projects. We will analyze a panel of 100cases for this Aim. Aim 2a: Biochemistry. We will perform multi-level protein extracts and run immunoblotswith quantitative measurements on each sample with astrocytic proteins (e.g. AQP4 Kir4.1 GFAP SLC1A2ABCC9/SUR2 Insulin receptor) being studied in the Projects. We will separately assess snap-frozenhippocampal samples as well as frontal cortex (Brodmann Area 9) white matter and gray matter seperately.Aim 2b: Neuropathology. Neuropathologic endpoints will be characterized in a quantitative manner in thesame panel of 100 cases: Astrocytosis (GFAP+) A plaques TDP-43 proteinopathy and Tau tangles. Wealso will perform highly quantitative assessments of blood vessel morphology using CD34 (capillaries) and ?-SMA (arteriole) markers. Double-label IFC will characterize IR and SUR2 proteins cellular distributions.Samples will also be genotyped for ABCC9 risk alleles. Aim 3: From existing clinical outcome measuresgenerate a set of biomarker (in vivo) data from human participants that represents a common basis fordownstream biofluids and neuroimaging endpoint assessments relevant to the projects. Aim 3A:Neuroimaging. A 3D anatomical magnetization-prepared rapid acquisition with gradient echo (MPRAGE)cerebrovascular reactivity (CVR) from existing human imaging on a 3T MRI scanner will be generated andprovided to Projects and Core D. Drs. Powell and Bahrani in Core C are also performing parallel neuroimagingexperiments in mice (Core B). Aim 3B: Fluid Biomarkers. Cerebrospinal fluid (CSF) and plasma that arebanked from UK-ADRC and UK-MarkVCID participants will be assayed for MMP9 and GFAP using QuanterixSimoa assays and AQP4 Kir4.1 and Dp71 will be assayed using a standard colorimetric ELISA method.

project_terms:
3-Dimensional;ABCC9 gene;Address;Alzheimer's disease related dementia;Amyloid beta-Protein;Anatomy;Astrocytes;Astrocytosis;Automobile Driving;Autopsy;Biochemical;Biochemistry;Biological Assay;Biological Markers;Blood Vessels;Blood capillaries;Brain;Brodmann's area;CD34 gene;CRSP3 gene;Cerebrospinal Fluid;Clinical;Clinical Research;Complement;Complex;Consultations;Data;Data Management Resources;Dementia;Diagnosis;Documentation;Enzyme-Linked Immunosorbent Assay;Experimental Models;Fostering;Freezing;Funding;Genotype;Glial Fibrillary Acidic Protein;Hippocampus;Human;Image;Immunofluorescence Immunologic;Infrastructure;Insulin Receptor;Label;Liquid substance;Longitudinal cohort;MMP9 gene;Magnetic Resonance Imaging;Measurement;Measures;Metabolic;Methods;Molecular;Morphology;Mus;Neocortex;Neurofibrillary Tangles;Neuropsychology;Participant;Phenotype;Plasma;Proteins;Research;Research Design;Resources;Running;Sampling;Senile Plaques;Structure;Syndrome;TDP43 proteinopathy;Testing;Therapeutic Intervention;Tissues;Translating;Translational Research;Translations;Triton X100;United States National Institutes of Health;Urea;Western Blotting;Work;alpha synuclein;arteriole;biobank;biomarker identification;blood oxygen level dependent;cerebrovascular reactivity;clinical diagnosis;clinical material;clinical outcome measures;clinically relevant;data modeling;data streams;endophenotype;experimental study;frontal lobe;gray matter;human data;human imaging;human subject;in vivo;meetings;mouse model;multimodal data;neuroimaging;neuropathology;pre-clinical;protein TDP-43;risk variant;sarkosyl;specific biomarkers;synergism;tau Proteins;white matter


application_id: 11126077
project_number: 5P01AG078116-04
project_title: Core B - Animal Vascular-Metabolic-Neural Network Core
administering_ic: NIA
award_notice_date: 2025-05-27
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7461
contact_pi_person_id: 10287198
contact_pi: SOMPOL, PRADOLDEJ
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:
CORE B - ABSTRACTThe goals of the Mouse VMN (vascular metabolism network) Core B are to serve the P01 Projects with cutting-edge methods specifically tailored to the P01 themes: Strategies for Targeting Astrocyte Reactivity in AD andADRD (STAR-AD-ADRD). Astrocytes support brain function by integrating their roles with several cell types.They support neurons and regulate blood flow to supply and preserve active brain regions. Astrocytes becomereactive in Alzheimers disease (AD) and Alzheimers disease related dementias (ADRD) and their functions arenot fully understood. Our group at the Sanders-Brown Center on Aging including Drs. Wilcock Thibault Norrisand Nelson investigate roles of astrocytes neurons and vascular pathology in aging and AD/ADRD brain. Theseresearch topics are inter-connected and the success of this P01 will move our understanding of reactiveastrocytes beyond neuroinflammation constraints. Our VMN Core will provide multiple approaches tocharacterize the roles of reactive astrocytes on cerebrovascular function brain metabolism and neuronal networkactivity. Moreover results uniformly generated from our core will permit useful comparisons across projects. TheSpecific aims are to: (1) Coordinate for small animal surgeries and intravital imaging techniques includingtraining and oversight. (2) Coordinate all brain slice electrophysiology experiments. (3) Coordinate and provideservice for microelectrode array experiments. (4) Coordinate and provide service for Magnetic ResonanceImaging experiments. Furthermore our Core will work with the DMB (Data Management and Biostatistics)Core D where the results will be stored processed and easily accessed from our collaborative groups both inUK and beyond.

project_terms:
Acute;Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease related dementia;Animals;Astrocytes;Biological Assay;Biological Markers;Biometry;Blood Vessels;Blood flow;Brain;Brain region;Cells;Cephalic;Cerebrovascular Disorders;Cerebrovascular system;Chronic;Consultations;Craniotomy;Data;Data Analyses;Data Collection;Dementia;Electrophysiology (science);Ensure;Faculty;Gene Delivery;Goals;Human;Human Pathology;Human Resources;Image;Image-Guided Surgery;Imaging Techniques;Impairment;Injections;Kentucky;Laser Speckle Imaging;Magnetic Resonance Imaging;Metabolic;Metabolism;Methods;Microelectrodes;Microscopy;Monitor;Mus;Neurons;Operative Surgical Procedures;Pathology;Phenotype;Physiological;Physiology;Postdoctoral Fellow;Preparation;Procedures;Process;Property;Protocols documentation;Research;Resources;Role;Services;Signal Pathway;Signal Transduction;Slice;Students;Synaptic Transmission;Synaptic plasticity;Techniques;Testing;Thinness;Training;Universities;Vibrissae;Work;brain cell;brain metabolism;cell type;cerebrovascular;cohesion;cranium;data management;experience;experimental study;imaging facilities;implantation;in vivo;intravital imaging;knock-down;molecular pathology;mouse model;neural network;neurochemistry;neuroinflammation;novel;patch clamp;preservation;success;two-photon


application_id: 11126073
project_number: 5P01AG078116-04
project_title: Core A - Administrative Core
administering_ic: NIA
award_notice_date: 2025-05-27
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7460
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
CORE A  ABSTRACT SUMMARYThe role of Core A (Administrative) is to provide leadership promote cohesion and ensure fiscal oversight forthe P01 Strategies for Targeting Reactive Astrocytes in AD and ADRD. En route to stimulating and fosteringinteractions among the P01 team Core A will provide common resources manage budgetary issues and fulfilladministrative obligations to the University and to the NIH/NIA. These services will allow the Projects and Coresof the P01 to focus on the Science and reconceptualize the role of reactive astrocytes in the pathophysiologyof Alzheimers disease (AD) and related dementias (ADRDs). The Aims of Core A are: (1) Provide coordinatedand coherent infrastructure that enhances scientific activities. (2) Oversee animal colonies andproduction/characterization of AAV reagents. And (3) provide fiscal management and administrative support.The Administrative Core will facilitate timely and consistent oversight so that Projects and Cores can worktogether as a unit to study reactive astrocyte signaling in ADRDs.

project_terms:
Advisory Committees;Aging;Alzheimer's Disease;Alzheimer's disease related dementia;Animals;Astrocytes;Behavioral;Breeding;Budgets;Collaborations;Electrophysiology (science);Endowment;Ensure;Faculty;Feedback;Fostering;Functional disorder;Funding;Future;Genotype;Health;IACUC;Infrastructure;Leadership;Learning;Maintenance;Memory;Neurons;Nutritional Science;Pharmacology;Production;Progress Reports;Protocols documentation;Reagent;Recombinants;Research;Research Personnel;Resources;Role;Route;Science;Services;Signal Transduction;Source;United States National Institutes of Health;Universities;University adminstration;Update;Viral;Work;animal colony;cohesion;data sharing;meetings;mouse model;professor;success;symposium;vascular cognitive impairment and dementia;welfare


application_id: 11126072
project_number: 5P01AG078116-04
project_title: Strategies for targeting astrocyte reactivity in Alzheimer's disease and related dementias
administering_ic: NIA
award_notice_date: 2025-05-27
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
program_official: OPANASHUK, LISA A
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8(M4)
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
OVERALL  ABSTRACT SUMMARYThis P01 Strategies for Targeting Astrocyte Reactivity in AD and ADRD (STAR-ADRD) addresses the(patho)physiologic roles of reactive astrocytes in Alzheimers disease (AD) and related dementias (ADRD).Though highly significant to many disease phenotypes astrocyte functions are under-investigated and have yetto benefit from large-scale programmatic support from the NIH. To fill this void we have assembled a highlyaccomplished and collaborative team from the University of Kentucky Sanders-Brown Center on Aging (UK-SBCoA). The overarching goals of this project are to: (1) Use cell-specific targeting to modulate distinct aspectsof the reactive astrocyte phenotype. (2) Use cutting-edge technologies to assess the functional impact of reactiveastrocytes in intact preclinical mouse models of AD and ADRD pathologies. (3) Leverage UK-SBCoA and UK-Alzheimers Disease Research Center (ADRC) resources to validate preclinical results in postmortem and livinghuman subjects. And (4) Use an integrated data pipeline approach to analyze and interpret data within andacross projects. Through these aims we will test the hypothesis that: interrelated reactive astrocytephenotypes drive major pathophysiologic features of dementia including cerebrovascular dysfunctionhypometabolism and impaired neuronal network function and fidelity. Projects are designed around aclear understanding that dementia does not exist as a single pathological entity most of the time but rather ischaracterized by multiple brain pathologies. Project 1 (Astrocytic end-feet and VCID) will use MMP9overexpression/knockdown in a model of cerebral small vessel disease to address astrocyte endfeetdegeneration. Project 2 (Astrocytic insulin signaling and AD) will overexpress/knockdown astrocytic insulinreceptors (IR) in an A model to study the impact of impaired astrocytic IR signaling. Project 3 (Astrocyticglutamate transport in AD and VCID) will overexpress/knockdown the astrocytic glutamate transporter SLC1A2in a mixed A-vascular model to assess the role of impaired glutamate transport in reactive astrocytes. Project4 (Astrocytic KATP channels in LATE+HS) will overexpress/eliminate astrocytic ABCC9/SUR2 in a model ofLATE + hippocampal sclerosis to assess the role of KATP channels. Four Cores will support and further integrateour Projects. Core B: Animal Vascular-Metabolic-Neural Network (VMN) will assess cerebrovascular metabolicand neural network properties in mice using two-photon microscopy MRI/MRS microelectrode array neuro-chemistry and electrophysiology. Core C: Human Consultation-Biosamples-Biomarkers (CBB) will validateresults in mice using well characterized autopsy tissue MRI EEG and fluid biomarker data from humans. AndCore D: Data Management and Biostatistics will establish a data pipeline for efficient categorizationtransformation and statistical analysis of complex relationships between astrocyte interventions and endpointmeasures within and between projects. Finally an Administrative Core (Core A) will provide leadershipcoordination integration and administrative structure so that the P01 goals are achieved.

project_terms:
ABCC9 gene;Address;Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease related dementia;Amyloid beta-Protein;Animals;Area;Astrocytes;Attention;Autopsy;Awareness;Back;Biochemical Pathway;Biological Markers;Biology;Biometry;Blood Vessels;Brain;Brain Pathology;CRSP3 gene;Categories;Cells;Cerebral small vessel disease;Cerebrovascular Disorders;Communities;Complex;Consultations;Data Analyses;Dementia;Disease;Electroencephalography;Electrophysiology (science);Functional disorder;Future;Gene Expression Profiling;Glutamate Transporter;Glutamates;Goals;Grant;Human;Imaging Techniques;Impaired cognition;Impairment;Insulin Receptor;Intervention;Kentucky;Leadership;Liquid substance;MMP9 gene;Magnetic Resonance Imaging;Measures;Metabolic;Microelectrodes;Microglia;Modeling;Mus;Neurons;Pathologic;Pathology;Phenotype;Physiological;Property;Receptor Signaling;Recording of previous events;Renaissance;Research;Resources;Role;Signal Transduction;Statistical Data Interpretation;Structure;Techniques;Technology;Testing;Therapeutic;Time;Tissues;United States National Institutes of Health;Universities;biomarker validation;cerebrovascular;data integration;data management;data pipeline;design;disease phenotype;hippocampal sclerosis;human data;human subject;in vivo;insulin signaling;intravital imaging;knock-down;limbic-predominant age-related TDP-43 encephalopathy;mouse model;neural network;neurochemistry;neuroinflammation;novel therapeutic intervention;overexpression;pre-clinical;pre-clinical research;risk variant;two photon microscopy;vascular cognitive impairment and dementia

public_health_relevance:
OVERALL - NARRATIVEThis P01 will use cell specific targeting approaches and cutting edge in vivo assessment techniques inpreclinical mouse models validated by biomarker measures in human subjects to unravel the role(s) ofreactive astrocytes in the pathophysiology of Alzheimers disease and related dementias.


application_id: 11125954
project_number: 5R01DK126777-05
project_title: ABIN1 dysfunction in Lupus Nephritis
administering_ic: NIDDK
award_notice_date: 2025-07-01
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DK
serial_number: 126777
program_official: CHAN, KEVIN E
project_start_date: 2021-09-01
project_end_date: 2026-06-30
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 8638278
contact_pi: POWELL, DAVID W.
other_pis: CASTER, DAWN
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 SummaryLupus nephritis (LN) is a common and severe complication of systemic lupus erythematosus (SLE) andcurrent therapies are toxic and frequently ineffective. LN is more prevalent and more likely to cause kidneyfailure in African American patients [1-3]. SLE has strong genetic components but the relationship ofgenetic susceptibility to prognosis in African Americans is poorly understood. Previous studies showedvariants of TNIP1 are associated with SLE and LN susceptibility [4-7]. We reported a strong association forthe TNIP1 rs4958881 polymorphism with LN in African American patients from a large-scale SLEgenotyping study [8]. Our preliminary data show an association of the rs4958881 variants with severity andprogression of LN in African Americans. TNIP1 encodes the protein ABIN1 that functions as a physiologicalinhibitor of NF-B a prominent immune regulator [9 10]. We reported previously that loss of the molecularfunction of ABIN1 in mice results in SLE-like autoimmunity and glomerulonephritis [8 11 12].While there is evidence that ABIN1 regulation of NF-B plays a role in autoimmunity and development ofLN a number of critical gaps in knowledge remain. First what molecular mechanisms mediate ABIN1-dependent enhanced risk of LN and are they specific for different immune cell types? Second does alteredABIN1 function induced by TNIP1 polymorphisms play a role in the racial disparity of LN? Third do TNIP1polymorphisms have different pathologic molecular and cellular effects in African Americans comparedwith White Americans?Three Specific Aims are proposed to address these significant questions. Aim 1: Compare the Associationof theTNIP1 variant rs4958881 on LN in White and African Americans. Aim 2: Determine the effects of theTNIP1 variant rs4958881 on monocyte neutrophils and B cell activity in patients with LN. Aim 3. Determinethe mechanisms by which loss of ABIN1 molecular function alters monocyte neutrophil and B cell functionusing ABIN1 transgenic mice. The animal experiments will be interpreted in conjunction with similarexperiments in Aim 2 using the same cells isolated from blood of LN patients with the TNIP1 rs4958881 riskvariant.This is a Multi-PI proposal with a Cell and Molecular Biologist/Biochemist (Dr. David W. Powell) and aClinical Nephrologist/Scientist (Dr. Dawn J. Caster). These investigators have published many of thereports pertaining to TINIP1/ABIN1 function in LN via genetic and animal studies and are now poised withrecent preliminary findings to evaluate causative roles for a TNIP1 polymorphism in severity andprogression and specific cellular and molecular events in human LN. The translational and population-targeted nature of these studies will provide impactful insights that will lead to precision diagnostics andtherapeutics for high-risk African American LN patients.

project_terms:
Address;African American;African American population;Alleles;Animal Experiments;Animals;Autoimmunity;B-Lymphocytes;Binding Proteins;Biological Response Modifiers;Blood;Bone Marrow;CXCL10 gene;CXCR3 gene;Cell Maturation;Cell Physiology;Cell Separation;Cells;Clinical;Complication;Data;Development;Diffuse;Disease;Disease Outcome;Event;Functional disorder;Genes;Genetic;Genetic Polymorphism;Genetic Predisposition to Disease;Genotype;Glomerulonephritis;Human;Immune;Immune Complex Glomerulonephritis;Immunomodulators;Inflammation Mediators;Inflammatory;Interleukin-6;Investigation;Kidney;Kidney Failure;Knowledge;Lupus Nephritis;Mature T-Lymphocyte;Mediating;Molecular;Mus;Mutation;Nature;Nuclear;Outcome;Pathologic;Patients;Peripheral;Physiological;Polyubiquitin;Precision therapeutics;Predisposition;Production;Prognosis;Proteins;Proteinuria;Publishing;Race;Regulation;Reporting;Research Personnel;Risk;Role;Sampling;Scientist;Serum;Severities;Severity of illness;Systemic Lupus Erythematosus;T-Lymphocyte;TNF gene;Target Populations;Transcriptional Regulation;Transgenic Mice;Transgenic Organisms;Transplantation;Validation;Variant;Wild Type Mouse;anti-dsDNA antibodies;caucasian American;cell type;chemokine;cohort;cytokine;diagnostic biomarker;disorder risk;experimental study;genetic variant;high risk;inhibitor;insight;monocyte;neutrophil;novel diagnostics;personalized diagnostics;podocyte;protein function;racial disparity;risk variant;therapeutic target

public_health_relevance:
Project NarrativeThis study will determine the cellular and molecular mechanisms by which genetic variants for theABIN1 gene TNIP1 regulates monocyte neutrophil and B cell activity in lupus nephritis. Successfulcompletion of this study will define novel and precision diagnostics and targets for the treatment ofhigh-risk African American systemic lupus erythematosus patients with lupus nephritis.


application_id: 11125826
project_number: 5R01DK112034-09
project_title: Mechanisms Regulating Neurotensin Secretion and Function
administering_ic: NIDDK
award_notice_date: 2025-07-16
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DK
serial_number: 112034
program_official: SHEA-DONOHUE, TEREZ
project_start_date: 2017-02-01
project_end_date: 2026-06-30
study_section: Nutrition and Metabolism in Health and Disease Study Section[NMHD]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Our multidisciplinary research team has been studying the function and effects of neurotensin (NT) atridecapeptide localized to specialized enteroendocrine cells predominantly in the small bowel for almost threedecades. The most potent stimulus for NT release is ingestion of dietary fats. NT facilitates fatty acid (FA)absorption in the intestine stimulates growth of cancers that have the high affinity NT receptor 1 (NTR1) andcontributes to overall metabolism although its precise role in these processes has not been clearly delineated.Recent studies have identified a significant association of increased fasting pro-NT (a stable NT precursorfragment produced in equimolar amounts relative to NT) levels with the development of diabetes increased riskof cardiovascular disease and mortality non-alcoholic fatty liver disease (NAFLD) and increased risk of breastcancer in women. These findings identify a possible role for NT in lipid metabolism and link increased NT levelsto various metabolic diseases certain cancers and increased morbidity and mortality. The signaling pathwaysand role for NT in the absorption and storage of ingested fats represents a major gap in our current knowledge. Epidemiological evidence clearly shows a direct linkage between overnutrition and obesity; however themolecular mechanisms linking adiposity to overnutrition remain unknown. We have shown that NT deficiency(using an NT knockout mouse model) decreases body weight gain insulin resistance and NAFLD associatedwith high fat consumption; we further demonstrated that NT attenuates the activation of AMP-activated proteinkinase (AMPK) and stimulates FA absorption through a mechanism involving NTR1 and NTR3/sortilin.Importantly in humans we show that increased levels of pro-NT strongly predict new onset obesity in a gradedmanner which is independent of body mass index and insulin resistance suggesting that NT may provide aprognostic marker of future obesity and a potential target for obesity prevention and treatment. Therefore toextend the findings made during this grant period the central hypothesis for this renewal application is that NTpromotes triglyceride synthesis and suppresses FA oxidation in the intestine and liver likely through a mechanisminvolving AMPK inhibition; moreover NT contributes to high-fat diet-disrupted adipocyte lipolysis via inhibitingactivity of hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL). We speculate thatoverconsumption of dietary fats which leads to excess NT secretion results in obesity (from continued fatstorage) and metabolic disorders (e.g. NAFLD and insulin resistance). To examine our long-term goal of betterdefining intestinal NT function we have assembled a highly collaborative team with defined expertise in NTphysiology and function; signal transduction metabolism and systems biochemistry; and biostatistics andcomputational biology. Ultimately our findings will: i) significantly advance the fields of gastrointestinalphysiology endocrinology and metabolism; ii) change existing paradigms regarding the systemic effects of NT;and iii) revolutionize our concept of gut hormones and their role in metabolic diseases.

project_terms:
5'-AMP-activated protein kinase;Adipocytes;Adipose tissue;Affinity;Amino Acids;Attenuated;Biochemistry;Biological Models;Biometry;Body Weight decreased;Body mass index;Breast Cancer Risk Factor;Cells;Clinical;Computational Biology;Consumption;Development;Diabetes Mellitus;Dietary Fats;Digestion;Disease;Disease Resistance;Distant;Drosophila genus;Endocrinology;Enteroendocrine Cell;Epidemiology;Epigenetic Process;Fasting;Fatty Acids;Fatty Liver;Fatty acid glycerol esters;Future;Gastrointestinal Hormones;Gastrointestinal Physiology;Genes;Genetic;Goals;Grant;Growth;Hepatic;High Fat Diet;Homeostasis;Hormone Activity Inhibition;Hormones;Human;Ingestion;Innovative Therapy;Insulin Resistance;Interdisciplinary Study;Intestinal Hormones;Intestinal Mucosa;Intestines;Knockout Mice;Knowledge;Laboratories;Length;Link;Lipase;Lipids;Lipolysis;Liver;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Metabolic Diseases;Metabolism;Molecular;Morbidity - disease rate;Mus;Neurotensin;Neurotensin Receptors;Nutrient;Obesity;Organ;Overnutrition;Physiological;Physiology;Play;Prevention;Process;Prognostic Marker;Publishing;Regulation;Reporting;Research;Role;Signal Pathway;Signal Transduction;Small Intestines;Stimulus;System;Technology;Time;Transgenic Organisms;Triglycerides;Weight Gain;Woman;absorption;blood glucose regulation;cardiovascular disorder risk;diet-induced obesity;drug development;experimental study;fatty acid oxidation;insight;lipid biosynthesis;lipid metabolism;metabolomics;mortality;mouse model;multidisciplinary;non-alcoholic fatty liver disease;novel;obesity prevention;obesity treatment;response;sortilin;sterol esterase;uptake

public_health_relevance:
Project NarrativeWe have shown that neurotensin (NT) a hormone localized predominantly to the small bowel acts as a thriftygene to efficiently absorb ingested fats; NT deficiency in mice protects against obesity insulin resistance andhepatic steatosis associated with high fat diet consumption. Moreover we found that elevated NT levels inhumans is strongly predictive of future obesity. Our current studies which will define the mechanisms regulatingNT-mediated intestinal lipid absorption and fat metabolism in liver and adipose tissues will significantly impactthe fields of GI physiology and metabolism and may eventually lead to innovative therapies for diet-inducedobesity and resultant metabolic disorders based on inhibition of NT signaling.


application_id: 11124934
project_number: 5R35GM142679-05
project_title: Chromatin Regulation of Tissue Regeneration and Stem Cell Function
administering_ic: NIGMS
award_notice_date: 2025-06-05
opportunity_number: PAR-20-117
application_type: 5
activity_code: R35
ic: GM
serial_number: 142679
program_official: SALAZAR, DESIREE LYNN
project_start_date: 2021-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZRG1-CB-J(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
arra_indicator: N
project_abstract:
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.

project_terms:
Adult;Animal Model;Animals;Biochemical;Biological Process;Cells;Chromatin;Cilia;Complex;Cues;Custom;Data;Development;Developmental Process;Dissociation;Embryonic Development;Enzymes;Epithelium;Essential Genes;Event;Gene Expression;Gene Expression Regulation;Gene Targeting;Genes;Genetic;Genetic Transcription;Genome;Genomic approach;Genomics;Heterogeneity;Injury;Laboratory Study;Link;MLL gene;Mediator;Methods;Molecular;Natural regeneration;Organism;Pattern;Planarians;Platyhelminths;Pluripotent Stem Cells;Population Heterogeneity;Process;Proteins;RNA Interference;Regenerative capacity;Regulation;Research;Role;Signal Induction;Signal Transduction;Structure;Techniques;Testing;Tissue Differentiation;Tissues;Translating;Work;cell type;comparative;comparative genomics;in vivo;innovation;interest;novel;regenerative;response;single cell analysis;stem cell function;stem cells;tissue regeneration;trait;transcription factor

public_health_relevance:
My research leverages the experimental tractability and remarkable regenerative abilities ofplanarian flatworms to uncover fundamental molecular mechanisms that link injury-inducedsignals to functional changes in gene expression. My lab uses custom techniques innovativebiochemical methods and comparative species approaches to identify specific protein factorsthat regulate genome accessibility at essential gene targets. Preliminary data from my labsuggests that the chromatin modifying protein MLL1/2 maintains its conserved molecular anddevelopmental role in planarians yet by regulating novel genomic targets.


application_id: 11124903
project_number: 5R01DC019634-04
project_title: The fungiform papilla as a multi-sensory end-organ
administering_ic: NIDCD
award_notice_date: 2025-06-26
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DC
serial_number: 019634
program_official: SABRI, MERAV
project_start_date: 2022-07-01
project_end_date: 2027-06-30
study_section: Neuroscience of Interoception and Chemosensation Study Section[NIC]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: BREZA, JOSEPH MICHAEL
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractOur perception of food in the mouth is a multi-modal sensory experience involving taste olfaction andsomatosensation. All of these stimuli combine to contribute to the recognition and palatability of food. The firststep leading to the perception of mouth feel in the oral cavity is activation of peripheral somatosensoryneurons. Multiple classes of these trigeminal somatosensory neurons innervate the oral cavity and can bedefined by the types of stimuli to which they respond. For example low threshold mechanoreceptors (LTMRs)carry information concerning touch or mechanical stimuli. In skin at least 7 clear subtypes of these neuronshave been defined by using gene expression to relate the anatomical features of these neurons with theirfunctions. We do not know how many specialized neuron subtypes mediate touch sensation in the tongue ortheir specialized anatomical and functional properties. Understanding the sensations evoked by a foodstimulus requires us to determine the unique anatomical and functional properties of each LTMR subtype in thetongue. Equally important is how each LTMRs activities are integrated with other oral sensory neuron types(i.e. taste and temperature). Toward these long-term goals we propose to use two genetic identifiers toexamine trigeminal neuron subtypes innervating the fungiform (taste) papillae. Our Aims specifically test thefollowing hypotheses: 1) Taste papillae are innervated by a A LTMRs with a small receptive fields thatexpress the neurotrophin receptor TrkC and that they neurons can further be divided into rapidly adapting andslowly-adapting types based on the presence or absence of Parvalbumin. 2) These A LTMRs project to the toa region of the brainstem immediately adjacent to the primary taste terminal field where they activatepostsynaptic neurons that are responsive to touch. 3) These A LTMRs are capable of modulating responsesto taste stimuli at the first gustatory synaptic relay. Successful completion of these experiments establishes thefungiform papilla as a mechanosensory end organ and provides the genetic tools to explore the contribution ofa specific subtype of LTMR in the integration of sensations produced by the multi-modal food stimulus.

project_terms:
Afferent Neurons;Amyloid beta-Protein;Anatomy;Attention;Behavior;Binding Proteins;Brain Stem;Burning Mouth Syndrome;C Fiber;Cell Nucleus;Central Nervous System;Characteristics;Code;Cream;Data;Electrophysiology (science);Epithelium;Esthesia;Fiber;Food;Fungiform Papilla;Gene Expression;Genes;Genetic;Genetic Identity;Genetic Markers;Goals;Housing;Image;Lateral;Light;Liquid substance;Location;Mechanoreceptors;Mediating;Modality;Mucous Membrane;Mus;Nerve Growth Factor Receptors;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 3;Oral;Oral cavity;Organ;Parvalbumins;Perception;Peripheral;Peripheral Nervous System Diseases;Potato;Property;Proprioceptor;Research;Rodent;Role;Sensory;Skin;Smell Perception;Stimulus;Structure;Structure of trigeminal ganglion;Surface;Synapses;Taste Buds;Taste Perception;Temperature;Testing;Texture;Thermoreceptors;Tongue;Touch sensation;Trigeminal Nuclei;Trigeminal System;Viral;awake;experience;experimental study;feeding;mechanical stimulus;multimodality;multisensory;nerve supply;olfactory stimulus;optogenetics;oral sensory;postsynaptic neurons;receptive field;repaired;response;somatosensory;taste stimuli;tongue papilla;tool

public_health_relevance:
Project NarrativeSomatosensory neurons innervating the tongue contribute to numerous perceptual qualities including textureof food and location of gustatory stimuli. Understanding their role in normal function is the first step indetermining how they might be repaired when disrupted (peripheral neuropathies and/or burning mouthsyndrome).


application_id: 11124178
project_number: 5T32CA165990-12
project_title: Interdisciplinary Research Training in Cancer Biology
project_terms: Cancer Biology;Interdisciplinary Study;Research Training
administering_ic: NCI
award_notice_date: 2025-07-17
opportunity_number: PA-20-142
application_type: 5
activity_code: T32
ic: CA
serial_number: 165990
program_official: LIM, SUSAN E
project_start_date: 2013-04-01
project_end_date: 2027-06-30
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
other_pis: EVERS, BERNARD MARK
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:
Our interdisciplinary program will focus on training pre-doctoral students and post-doctoral fellows in cancer biology so they can effectively decipher important research questions associated with human cancer. This will be accomplished by integrating established successful programs in various cancer biology themes together with clinical exposure into one cohesive program. Trainees will receive didactic and non-didactic instruction; laboratory-based basic science research training in cancer research and cutting-edge clinical applications; and career development as independent cancer biologists. To further growth as important members of the scientific community students and fellows will receive ample training to articulate their ideas and communicate them effectively evaluate biomedical research and mentor others in scientific excellence. This program assembles a cohesive group of faculty from various departments at the University of Kentucky (UK) College of Medicine College of Arts and Sciences and College of Pharmacy. In the past 10 years our program faculty trained 104 doctoral students and 109 post-doctoral students; our faculty have the experience and interdisciplinary focus to guide this group of trainees to function in research teams pursuing multidisciplinary investigations. We mentor trainees to be proficient at utilizing hypothesis-driven approaches as well as discovery-oriented research design to address key problems. All trainees are required to complete foundation courses in graduate-level Genetics Biochemistry Immunology Pharmacology Physiology Cell Biology Molecular Biology Ethics Biostatistics and Bioinformatics as well as Biology and Therapy of Cancer which emphasizes clinical aspects of human cancer. Unique features of this program include interdisciplinary training emphasizing bench to bedside (and vice versa) research topics as well as a mandatory Clinical Perspectives in Oncology workshop that encompasses tumor boards and clinician shadowing to provide a bridge between the fundamental biology of cancer and clinical cancer. Training also involves mandatory participation in the weekly Markey Cancer Center (MCC) Seminars Cancer Biology journal club training workshops in specialized topics and the Fellowship Boot Camp to increase the number of individual fellowships and grants from our trainees. The ultimate objective of this program is to develop a cadre of future scientists who will lead integrative team approaches and understand the complex issue of cancer as it relates to potential prevention and treatment strategies. To ensure our commitment to the clinical translation of basic science discoveries MCC Associate Director Kathleen OConnor PhD and Director B. Mark Evers MD will serve as PIs for this team-based training program. Accordingly with the enthusiastic support of the MCC and the UK Vice President for Research this training program will mentor the next generation of cancer researchers to better understand and treat cancers.

public_health_relevance:
PROJECT NARRATIVEThis multidisciplinary training program represents a team approach involving multiple principal investigators whowill continue to mentor predoctoral students and post-doctoral fellows. The program will emphasize fundamentalaspects of cancer biology translational science of cancer and therapeutics and clinical cancer as well asprepare trainees as independent scientists and investigators who can become fully integrated in multidisciplinarycancer care teams.


application_id: 11123708
project_number: 2R01EY030933-06
project_title: Blood outer retina barrier regulation
administering_ic: NEI
award_notice_date: 2025-05-30
opportunity_number: PA-20-185
application_type: 2
activity_code: R01
ic: EY
serial_number: 030933
program_official: COOK, TIFFANY
project_start_date: 2020-02-01
project_end_date: 2030-05-31
study_section: Pathophysiology of Eye Disease - 2 Study Section[PED2]
contact_pi_person_id: 1877760
contact_pi: DEAN, DOUGLAS CHASE
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:
AbstractAs with other neurons photoreceptor metabolism is significantly focused on glucose which is transportedto the outer retina from the choroid circulation via the RPE that serves as the blood-outer retinal barrier.The RPE also transports other key metabolites back-and-forth between the outer retina and the choroidcirculation and it metabolizes circulating compounds into important metabolites that are passed on tophotoreceptors providing evidence that the RPE and choroid vasculature act as a metabolic unit.Mounting evidence suggests that retinal diseases including retinitis pigmentosa (RP) and AMD are linkedto metabolic changes. Taking advantage of perfusion differences in retinal compartments during theprevious grant period we have developed a protocol to selectively deliver labeled metabolites in vivo tothe pig RPE and in turn outer retina and to quantify uptake and secretion of metabolites from the RPEand choroid circulation by comparing levels in entering arteries to draining veins using mass spectroscopy.These findings were coupled with single cell RNA sequencing analysis to generate metabolomes of pigand human retina and retina-related cells. We utilized these metabolomes to follow metabolism in the WTretina and RPE in vivo and to examine how metabolic changes contribute to pathology in progression ofRP while addressing each of the Aims in the original grant. We have uncovered new pathways andunanticipated roles for established pathways in vivo that highlight bidirectional interplay between the RPEand outer retinal photoreceptors and emphasize the key role of the choroid vasculature and RPE as ametabolic unit and we propose to investigate these pathways in this renewal. We concluded from thesestudies that the complex interplay between retinal and extraretinal cell types and the notion of a choroidcirculation-RPE metabolic unit emphasize the importance of vivo studies where cell and vascular architectureis intact. Because of the key role of the choroid vasculature in RPE and outer retinal metabolism weexpanded our studies during the previous grant period to include new vascular sprouting in response todisease and damage examining endothelial tip cells that lead sprout migration and macrophages that arecrucial for new vessel formation. At the molecular level we show formation and migration of new vascularsprouts in multiple models of neovascularization are linked to mesenchymal transition using lineage tracingand depend upon induction of the mesenchymal-driving transcription factor ZEB1 using cell-specific geneknockouts. In the outer retina such sprouts from the choroid vasculature bypass the RPE to invade thesubretinal space and eventually enter the retina and these vessels also show altered metabolite permeability.This lack of an RPE barrier and permeability differences suggest altered delivery of metabolites from thesenew sprouts affect retinal and RPE metabolic pathways which we propose to investigate.

project_terms:
Address;Affect;Age related macular degeneration;Architecture;Arteries;Automobile Driving;Back;Blood;Blood Vessels;Bypass;Cells;Choroid;Circulation;Citric Acid Cycle;Complex;Cone;Coupled;Disease;Endothelium;Family suidae;Fatty Acids;Feedback;Gene Expression;Glucose;Glutamates;Glutamine;Grant;Human;Individual;Invaded;Investigation;Label;Lead;Lineage Tracing;Link;Macrophage;Mass Spectrum Analysis;Mesenchymal;Metabolic;Metabolic Pathway;Metabolism;Modeling;Molecular;Morphology;Mus;Neurons;Pathology;Pathway interactions;Perfusion;Permeability;Phagocytosis;Photoreceptors;Process;Progress Reports;Proline;Protocols documentation;Publications;Regulation;Retina;Retinal Diseases;Retinal Photoreceptors;Retinitis Pigmentosa;Role;Structure of retinal pigment epithelium;Tracer;Veins;aerobic glycolysis;carboxylation;cell type;fatty acid oxidation;glucose metabolism;glucose transport;in vivo;knockout gene;metabolome;migration;multiple datasets;neovascularization;response;response to injury;restoration;retina circulation;single-cell RNA sequencing;transcription factor;uptake

public_health_relevance:
NarrativeMounting evidence suggests that retinal diseases including retinitis pigmentosa (RP) andAMD are linked to metabolic changes in photoreceptors and the RPE. During the previousgrant period we have taken advantage of perfusion differences in retinal compartments toselectively deliver labeled metabolites in vivo to pig retinal regions and even individual cellsto identify metabolic pathways and to analyze uptake and secretion of metabolites from theRPE by comparing levels in entering arteries to draining veins using mass spectroscopy(MS) and these findings were coupled with single cell RNA sequencing analysis to generatemetabolomes of pig and human retinal and retina-related cells. The studies uncovered newpathways and unanticipated roles for established pathways highlighting bidirectional interplaybetween the RPE and outer retinal photoreceptors in vivo and emphasize a key role for thechoroid vasculature and RPE as a metabolic unit and studies are proposed in this renewal tocharacterize these pathways and evaluate metabolic changes in the retina and RPE resultingfrom new vascular sprouts from the choroid that bypass the RPE and invade the outer retina inresponse to injury and disease.


application_id: 11123534
project_number: 2R15GM143662-02
project_title: Inteins: Expanding Biological Roles and Biotechnological Applications
administering_ic: NIGMS
award_notice_date: 2025-09-10
opportunity_number: PAR-24-152
application_type: 2
activity_code: R15
ic: GM
serial_number: 143662
program_official: RIGAS, MARC
project_start_date: 2021-09-01
project_end_date: 2028-08-31
study_section: Special Emphasis Panel[ZRG1 BTC-C (80)]
contact_pi_person_id: 9439652
contact_pi: LENNON, CHRISTOPHER WILLIAM
other_pis: Not Applicable
congressional_district: 01
department: BIOLOGY
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTACTThe long-term goals of this application are to better understand the biological importance of inteins as post-translational regulatory elements their emerging role in pathogen stress response and to harness the powerof their unique chemistry to invent useful technologies for the biomedical research community. Inteins orintervening proteins are self-catalytic mobile genetic elements removed from host genes through proteinsplicing. From the applied perspective the ability of inteins to shuffle peptide bonds in highly specific ways hasproven exceptionally useful in protein engineering leading to the development of numerous technologies.While intein applications have dominated their investigation and new intein-based technologies are developedfrequently the biological importance of inteins in nature is poorly understood. Inteins are abundant mobilegenetic elements in the microbial world found in approximately one-half of archaea and one-quarter ofbacteria. Contrary to long-standing assumption that inteins are molecular parasites mounting recent evidencesuggests that some intein-containing proteins have evolved to couple splicing and thus host protein activationto environmental signals. This represents a novel and potentially widespread form of post-translationalregulation. Further as inteins are absent in humans and located within essential genes of several pathogensunderstanding environmental factors that regulate protein splicing may inform antimicrobial development.We propose the following three aims building upon recent discoveries as well as expanding into new arenas.Aim 1 challenges the assumption that unspliced precursor proteins are inert for the first time systematicallyinvestigating the potential functions of an intein-containing DNA helicase prior to splicing. Aim 1 will alsoexamine the importance of protein splicing within the natural context of the intein determining theconsequences of intein deletion and mutation on host physiology. Aim 2 will systematically examine splicing ofall fifteen inteins from a model archaeon to examine the diversity of splicing within one host as well asexamine potential regulation. Aim 3 seeks to expand upon a recently developed intein-based protein stabilitybiosensor. Through these Aims this work will enhance our understanding of the roles these exciting andunderstudied elements play in nature as well as develop a new intein-based biosensor to examine andimprove protein folding in vivo.

project_terms:
Active Sites;Archaea;Bacteria;Binding;Biochemical;Biological;Biomedical Research;Biomedical Technology;Biosensor;Biotechnology;Chemistry;Communities;Cryptococcus neoformans;Cues;DNA;DNA biosynthesis;Data;Development;Directed Molecular Evolution;Elements;Environment;Environmental Risk Factor;Essential Genes;Funding;Genes;Genetic;Genetic Recombination;Genome;Goals;Human;Investigation;Low income;Measures;Mobile Genetic Elements;Modeling;Molecular;Monitor;Mutation;Mycobacterium tuberculosis;Nature;Organism;Parasites;Peptides;Physiology;Play;Post-Translational Regulation;Process;Protein Engineering;Protein Precursors;Protein Splicing;Proteins;Publishing;RNA Splicing;Reaction;Regulation;Regulatory Element;Role;Rural;Signal Transduction;Stress;Techniques;Technology;Thermococcus;Time;Translating;Work;Writing;antimicrobial;applied biomedical research;biological adaptation to stress;environmental stressor;experimental study;fitness;helicase;high risk;human disease;human pathogen;improved;in vivo;intein;invention;microbial;mycobacterial;novel;pathogen;polypeptide;primarily undergraduate institution;protein activation;protein folding;protein misfolding;repaired;sensor;stability testing;tool;undergraduate research experience;undergraduate student

public_health_relevance:
PROJECT NARRATIVEDue to their unique ability to rearrange peptide bonds during protein splicing inteins (intervening proteins)have led to numerous exciting technologies used across several fields of biomedical research. Inteins are alsofound within essential proteins of devastating human pathogens including Mycobacterium tuberculosis andCryptococcus neoformans whereby understanding environmental regulation of protein splicing may lead tonovel antimicrobial strategies. The overall goals of this application are to discover mechanisms by whichinteins act as stress sensors and to develop new intein-derived applications for protein engineering.


application_id: 11123395
project_number: 5P30AG072946-05
project_title: Core G: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2025-07-09
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9600
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Revised Project Summary/Abstract: Research Education Component: The Research Education Component (REC) of the UK-ADRC offers a variety of research educational activities and comprehensive mentored research skills development programs that will enhance the development of the future workforce to meet the nations biomedical behavioral and clinical needs in Alzheimers disease and related dementias (ADRD) research. The REC will leverage resources within and outside the UK-ADRC to create an outstanding multidisciplinary and collaborative environment for training the next generation of researchers in scientific areas that parallel the theme of our ADRC (Transitions from Normal to Late-Life Multi- Etiology Dementias). We will continue to build on a long history of collaborative and dedicated faculty a strong foundation in multidisciplinary team science and an outstanding track record of success in mentoring and education of researchers across the training spectrum. We will also establish a new REC Scholar program aimed at junior investigators (Assistant Professors senior research associates or clinical fellows). This program will support junior investigators from diverse multidisciplinary fields to pursue mentored basic translational or clinical research in ADRD and follow a customized training plan to help the scholars move toward their career development goals. This training will be done in a supportive and collaborative academic environment with substantial training resources and an experienced and dedicated training faculty. Scholars will have the opportunity to learn state-of-the-art research skills in disciplines that have been identified as critically needed areas for the ADRC workforce of the future. Examples of training areas where the UK-ADRC has strong expertise include analysis of longitudinal clinical outcomes clinical trial design MRI imaging and novel fluid biomarkers quantitative neuropathology and AD mimics data analysis/ study design in mixed dementias and health literacy and inequities. REC goals will involve interactions with all the UK-ADRC Cores and will be achieved through the following specific aims. Aim 1. Provide education programs and research skills development opportunities for investigators at UK. Aim 2. Identify select support and retain REC scholars to engage in ADRD research. Aim 3. Develop an individualized mentoring plan and educational program for each REC scholar to enable advancement to independent research and funding in ADRD research. Aim 4. Evaluate progress of the REC scholars address barriers towards the goal of independence in ADRD research and refine delivery of the programs educational structure and processes. Following completion of the Program participants will have the knowledge expertise and confidence to successfully pursue a long-term career in dementia research.

project_terms:
Address;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimer's disease related dementia;Area;Basic Science;Behavioral;Biological Markers;Clinical;Clinical Research;Clinical Trials Design;Data Analyses;Dedications;Dementia;Development;Discipline;Education;Educational Activities;Environment;Etiology;Faculty;Foundations;Funding;Future;Goals;Image;Kentucky;Knowledge;Learning;Liquid substance;Magnetic Resonance Imaging;Mentors;Outcome;Participant;Postdoctoral Fellow;Process;Program Development;Recording of previous events;Research;Research Design;Research Personnel;Resources;Scholars Program;Science;Structure;System;Teacher Professional Development;Training;Translational Research;Universities;career;career development;collaborative environment;education research;experience;health inequalities;health literacy;late life;longitudinal analysis;mixed dementia;multidisciplinary;neuropathology;next generation;novel;professor;programs;skill acquisition;skills;success;training opportunity

public_health_relevance:
Per RFA-AG-21-019: Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.


application_id: 11123391
project_number: 5P30AG072946-05
project_title: Core F: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2025-07-09
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9599
contact_pi_person_id: 7993908
contact_pi: GOLD, BRIAN TIMOTHY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: Biomarker CoreThe theme of our UK-ADRC is Transitions from normal to late-life multi-etiology dementia and the role ofthe Biomarker Core is to provide data and support efforts to develop biomarker profiles for the spectrum ofunderlying pathologies that can contribute to an individuals cognitive decline. The Biomarker core will providecritical characterization of our cohort during their cognitively normal state and through their cognitivetransitions. The utility of biomarkers is expanding rapidly as the dementia field identifies potentially disease-modifying therapies. Rather than focusing on a single biomarker modality (i.e. MRI PET plasma etc.) wehave adopted a multimodal approach to biomarker characterization. Because our center is particularlyinterested in multi-etiology dementia the most common dementia in the normal aging population we believe amultimodal approach to biomarkers will yield novel insights into the progression of such complex dementias.We propose to measure blood- and CSF-based biomarkers for AD cerebral small vessel disease (cSVD)large-vessel ischemic disease and inflammation. In addition we will perform state-of-the-art MRI imagingincorporating biomarkers of AD cSVD and neuroinflammation. We will also explore the utility of wearabledevices to collect digital biomarkers tracking sleep and physical activity especially given that Lewy bodypathology can lead to early sleep disturbances. Finally digital gait assessment will provide physical biomarkersof gait which has been shown to decline early in individuals with cSVD and Lewy body dementia. Importantlythe Biomarker Core has been established for several years and is fully integrated within the UK-ADRCworking closely with the other cores to maximize the utility of the biomarker data collected to date. We willcontinue to support internal and external research projects on biomarkers and will also contribute significantlyto national and international consortium efforts to develop clinic-ready biomarkers for AD VCID and otherunderlying causes of dementia. Our specific aims are:Aim 1: Collect bi-annual blood-based biomarkers of AD cSVD large vessel disease and inflammation.Aim 2: Collect baseline MRI scans and accompanying CSF ATN biomarkers on all cognitively normalparticipants in the longitudinal cohort.Aim 3: Fully characterize biomarkers on all participants at their clinical transition from cognitively normal /preMCI to MCI and from MCI to dementia.Aim 4: Determine the utility of digital biomarkers including activity sleep and gait in predicting cognitivedecline and / or brain pathology.Aim 5: Contribute to national efforts to establish harmonize and standardize biomarkers including NACCADNI and NCRAD.Aim 6: Integrate with the other cores of the UK-ADRC.

project_terms:
Adopted;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimers disease biomarker;Biological Markers;Blood;Brain Pathology;Cerebral small vessel disease;Clinical;Cognitive;Collection;Complex;Consensus;Data;Dementia;Digital biomarker;Disease;Etiology;Gait;Goals;Image;Impaired cognition;Individual;Inflammation;International;Ischemia;Kentucky;Lewy Body Dementia;Lewy body pathology;Liquid substance;Longitudinal cohort;MRI Scans;Magnetic Resonance Imaging;Measures;Modality;Participant;Pathologic;Pathology;Physical activity;Plasma;Positron-Emission Tomography;Research;Research Project Grants;Role;Sleep;Sleep disturbances;Standardization;System;Universities;aging population;biomarker development;biomarker identification;biomarker performance;blood-based biomarker;clinic ready;cohort;digital;insight;interest;late life;meetings;multimodality;neuroinflammation;normal aging;novel;novel marker;precision medicine;wearable device

public_health_relevance:
Per RFA-AG-21-019:Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachmentindicating it is required. However eRA systems only enforce this requirement in the Overallcomponent and applications will not receive an error if omitted in other components.


application_id: 11123387
project_number: 5P30AG072946-05
project_title: Core E: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2025-07-09
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9598
contact_pi_person_id: 9662252
contact_pi: SCHMITT, FREDERICK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: Outreach Recruitment and Engagement CoreThe Outreach Recruitment and Engagement (ORE) Core plays a central role in achieving UK-ADRC goals byfunctioning as a key link between the Center and the local and state communities. ORE Core programs andactivities have created and will maintain an educated local community eager to receive updated information onAD and to participate in our Centers research. Through ORE Core efforts the UK-ADRC will continue to workwith both the Commonwealth of Kentucky and UK partners in directing state and institutional responses tomeeting dementia health care needs and increasing health literacy in the elderly. ORE Core activities includerecruitment and retention of diverse participants into a longitudinal cohort with annual clinical examinations andbrain donation upon death. Other activities involve the development and testing of innovative outreach andengagement activities in the community to increase awareness of AD/ADRD plus the importance of researchand research participation. Over the past five years the ORE Core has taken the lead in developing innovativepartnerships and products to support research participation by African Americans the largest minority group inKentucky. We will continue to emphasize recruitment and retention of research participants at the earlieststages of the cognitive continuum (Cognitively Normal and MCI). These efforts involve engaging theseparticipants in the ADRC longitudinal cohort as well as activities to enhance agreement to brain donationwillingness to engage in affiliated clinical studies and therapeutic trials and donation of antemortembiospecimens. In the next cycle we will maintain and further build on these efforts and partnerships throughthe following specific aims:Aim 1. Recruit and retain participants into our longitudinal cohort affiliated research and NIA initiativesfocusing on improving recruitment and retention of African Americans and other URGs.Aim 2. Increase community awareness of AD and ADRD through the promotion of health literacy that furtherenhances recruitment and retention of minority participants in research.Aim 3. Evaluate the effectiveness of our activities with both qualitative and quantitative metrics.Aim 4. Support the UK-ADRC Cores to maximize national and international collaborations.The ORE Core plays a critical role in the UK-ADRC and works closely with the other Cores to supportrecruitment and retention activities for research protocols clinical trials and national initiatives; increasecommunity awareness of AD and maintain a strong presence in the African-American community; and supportoutreach initiatives for the lay community in collaboration with key partners. These functions are vital to the UK-ADRC mission to catalyze outstanding and innovative research outreach education and clinical programs.

project_terms:
Address;African American;African American population;Aging;Agreement;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimer's disease related dementia;American;Autopsy;Awareness;Biological Markers;Brain;Brothers;Caring;Catchment Area;Censuses;Cessation of life;Church;Clinic;Clinical;Clinical Research;Clinical Trials;Cognitive;Collaborations;Communities;Consent;Data;Databases;Dementia;Development;Disease;Education;Elderly;Elements;Enrollment;Etiology;Event;Extramural Activities;Faith-based organization;Fostering;Foundations;Genetic;Goals;Grant;Health Care;Health Promotion;Institution;International;Kentucky;Lead;Link;Longitudinal cohort;Measures;Minority;Minority Groups;Mission;Neck;Outcome;Participant;Pathology;Play;Protocols documentation;Reporting;Research;Research Activity;Research Support;Resources;Risk;Risk Assessment;Role;System;Testing;Therapeutic Trials;Time;Underrepresented Populations;Universities;Update;Work;checkup examination;clinical examination;cohort;community engagement;dementia risk;demographics;disparity reduction;effectiveness evaluation;efficacy evaluation;ethnic minority population;ethnoracial;health disparity;health literacy;improved;innovation;late life;meetings;mixed dementia;neuropathology;outreach;outreach program;participant retention;patient engagement;programs;racial minority population;recruit;research study;response;success;volunteer;willingness

public_health_relevance:
Per RFA-AG-21-019:Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachmentindicating it is required. However eRA systems only enforce this requirement in the Overallcomponent and applications will not receive an error if omitted in other components.


application_id: 11123382
project_number: 5P30AG072946-05
project_title: Core D: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2025-07-09
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9597
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: Neuropathology CoreThe overall objective of the Neuropathology Core of the UK-ADRC is to support research on normal brainaging presymptomatic AD MCI early and late AD mixed dementia syndromes and other dementingdisorders. Autopsies will be performed by our Rapid Autopsy Team on longitudinally followed subjects from ourClinical Core. We will perform short post-mortem interval autopsies and we will maintain a high autopsy rate.This Core is optimally tailored to help address important research questions. The Core will provide brain tissueCSF and other biospecimens for investigators at UK other ADRCs and outside investigators. The Core willalso provide consensus conference determined diagnoses quantitation of neurofibrillary tangles neuriticplaques and diffuse plaques from 8 brain regions Ab quantitation Braak staging CERAD and NIA-ReaganInstitute staging on all autopsied cases along with evaluation of alpha-synuclein and TDP-43 proteinopathy.This brain bank has been operating continuously for over three decades with a strong track record so specialcare will be taken to ensure diagnostic excellence consistency and continuity. The Core will maintain a tissuebank of the above specimens and frozen serum plasma buffy coats and CSF from living patients. Specialemphasis will be placed on generating rigorous quantititative pathologic metrics from digital pathology andproviding investigators with specimens from cognitively intact control subjects with no Ab deposition andsparse tau pathology (successful cerebral aging) and many cases with mixed pathologies. Providing thesesamples will contribute to clinical-pathological correlation studies and cutting-edge research that includesponsored studies related to AD genomics oxidative stress hippocampal sclerosis/LATE dementia with Lewybodies Down syndrome and neuroinflammation. Frequent consensus conferences will be held with theClinical Biomarker and Data Management and Statistics Cores to help define clinical-pathological diagnoseson all autopsied subjects. The Neuropathology Core is strongly integrated with other Cores of the UK-ADRCand exploits unique opportunities to conduct clinical-pathological correlative studies on longitudinally followedsubjects. Through these methods we will better understand normal brain aging and the transition to multi-etiology dementia with the goal of contributing to therapeutic or preventive measures. The NeuropathologyCore complements the other Cores of the UK-ADRC to provide extremely essential diagnoses and tissuesamples that are required for many cutting-edge researchers at the University of Kentucky and elsewhere. Wewill build on our track record of excellence using innovative tools related to brain autopsies neuropathologicaldiagnoses tissue banking and clinical-pathological correlation. Our specific aims are:Aim 1: Provide state-of-the-art neuropathological and biospecimen repository servicesAim 2: Leverage neuropathology resources and expertise to contribute to research effortsAim 3: Integrate with other cores to contribute to administrative research and educational missions

project_terms:
Address;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Autopsy;Biological;Biological Markers;Biological Specimen Banks;Biometry;Brain;Brain Diseases;Brain imaging;Brain region;Caring;Catalogs;Cerebrospinal Fluid;Cerebrovascular Disorders;Cerebrum;Clinical;Clinical Trials;Cognitive;Collaborations;Consensus;Correlation Studies;Correlative Study;DNA;Data;Databases;Dementia;Dementia with Lewy Bodies;Deposition;Diagnosis;Diagnostic;Disease;Down Syndrome;Education;Ensure;Etiology;Evaluation;Freezing;Frontotemporal Lobar Degenerations;Genetic;Genetic study;Genomics;Goals;Impaired cognition;Individual;Infrastructure;Investigation;Kentucky;Laboratory Research;Lesion;Memory;Methodology;Methods;Mission;Nerve Degeneration;Neurofibrillary Tangles;Oxidative Stress;Pathologic;Pathology;Patients;Plasma;Preventive measure;Process;Protocols documentation;Publishing;Research;Research Personnel;Research Support;Resources;Running;Sampling;Senile Plaques;Serum;Services;Specimen;Staging;Standardization;Syndrome;System;TDP43 proteinopathy;Tauopathies;Therapeutic;Thinness;Tissue Banks;Tissue Sample;Tissues;Universities;Work;age related;age related neurodegeneration;aging brain;alpha synuclein;blood product;brain tissue;cerebrovascular pathology;clinical center;cohort;data management;demented;digital;digital measure;digital pathology;experience;genome wide association study;hippocampal sclerosis;innovation;late life;limbic-predominant age-related TDP-43 encephalopathy;meetings;mixed dementia;neuroinflammation;neuropathology;novel;pre-clinical;protein TDP-43;religious order study;statistics core;symposium;synucleinopathy;tau Proteins;tool

public_health_relevance:
Per RFA-AG-21-019:Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachmentindicating it is required. However eRA systems only enforce this requirement in the Overallcomponent and applications will not receive an error if omitted in other components.


application_id: 11123378
project_number: 5P30AG072946-05
project_title: Core C: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2025-07-09
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9596
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: Data Management and Statistics CoreThe Data Management and Statistics (DMS) Core can be conceptualized as the lynchpin for integration of theADRC Cores and is vital to the success of the UK-ADRC. Its critical roles include managing a large centralizeddatabase consulting with ADRC-affiliated researchers and working to develop and apply innovative statisticalmethodology for data analysis. Data management efforts focus on collecting storing and sharing high qualitydata using a web-based platform. This focus begins with the leadership and vision and attention to detailprovided by the DMS Core. This core has an enviable track record of timely and accurate reporting of a highvolume of data to NACC. Further weekly Core meetings are popular with UK-ADRC investigators who find thatthe expert advice provided by our seasoned investigators improves their success in pilot studies grantapplications and publications. The Core also participates as a full partner to the research mission of the UK-ADRC emphasizing transitions in late life from normal to multiple etiology dementia. A key element of thisCore is the well-established track record of developing novel methodology to analyze data collected at the UK-ADRC and from other cohorts with a focus on elderly subjects transitions to MCI and eventually dementia. TheCore also provides training for students enrolled in the graduate programs in Gerontology Public HealthEpidemiology and Biostatistics Psychology and Statistics. It is committed to developing younger faculty tobecome productive ADRC investigators. In keeping with the mission of the UK-ADRC faculty in this Core alsocontribute to the dementia research community at large through service on external advisory committeesstudy sections manuscript reviews and data safety monitoring boards. The DMS Core will continue thesecritical responsibilities through the following specific aims.Aim 1: Maintain and expand an integrated data warehouse and suite of web-based data collection applicationsand reporting platforms for ADRC Cores and projects.Aim 2: Provide expertise on experimental design and statistical analysis.Aim 3: Support the clinical biomarker neuropathological educational and outreach missions of the ADRC.Aim 4: Contribute to the activities of the dementia community at large through service and research.

project_terms:
Advisory Committees;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Applications Grants;Attention;Bioinformatics;Biological Markers;Biometry;COVID-19 pandemic;Clinical;Clinical Data;Clinical Trials;Clinical Trials Data Monitoring Committees;Cognitive;Collaborations;Communities;Data;Data Analyses;Data Collection;Dementia;Development;Education;Education and Outreach;Elderly;Elements;Enrollment;Environment;Epidemiology;Etiology;Evaluation;Event;Experimental Designs;Extramural Activities;Faculty;Funding;Generations;Genetic;Gerontology;Information Systems;Interruption;Kentucky;Leadership;Life;Literature;Manuscripts;Methodology;Mission;Neuroepidemiology;Observational Study;Online Systems;Participant;Pathology;Pilot Projects;Procedures;Productivity;Psychology;Public Health;Publications;Reporting;Research;Research Design;Research Methodology;Research Personnel;Resources;Risk Factors;Role;Sampling;Seasons;Services;Statistical Data Interpretation;Study Section;System;Tablets;Time;Training;Universities;Vision;central database;cohort;dashboard;data dictionary;data integration;data management;data management center;data warehouse;direct application;doctoral student;education research;electronic data capture system;improved;innovation;interest;late life;meetings;member;mixed dementia;neuropathology;novel;outreach;programs;recruit;statistics;statistics core;student training;success;user-friendly;web app;web platform;web site


application_id: 11123376
project_number: 5P30AG072946-05
project_title: Core B: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2025-07-09
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9595
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: Clinical CoreThe Clinical Core of the UK-ADRC maintains a well-characterized community-based cohort focused onnormal aging and early transitional disease states and follows individuals longitudinally until brain autopsy.We maintain a mandatory autopsy requirement for all subjects (with the exception of our Minority GatewayClinic where autopsy is promoted but not required) allowing major contributions in the area of clinical-pathological correlative studies and definition of early preclinical and pre-dementia disease states. Theseefforts have been a driving force in our recognition of the heterogeneity of community-acquired dementiaincluding major contributions to the field in regard to LATE PART VCID and the role these pathologicstates play in conjunction with traditional AD LBD and FTLD disease states. A major focus of our work hasalso been on defining early clinical transitions involving the interplay of these disease states that has driventhe widespread exploration of late-life multi-etiology dementia syndromes. To further such advances theUK-ADRC Clinical Core emphasizes deep clinical biomarker genetic and post-mortem phenotyping of adiverse cohort of elderly subjects at high risk for multi-etiology dementia. Major initiatives in the area of ADmimics and transitions from normal to late-life multi-etiology dementia are well-poised to continue to move thefield forward in the areas of both diagnosis and translational interventional discoveries. We have introducedexciting new initiatives in our expansion of antemortem biomarker research allowing an even deeper clinicalphenotyping of our participants as we work towards translational discoveries for multi-etiology dementia. TheUK-ADRC will continue to constantly evolve in dynamic ways through our proposed specific aims.Aim 1: Maintain & longitudinally characterize a central longitudinal cohort enrolling cognitively normal subjectsto facilitate our understanding of preclinical disease and early cognitive transitions to multi-etiology MCI &dementia.Aim 2: Maintain and expand our successful Minority Gateway Clinics to maintain and grow our (significantly)above-parity for population minority engagement.Aim 3: Further develop and maintain an infrastructure to support translational therapeutic development throughall clinical trial phases in support of NIH ADCS ACTC initiatives industry-sponsored drug trials andinvestigator-initiated projects.Aim 4: Foster education and support of research participants and families to ensure that our efforts areclinically meaningful both in novel prevention studies as well as treatment in established diseaseOverall the Clinical Core will continue to provide an infrastructure and environment that will continue tocontribute to our success in advancing multidisciplinary innovative AD research supporting our center themeof Transitions from Normal to Late-Life Multi-Etiology Dementia.

project_terms:
Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimer's disease related dementia;Area;Automobile Driving;Autopsy;Biological Markers;Brain;Clinic;Clinical;Clinical Trials;Cognitive;Collaborations;Communities;Correlative Study;Dementia;Development;Diagnosis;Disease;Education;Elderly;Enrollment;Environment;Etiology;Family;Fostering;Frontotemporal Lobar Degenerations;Funding;Genetic;Goals;Heterogeneity;Image;Individual;Industry;Infrastructure;Intervention;Kentucky;Link;Liquid substance;Longitudinal cohort;Measures;Minority;Minority Groups;Mission;Participant;Pathologic;Pharmaceutical Preparations;Phase;Phenotype;Play;Prevention;Productivity;Publications;Recommendation;Research;Research Personnel;Research Project Grants;Research Support;Role;Syndrome;System;Trademark;United States National Institutes of Health;Universities;Work;clinical phenotype;cohort;design;driving force;high risk;innovation;late life;minority engagement;multidisciplinary;normal aging;novel;novel therapeutic intervention;parity;pre-clinical;preclinical study;research clinical testing;success;therapeutic development;translational therapeutics


application_id: 11123375
project_number: 5R01CA256893-05
project_title: Enhancing the efficacy of androgen signaling inhibitors in prostate cancer
administering_ic: NCI
award_notice_date: 2025-04-07
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 256893
program_official: KONDAPAKA, SUDHIR B
project_start_date: 2021-07-01
project_end_date: 2026-06-30
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Title: Enhancing the efficacy of androgen signaling inhibitors in prostate cancerAbstractIt has been documented that androgen receptor (AR) signaling remains to play a critical role in castration-resistant prostate cancer (CRPC). Indeed Androgen Signaling Inhibitors (ASI) such as abiraterone aninhibitor of de novo androgen synthesis pathway and enzalutamide a direct AR inhibitor are major drugsused in clinic to manage CRPC now. Unfortunately ASI-based treatment only improves the overallpatient survival by several months. Therefore understanding the underlying mechanisms of ASIresistance and development of novel avenues to increase the efficacy of ASI-based therapy are urgentlyneeded. With the goal to identify new pathways/targets whose inhibition might overcome ASI resistancewe performed extensive bioinformatics analyses of RNA-seq data including those from paired prostatecancer (PCa) cells with different sensitivities to enzalutamide 498 PCa tumors with different responsesto hormone therapy and 52 pairs of PCa specimen (tumors vs adjacent normal). Both the -catenin-dependent canonical Wnt cascade and the -catenin-independent non-canonical Wnt signaling wereidentified as pathways whose elevation might contribute to acquisition of ASI resistance. The objectiveof the proposed research is to define the roles of Wnt signaling in acquisition of ASI resistance in CRPCand to exploit these pathways as novel therapeutic targets for CRPC patients who no longer respond toASIs. The central hypothesis is that Wnt signaling causes constitutive activation of AR signaling thusCRPC progression and development of ASI resistance. This hypothesis will be tested by pursuing threeSpecific Aims - (1) to dissect the role of-catenin signaling in enzalutamide resistance of PCa; (2) toexamine how activation of the non-canonical Wnt signaling contributes to enzalutamide resistance inPCa; and (3) to test whether simultaneous inhibition of canonical and non-canonical Wnt cascades is aneffective approach to treat enzalutamide-resistant PCa and to probe the significance of tumormicroenvironment Wnt in the acquisition of enzalutamide resistance. These complementary aims will beaccomplished using biochemical analyses of signaling intermediates and employing gain-of-function andloss-of-function strategies with inducible PCa mouse models culture systems human PCa xenograftand patient-derived organoid methodologies. The rationale for the research is that it will be the first tocomprenhensively probe the importance of Wnt signaling in acquisition of ASI resistance of CRPC. Thiscontribution is significant because it will (i) define the molecular mechanism by which Wnt signalingactivates AR; (ii) genetically evaluate how these pathways contribute to PCa progression and metastasis;and (iii) demonstrate Wnt cascades as critical therapeutic targets to enhance the efficacy of ASI.

project_terms:
Acetates;Affect;Androgen Antagonists;Androgen Receptor;Androgens;Autocrine Communication;Biochemical;Bioinformatics;Cancer Patient;Castration;Cells;Clinic;Clinical;Coculture Techniques;Creativeness;Cultured Cells;Data;Development;Disease;Drug usage;Event;Fibroblasts;Fostering;Genetically Engineered Mouse;Goals;Health;Human;Investigation;Malignant Neoplasms;Malignant neoplasm of prostate;Methodology;Mission;Modeling;Molecular;Mus;Mutation;Neoplasm Circulating Cells;Neoplasm Metastasis;Organoids;Outcome;Paracrine Communication;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacotherapy;Play;Protein Family;Public Health;RNA analysis;Receptor Activation;Receptor Signaling;Research;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Specimen;System;Testing;Therapeutic;Tissue Microarray;United States National Institutes of Health;WNT Signaling Pathway;Withdrawal;Xenograft procedure;abiraterone;androgen independent prostate cancer;clinical translation;clinically relevant;docetaxel;enzalutamide;gain of function;hormone therapy;improved;inhibitor;inhibitor therapy;innovation;loss of function;mouse model;new therapeutic target;novel;novel strategies;patient derived xenograft model;pharmacologic;planar cell polarity;prostate cancer cell;prostate cancer progression;receptor;response;therapeutic target;transcriptome;transcriptome sequencing;tumor;tumor microenvironment

public_health_relevance:
NarrativeThe proposed research is relevant to public health because it focuses on discovery of novel signaling pathwaysthat drive castration-resistant prostate cancer. These studies will establish new avenues of investigation todevelop improved therapeutics to treat this deadly disease and to greatly improve patient outcome. Thus theproposed research is relevant to NIH's mission of fostering creative discoveries and innovativeresearch strategies for protecting and improving health and reducing the burdens associated with cancer.


application_id: 11123373
project_number: 5P30AG072946-05
project_title: Core A: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2025-07-09
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9594
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: Administrative CoreThe ultimate goal of the UK-ADRC is to catalyze innovative and outstanding AD research while ensuring amore rapid rate of progress toward new therapies to delay or prevent AD so that our human volunteerspatients and caregivers become the beneficiaries of our advances in knowledge. The Administrative Coreprovides the foundation infrastructure leadership overall direction strategic planning and integration of allADRC components to more rapidly achieve this goal and advance our overall theme: Transitions from Normalto Late-Life Multi-Etiology Dementia. This theme builds on our traditional strengths in defining mechanismsunderlying the early changes that occur in individuals as they transition through the cognitive continuum riskfactors associated with these cognitive states and how mixed pathology and co-morbidities influence risk andprogression. Two historically outstanding resources of the UK-ADRC that enable research relevant to thistheme are: 1) a strong autopsy program providing clinical-neuropathological correlation and very short (2-4 hrs)postmortem interval (PMI) research material and 2) a unique continuously replenished group of ~500cognitively intact subjects followed longitudinally together with another ~300 initially normal individuals whotransition to pre-MCI MCI or dementia and all committed to brain autopsy upon death. These signatureresources have contributed to our becoming one of the premier centers defining pathogenic mechanismsunderlying the transitions from normal cognitive aging to the earliest stages of cognitive impairment. The UK-ADRC functions in a multidisciplinary integrated collaborative and supportive team science environment thatcatalyzes high-quality AD research within the UK community region nation and beyond. We will continue toprovide the infrastructure resources and intellectual capital to enhance transdisciplinary research and scientificinteractions develop new collaborations and partnerships contribute to national initiatives and offer innovativeeducation and training opportunities in the basic and clinical neurosciences. An effective Administrative Core isessential for transforming our goals into accomplishments. Therefore the Core will continue to support theability of our UK-ADRC to accomplish its goals and to promote the NAPA research implementation milestonesand goals through the following specific aims.Aim 1: Provide leadership administrative structure coordination and financial management to ensure optimalresource utilization to meet the overall goals of the UK-ADRC.Aim 2: Promote and catalyze clinical/translational research activities maximize interactions with otherdepartments and centers and foster new avenues of innovative research.Aim 3: Solicit review select and monitor the Developmental Projects.Aim 4: Contribute to and interact with other ADRCs and other national collaborative activities and increasevisibility in the local and national community.

project_terms:
Administrator;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimer's disease related dementia;Autopsy;Biological;Brain;Brain Pathology;Capital;Caregivers;Cessation of life;Clinical;Cognitive;Cognitive aging;Collaborations;Communication;Communities;Decision Making;Dementia;Development;Doctor of Philosophy;Elderly;Ensure;Environment;Etiology;Fostering;Foundations;Goals;Heterogeneity;Human Resources;Human Volunteers;Impaired cognition;Individual;Infrastructure;Kentucky;Knowledge;Leadership;Modality;Monitor;Neurosciences;Occupational activity of managing finances;Pathogenicity;Pathology;Patients;Prevention;Research;Research Activity;Research Personnel;Resources;Risk;Risk Factors;Science;Strategic Planning;Structure;System;Tissues;Training and Education;Translational Research;United States;Universities;accurate diagnostics;beneficiary;cohort;comorbidity;diagnostic strategy;disease heterogeneity;effective therapy;innovation;late life;meetings;multidisciplinary;neuropathology;novel therapeutics;pre-clinical;prevent;programs;success;training opportunity;treatment strategy;volunteer


application_id: 11123372
project_number: 5P30AG072946-05
project_title: University of Kentucky Alzheimer's Disease Research Center
administering_ic: NIA
award_notice_date: 2025-07-09
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
program_official: ELLIOTT, CERISE
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G(M1)
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: OverallThe University of Kentucky Alzheimers Disease Research Center (UK-ADRC) is an experienced andcollaborative center that has facilitated pioneering research in AD and related dementias (ADRD) since itsinception in 1985. Our principal mission is to serve as the focal point for all AD-related activities at UK and thisregion of the United States by providing an environment and core resources that catalyze innovative researchoutreach education and clinical programs. Our signature resources include: 1) a cognitively normal group of~500 subjects followed longitudinally together with ~300 additional subjects who transitioned to MCI ordementia and all committed to brain autopsy upon death; 2) a strong autopsy program with clinical-neuropathological correlations and short postmortem interval research material; 3) a maturing programstudying the early preclinical biological emergence of mixed pathologies and how they contribute to late lifedementia states with an increasing focus on antemortem biomarker collection; 4) an integrated centralizeddatabase and innovative biostatistical expertise to characterize clinical and biological transitions; 5) asuccessful and close partnership with the African-American community and increased participation ofunderrepresented individuals in our longitudinal cohort and ADRC-affiliated research studies and clinical trials;and 6) a rich interdisciplinary training environment that provides multi-faceted educational opportunities forresearchers healthcare providers and our community partners. The overarching theme of the UK-ADRC is:Transitions from Normal to Late-Life Multi-Etiology Dementia. Our well-characterized longitudinal cohortand historically strong neuropathology program focused on normal aging preclinical disease states and earlycognitive transitions have been central to our success in defining early pathogenic mechanisms underlying thetransitions from normal cognitive aging to impairment. In addition these efforts have been a driving force in ourrecognition of the heterogeneity and multiple pathologies that characterize late-life dementia. The UK-ADRCwill continue to leverage our strengths to enhance our impact and Centerness by our focus on thisoverarching theme and the pursuit of four overall specific aims.Aim 1. Facilitate and enhance basic translational and clinical research in AD and related dementias.Aim 2. Provide the necessary resources and interactive environment to support and create new opportunitiesfor innovative research.Aim 3. Maintain and grow educational opportunities and community partnerships to promote awarenessincrease participation in research and provide an innovative and interdisciplinary training environment.Aim 4. Contribute to the national efforts and collaborative activities with other centers programs and groups toadvance AD/ADRD research education and care.

project_terms:
Address;African American;Aging;Alzheimer's Disease;Area;Autopsy;Awareness;Basic Science;Biological;Biological Markers;Biometry;Brain;Caring;Cessation of life;Clinical;Clinical Research;Clinical Trials;Cognitive;Cognitive aging;Collaborations;Collection;Communities;Community Health Education;Community Outreach;Dedications;Dementia;Development;Disease;Early identification;Education;Elderly;Ensure;Environment;Etiology;Family;Goals;Health Personnel;Heterogeneity;Impaired cognition;Impairment;Individual;Infrastructure;Institution;Kentucky;Knowledge;Longitudinal cohort;Mission;Neurodegenerative Disorders;Outcome;Pathogenicity;Pathology;Recommendation;Research;Research Personnel;Research Project Grants;Resources;Risk;Scholars Program;Training;Translating;Translational Research;United States;United States National Institutes of Health;Universities;aging brain;beneficiary;central database;clinical practice;cohort;collaborative environment;community partners;community partnership;comorbidity;data management;driving force;education research;experience;innovation;late life;neuropathology;next generation;normal aging;novel therapeutics;outreach;pre-clinical;programs;recruit;research study;statistics core;success;volunteer

public_health_relevance:
NARRATIVE: OVERALLThe University of Kentucky Alzheimers Disease Research Center (UK-ADRC) facilitates and supportsbasic/translational and clinical research efforts to identify the early manifestations of disease and thepathogenic mechanisms underlying the transitions from normal aging to the development of cognitiveimpairment with a special focus on mixed pathology and co-morbidities that influence risk and outcomes inlate-life multi-etiology dementia. We are also dedicated to training the next generation of researchers and togrowing our educational programs and community partnerships to promote awareness of AD and relateddisorders and the importance of research and research participation.


application_id: 11123309
project_number: 5R01LM014510-02
project_title: Structure-Function-Aware Large Protein Language Models for Enhanced Biomedical Applications
administering_ic: NLM
award_notice_date: 2025-05-12
opportunity_number: PAR-23-034
application_type: 5
activity_code: R01
ic: LM
serial_number: 014510
program_official: BINGHAM, CLAYTON SCOTT
project_start_date: 2024-06-21
project_end_date: 2028-05-31
study_section: Biomedical Informatics, Library and Data Sciences Review Committee[BLR]
contact_pi_person_id: 14274655
contact_pi: SHAO, QING
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Large protein language models have shown their foundational role in biomedical research. However twochallenges are roadblocking their broad applications: (a) the absence of critical knowledge about proteinstructure and functions in the models and (b) the lack of efficient approaches to adapt a trained proteinlanguage model. To address the two challenges we propose to develop protein language models withknowledge of protein structures and functions and adaptation methods that can provide accurate predictionsfor protein properties. The goal is to develop and validate the structure-function-aware large proteinlanguage models (SF-PLM) that could be adapted to operate challenging biomedical research tasksusing few-shot learning. We hypothesize that (a) multi-view contrastive learning can fuse 2D/3D structuralinformation into 1D representation (b) well-developed reinforcement learning can align a large protein languagemodel with the related function annotation and (c) prompt tuning can realize a few-shot learning process toadapt the trained models to specific biomedical tasks. Inspired by the hypotheses we develop three SpecificAims to help achieve the proposal's goal. Aim 1: Develop large protein language models aware of 2D and 3Dstructures using multi-view contrastive learning. We will develop the encoders for the protein 1D 2D and 3Dstructures; optimize the model training procedure and contrastive loss functions and validate and select thedeveloped models using structure-oriented downstream tasks. Aim 2: Develop a reinforcement learning-based method to align knowledge of protein functions with the structure-aware large protein language models.We will start by developing an initial policy model further develop the reward model and proximal policyoptimization to align the trained large protein language models and validate and select the aligned largeprotein language models. Aim 3: Develop prompt technologies and tools to adapt structure-function-awarelarge protein language models for downstream tasks. We will develop prompt tuning to adapt the trainedprotein language models for antimicrobial peptide design and predict the targets and phosphorylationstrengths for polo-like kinase 1 (PLK1) an overexpressed kinase in cancer cells. We will build utilities toenable the community usage of the prompt tuning. The success of the proposed research will lead to (a) thedevelopment of novel large protein language models aware of structures and functions (b) prompt-basedefficient adaptation of trained large protein language models for downstream tasks (c) several novelantimicrobial peptides (d) a list of predicted substrates and their phosphorylation strengths of PLK1 and (f)a library of Python code that enables the development of the pre-trained protein language models andefficient prompt tuning. These outcomes will provide and validate fundamental deep learning tools forbiomedical research. The outcome (c) and (d) will further enhance biomedical research in bacterialresistance and cancer treatment.

project_terms:
3-Dimensional;Address;Amino Acid Sequence;Awareness;Base Sequence;Biomedical Research;Classification;Code;Collaborations;Communities;Data;Data Set;Databases;Development;Enzymes;Generations;Goals;Individual;Knowledge;Language;Learning;Libraries;Methods;Modeling;Molecular;Outcome;PLK1 gene;Performance;Phosphorylation;Phosphotransferases;Policies;Procedures;Process;Property;Proteins;Psychological reinforcement;Pythons;Research;Rewards;Role;Structure;SwissProt;Technology;Therapeutic;Training;Work;anti-microbial peptide;bacterial resistance;cancer cell;cancer therapy;deep learning;design;human disease;in silico;learning algorithm;loss of function;model development;novel;overexpression;protein function;protein structure;shot learning;success;three dimensional structure;tool;training data;vector

public_health_relevance:
Large protein language models have shown their foundational role in biomedical research but the currentmodels miss critical knowledge about protein structure and functions and lack efficient approaches to beadapted for challenging biomedical tasks. To address these two challenges we propose to developstructure-function-aware large protein language models and adaptation methods for accurate predictions ofprotein properties. The success of this project will provide novel large protein language models andfundamental deep learning tools for various biomedical applications.


application_id: 11122294
project_number: 5R01CA157429-12
project_title: Overcoming Drug Resistance of Castration-Resistant Prostate Cancer
administering_ic: NCI
award_notice_date: 2025-06-12
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 157429
program_official: FORRY, SUZANNE L
project_start_date: 2011-09-01
project_end_date: 2027-06-30
study_section: Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Title: Overcoming drug resistance of castration-resistant prostate cancerAbstractBecause androgen receptor (AR) signaling is essential for development of prostate cancer (PCa) includingcastration-resistant prostate cancer (CRPC) androgen signaling inhibitors (ASI) are becoming the first linetreatment for CRPC. However the limited success of ASIs makes it urgent to develop approaches to treatASI-resistant CRPC. EZH2 (enhancer of zeste homolog 2) the catalytic subunit of the Polycomb RepressiveComplex (PRC2) responsible for H3K27me3 and gene repression has been identified as a promising targetin PCa. However it was also discovered that oncogenic function of EZH2 in CRPC is PRC2-independent.Thus identifying regulators that control EZH2 function is of significance as it may provide an avenue toenhance the efficacy of EZH2 inhibitors (EZH2i) in CRPC. The long-term goals of this study are to identifydruggable signaling pathways that offer effective treatment options for patients with ASI-resistant CRPC.The objective is to define the role of polo-like kinase 1 (Plk1) in regulating EZH2 to exploit this pathway asa therapeutic target for ASI-resistant CRPC patients and to examine whether Plk1-dependentphosphorylation of EZH2 is a novel biomarker for CRPC. The central hypothesis is that Plk1 phosphorylationof EZH2 leads to a functional switch from PRC2-dependent gene repression to PRC2-independent but AR-dependent transcription activation eventually contributing to disease progression into CRPC stage. Ourdata show that Plk1 inhibition leads to an increased level of H3K27me3 and that Plk1 directly phosphorylatesEZH2 at T144. We also show that Plk1 phosphorylation of EZH2 results in decreased levels of H3K27me3destabilization of the PRC2 complex and increased association between EZH2 and AR. Our hypothesis willbe tested by pursuing three Aims - (1) to dissect how Plk1 phosphorylation of EZH2 regulates the PRC2complex; (2) to test whether expression of unphosphorylatable EZH2 antagonizes PCa progression andenhances the efficacy of EZH2i in genetically engineered mouse (GEM) models; and (3) to determinewhether Plk1 inhibitor (Plk1i) plus EZH2i is a novel approach to treat ASI-resistant CRPC and whetherpT144-EZH2 is a novel biomarker for CRPC. These complementary aims will be accomplished usingbiochemical analyses of signaling intermediates and employing genetic strategies with inducible PCa mousemodels culture systems and patient-derived xenograft (PDX) methodologies. The rationale for the researchis that it will probe the importance of Plk1 to PRC2 complex examine whether a combination of Plk1i withEZH2i is a novel approach to treat ASI-resistant CRPC and ask whether pT144-EZH2 is a new biomarkerto predict PCa progression. This contribution is significant because if positive the results of the proposedstudy will support an immediate clinical trial for Plk1i plus EZH2i to treat ASI-resistant CRPC. The researchis innovative as it approaches the disease from a novel Plk1 signaling pathway challenging the traditionalview that Plk1 functions solely to regulate mitotic events.

project_terms:
Affect;Androgen Receptor;Androgens;Apoptosis;Automobile Driving;Binding;Biochemical;Biological Markers;Breeding;Cancer Patient;Castration;Catalytic Domain;Cell Nucleus;Cells;Clinic;Clinical Research;Clinical Trials;Complex;Creativeness;Cytokine-Inducible Kinase;Cytoplasmic Receptors;Data;Development;Disease;Disease Progression;Drug resistance;Enhancers;Epigenetic Process;Event;Fostering;Genetic Transcription;Genetically Engineered Mouse;Goals;Health;Homologous Gene;Investigation;Knock-out;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Methodology;Methylation;Mission;Mitotic;Mus;Neuroendocrine Prostate Cancer;Oncogenic;Operative Surgical Procedures;Outcome;PLK1 gene;PTEN gene;Pathway interactions;Patient-Focused Outcomes;Patients;Phosphorylation;Polycomb;Prostate;Public Health;Receptor Signaling;Research;Resistance;Resources;Role;Signal Pathway;Signal Transduction;Specimen;System;Testing;Therapeutic;Transcriptional Activation;United States National Institutes of Health;Withdrawal;Work;Xenograft Model;abiraterone;androgen independent prostate cancer;androgen sensitive;cancer therapy;design;diagnostic biomarker;effective therapy;enzalutamide;gene repression;genetic approach;improved;inhibitor;innovation;mouse model;mutant;novel;novel marker;novel strategies;patient derived xenograft model;pharmacologic;programs;prostate cancer cell;prostate cancer model;prostate cancer progression;success;therapeutic target;tumor

public_health_relevance:
NarrativeThe proposed research is relevant to public health because it focuses on discovery of novel signaling pathwaysthat drive castration-resistant prostate cancer. These studies will establish new avenues of investigation todevelop improved therapeutics to treat this deadly disease and to greatly improve patient outcome. Thus theproposed research is relevant to NIH's mission of fostering creative discoveries and innovativeresearch strategies for protecting and improving health and reducing the burdens associated with cancer.


application_id: 11122183
project_number: 5T32ES011564-20
project_title: UOFL ENVIRONMENTAL HEALTH SCIENCES TRAINING PROGRAM
project_terms: Environmental Health;Training Programs
administering_ic: NIEHS
award_notice_date: 2025-06-14
opportunity_number: PA-20-142
application_type: 5
activity_code: T32
ic: ES
serial_number: 011564
program_official: SHREFFLER, CAROL A
project_start_date: 2002-07-01
project_end_date: 2026-06-30
study_section: Environmental Health Sciences Review Committee[EHS(T)]
contact_pi_person_id: 6094413
contact_pi: WISE, JOHN PIERCE
other_pis: HEIN, DAVID W
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
ABSTRACTWe have made strategic changes in our environmental health sciences training program in response to theannounced restructuring and redirection of NIEHS training programs. Participating Centers Institutes andSchools and the members of the training faculty provide critical resources for cutting edge basic science clinicalresearch computational sciences and public health. Environmental health science partnerships have resulted ina very successful NIEHS training program in environmental health sciences. Our renewal proposal incorporatesand integrates several Schools Centers and Institutes including the new Envirome Institute the recently fundedNIEHS P42 Superfund Research Program and the soon to be funded NIEHS P30 Core Center in EnvironmentalHealth Sciences. We propose a substantially improved predoctoral and postdoctoral training program that servesas an umbrella for interdisciplinary and integrated approaches to environmental health sciences. The trainingprogram will support six predoctoral and three postdoctoral trainees. Initial student recruitment and funding forpredoctoral trainees is provided by the University of Louisville Integrated Programs in the Biomedical Sciencesrecruitment gateway. As in the previous cycle predoctoral trainees will not be recruited directly into theenvironmental health sciences training program. All faculty mentors are asked to nominate trainees who havecompleted an approved dissertation proposal with a defined focus in environmental health sciences research.Faculty mentors will be asked to nominate either existing postdoctoral fellows or from trainees to be recruited.Teams of mentors (basic and clinical scientists or basic and population-based scientists) will be particularlyencouraged to emphasize the importance of multidisciplinary training and translation of basic science findings tothe patient and/or community. Our training program facilitates multidisciplinary approaches for effectiveintervention and interfaces exceptionally well with the NIH Roadmap as well as with the strategic plans of NIEHSand the University of Louisville.

public_health_relevance:
PROJECT NARRATIVEThe environmental health problems faced by the nation are multi-factorial in nature and thereforerequire multi-disciplinary approaches for effective intervention. Our training program emphasizesthe importance of multidisciplinary training and translation of basic science findings to obtainrigorous reproducible and transparent results that benefit the patient and/or community. Thismulti-disciplinary translational program interfaces with the NIH Roadmap and the NIEHS strategicplan.


application_id: 11122173
project_number: 5R35GM152104-02
project_title: Obesity-mediated protection in sepsis
administering_ic: NIGMS
award_notice_date: 2025-05-06
opportunity_number: PAR-22-180
application_type: 5
activity_code: R35
ic: GM
serial_number: 152104
program_official: ZHAO, XIAOLI
project_start_date: 2024-07-01
project_end_date: 2029-04-30
study_section: Maximizing Investigators' Research Award - D Study Section[MRAD]
contact_pi_person_id: 10399494
contact_pi: STARR, MARLENE ELENA
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTSepsis is a major burden to the healthcare system being the most common cause for admission to the intensivecare unit and the most expensive condition treated in US hospitals. It is a complex physiologic condition involvinga heterogenous patient population with high morbidity and mortality and no specific therapies aside fromsupportive measures. Clinical studies indicate that obesity is paradoxically associated with improved survival insepsis; however the mechanisms behind this obesity-mediated protection are not known. Capitalizing on theunique resistance in this patient population may allow for the development of novel therapies to prevent themorbidity and mortality associated with sepsis. The primary goals of my research program are to 1) investigatedifferences in sepsis pathophysiology in patients stratified by obesity status with a major focus on immunealterations and 2) define shifts in immune cell function and metabolism in obesity and determine their roles inconferring protection during sepsis utilizing a validated murine model and patient samples. The gainedinformation will aid in the development strategies to reduce morbidity and mortality in sepsis.

project_terms:
Admission activity;Cell Physiology;Cells;Cellular Metabolic Process;Clinical Research;Complex;Development;Functional disorder;Goals;Health Care Systems;Hospitals;Immune;Intensive Care Units;Measures;Mediating;Metabolism;Morbidity - disease rate;Obesity;Patients;Phenotype;Physiological;Research;Resistance;Rodent;Role;Sampling;Sepsis;improved;mortality;mouse model;novel therapeutics;patient population;patient stratification;prevent;programs;sepsis mortality

public_health_relevance:
PROJECT NARRATIVEObesity is paradoxically associated with improved survival during sepsis; however the mechanistic basis for thisprotection is not understood. This project will investigate alterations in immune cell phenotype function andmetabolism during sepsis in patients and rodents with underlying obesity.


application_id: 11121768
project_number: 5F32AR083259-02
administering_ic: NIAMS
award_notice_date: 2025-08-14
opportunity_number: PA-21-048
application_type: 5
activity_code: F32
ic: AR
serial_number: 083259
program_official: BELKIN, ALEXEY
project_start_date: 2024-08-01
project_end_date: 2027-07-31
study_section: Special Emphasis Panel[ZRG1-F10B-Q(20)L]
contact_pi_person_id: 11434627
contact_pi: ALLEN, ROBYN S.
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-08-01
project_title:
A multispecies system for elucidating proliferative control mechanisms during mammalian skin and musculoskeletal regeneration

project_abstract:
Abstract While antifibrotic therapies continue to advance they fall short when treating large or chronic wounds.Essential to developing new regenerative strategies is a comprehensive understanding of how cell proliferationis activated maintained and eventually terminated to accurately restore missing tissue. The objective of thisproposal is to determine the cell autonomous mechanisms that permit and control proliferation during complextissue regeneration in highly regenerative mammals (spiny mice and rabbits). Spiny mice are unique amongrodents in their ability to regenerate complex skin and musculoskeletal tissues and as such they represent apromising model for pinpointing molecular and cellular mechanisms that prevent regeneration in humans.Fascinatingly primary dermal fibroblasts from spiny mice and rabbits maintain proliferation in the face of reactiveoxygen species gamma irradiation and contact inhibition. These same conditions induce senescence orquiescence in primary dermal fibroblasts from poorly regenerative mammals (lab mice and rats). This proposaluses cells from these species to identify how identical signals trigger regeneration in some species and scarringin others. Further this proposal utilizes spiny mouse ear pinna regeneration a highly reproducible and tractablemodel of mammalian skin and musculoskeletal regeneration to further explore pro-regenerative signals in vivo.In Aim 1 I will examine how stress signals are differentially transduced by cells to determine how fibroblastsfrom highly regenerative mammals maintain proliferation in senescence inducing conditions in vitro. I will thenuse spiny mouse ear pinna regeneration to determine how this differential stress transduction leads to activationand maintenance of regenerative response following injury in vivo. In Aim 2 I will identify the mechanisms thatpermit primary fibroblasts from spiny mice and rabbits to proliferate at very high cell densities in vitro. I will thenuse spiny mouse ear pinna regeneration to determine how these mechanisms regulate proliferation and tissuesize in vivo. I hypothesize that cells from highly regenerative mammals differentially activate signaling pathwaysthat facilitate cell cycle progression in response to stress and maintain this activity in excess of inhibitory signalsthat terminate proliferation in non-regenerative mammals. These studies will generate RNA-seq datasets andidentify candidate genes that will drive discovery in the field and form a basis for my own independent research.By studying proliferative control during regeneration we can build a blueprint for the recapitulation ofregeneration in human medicine.

project_terms:
Adult;Candidate Disease Gene;Cell Cycle;Cell Cycle Progression;Cell Cycle Proteins;Cell Cycle Regulation;Cell Density;Cell Proliferation;Cell Senescence Induction;Cells;Cicatrix;Complex;Contact Inhibition;Data;Data Set;Defect;Dependovirus;Dermal;Ear;Equilibrium;Exposure to;Fibroblasts;Fibrosis;Gene Activation;Gene Expression;Genes;Gerbils;Growth;Health Care Industry;Human;In Vitro;Injury;Lentivirus;Long-term disability;Maintenance;Mammals;Medicine;Modeling;Molecular;Mus;Musculoskeletal;Natural regeneration;Oryctolagus cuniculus;Outcome;Oxidative Stress;Pathway interactions;Phenotype;Physiological;Process;Proliferating;Proteins;Psychological Stress;Rattus;Reactive Oxygen Species;Regenerative Medicine;Regenerative response;Regulation;Reproducibility;Research;Resistance;Resolution;Rodent;Role;Screening procedure;Signal Pathway;Signal Transduction;Skin;Stress;System;Testing;Tissues;Work;antifibrotic treatment;candidate identification;cellular transduction;chronic wound;density;experimental study;external ear auricle;fascinate;gamma irradiation;high throughput screening;in vitro Assay;in vivo;innovation;insight;knock-down;model building;non-healing wounds;novel;novel strategies;organ injury;organ repair;prevent;programs;regenerative;regenerative approach;regenerative therapy;repaired;response;response to injury;screening;senescence;sensor;skills;skin regeneration;skin wound;small hairpin RNA;targeted treatment;tissue regeneration;tool;transcriptome sequencing

public_health_relevance:
Project NarrativeSkin and musculoskeletal regenerative therapies for large and chronic wounds are limited by an incompleteunderstanding of proliferative regulation. This proposal investigates how highly regenerative mammals activateand maintain cell proliferation in the face of inhibitory conditions to drive regeneration. This work will generatenovel targets for regenerative therapies and high throughput screening tools for evaluating phenotypesassociated with regenerative ability.


application_id: 11121738
project_number: 5R01CA264652-05
project_title: Plk1 as a prognostic biomarker for prostate cancer
administering_ic: NCI
award_notice_date: 2025-07-01
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 264652
program_official: WEINREICH, MICHAEL DALE
project_start_date: 2021-07-01
project_end_date: 2026-06-30
study_section: Cancer Biomarkers Study Section[CBSS]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Title: Plk1 as a prognostic biomarker for prostate cancerAbstractBecause androgen receptor (AR) signaling is essential for development of prostate cancer (PCa)including castration-resistant prostate cancer (CRPC) androgen signaling inhibitors (ASI) arebecoming the first line treatment for CRPC. However the limited clinical success of ASIs makes iturgent to develop new approaches to treat ASI-resistant CRPC. Ionizing radiation is another majorapproach to treat CRPC with limited efficacy. Olaparib a PARP1 inhibitor is recently developed andused to target cancers with a defect in DNA repair such as BRCA mutations. Unfortunately the usageof olaparib in CRPC is profoundly limited by the fact that BRCA mutations only occur in lowpercentages of PCa. Thus identifying additional critical regulators that control DNA damage response(DDR) is of significance as it will identify specific patient populations who will be responsive to olaparib.The objective is to define the role of polo-like kinase 1 (Plk1) in regulating DDR and to exploit its uniqueimpact on the efficacy of olaparib for ASI-resistant CRPC patients. The central hypothesis is that Plk1phosphorylation of Mre11 a component of MRN (Mre11/Rad50/Nbs1) complex and MDC1 (mediatorof DNA damage checkpoint 1) leads to premature termination of DNA damage checkpoint reducedDNA repair thus increased olabparib efficacy based on the concept of synthetic lethality. Our datashow that Plk1 directly phosphorylates Mre11 whose activation is the first step in response to DNAdamage and that Plk1 phosphorylation of Mre11 leads to recovery from DNA damage checkpoint andreduced DNA repair. We also show that MDC1 a protein that further amplifies DDR signals is a Plk1substrate. Our hypothesis will be tested by pursuing three Specific Aims - (1) to dissect how Plk1phosphorylation of Mre11 regulates the MRN complex; (2) to test whether Plk1 phosphorylation ofMDC1 contributes to premature termination of checkpoint; and (3) to determine whether Plk1 is aprognostic biomarker for PCa. These complementary aims will be accomplished using biochemicalanalyses of signaling intermediates and employing both cell culture systems and genetic strategieswith inducible mouse models. The rationale for the research is that it will probe the importance of Plk1to DDR and to examine whether Plk1 can be a predictable biomarker for the efficacy of olaparib inCRPC. This contribution is significant because if positive the results of the proposed study will supportan immediate clinical trial to compare the efficacy of olaparib in CRPC patients carrying different levelsof Plk1. The research is innovative as it approaches the disease from a novel Plk1 signaling pathwaychallenging the traditional view that Plk1 functions solely to regulate mitotic events. These studiesprovide a new paradigm for therapies by identifying the key regulator of DDR that is critical for theefficacy of olaparib in CRPC.

project_terms:
Affect;Androgen Receptor;Androgens;BRCA mutations;Biochemical;Biological Markers;Cancer Patient;Castration;Cell Culture System;Cells;Chromatin;Clinic;Clinical;Clinical Research;Clinical Trials;Complex;Creativeness;DNA Damage;DNA Repair;DNA Repair Gene;DNA Repair Inhibition;DNA Repair Pathway;DNA amplification;DNA damage checkpoint;Data;Defect;Development;Disease;Event;Exhibits;Fostering;Frequencies;Genetically Engineered Mouse;Goals;Health;Investigation;Ionizing radiation;Malignant Neoplasms;Malignant neoplasm of prostate;Mediator;Meiotic Recombination;Mission;Mitotic;Mus;Mutation;Outcome;PLK1 gene;Patient-Focused Outcomes;Patients;Phosphorylation;Phosphotransferases;Poly(ADP-ribose) Polymerase Inhibitor;Prognostic Marker;Proteins;Public Health;Receptor Signaling;Recovery;Research;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Testing;Therapeutic;Tumor Subtype;Withdrawal;Work;abiraterone;androgen independent prostate cancer;ataxia telangiectasia mutated protein;brca gene;cancer cell;clinically relevant;comparative efficacy;cytotoxic;design;efficacy evaluation;enzalutamide;genetic approach;improved;inhibitor;innovation;mouse model;novel;novel strategies;overexpression;patient population;premature;prostate cancer cell;prostate cancer progression;response;success;synthetic lethal interaction;tumor

public_health_relevance:
NarrativeThe proposed research is relevant to public health because it focuses on discovery of novel signaling pathwaysthat drive castration-resistant prostate cancer. These studies will establish new avenues of investigation todevelop improved therapeutics to treat this deadly disease and to greatly improve patient outcome. Thus theproposed research is relevant to NCI's mission of fostering creative discoveries and innovative researchstrategies for protecting and improving health and reducing the burdens associated with cancer.


application_id: 11120828
project_number: 5R00CA249048-04
project_title: A pro-metastatic secretory program activated by epithelial-to-mesenchymal transition
administering_ic: NCI
award_notice_date: 2025-02-14
opportunity_number: PA-20-188
application_type: 5
activity_code: R00
ic: CA
serial_number: 249048
program_official: BENAVIDEZ, JUSTIN MICHAEL
project_start_date: 2024-03-12
project_end_date: 2027-02-28
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 15823901
contact_pi: XIAO, GUAN-YU
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ProjectSummary/AbstractCandidate:Dr.XiaohasreceivedbroadtrainingincellandcancerbiologyincludingpostdoctoraltrainingatUT-SouthwesternMedicalCenter(UTSW)andMDAndersonCancerCenter(MDACC).Heseekstounderstandhowepithelial-to-mesenchymaltransition(EMT)drivesmalignantsecretiontopromotelungcancermetastasis.Dr.Xiaoisahighlyproductiveinvestigatorwith4first-authoredpeer-reviewedpapers.Asrecognitionofhisachievementshereceivednumerousawardsduringhisdoctoralandpostdoctoraltraining.Career Development/Training: Dr. Xiaos primary mentor is Dr. Jonathan Kurie a physician-scientist withexpertise in cancer biology and mouse modeling of human lung adenocarcinoma (LUAD). His co-mentor is Dr.SandraSchmidwhowashismentoratUTSWandisaleaderinthefieldofendocyticvesicletrafficking.Additionalinput will come from Dr. Angela Wandinger-Ness (University of New Mexico) who identified Rab GTPases asregulatorsofendosomaltraffickingandisdevelopingGTPase-targetedtherapiesforcancer.TheseinvestigatorshavedesignedatrainingprogramcenteredontheirkeyscientificdisciplinesthatwillstrengthenDr.Xiaosabilitiesintheirrespectivefieldsandprovidetheskillsneededforasmoothtransitiontoindependence.Research:EMTinductionincancercellsinitiatesthemetastaticcascadebypromotingmotilityandinvasivenessthrough cell-autonomous mechanisms. Our group has shown thatEMT also increases the secretion of proteinsthat maintain LUAD cell viability and create an immunosuppressive and fibrotic tumor microenvironment (TME)that facilitates LUAD metastasis. These findings are the basis for our hypothesis that EMT promotes LUADmetastasisthroughdualcell-autonomousandnon-autonomousmechanisms.TheobjectiveofmyproposalistoelucidatethemolecularunderpinningsofEMT-dependentsecretioninLUAD.InmypreliminaryresultsIshowthatthe EMT-activating transcription factor ZEB1 upregulates the expression of Rab6A and Rab8A by silencingmicroRNAsthattargettheseeffectors.IshowthatZEB1requiresRab6AandRab8AtodrivepolarizedtraffickingofsecretoryvesiclestowardtheleadingedgeofmigratingLUADcellstoincreasecytokinesecretiontogenerateanimmunosuppressiveTMEandtopromoteLUADcellmigrationinvasionandmetastasis.Becausesecretoryvesicle exocytosis occurs at hot spots juxtaposed to focal adhesions I hypothesize that ZEB1 coordinatelyregulates anterograde trafficking of secretory vesicles and remodeling of actin-based cytoskeletal structures toinitiate polarized secretion of pro-tumorigenic effector proteins that drive LUAD progression. I will test thishypothesis by determining how ZEB1 coordinately regulates anterograde vesicle trafficking and cytoskeletalremodelingtodrivepolarizedsecretionofpro-tumorigeniceffectorproteinsandLUADprogression.InsummyproposalwilladdresstheclinicalproblemofLUADmetastasis.Thenoveltyrestsinpreliminaryresultsthat demonstrate a transcriptional governance of polarized vesicular transport providing the potential to targetZEB1-drivensecretorypathwaysforthepurposeofblockingmetastasisinLUAD.

project_terms:
Achievement;Actins;Adenocarcinoma Cell;Aerosols;Alleles;Apical;Award;Belief;Biogenesis;Biological;Cancer Biology;Cancer Center;Cancer Etiology;Cell Line;Cell Survival;Cell membrane;Cells;Cellular biology;Clinical;Cytoskeleton;Data;Discipline;Endocytic Vesicle;Endosomes;Exocytosis;Focal Adhesions;Genetic Transcription;Growth;Guanosine Triphosphate Phosphohydrolases;Hot Spot;Human;Immunocompetent;Immunosuppression;Invaded;KRASG12D;Kinetics;Knowledge;Laboratories;Lentivirus;Lung Adenocarcinoma;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Medical center;Mentors;MicroRNAs;Microtubules;Molds;Molecular;Monomeric GTP-Binding Proteins;Motility;Mus;Neoplasm Metastasis;New Mexico;Organelles;Paper;Pathway interactions;Peer Review;Physicians;Positioning Attribute;Process;Productivity;Property;Protein Secretion;Proteins;Proxy;Receptor Protein-Tyrosine Kinases;Research;Research Personnel;Rest;Scientist;Secretory Vesicles;Signal Transduction;Site;Source;Stains;Structure;Survival Rate;Testing;The Cancer Genome Atlas;Tissues;Training;Training Programs;Translating;Tumor Promotion;Universities;Vesicle;Vimentin;Work;actionable mutation;activating transcription factor;anti-cancer research;cancer cell;career development;cell fixing;cell motility;cohort;congenic;cytokine;design;epithelial to mesenchymal transition;human model;imaging study;inhibitor;loss of function;migration;mouse model;paxillin;post-doctoral training;programs;rab GTP-Binding Proteins;skills;small hairpin RNA;targeted cancer therapy;therapeutically effective;trafficking;transcriptome;tumor;tumor microenvironment;tumor-immune system interactions;tumorigenic;vesicle transport

public_health_relevance:
ProjectNarrativeTherearefeweffectivetherapeuticoptionsformetastaticlungadenocarcinomas(LUADs)thatlackactionablemutations in receptor tyrosine kinases and there is an urgent need to develop a better understanding of thebiological basis of LUAD growth and metastasis. On the basis of the preliminary results presented here Ipostulate that LUAD growth and metastasis is driven by a secretory program activated by epithelial-to-mesenchymaltransition(EMT).IfproventruethesefindingswouldshowthatEMTpromotesmetastasisthroughacellnon-autonomousmechanismwhichwouldadvanceourunderstandingofthemolecularunderpinningsofLUAD progression and would provide a rationale to identify actionable targets in the EMT-activated secretoryprogram.


application_id: 11119241
project_number: 1R21EY037437-01
project_title: Neurexin Isoforms in Retina Structure and Function
administering_ic: NEI
award_notice_date: 2025-08-29
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: EY
serial_number: 037437
program_official: WRIGHT, CHARLES BAKER
project_start_date: 2025-09-01
project_end_date: 2027-08-31
study_section: Biology and Development of the Eye Study Section[BDE]
contact_pi_person_id: 1885008
contact_pi: GREGG, RONALD G
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The long-term goal of this project is understand the molecular interactome that establishes and maintainshighly specialized retinal cell interactions that establish parallel pathways within the retina. The focus in thisproposal is to determine the function of 3 Neurexin genes and their isoform specific expression pattern withinthe retina. Neurexins are trans-synaptic organizers that interact with several ligands and are important inestablishing functional properties at excitatory and inhibitory synapses. Neurexins undergo extensivealternative splicing creating potentially hundreds of isoforms which are known to be important in disease.However to date the role of this important class of protein in retina is unexplored. Emerging technologies owmake it possible to obtain a more complete picture of isoform structure in a tissue and/or specific cell typeswithin a tissue. Therefore in the project we will1) Determine the function of Neurexins in the retina and 2)determine the retinal cell type expression pattern of Neurexin isoforms using single cell iso-Seq. At the completion of this project we will have characterized for the first time the cell class specificexpression of neurexins and their role in maintaining the structure and/or function of the first retinal synapse.

project_terms:
Address;Alternative Splicing;Amacrine Cells;Axon;Bar Codes;Brain;Brain region;Calcium;Cell Adhesion;Cell Adhesion Molecules;Cell Communication;Cell Physiology;Cell Separation;Cells;Code;Communities;Cone;Data;Dendrites;Development;Disease;Dystroglycan;Electroretinography;Emerging Technologies;Evaluation;Excitatory Synapse;Exploratory/Developmental Grant for Diagnostic Cancer Imaging;Family;Family member;Family suidae;Genes;Goals;Image;Inhibitory Synapse;Ions;Knockout Mice;Knowledge;Lead;Ligands;Methods;Molecular;Mus;Output;Pathway interactions;Pattern;Photoreceptors;Printing;Property;Protein Isoforms;Proteins;RNA Splicing;Research Personnel;Research Project Grants;Resources;Retina;Retinal Ganglion Cells;Rod;Role;Sampling;Series;Signal Transduction;Structure;Synapses;Technology;Time;Tissues;Variant;Vision;Visual;cDNA Library;cell type;ganglion cell;gene function;horizontal cell;member;neuroligin 2;outer plexiform layer;promoter;receptor;retinal neuron;single-cell RNA sequencing;transcriptome sequencing;transmission process;visual coding

public_health_relevance:
Retinal function requires the accurate assembly of synapses between cells in in a celltype specific to create parallel vertical pathways that transmit various aspects of thevisual scene to higher brain structures. The studies in this proposal will characterize thefunction and cell type isoform distribution of one family of adhesion molecules that hasthe potential to set up a cell type code Neurexins and which are likely critical to visualfunction.


application_id: 11119003
project_number: 5TL1TR001997-09
project_title: NRSA Training Core
administering_ic: NCATS
award_notice_date: 2025-07-29
opportunity_number: PAR-18-940
application_type: 5
activity_code: TL1
ic: TR
serial_number: 001997
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2027-06-30
study_section: ZTR1-SRC(99)
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: PENDERGAST, JULIE S
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Kentucky (UK) Center for Clinical and Translational Science (CCTS) proposes to sustain and enhance the current pre-doctoral and post-doctoral TL1 program currently in its ninth year of National Institutes of Health (NIH) support. By providing a multidisciplinary training program that integrates trainees across a range of fields and offers rigorous and solid translational research education the TL1 program has effectively prepared clinicians- and scientists-in-training for careers as leaders in clinical and translational science. The UK TL1 program features substantial collaborations across a robust cohort of productive investigators a talented pool of qualified applicants solid infrastructure and strong institutional support. The program takes advantage of the physical juxtaposition of UKs six health care colleges (Medicine Nursing Pharmacy Public Health Health Sciences Dentistry) and key disciplines on the main campus (e.g. Engineering Social Work Biology Psychology Education) to train scholars across wide-ranging fields necessary for successful clinical and translational research (CTR). The program supports career development of scholars with research interests that cross the lifespan (prenatal through elderly) and the full spectrum of clinical and translational science including translational clinical community/policy studies and CTR methods/processes (e.g. biomedical informatics) focusing on a broad array of health topics. The TL1 trainees are making important contributions to science through published work and all the program graduates are actively engaged in CTR. This program and other CCTS-sponsored efforts are engaging students in projects focused on health challenges that are prevalent in Kentucky and the Central Appalachian area. We are requesting renewed NIH support for eight TL1 scholars. The foundation of the proposed program will continue to be practical research experiences within multidisciplinary teams guided by experienced mentors along with educational and training offerings such as certificate Masters and PhD degrees to ensure successful career development of these future CTR leaders. Scholar competency assessments based on the Clinical Research Appraisal Inventory serve to guide new program offerings with the theory that trainees who have high confidence in their skills are more likely to pursue a career in CTR. UK CCTS-developed pipeline programs targeting professional and graduate students will ensure the availability of a strong pool of candidates for the TL1 program. In sum the TL1 program is designed to accelerate career development of future leaders in the translational science workforce who will be prepared to address todays complex research challenges and spearhead advances in human health.

project_terms:
Acceleration;Address;Appalachian Region;Area;Biology;Clinical;Clinical Research;Clinical Sciences;Collaborations;Communities;Competence;Complex;Dentistry;Discipline;Discipline of Nursing;Doctor of Philosophy;Education;Elderly;Engineering;Ensure;Equipment and supply inventories;Foundations;Future;Health;Health Care;Health Sciences;Human;Infrastructure;Institution;Kentucky;Medicine;Mentors;National Research Service Awards;Pharmacy facility;Policies;Postdoctoral Fellow;Process;Productivity;Psychology;Public Health;Publishing;Qualifying;Research;Research Methodology;Research Personnel;Science;Scientist;Social Work;Solid;TNFSF15 gene;Talents;Training;Training Programs;Training and Education;Translational Research;United States National Institutes of Health;Universities;Work;biomedical informatics;career;career development;clinical center;cohort;college;design;education research;experience;graduate student;interest;life span;multidisciplinary;pre-doctoral;prenatal;professional students;programs;skills;student participation;theories


application_id: 11117284
project_number: 1R03EB037115-01
project_title: In situ forming implant drug delivery for non-addictive post-operative analgesia
administering_ic: NIBIB
award_notice_date: 2025-01-08
opportunity_number: PA-20-200
application_type: 1
activity_code: R03
ic: EB
serial_number: 037115
program_official: KULWATNO, JONATHAN P
project_start_date: 2025-01-10
project_end_date: 2026-12-31
study_section: Drug and Biologic Therapeutic Delivery Study Section[DBTD]
contact_pi_person_id: 16098065
contact_pi: GIVENS RASSOOLKHANI, BRITTANY ESTELLE
other_pis: GUPTA, NIKITA ;HILT, JAMES ZACH
congressional_district: 06
department: ENGINEERING (ALL TYPES)
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe opioid crisis in the United States resulted in over 100000 overdose deaths in 2022. Reducing opioidprescriptions particularly for acute pain is crucial for minimizing substance use disorders. However currentalternatives for pain management are insufficient leaving opioids as the predominant treatment strategy.Currently the longest-acting analgesia available lasts only 72 hours; however patients may experience pain forup to 168 hours following oral facial surgery. Therefore extending analgesia beyond 72 hours is critical foreffective postoperative pain relief. The proposed in-situ forming implant (ISFI) offers the potential for localanesthetic release regional nerve blocks and acute and chronic pain treatment. We will use a poly(beta-aminoester) (PBAE) microparticle derived from poly(ethylene glycol) diacrylate (PEGDA) and hyaluronate acrylate(HA) incorporated into a poly(lactic-co-glycolic acid) (PLGA) system. This ISFI design will be gel-like prior tocomplexation and upon injection into an aqueous solution will form a solid. The PEGDA-HA microparticle willbe loaded with bupivacaine ensuring all of the drug is in the inner layer of the polymer matrix which ishypothesized to reduce and potentially eliminate burst release and rather yield a monophasic zero-order releaseprofile to ensure consistent drug release in the therapeutic window. Clinical oversight on this project is providedby Dr. Gupta and materials design is provided by Dr. Givens and Dr. Hilt who each have expertise in polymericdrug delivery. The team has a history of successful collaboration and mentoring ensuring effective researchexecution. The research focuses on materials synthesis characterization and evaluation of bupivacaine releaseprofiles at different pH levels. Preliminary data indicate the feasibility of generating crosslinked acrylate systemsand ISFIs from these systems. The research objectives in this proposal are to achieve high bupivacaine loadingto minimize polymer volumes per injection and sustained release over a 168-hour therapeutic window. We willalso develop a biomimetic model to evaluate ISFI formation degradation and drug release in the orofacialregion. The successful completion of this project will provide novel information on PEGDA-HA systems for drugdelivery and the potential for ISFIs as long-term analgesic delivery for post-operative pain management.

project_terms:
Absence of pain sensation;Acrylates;Acute Pain;Address;Analgesics;Anesthetics;Biomimetics;Breakthrough Pain;Buffers;Bupivacaine;Cell Culture Techniques;Centers for Disease Control and Prevention (U.S.);Cessation of life;Clinical;Collaborations;Data;Doctor of Philosophy;Dose;Drops;Drug Delivery Systems;Drug Implants;Encapsulated;Engineering;Ensure;Environment;Esters;Evaluation;Face;Fracture;Gel;Generations;Glycolates;Health;Hour;Hydrogels;Hydrophobicity;Implant;Implantable Infusion Pumps;In Situ;Injections;Investigation;Lidocaine;Lipid Bilayers;Local Anesthetics;Managed Care;Measures;Mentors;Methods;Modeling;Molecular Weight;Nasal cavity;Nerve Block;Operative Surgical Procedures;Opiate Addiction;Opioid;Oral;Outpatients;Overdose;Pain;Pain management;Patients;Pharmaceutical Preparations;Physiological;Polyesters;Polymers;Postoperative Pain;Postoperative Period;Preclinical Testing;Property;Pyrrolidinones;Reconstructive Surgical Procedures;Recording of previous events;Regimen;Reproducibility;Research;Research Project Grants;Risk Reduction;Sodium Acetate;Solid;Solvents;Structure;Substance Use Disorder;System;Testing;Therapeutic;Thick;Time;Trauma;United States;United States Food and Drug Administration;Water;Woman;Work;addiction;aqueous;biomaterial interface;chronic pain management;copolymer;crosslink;design;experience;flexibility;hyaluronate;hydrophilicity;implant design;improved;in vivo;innovation;insight;liposomal formulation;men;mortality;novel;opioid epidemic;opioid overdose;orofacial;overdose death;pain relief;particle;poly(ethylene glycol)diacrylate;pre-clinical;preclinical study;prescription opioid;scaffold;statistics;treatment strategy;undergraduate student;uptake

public_health_relevance:
PROJECT NARRATIVEAcute pain relief may be treated through several analgesic strategies including opioids; unfortunately opioidaddictions often lead to drug overdose and death and therefore present a significant health problem in the UnitedStates. The objective of this research project is to address acute pain relief with an in-situ forming implant (ISFI)loaded with bupivacaine hydrochloride for analgesia. Achieving this design will move us one step closer toreducing the burden of opioid prescriptions addictions and mortality without sacrificing patient comfort.


application_id: 11117139
project_number: 5R01DC021445-02
project_title: Neural Mechanisms of Ingestive Behavior
administering_ic: NIDCD
award_notice_date: 2025-06-13
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DC
serial_number: 021445
program_official: SABRI, MERAV
project_start_date: 2024-06-10
project_end_date: 2029-05-31
study_section: Neuroscience of Interoception and Chemosensation Study Section[NIC]
contact_pi_person_id: 2239737
contact_pi: LUNDY, ROBERT F
other_pis: BICKFORD, MARTHA E
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:
Interoception includes processes by which an organism senses integrates interprets andregulates internal signals that contribute to physiological processes such as eating. In this contextmore is known about ascending brain pathways for postoral signals than about descendingpathways (e.g. central regulators) that alter processing of this sensory information. In fact NIHhas identified our limited understanding of how forebrain central regulators modulate ascendinginteroceptive signals and its impact on behavior as critical knowledge gaps. Importantly eating isnot only regulated by postoral sensory signals but also by oral sensory signals (e.g. taste). Despiteits public health importance major gaps exist in our understanding of how central regulator nucleiinfluence neural coding of ascending sensory information and its impact on ingestive behavior.This proposal seeks to broaden our knowledge of how an anatomically/molecularly defined centralregulator pathway contributes to taste coding and ingestive behavior. We have identifiedamygdala (CeA) cells that express GABA and somatostatin (Sst) as a source of several distinctcentral regulator pathways. One such pathway provides input to a region of the pons called theparabrachial nucleus (PBN - CeA/Sst-to-PBN pathway). The PBN is critical to processing oral andpostoral signals that strongly influence the foodstuff an animal chooses to ingest. Our centralpremise is that this central regulator pathway mediates in part the neural processing ofinteroceptive information and consequently influences ingestive behavior. We will use Sst-cremice in conjunction with cre-dependent retrograde viruses to specifically label andoptogenetically manipulate CeA/Sst neurons. Our complimentary aims will expand knowledge ofhow CeA/Sst-to-PBN neurons influence ingestive behavior driven by oral and postoral signalsneural processing of taste information in the PBN and neural activity of other CeA/Sst regulatorneurons that differ in terms of where they project in the brainstem (i.e. NST vs. PBN).

project_terms:
Affect;Altered Taste;Amygdaloid structure;Anatomy;Animals;Behavior;Brain;Brain Stem;Cannulas;Cell Nucleus;Cells;Citric Acid;Code;Coin;Data;Eating;Electric Stimulation;Feeding behaviors;Fiber Optics;Gastrointestinal tract structure;Hypothalamic structure;Implant;In Vitro;Ingestion;Injections;Intake;Interoception;Knowledge;Label;Measures;Mediating;Modeling;Molecular;Mus;Nerve;Neurons;Nucleus solitarius;Opsin;Oral;Oral cavity;Organism;Pathway interactions;Physiological;Physiological Processes;Pontine structure;Process;Prosencephalon;Proteins;Public Health;Quinine;Sensory;Signal Transduction;Simplexvirus;Somatostatin;Source;Specificity;Stimulus;Structure;Structure of terminal stria nuclei of preoptic region;Sucrose;System;Taste Perception;United States National Institutes of Health;Vagus nerve structure;Virus;Visceral;Water;behavioral response;brain pathway;experimental study;extracellular;food consumption;gamma-Aminobutyric Acid;in vivo;insight;neural;neuromechanism;optogenetics;oral sensory;parabrachial nucleus;photoactivation;response;signal processing;taste system;transmission process

public_health_relevance:
Food consumption is an important energy regulatory function that is strongly influenced bysensory signals that originate from the oral cavity and gastrointestinal tract. This project aims todiscover how molecularly defined central regulator cells contribute to sensory processing andingestive behavior.


application_id: 11116109
project_number: 3P01AG078116-03S1
project_title: Strategies for Targeting Astrocyte Reactivity in Alzheimer's Disease and Related Dementias
administering_ic: NIA
award_notice_date: 2025-03-14
opportunity_number: PA-20-272
application_type: 3
activity_code: P01
ic: AG
serial_number: 078116
suffix: S1
program_official: OPANASHUK, LISA A
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1(M4)
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
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:
CM Norris Parent P01  ABSTRACT SUMMARYThis P01 Strategies for Targeting Astrocyte Reactivity in AD and ADRD (STAR-ADRD) addresses the(patho)physiologic roles of reactive astrocytes in Alzheimers disease (AD) and related dementias (ADRD).Though highly significant to many disease phenotypes astrocyte functions are under-investigated and have yetto benefit from large-scale programmatic support from the NIH. To fill this void we have assembled a highlyaccomplished and collaborative team from the University of Kentucky Sanders-Brown Center on Aging (UK-SBCoA). The overarching goals of this project are to: (1) Use cell-specific targeting to modulate distinct aspectsof the reactive astrocyte phenotype. (2) Use cutting-edge technologies to assess the functional impact of reactiveastrocytes in intact preclinical mouse models of AD and ADRD pathologies. (3) Leverage UK-SBCoA and UK-Alzheimers Disease Research Center (ADRC) resources to validate preclinical results in postmortem and livinghuman subjects. And (4) Use an integrated data pipeline approach to analyze and interpret data within andacross projects. Through these aims we will test the hypothesis that: interrelated reactive astrocytephenotypes drive major pathophysiologic features of dementia including cerebrovascular dysfunctionhypometabolism and impaired neuronal network function and fidelity. Projects are designed around aclear understanding that dementia does not exist as a single pathological entity most of the time but rather ischaracterized by multiple brain pathologies. Project 1 (Astrocytic end-feet and VCID) will use MMP9overexpression/knockdown in a model of cerebral small vessel disease to address astrocyte endfeetdegeneration. Project 2 (Astrocytic insulin signaling and AD) will overexpress/knockdown astrocytic insulinreceptors (IR) in an A model to study the impact of impaired astrocytic IR signaling. Project 3 (Astrocyticglutamate transport in AD and VCID) will overexpress/knockdown the astrocytic glutamate transporter SLC1A2in a mixed A-vascular model to assess the role of impaired glutamate transport in reactive astrocytes. Project4 (Astrocytic KATP channels in LATE+HS) will overexpress/eliminate astrocytic ABCC9/SUR2 in a model ofLATE + hippocampal sclerosis to assess the role of KATP channels. Four Cores will support and further integrateour Projects. Core B: Animal Vascular-Metabolic-Neural Network (VMN) will assess cerebrovascular metabolicand neural network properties in mice using two-photon microscopy MRI/MRS microelectrode array neuro-chemistry and electrophysiology. Core C: Human Consultation-Biosamples-Biomarkers (CBB) will validateresults in mice using well characterized autopsy tissue MRI EEG and fluid biomarker data from humans. AndCore D: Data Management and Biostatistics will establish a data pipeline for efficient categorizationtransformation and statistical analysis of complex relationships between astrocyte interventions and endpointmeasures within and between projects. Finally an Administrative Core (Core A) will provide leadershipcoordination integration and administrative structure so that the P01 goals are achieved.

project_terms:
ABCC9 gene;Address;Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease related dementia;Amyloid beta-Protein;Animals;Area;Astrocytes;Autopsy;Behavioral;Biochemical Pathway;Biological Markers;Biometry;Blood Vessels;Brain Pathology;CRSP3 gene;Calibration;Categories;Cells;Cerebral small vessel disease;Cerebrovascular Disorders;Complex;Consultations;Coupling;Craniotomy;Data Analyses;Dementia;Department chair;Diabetes Mellitus;Disease;Electroencephalography;Electrophysiology (science);Ensure;Environment;Fluorescence;Functional disorder;Funding;Funding Agency;Glutamate Transporter;Glutamates;Goals;Health;Human;Image;Impairment;Insulin Receptor;Intervention;Kentucky;Lasers;Leadership;Letters;Liquid substance;MMP9 gene;Magnetic Resonance Imaging;Measures;Medicine;Metabolic;Metabolism;Microelectrodes;Microscope;Modeling;Monitor;Mus;Neurons;Nutritional Science;Obesity;Optics;Parents;Pathologic;Pathology;Performance;Pharmacology;Phenotype;Physics;Physiological;Positioning Attribute;Procedures;Program Research Project Grants;Progress Reports;Property;Published Comment;Receptor Signaling;Recommendation;Research;Research Priority;Resources;Role;Secure;Source;Statistical Data Interpretation;Structure;Techniques;Technology;Testing;Time;Tissues;United States National Institutes of Health;Universities;adenovirus mediated delivery;awake;biomarker validation;cell type;cerebrovascular;college;cost;data integration;data management;data pipeline;design;disease phenotype;experimental study;foot;hippocampal sclerosis;human data;human subject;imaging capabilities;impression;in vivo;innovation;insight;insulin signaling;knock-down;microscopic imaging;mouse model;nanosensors;neural network;neurochemistry;neurovascular coupling;neurovascular unit;overexpression;pre-clinical;prevent;programs;ratiometric;success;two photon microscopy;two-photon;vibration

public_health_relevance:
OVERALL - NARRATIVEThis P01 will use cell specific targeting approaches and cutting edge in vivo assessment techniques inpreclinical mouse models validated by biomarker measures in human subjects to unravel the role(s) ofreactive astrocytes in the pathophysiology of Alzheimers disease and related dementias.


application_id: 11115681
project_number: 5R01AG081356-02
project_title: Phase I Cell Therapy for Maintaining Cholinergic Circuits in the Spectrum of Alzheimers Disease
administering_ic: NIA
award_notice_date: 2025-07-15
opportunity_number: PAR-23-081
application_type: 5
activity_code: R01
ic: AG
serial_number: 081356
program_official: CLARKE, AKANNI YAO
project_start_date: 2024-06-15
project_end_date: 2029-05-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
other_pis: QUINTERO, JORGE E;SLEVIN, JOHN T.;VAN HORNE, CRAIG
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTCognitive decline in the spectrum of Alzheimers disease (AD) including Dementia with Lewy Bodies (DLB) andParkinsons disease with dementia (PDD) takes a severe toll on patients family and society in suffering andcost. The memory and cognitive deficits observed in AD DLB and PDD are attributable in large part to a loss ofcholinergic function and neurons in the brain especially but not limited to cells in the nucleus basalis of Meynert(NBM). The greatest unmet need for AD DLB and PDD are therapies that can go beyond symptom treatment topossibly stabilize or maintain cholinergic circuits. As part of clinical trials we have been delivering mixed-cellpro-regenerative peripheral nerve tissue (PNT) to areas of the brain affected in neurodegenerative disease. Herewe propose a Phase I single surgical-center double-blinded clinical trial involving bilateral autologous PNT intothe NBM to address repair cell support of cholinergic neurons. The major goal of this trial is to identify thefeasibility and safety of bilateral implantation of reparative PNT to the NBM with the eventual goal to improvefunction of cholinergic neurons in dementias. Twenty-four participants diagnosed with PD and who haveselected qualified and agreed to undergo DBS surgery of the globus pallidus internus (GPi) will be followed for24 months as part of a trial to receive at the time of DBS surgery PNT implanted bilaterally into the NBM (twelveparticipants) or an alternate target also affecting cognition in this population the substantia nigra (SN). DBS willbe implanted and programmed to provide the standard of care. Feasibility objectives will be based on the numberof participants receiving PNT delivery and the number of participants completing the 12- month and 24-monthstudy visits. For the safety objective the number of serious adverse events related to the procedure will becollected for 24 months following surgery. Cognitive safety endpoints at 12 and 24-months following surgery willbe defined as  1.5 standard deviation decrement relative to the participants estimated pre-morbid functioning.To aid in future trial designs secondary outcome analyses will use neuropsychological testing of subjects (at 12and 24-months after surgery compared to baseline) and Movement Disorder Society  Unified ParkinsonsDisease Rating Scale (MDS-UPDRS) evaluations and quality of life assessments at 6 12 and 24-months aftersurgery compared to baseline. We will continue to expand our brain bank activities in conjunction with theUniversity of Colorado Anschutz Medical Campus to assess the histological effects of the investigational celltherapy in participants who have donated their brain after death and to better characterize the disease processin our study subjects. This study is a critical step for identifying the feasibility of this NBM vs. SN design for trialingin subsequent multicenter Phase II studies and for continuing to move this approach forward as an eventualmonotherapy for the treatment of the Spectrum of AD.

project_terms:
Address;Affect;Agreement;Alzheimer's Disease;Amyloid beta-Protein;Area;Autologous;Autopsy;Basal Nucleus of Meynert;Bilateral;Brain;Cell Therapy;Cell Transplantation;Cells;Cessation of life;Classification;Clinical;Clinical Trials;Cognition;Cognitive;Cognitive deficits;Colorado;Contralateral;Data;Deep Brain Stimulation;Dementia;Dementia with Lewy Bodies;Deposition;Development;Diagnosis;Disease;Double-Blind Method;Etiology;Evaluation;Family;Future;Globus Pallidus;Goals;Health Care Costs;Histologic;Impaired cognition;Implant;Individual;Literature;Measures;Medical;Memory impairment;Morphology;Motor;Movement Disorder Society Unified Parkinson's Disease Rating Scale;Nerve Tissue;Neurodegenerative Disorders;Neurologic;Neurons;Neuropsychological Tests;Operative Surgical Procedures;Outcome;Parkinson's Dementia;Participant;Pathology;Patients;Performance;Peripheral Nerves;Pharmacotherapy;Phase;Phase I Clinical Trials;Phenotype;Population;Procedures;Process;Qualifying;Quality of Life Assessment;Safety;Secondary to;Serious Adverse Event;Side;Societies;Study Subject;Substantia nigra structure;Supporting Cell;System;Time;Universities;Vascular Diseases;Visit;alpha synuclein;basal forebrain;cholinergic;cholinergic neuron;cognitive change;cognitive testing;cost;design;dopaminergic neuron;functional improvement;implantation;improved;in vivo;neurocognitive test;neuropathology;open label;pharmacologic;phase 2 study;regenerative;repaired;restoration;safety and feasibility;secondary outcome;standard of care;sural nerve;symptom treatment;tau Proteins;trial design

public_health_relevance:
PROJECTIVE NARRATIVEThe memory and cognitive deficits observed in Alzheimers disease (AD) dementia with Lewy bodies(DLB) and Parkinsons disease dementia (PDD) are largely attributable to a loss of cholinergic function andneurons in the nucleus basalis of Meynert (NBM). Here we propose a Phase I single surgical-centerdouble-blinded clinical trial involving bilateral autologous peripheral nerve tissue (PNT) into the NBM toaddress repair cell support of cholinergic neurons. The major goal of this trial is to identify the feasibility andsafety of bilateral implantation of reparative PNT to the NBM with the eventual goal to improve function ofcholinergic neurons in dementia.


application_id: 11115520
project_number: 3U24GM146576-03S1
project_title: University of Kentucky SuRE Resource Center
administering_ic: NIGMS
award_notice_date: 2024-09-06
opportunity_number: PA-20-272
application_type: 3
activity_code: U24
ic: GM
serial_number: 146576
suffix: S1
program_official: BASKIR, RUBIN SAM
project_start_date: 2022-09-05
project_end_date: 2027-08-31
study_section: ZGM1(RC)
contact_pi_person_id: 1879406
contact_pi: SPEAR, BRETT
other_pis: MURPHY, MICHAEL PAUL
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:
SUMMARYThe overarching goal of the University of Kentucky SuRE Resource Center (UK-SuRE) supported by anNIGMS U24 grant is to assist faculty and Office of Sponsored Project (OSP) staff at SuRE-eligibleinstitutions (<$6 million in NIH funding >25% PELL eligible students) prepare and submit competitive NIHgrants applications with an emphasis on SuRE and SuRE-First awards. To accomplish this goal UK facultyand research support staff with experience in all aspects of NIH grant applications will share theirknowledge with those at SuRE-eligible institutions through a series of webinars workshops and directconsultation. Three regional coordinators will provide vital links between faculty and OSP staff at SuRE-eligible institutions and faculty and research support staff at UK-SuRE. This center will also coordinatebiennial SuRE Conferences and oversee a competitive seed grant program that will provide funds forSuRE-eligible institutions to establish or grow OSPs. Specifically four aims are proposed: (1) Assist SuRE-eligible faculty write grants and manage research programs with success being measured by number ofgrants submitted scored and funded; number of publications seminars; and meeting presentations; andtenure and promotion outcomes; (2) Assist SuRE-eligible institutions to establish and grow OSPs andresearch infrastructure with success being measured by growth/establishment of OSPs in SuRE-eligibleinstitutions number of research grants received and overall research funding at these institutions andquestionnaires for SuRE faculty regarding the quality of in-house OSP services; (3) Grow the number ofinstitutions that participate in the SuRE Program and establish an interactive community of SuRE-eligibleinstitutions with success being measured by the number of institutions that participate in webinars attendthe biennial conference and submit NIH grants (with an emphasis on SuRE applications) as well as theamount of peer-to-peer faculty mentoring and social media engagement; and (4) Enhance the researchexperience for students who are working in NIH-funded labs in SuRE-eligible institutions with successbeing measured by student conference presentations authorship on publications degrees earned andpost-graduate employment. Taken together these activities will enhance the research capacity at SuRE-eligible institutions and promote high-quality student-centric biomedical research. In the process theseoutcomes will contribute to diversifying and strengthening the nations research enterprise.

project_terms:
Applications Grants;Area;Authorship;Award;Biomedical Research;Communication;Communities;Consultations;Data;Educational workshop;Eligibility Determination;Employment;Ensure;Face;Faculty;Feedback;First Independent Research Support and Transition Awards;Fostering;Funding;Goals;Grant;Growth;Individual;Infrastructure;Institution;Kentucky;Knowledge;Link;Marketing;Measures;Mentors;Methods;Minority-Serving Institution;Modality;National Institute of General Medical Sciences;Outcome;Population;Preparation;Process;Publications;Questionnaires;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Schools;Science;Series;Services;Site;Students;Training;United States;United States National Institutes of Health;Universities;Writing;career;college;expectation;experience;faculty mentor;faculty support;human disease;meetings;next generation;peer;programs;skills;social media;student conference;student mentoring;success;symposium;webinar

public_health_relevance:
NARRATIVEThe overarching goal of the University of Kentucky (UK) SuRE Resource Center is to build research capacityat SuRE-eligible institutions recognizing the vital contribution these colleges and universities make to thenation's research enterprise. Through a series of webinars and other training modalities direct consultation acompetitive seed grant program to create or enhance offices of sponsor projects (OSPs) and biennialconferences experienced UK faculty and research support staff will assist faculty and OSP staff at SuRE-eligible institutions prepare and submit competitive NIH grants applications with an emphasis on SuRE andSuRE-First awards. Multiple methods will be used to collect and analyze data to measure the success of thiscenter.


application_id: 11114847
project_number: 1R21CA301113-01
project_title: Pathways to Prevention: Exploring Social Determinants of Health in Early Onset Colorectal Cancer
administering_ic: NCI
award_notice_date: 2025-02-27
opportunity_number: PAR-23-255
application_type: 1
activity_code: R21
ic: CA
serial_number: 301113
program_official: DORIA-ROSE, PAUL P
project_start_date: 2025-04-01
project_end_date: 2027-03-31
study_section: Organization and Delivery of Health Services Study Section[ODHS]
contact_pi_person_id: 14376529
contact_pi: MOORE, JUSTIN XAVIER
other_pis: TSAI, MENG-HAN
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT ABSTRACTBackground: Early-onset colorectal cancer (EOCRC) defined as colorectal cancer (CRC) diagnosed before age 50has been on the rise in the United States with age-adjusted incidence increasing from 5.9 cases per 100000individuals in 2000 to 8.4 cases in 2017 and mortality rising by approximately 1.3% annually from 2008 to 2017.Factors contributing to EOCRC include lifestyle factors chronic diseases family history and multi-level socialdeterminants of health (SDoH) which encompass conditions such as economic stability education access and qualityhealthcare access and quality neighborhood and built environment and social and community context. NotablyBlack/African American people and individuals in rural communities face greater SDoH burdens and significantinequities in EOCRC outcomes. Our preliminary research shows that EOCRC mortality hotspots are more prevalent insouthern U.S. counties with higher proportions of Black residents. However lack of research including integration ofcomprehensive and multifaceted SDoH factors into evaluation of EOCRC disparities. Objective/Hypothesis: Theprimary objective of this study is to evaluate the impact of various SDoH on EOCRC diagnosis and delays in the firstcourse of treatment and survival focusing on geographically and racially underserved populations in Kentucky andGeorgia. We hypothesize that SDoH measures related to economic stability education healthcare accessneighborhood environment and social context significantly influence EOCRC outcomes with a greater impact onyounger populations (under 50 years). Specific Aims: The study will utilize an epidemiologic approach analyzingsecondary data within two specific aims. Aim 1: To elucidate the relationship between standardized measures ofSDoH and CRC diagnosis and whether these associations are modified by age at diagnosis sex and race/ethnicity.We will analyze cohort data from the All of Us research program (Nov 2021-2024) to examine the association betweenSDoH and CRC diagnosis stratified by different ages at diagnosis (<50 and 50 years; <45 and 45 years) sex andrace/ethnicity. Aim 2: To examine the relationship between area-level SDoH and delays in treatment and survival forCRC in Georgia and Kentucky and whether these associations are modified by age at diagnosis. We will useretrospective cohort data from the 2014-2024 Kentucky and Georgia cancer registries. Cox proportional hazardsmodels will assess the association between area-level SDoH (defined by the social vulnerability index [SVI]) anddelays in the first course of treatment (time between diagnosis and treatment start) and survival stratified by age atdiagnosis (<50 and 50 years; <45 and 45 years). Cancer Relevance: This research addresses critical gaps inunderstanding how various SDoH impact EOCRC outcomes among younger populations in underservedcommunities. Findings will inform public health initiatives and policies to improve equitable access to cancer diagnosisand treatment resources for young adults in Kentucky and Georgia ultimately contributing to EOCRC mortalityreduction and better health outcomes in these populations/communities.

project_terms:
Address;Adult;African American population;Age;All of Us Research Program;Antibiotics;Area;Black Populations;Black race;Cessation of life;Chronic Disease;Colorectal Cancer;Communities;County;Cox Proportional Hazards Models;Data;Diagnosis;Dimensions;Discrimination;Disparity;Economics;Education;Educational Status;Employment;Environment;Epidemiology;Equity;Ethnic Origin;Evaluation;Examinations and Diagnoses;Face;Family;Family history of;Fostering;Geography;Goals;Health;Health Food;Hot Spot;Housing;Incidence;Income;Individual;Inequity;Intervention;Kentucky;Language;Location;Malignant Neoplasms;Measures;Modeling;Neighborhoods;Obesity;Outcome;Pathway interactions;Persons;Policies;Population;Prevalence;Prevention;Provider;Public Health;Race;Recording of previous events;Research;Resources;Retrospective cohort;Rural Community;Sampling;Sex Differences;Social Environment;Social support;Testing;Time;Transportation;Underserved Population;United States;Work;age stratification;aged;built environment;cancer diagnosis;cancer health disparity;cancer therapy;cohort;colon cancer patients;colorectal cancer risk;colorectal cancer treatment;data registry;early onset colorectal cancer;education access;epidemiology study;ethnic difference;food insecurity;health care availability;health care resources;housing insecurity;improved;indexing;innovation;lifestyle factors;literacy;mortality;neoplasm registry;physical inactivity;public health intervention;racial difference;rural area;sex;social;social cohesion;social health determinants;social inclusion;social vulnerability;standardize measure;survival disparity;underserved community;western diet;young adult

public_health_relevance:
PROJECT NARRATIVEEarly-onset colorectal cancer (EOCRC) has been rising in incidence and mortality in the United States with significantdisparities observed among Black/African American individuals and those in rural communities highlighting a criticalresearch gap in understanding the impact of social determinants of health (SDoH) on these outcomes. The goal of thisstudy is to understand the specific individual-level and area-level SDoH factors that contribute to CRC diagnosisdelays in first course of treatment for CRC and CRC-specific survival disparities and whether these associations aremodified by age at diagnosis. Ultimately these findings will inform targeted public health interventions and policies toimprove health outcomes and reduce mortality associated with EOCRC in underserved populations/communities.


application_id: 11113899
project_number: 5R01AR080708-03
project_title: Leveraging Wearables to Transform Patient Recovery after Tibial Fracture Surgery
administering_ic: NIAMS
award_notice_date: 2025-08-08
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AR
serial_number: 080708
program_official: WASHABAUGH, CHARLES H
project_start_date: 2023-08-10
project_end_date: 2028-06-30
study_section: Musculoskeletal Rehabilitation Sciences Study Section[MRS]
contact_pi_person_id: 10137938
contact_pi: NOEHREN, BRIAN
other_pis: ZELIK, KARL E
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: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Over 490K Americans fracture their tibia (shinbone) yearly and require surgery. However patient recovery 1year following surgery is poor and inconsistent with 2/3 of patients reporting an inability to do pre-injury leisureactivities and 1/2 still not having recovered enough to return to work. A key role of clinicians after tibial shaftfracture surgery is to prescribe a rehabilitation exercise program that exposes each patient's tibia to increasingforces to gradually recover the ability to do pre-injury activities. However major limitations holding backprogress in the field are the lack of knowledge on how much tibial force patients experience during dailyactivities in their rehabilitation program throughout recovery and how tibial force early in recovery affectslonger-term functional recovery. The overarching goal of this work is to generate the knowledgebase and toolsthat will enable us to reimagine and elevate the standard of care for individuals after tibial shaft fracturesurgery by monitoring and managing tibial bone forces in daily life. We propose to accomplish the overarchingobjective through the following aims. Aim 1: Characterize tibial bone force in patients at home over the firstyear following surgery. Aim 2: Create the first clinical reference guide that ranks tibial forces during commonly-prescribed rehabilitation exercises. Aim 3: Assess if higher tibial forces during early recovery correspond withbetter functional outcomes at 6- and 12-month follow up. If our hypothesis is supported then these resultswould inform new clinical guidelines (target bone force thresholds) and biofeedback interventions to monitorand promote healthy bone forces in recovery. This wearable monitoring paradigm has unparalleled potential tobe adapted to elevate care for recovery from numerous musculoskeletal disorders.

project_terms:
Address;Affect;Algorithms;American;Back;Biofeedback;Biological Markers;Caring;Clinic;Clinical;Data;Data Set;Dose;Early Intervention;Ensure;Exercise;Fill-It;Fracture;Future;Goals;Guidelines;Health Care Costs;Home;Hospitals;Individual;Injury;Intervention;Journals;Knowledge;Laws;Leisure Activities;Length of Stay;Life;Limb structure;Link;Longitudinal Studies;Measurement;Measures;Modeling;Monitor;Muscle;Musculoskeletal Diseases;Office Visits;Operative Surgical Procedures;Outcome;Pain;Pathway interactions;Patient-Focused Outcomes;Patients;Physical therapy;Postoperative Period;Publishing;Reaction;Recovery;Recovery of Function;Rehabilitation therapy;Reporting;Risk;Severities;Shoes;System;Techniques;Testing;Tibial Fractures;Time;Training;Walking;Work;bone;demographics;design;empowerment;exercise program;exercise rehabilitation;experience;follow-up;functional outcomes;improved;in vivo;innovation;knowledgebase;light weight;limb injury;mechanotransduction;novel;pressure;programs;remote monitoring;sample fixation;sensor;standard of care;tibia;tool;wearable data;wearable device;wearable monitor;wearable sensor technology

public_health_relevance:
Project Narrative: Tibial shaft fractures are a common injury resulting in significant problems includinginability to return to work and societal functions. The identification of how individuals load their limb over timeand how physical therapy contributes to tibial loading is unknown. We propose to define how individualsincrease load over time how physical therapy loads the tibia and how recovery is influenced by loading.


application_id: 11112498
project_number: 4P42ES023716-09
project_title: Community Engagement Core
administering_ic: NIEHS
award_notice_date: 2025-08-15
opportunity_number: RFA-ES-20-014
application_type: 4
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S
subproject_number: 7386
contact_pi_person_id: 15852364
contact_pi: SMITH, TED R.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Affect;Air;Area;Awareness;Cardiometabolic Disease;Chronic;Chronic Disease;Communication;Communities;Development;Diabetes Mellitus;Elements;Ensure;Environmental Engineering technology;Environmental Exposure;Environmental Health;Environmental Science;Equipment and supply inventories;Exposure to;Farm;Geographic Locations;Goals;Green space;Hazardous Substances;Hazardous Waste;Health;Health Food;Health Sciences;Heart Diseases;Home;Housing;Hypertension;Industry;Institution;Intervention;Knowledge;Natural Sciences;Neighborhoods;Obesity;Outcome;Patient Recruitments;Persons;Play;Policy Maker;Population;Prevention;Productivity;Research;Research Personnel;Research Project Grants;Resources;Risk;Role;Science;Site;Social Sciences;Source;Superfund;Syndrome;Toxic effect;Toxin;Training;Transcend;Transportation;biological systems;cardiometabolic risk;cardiometabolism;community advisory board;community center;community empowerment;community engaged approach;community engagement;community involvement;community partners;fatty liver disease;interest;landfill;meetings;member;pollutant;risk mitigation;social;superfund site;therapy design

public_health_relevance:
Relevance: We are beginning to understand that toxin exposure can initiate/exacerbate multiple adverse health outcomes especially cardiometabolic diseases. Kentuckians are disproportionately affected by many chronic diseases including obesity hypertension heart disease diabetes fatty liver disease etc. which are all aspects of cardiometabolic syndrome. Certain communities are more highly impacted than others and it is critical to understand why. We hypothesize that exposure to toxics specifically VOCs initiates/exacerbates these conditions. It is fundamental to our understanding of the effects of these toxics to engage the communities most deeply affected by exposure to these pollutants and to try to mitigate the effects of these exposures. Thus determining the influence of pollutant exposures on the development/progression of these chronic conditions is vital. Bidirectional research with our community will support understanding of the impacts of VOCs on cardiometabolic disease and community empowerment.


application_id: 11112492
project_number: 4P42ES023716-09
project_title: Metabolism and Toxicity Core
administering_ic: NIEHS
award_notice_date: 2025-08-15
opportunity_number: RFA-ES-20-014
application_type: 4
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S
subproject_number: 7385
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY (METABOLISM AND TOXICITY CORE)The overall purpose and the function of the Metabolism and Toxicity Core is to provide high quality analyticalservices and validated data in support of all projects at the University of Louisville Superfund Research Center.The Core personnel will conduct measurements and assays of biomarkers and indices of cardiovascularmetabolism and hepatic function used for assessing the risk and progression of cardiometabolic disease uponexposure to volatile organic compounds (VOCs). The Core personnel will also provide intellectual input andadvice in selection of specific methodological approaches and provide training to students fellows techniciansand junior faculty. The Core will employ strict quality control procedures to validate data and generateharmonized data reports and data dictionaries to be stored in the Data Management and Analysis Core. Thecore will support all Superfund Center research projects through its state-of-the-art equipment and assay. Thesupport offered by the core encompasses three main components  a flow cytometry component for the detectionand characterization of circulating cells and microparticles; a metabolism component for measuring biochemicaland metabolic endpoints such as urinary metabolites of VOCs bile acids and catecholamines by LC/MS/MS andGC/MS; and a pathology component to assay systemic toxicity using a battery of tests relating to glucose controlliver function and hepatic toxicity. However the scope of the core exceeds that of the projects to encompassthe development of cutting-edge techniques and analytical platforms to expand its repertoire of services. TheCore will continually upgrade its infrastructure as well as its technical capabilities to remain at the leading edgeof assays relating to biomarkers of exposure and harm. The core is also committed to the continued educationof its users as well as the research community at the university. The Core will also disseminate educationalinformation regarding the potential utility and accessibility of its services to enhance environmental healthresearch. By ensuring central deposition of harmonized and validated data the core will provide a firm foundationfor research not only by the University of Louisville Superfund investigators but investigators at other SuperfundCenters as well. Because of its state-of-the-art equipment highly sophisticated technologies and skilledtechnical personnel the Core will provide premier toxicological and clinical pathology services. By meeting thesegoals the core will continue to be an essential vehicle for growth and innovation within the Center as well as aneducational hub for the training the next generation of scientists in the field of environmental health research.

project_terms:
Address;Analytical Chemistry;Animals;Bile Acids;Biochemical;Biological Assay;Biological Markers;Biology;Blood;Bone Marrow;Cardiometabolic Disease;Cardiovascular system;Catecholamines;Cells;Chemical Exposure;Clinical;Clinical Pathology;Communities;Complex;Continuing Education;Data;Data Management and Analysis Core;Data Reporting;Deposition;Detection;Development;Dimensions;Education;Ensure;Environmental Exposure;Environmental Health;Equipment;Exposure to;Extramural Activities;Faculty;Flow Cytometry;Foundations;Functional disorder;Future;Goals;Growth;Health;Hepatic;Hepatotoxicity;Histologic;Human;Human Resources;Individual;Infrastructure;Injury;Laboratories;Measurement;Measures;Metabolic;Metabolism;Methodology;Methods;Mus;Pathologic;Pathology;Physiological;Population;Postdoctoral Fellow;Procedures;Property;Protocols documentation;Quality Control;Research;Research Personnel;Research Project Grants;Resolution;Resources;Risk Assessment;Sampling;Scientist;Services;Signal Transduction;Students;Superfund;Technical Expertise;Techniques;Technology;Testing;Toxic effect;Toxicology;Training;Training and Education;Universities;Urine;blood glucose regulation;cardiometabolism;career development;data dictionary;data harmonization;flexibility;graduate student;indexing;innovation;interest;investigator training;liquid chromatography mass spectrometry;liver function;meetings;member;next generation;novel;operation;particle;response;superfund chemical;systemic toxicity;urinary;volatile organic compound

public_health_relevance:
RELEVANCEThe primary function of the research within the Metabolism and Toxicity Core is to measure environmentalexposures and their resulting effects on health. Using state-of-the-art analytical approaches to measure urineand blood components the core will provide quantitative data on the extent of chemical exposures and theextent to which these exposures cause injury and dysfunction.


application_id: 11112486
project_number: 4P42ES023716-09
project_title: Research Experience and Training Coordination Core
administering_ic: NIEHS
award_notice_date: 2025-08-15
opportunity_number: RFA-ES-20-014
application_type: 4
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S
subproject_number: 7384
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID W
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary. The RETCC has played a coordinating role in the success of ULSRC since its inception in September 2017. By working closely with other NIEHS-supported training programs at the UofL (T32ES011564; T35ES014559) the RETCC has developed a rich multidisciplinary and comprehensive training program. In addition to the course work and on the bench training activities RETCC routinely organizes participatory field trips to the Lees Lane Superfund site to better understand and appreciate health concerns of residents in the adjacent community of Riverside Gardens; facilitates the meeting of trainees with regional Superfund site coordinators and officials and the Metro Louisville Public Health and Wellness Department. Our training core in collaboration with Superfund Research Centers at Duke University University of Kentucky and University of Pennsylvania organized a trip to Washington D.C. so trainees could attend a Science and Policy Institute meeting that included interactions with congressional leaders and their staff. Such activities have been instrumental in the well-rounded growth of our trainees. Moreover these trainees not only provide the force that turns the wheel but also are the focus and hub of intellectual crosstalk and fertilization across projects cores other SRCs and the National SRP. To date ULSRC success is the product of our trainees successes through their many accomplishments including publications presentations awards degrees fellowships interactions with community partners and environmental health sciences-related career opportunities. Thus although we are proud of our current success via integration of trainee activities across the ULSRC we continue to strive to build on these successes by implementing innovative and unifying features into RETCC-directed activities that focus on fulfilling the goals and furthering the success of our trainees.

project_terms:
Advisory Committees;Age;Arts;Award;Awareness;Cardiometabolic Disease;Chemistry;Collaborations;Communication;Communities;Community Health Education;Congresses;County;Data;Data Management and Analysis Core;Dentistry;Development;Discipline of Nursing;Disparate;Engineering;Environmental Exposure;Environmental Health;Exposure to;Fellowship;Fertilization;Fostering;Goals;Government;Growth;Hazardous Substances;Health;Health Professional;Human;Institution;Kentucky;Laboratories;Medicine;Metals;Mission;National Institute of Environmental Health Sciences;Pennsylvania;Phase;Play;Policies;Postdoctoral Fellow;Public Health;Publications;Research;Research Project Grants;Role;Schools;Science;Scientist;Statistical Data Interpretation;Students;Superfund;Training;Training Activity;Training Programs;Training Support;Translational Research;Universities;Washington;Work;cardiometabolism;career;career development;cohort;college;community engagement;community partners;community research;experience;field trip;graduate student;health science research;innovation;interdisciplinary approach;knowledge base;meetings;multidisciplinary;next generation;pre-doctoral;programs;skills;success;superfund site;training opportunity

public_health_relevance:
Relevance: The overall goal of the Research Experience and Training Coordination Core (RETCC) is to direct successful training of graduate students and post-doctoral fellows (designated trainees) in the University of Louisville Superfund Research Center (ULSRC). This includes scientific interdisciplinary training within defined ULSRC projects and cores as well as promoting development of a broad knowledge base and the skills needed to communicate and engage with relevant community partners government liaisons and health-care professionals regarding the importance of environmental health sciences research in the Superfund Program.


application_id: 11112481
project_number: 4P42ES023716-09
project_title: Data Management and Analysis Core
administering_ic: NIEHS
award_notice_date: 2025-08-15
opportunity_number: RFA-ES-20-014
application_type: 4
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S
subproject_number: 7383
contact_pi_person_id: 14102277
contact_pi: RIGGS, DANIEL WILLIAM
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY The primary objective of the Sample and Data Management Core (DMAC) is to provide statistical support and data management and storage capabilities to all components of the University of Louisville Superfund Research Center (ULSRC). The functions of the Core are matched to the needs of each project and cover a full range of services from collaboration and routine service to protocol preparation to procedural review and oversight. The Core will provide two main services: it will establish a repository for the long-term storage and archiving of data; and it will assist Center investigators in the statistical analysis of their results. The core will assure the authenticity and quality of these specimens and it will prepare these samples for long-term storage or dispense samples as needed. The Core will also provide scientifically valid and rigorous statistical analysis of data and support the development of innovative methods to enhance the basic and translational research efforts of Center investigators. It will provide state-of-the-art biostatistics and bioinformatics expertise and analytical support. Core biostatisticians will also develop new statistical methods such as quantitative risk assessment models multipollutant exposure analysis and land-use regression models for estimating cardiometabolic disease risk in exposed populations and for the analysis and evaluation of exposures and health effects. In collaboration with other projects and cores DMAC statisticians will harmonize the data by defining standards (e.g. creating searchable data dictionaries and defining variables relevant for each project. In the next funding cycle we will continue to use these procedures. The core will serve as a unique educational resource for training graduate students post-doctoral fellows residents and junior faculty and in collaboration with the Training and Administration Cores. This Core will allow Center investigators easy access to high quality centralized data management and statistical services and thereby will strengthen the organizational cohesion of the Center. This comprehensive and integrated service permits one or more biostatisticians to be involved from the initial planning stage of a project (when statistical consultation is most beneficial) throughout its implementation analysis and completion. The Core will provide a stable and collegial environment that fosters long-term working relationships between biostatisticians and investigators and continues to promote sophisticated approaches to experimental design and analysis. The biostatisticians of this Core are knowledgeable about clinical research and have broad expertise in statistical applications for epidemiological investigations clinical trials pre-clinical studies and prevention and control research. Their interdisciplinary interactions with basic scientists and clinical investigators will add a new dimension to the interpretation of experimental results one that is only possible when collaborators share a mutual appreciation of problems and issues.

project_terms:
Anacondas;Animal Experiments;Animals;Artificial Intelligence;Atmosphere;Basic Science;Bioinformatics;Biological Assay;Biometry;Cardiometabolic Disease;Characteristics;Clinical Investigator;Clinical Research;Clinical Trials;Code;Collaborations;Consultations;Data;Data Analyses;Data Collection;Data Files;Data Management and Analysis Core;Data Set;Data Storage and Retrieval;Databases;Development;Dimensions;Disease;Educational workshop;Ensure;Environment;Environmental Exposure;Evaluation;Experimental Designs;Exposure to;FAIR principles;Faculty;Fostering;Funding;Future;Gases;Geography;Hazardous Chemicals;Health;Health protection;Human;Human Resources;Individual;Institution;Linux;Machine Learning;Manuscripts;Maps;Mass Spectrum Analysis;Measurement;Methods;Modeling;Molecular;Operating System;Output;Participant;Population;Postdoctoral Fellow;Preparation;Prevention;Procedures;Process;Protocols documentation;Pythons;Quality Control;Research;Research Design;Research Personnel;Resources;Risk;Risk Assessment;Risk Estimate;Sampling;Scientist;Secure;Series;Services;Site;Source;Spatial Distribution;Specimen;Statistical Data Interpretation;Statistical Methods;Study Subject;Superfund;Testing;Toxic effect;Training;Translational Research;Universities;Validation;Variant;Visual;Work;archive data;cardiometabolism;central database;cohesion;computing resources;data curation;data dictionary;data exchange;data harmonization;data hub;data interoperability;data management;data management center;data quality;data sharing;data streams;data structure;data submission;design;detection limit;disorder risk;education resources;efficacy testing;epidemiology study;experience;experimental analysis;graduate student;improved;innovation;land use;large datasets;lipidomics;meetings;metabolomics;novel;novel strategies;operation;platform-independent;pollutant;portability;preclinical study;privacy protection;quality assurance;remediation;repository;statistical service;tool;transcriptomics;usability;volatile organic compound

public_health_relevance:
RELEVANCE By ensuring proper study designs and supporting appropriate data analysis and by providing efficient and organized data management and storage capabilities the core will further our understanding of risk sources and cardiometabolic disease risk estimation due to exposure to hazardous chemicals. Well annotated data bases created and supported by the core will facilitate data sharing and collaborative projects within the Center and with other Superfund Centers and academic institutions.


application_id: 11112476
project_number: 4P42ES023716-09
project_title: Administrative Core
administering_ic: NIEHS
award_notice_date: 2025-08-15
opportunity_number: RFA-ES-20-014
application_type: 4
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S
subproject_number: 7382
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe Administrative Core of the Louisville Superfund Center (LSC) will provide administrative and fiscal supportto all Projects and Cores supported by the Center. The Core will be directed by the Center Director who withassistance from the Program Administrator will facilitate communication and collaboration between individualCores and Projects and provide scientific and logistic oversight to Center activities. The Core will act as a liaisonfor individual Center members in order to best promote collaboration to ensure all Center work effectivelycontributes issues relevant to the SRP. The Core will also disseminate scientific knowledge acquired from theUniversity of Louisville Superfund Research Center (ULSRP) in a timely manner to key constituencies in formsthat are targeted and useful to our audience. These include scientists and public health professionals; localstate and federal policy makers; and the media and press. To assist in the planning and coordination of researchand core activities the Core personnel will organize scientific work-in-progress sessions monthly meetingsrelevant focus groups and frequent formal and informal interactions. To integrate cross-disciplinary researchthe Core will provide leadership and administrative support needed for integration and coordination of research.The Core will leverage existing resources on campus to optimize the productivity of the Center and will seekinput from both an Internal Advisory Committee and an External Advisory Committee in evaluating progress andin maintaining the relevance of Center activities to the Superfund Research Program mandate. Core leaderswill maintain close contact with NIEHS program officials and with UofL administration. Core administrators willalso manage the finances and resources of the Center to optimize usage and appropriate allocation. They willalso coordinate the timely development of progress reports and financial statements. To ensure qualitymanagement the Core will monitor and facilitate attainment of Center objectives in research training educationand community engagement and ensure compliance with state and federal regulations. The Administrative Corewill be the go-to place for students and trainees community members public media and press so that all suchactivities can be appropriately facilitated and coordinated.

project_terms:
Achievement;Administrator;Advisory Committees;Cardiometabolic Disease;Collaborations;Communication;Communities;Consultations;Core Facility;Counseling;Data;Development;Diabetes Mellitus;Discipline;Education;Emergency response;Ensure;Environment;Environmental Exposure;Evaluation;Focus Groups;Funding;Future;Goals;Hazardous Chemicals;Health;Health Professional;Heart Diseases;Human Resources;IACUC;Individual;Institution;Institutional Review Boards;Knowledge acquisition;Leadership;Link;Liver diseases;Logistics;Medical;Mentors;Monitor;National Institute of Environmental Health Sciences;Nongovernmental Organizations;Policies;Policy Maker;Productivity;Progress Reports;Protocols documentation;Public Health;Quality Control;Reagent;Regulation;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Scientific Evaluation;Scientist;Selection Criteria;Specimen;Students;Superfund;Training;Training Activity;Training and Education;Translational Research;Universities;Work;community engagement;effectiveness research;experimental study;federal policy;meetings;member;operation;participant enrollment;programs;scientific organization;tool;training opportunity;web site

public_health_relevance:
RELEVANCEThe Administrative Core is essential for the efficient functioning of the Center. It is required for the Centersfiscal management and resource sharing and will ensure quality control and compliance with regulations andevaluation of Center activities. It will facilitate and optimize research training community engagement andresearch translational activities of the Center and assist in developing a new understanding of the effects ofhazardous chemicals on liver disease diabetes and heart disease.


application_id: 11112469
project_number: 4P42ES023716-09
project_title: Project 4 - Advancing VOC Treatment with Novel Materials and Processes
administering_ic: NIEHS
award_notice_date: 2025-08-15
opportunity_number: RFA-ES-20-014
application_type: 4
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S
subproject_number: 7381
contact_pi_person_id: 15792674
contact_pi: FORTNER, JOHN
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:
SUMMARYVolatile organic compound (VOC) exposure increases the risk for a variety of adverse health outcomes includingcardiometabolic disease (CMD). VOC management including remediation is thus necessary to mitigateexposure and thereby adverse health outcomes. Within the University of Louisville Superfund Research Centersoverall mission the primary goal of Project 4 is to develop and demonstrate novel material-driven processes fornew VOC treatment strategies and technologies to meet the challenge of the complicated nature of VOC occurrenceand exposure. Towards this goal Project 4 aims to achieve broad-based VOC treatment capacities in both the gas and liquidphases with high efficiencies flexible operation low energy inputs no chemical additives and no harmful products.We propose an innovative three-pronged (as Project Aims) project structure focused on materials that arecapable of harnessing various irradiation energies (e.g. solar irradiation microwaves) for broad VOC treatment.Specifically three integrated Project Aims are designed to: 1) Develop and demonstrate a unique class ofhyperthermic nanomaterials defined by their capacity to emit (localized surface-based) heat when subjected tomicrowaves effectively acting as energy antennas to generate extreme surface localized heat gradients forthermal treatment of VOCs; 2) Develop and demonstrate metal/oxide hybrid materials to achieve synergisticphotothermocatalytic effects for oxidative VOC degradation at significantly reduced temperatures (even roomtemperature) compared with conventional thermocatalytic oxidation; and 3) Develop and demonstrate 3Dcrumpled graphene oxide (CGO) composites as a material platform for improving performance and in somecases underpinning novel (re)design strategies for membrane-based (flow-through) photo-enhanced VOCtreatment. Project 4 is integrated into the larger Center effort(s) through training shared and coordinated(advance) analytical techniques advanced data analyses and critical data sharing regarding VOC compositionand concentrations as a function of source(s) relating to the mission of the Center. Upon the successfulcompletion of the Project newly developed materials technologies and processes as well as fundamentalinsights will directly advance VOC treatment paradigms leading to better VOC exposure management strategiesand thus potential health benefits.

project_terms:
3-Dimensional;Area;Benign;Carbon;Carbon Dioxide;Cardiometabolic Disease;Catalysis;Chemicals;Complex;Data Analyses;Development;Electromagnetics;Electronics;Engineering;Environment;Environmental Exposure;Exclusion;Film;Filtration;Gases;Generations;Geometry;Goals;Health;Health Benefit;Heating;Hybrids;Hyperthermia;In Situ;Library Materials;Lighting;Liquid substance;Magnetism;Membrane;Metals;Mission;Modeling;Nature;Outcome;Oxides;Pathway interactions;Performance;Phase;Predisposition;Process;Production;Property;Reaction;Reactive Oxygen Species;Recovery;Research;Resistance;Risk;Series;Shapes;Source;Specificity;Structure;Superfund;Surface;Techniques;Technology;Temperature;Thinness;Training;Universities;Volatilization;Water;absorption;analog;catalyst;cost;data sharing;design;disorder risk;flexibility;graphene;improved;innovation;insight;irradiation;membrane assembly;microwave electromagnetic radiation;nano;nanocomposite;nanomaterials;nanoparticle;nanoscale;novel;operation;oxidation;radio frequency;reaction rate;remediation;self assembly;titanium dioxide;treatment strategy;ultraviolet irradiation;volatile organic compound

public_health_relevance:
NARRATIVEThe overarching goal of this project is to develop and demonstrate novel material-driven processes for newVOC treatment technologies. Based on the complex nature of VOC occurrence the project is focused onadvanced materials and related processes designed for broad capacity to efficiently treat a range of volatileorganic molecules in both the gas and liquid phase with no continuous chemical supply minimal/low energyinputs resulting in benign products.


application_id: 11112461
project_number: 4P42ES023716-09
administering_ic: NIEHS
award_notice_date: 2025-08-15
opportunity_number: RFA-ES-20-014
application_type: 4
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S
subproject_number: 7380
contact_pi_person_id: 10828196
contact_pi: TURNER, JAY ROBERT
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-07-01
project_title:
Project 3 - Development and Field Application of Novel Ultrasensitive Devices for the Measurement of Airborne VOCs

project_abstract:
PROJECT SUMMARY (Project 3) This proposed work is to advance airborne volatile organic compound (VOC) detection and quantification technologies and to robustly characterize indoor/outdoor contrast and in-home determinants for exposures to target Superfund-relevant VOCs. This research will continue to grow and expand two VOC real-time in situ measurement platforms developed by the University of Louisville Superfund Research Center established in 2017. One platform comprises small low-cost sensors that can be deployed alone or in networks. Novel gas sensors and sensor arrays are being developed to measure target Superfund-relevant VOCs including acrolein trichloroethene (TCE) benzene toluene ethylbenzene and xylene (BTEX). The devices use novel surface chemistries to address the common challenges of selectivity and sensitivity and are fabricated using microelectromechanical systems (MEMS) technology. Another platform addresses the need for flexibly designed field-deployable instruments that can measure with high sensitivity a large range of compounds to interrogate microenvironments with complex VOC mixtures. The Multichannel Organics In-situ enviRonmental Analyzer (MOIRA) instrument developed in the first cycle of Center funding for mobile monitoring will be expanded and optimized for indoor/outdoor VOC monitoring studies. MOIRA is a gas chromatographymass spectrometry (GC-MS) instrument with high time resolution (e.g. ten minutes). Its capabilities will be expanded to measure both higher and lower volatility compounds than can be achieved with the current design. These innovative high time resolution in situ measurements will be coupled with conventional time-integrated VOC passive sampling to measure target Superfund-relevant VOCs at homes of some participants in the allied clinical study. These data will be used to build spatiotemporal models to estimate ambient VOCs at the homes of all clinical study participants and to gain new insights into VOC levels and their determinants in the home microenvironment. In addition to exposure assessment the two measurement platforms are responsive to ongoing Superfund program advancements; these innovative developments will expand future capacities to monitor VOC indoor vapor intrusion monitor outdoor VOC levels during site remediation and monitor both indoors and outdoors during post-remediation surveillance.

project_terms:
Acrolein;Address;Air;Ally;Automobile Driving;Benzene;Cardiometabolic Disease;Chemistry;Clinical Research;Collection;Complex;County;Coupled;Custom;Data;Detection;Development;Devices;Electrodes;Environmental Exposure;Exhibits;Exposure to;Funding;Future;Gases;Goals;Gold;Home;Hour;In Situ;Indoor environment;Industrialization;Infiltration;Investigation;Mass Fragmentography;Measurement;Measures;Modeling;Modification;Monitor;Participant;Pattern;Process;Protons;Reaction;Research;Residual state;Resolution;Sampling;Signal Transduction;Site;Small-Area Variations;Source;Sulfhydryl Compounds;Superfund;Surface;System;Technology;Temperature;Testing;Time;Toluene;Trichloroethylene;Universities;Work;Xylene;cost;design;ethylbenzene;exposed human population;flexibility;gas analyzer;innovation;insight;instrument;mass spectrometer;metal oxide;miniaturize;nanoGold;new technology;novel;programs;remediation;residence;sensor;spatiotemporal;superfund chemical;superfund site;technology platform;time use;tool;urban setting;vapor intrusion;volatile organic compound

public_health_relevance:
RELEVANCE This proposed work is to support continued research within the University of Louisville Superfund Research Center on novel technologies to detect and quantify Superfund-relevant volatile organic compounds (VOCs) in air. These technology platforms will be used to better understand VOC sources and human exposures.


application_id: 11112454
project_number: 4P42ES023716-09
project_title: Project 2 - Molecular and Cellular Mechanisms of Cardiometabolic Toxicity of VOCs
administering_ic: NIEHS
award_notice_date: 2025-08-15
opportunity_number: RFA-ES-20-014
application_type: 4
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S
subproject_number: 7379
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARYExposure to toxicants has been linked to the development or exacerbation of chronic disease. However little isknown about how volatile organic chemicals (VOC)a class of toxicants associated with higher prevalence oftype 2 diabetes (T2D) and strokepromote the development of cardiometabolic disease (CMD). Accordinglythe overarching goals of this Superfund project are to determine the mechanisms by which VOCs negativelyimpact cardiovascular health and metabolism identify biomarkers for VOC exposure and vascular injury andtest therapeutic strategies to minimize VOC-induced CMD. Our studies in the current funding cycle andpreliminary data suggest that VOC such as benzene vinyl chloride and crotonaldehyde promote endoplasmicreticulum (ER) stress and trigger the unfolded protein response (UPR) in endothelial cells. Specifically wehypothesize that aldehyde metabolites of VOC which are generally more toxic than their parent compounddiminish endothelial toxicity by inducing ER stress which triggers metabolic changes that accelerate ectopic lipiddeposition and promote cardiometabolic dysfunction. To test this hypothesis we will: (1) examine the effects ofVOC exposure on endothelial function and insulin resistance; (2) delineate the contribution of protein misfoldingto the cardiometabolic toxicity of VOC. The design of these studies includes molecular and pharmacologicalinterventions designed to detoxify or quench the reactive intermediates evoked by VOC exposure as well asstudies that could lead to the identification of novel sensitive and robust biomarkers of both VOC exposure andvascular injury. These studies were designed to synergize with and provide biological plausibility for theassociations identified in Project 1. Successful completion of this project will lead to identification of theunderlying cellular and molecular mechanisms by which VOC affect cardiometabolic function and provideinsights into how VOC toxicity could be prevented or therapeutically minimized by targeting aldehydes or protein-folding pathways.

project_terms:
13-Butadiene;2-butenal;ATF6 gene;Acceleration;Acrolein;Adipose tissue;Adult;Affect;Aldehydes;Animal Model;Apoptosis;Apoptotic;Atherosclerosis;Benzene;Biological;Biological Markers;Blood Vessels;Body Burden;Butadiene;Cardiometabolic Disease;Cardiovascular Physiology;Cardiovascular system;Carnosine;Cell Physiology;Chemical Exposure;Chemical-Induced Change;Chemicals;Chronic Disease;Data;Deposition;Development;Diabetes Mellitus;Disease Resistance;Dose;Drug Metabolic Detoxication;Endoplasmic Reticulum;Endothelial Cells;Endothelium;Environmental Exposure;Environmental Impact;Exposure to;Fatty acid glycerol esters;Formaldehyde;Functional disorder;Funding;Glutathione;Goals;Hazardous Chemicals;Hazardous Substances;Health;Heart Diseases;Heart failure;Heat shock proteins;Hepatic;High Prevalence;Human;Hypertension;Individual;Inflammatory;Inhalation;Injury;Insulin Resistance;Investigation;Link;Lipid Peroxidation;Lipids;Measures;Mediating;Mediator;Metabolic;Metabolism;Molecular;Molecular Chaperones;Mus;Non-Insulin-Dependent Diabetes Mellitus;Nutritional;Nutritional status;Obesity;Oxidative Stress;Oxidative Stress Induction;Parents;Pathway interactions;Pharmacotherapy;Plasma;Platelet Activation;Poison;Process;Production;Property;Proteins;Protocols documentation;Reporting;Risk;Role;Signal Transduction;Source;Stroke;Structure;Superfund;Surveys;Testing;Therapeutic;Tobacco smoke;Toxic effect;Trichloroethylene;Vinyl Chloride;Work;ambient air pollution;biomarker identification;cardiometabolic risk;cardiometabolism;cardiovascular health;cardiovascular injury;design;diet-induced obesity;disorder risk;endoplasmic reticulum stress;endothelial dysfunction;fatty liver disease;heart function;indexing;insight;insulin sensitivity;metabolomics;mouse model;novel;overexpression;preclinical study;prevent;protein folding;protein misfolding;response;superfund site;synergism;systemic inflammatory response;therapeutic evaluation;therapy design;toxicant;urinary;vascular inflammation;vascular injury;volatile organic compound;western diet

public_health_relevance:
PROJECT NARRATIVEExposure to hazardous substances has been linked to the development or worsening of chronic disease. Thepurposes of this Superfund project are to understand how a particular class of compounds i.e. volatile organiccompounds affect cardiovascular health and the onset or progression of diabetes heart disease and fatty liverdisease as well as to develop therapeutic strategies to minimize these affect after exposure to toxic compounds.


application_id: 11112447
project_number: 4P42ES023716-09
project_title: Project 1 - Cardiometabolic Injury due to VOCs
administering_ic: NIEHS
award_notice_date: 2025-08-15
opportunity_number: RFA-ES-20-014
application_type: 4
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S
subproject_number: 5053
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe overall goal of this project is to assess the impact of exposure to Superfund-relevant volatileorganic compounds (VOCs) on cardiometabolic disease the underlying conditions thatcontributes to diabetes cardiovascular and liver diseases. VOCs such as trichloroethylenebenzene acrolein formaldehyde xylene and butadiene are major chemicals of concern at mostSuperfund sites and extensive previous work suggests the exposure to VOC could have a varietyof adverse health effects. Nevertheless whether exposure to VOCs at levels relevant toneighborhood adjacent to Superfund sites could adversely affect cardiometabolic health remainsunknown. Our extensive studies with animal exposed to different VOCs suggest that chronicexposure to low dose VOCs could increase blood pressure inflict vascular injury accelerateatherosclerosis and induce liver disease. Nevertheless the cardiometabolic risk of VOCs hasnot been evaluated and longitudinal data to interrogate exposure-response relationships aremissing. Hence to assess CMD risk imposed by VOCs we will test the hypothesis that exposureto VOCs exacerbates/induces vascular and hepatic dysfunction leading to a cascade of eventsthat increase CMD risk. To assess the impact of VOC exposures we will examine 1200 residentsof Jefferson County including those who live in areas adjacent to Superfund sites such as LeesLane and Distiller Farm as well as high VOC emission such as the Rubbertown neighborhood.In each participant we will assess CMD risk by measuring arterial stiffness marker of hepatocytedeath as well as suite of biomarkers indicative of risk for diabetes cardiovascular and liverdiseases. To determine population-level VOC exposure and its relationship with CMD-relatedhospital admissions and mortality we will establish a network of VOC monitors to measure VOClevels throughout Jefferson County and monitor domestic wastewater for urinary VOCmetabolites. We will monitor wastewater every other month for 3 years and assess the extent towhich population-level exposure estimates reflect ambient air VOC levels and individual-levelexposure (Aim 1) and how these estimates relate to population-level and individual-level CMDrisk. To obtain longitudinal data we will examine CMD progression and determine theassociation between individual-level and community-level VOC exposures with vascular andhepatic function and other indices of cardiometabolic risk. This will help us in assessing how VOCexposure and/or residential proximity to Superfund sites affects the risk of CMD and thisexcessive risk differs from that imposed by background VOC exposures in urban neighborhood.We expect that completion of this project will lead to the development of quantitative risk modelsand rigorous estimates of the additional CMD risk attributable to residential VOC exposures.

project_terms:
Acceleration;Acrolein;Affect;Air;Animals;Area;Atherosclerosis;Benzene;Bile Acids;Biological Markers;Blood Platelets;Blood Pressure;Blood Vessels;Butadiene;Carcinogens;Cardiometabolic Disease;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Chemicals;Chronic;Collaborations;Communities;County;Data;Data Management and Analysis Core;Development;Diabetes Mellitus;Disease Progression;Dose;Environmental Exposure;Enzymes;Event;Exposure to;Farm;Formaldehyde;Functional disorder;Goals;Hazardous Chemicals;Health;Hepatic;Hepatocyte;Hepatotoxicity;Hospital Mortality;Hospitalization;Human;Individual;Injury;Insulin Resistance;Kentucky;Keratin;Lipids;Liquid substance;Liver;Liver diseases;Location;Measurement;Measures;Metabolic Diseases;Metabolism;MicroRNAs;Modeling;Monitor;Neighborhoods;Participant;Plasma;Population;Process;Risk;Serology;Serum;Steatohepatitis;Superfund;Target Populations;Testing;Toluene;Trichloroethylene;Variant;Vascular Diseases;Water;Work;Xylene;arterial stiffness;attributable risk;blood glucose regulation;blood pressure elevation;carcinogenicity;cardiometabolic risk;cardiometabolism;cardiovascular disorder risk;circulating biomarkers;cohort;diabetes risk;disorder risk;exposed human population;fatty liver disease;indexing;land use;landfill;liver biopsy;monocyte;mortality;particle;primary endpoint;response;stem cells;superfund site;toxicant;urinary;vascular injury;volatile organic compound;wastewater monitoring

public_health_relevance:
NARRATIVEThis project is to identify assess and evaluate the potential health effects due to exposure to hazardouschemicals prevalent in urban neighborhoods and areas around Superfund sites.


application_id: 11112446
project_number: 4P42ES023716-09
project_title: Environmental Exposure and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2025-08-15
opportunity_number: RFA-ES-20-014
application_type: 4
activity_code: P42
ic: ES
serial_number: 023716
program_official: CARLIN, DANIELLE J
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S(SF)
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This proposal is to continue to grow and expand the University of Louisville SuperfundCenter established in 2017. Currently the Center supports research on thecardiometabolic effects of volatile organic chemicals (VOCs) that are of high relevanceto the Superfund Program. Center investigators conduct mode-of-action research tounravel critical pathways of toxicity and to identify toxicological endpoints(cardiometabolic changes) of chemicals (VOCs) found at Superfund and related sites.Using high throughput mass spectrometry and an innovative suite of mechanism-basedbiomarkers animal experiments and human population studies Center investigationshave contributed to the discovery and validation of novel biomarkers of both exposureand cardiometabolic injury that would lay the foundation for future remediationstrategies. These studies employ state-of-the-art tools to develop pollutant atmospheresfor animal exposure and to measure unique and sensitive biological endpoints reflectiveof cardiometabolic injury. In addition work supported by the Center is leading to thedevelopment of new methods and devices for quantifying atmospheric levels of VOCsthat employ advanced technologies and offer precise but low-cost measurements ofhazardous waste sites. As before the major objectives of the Center are to conductstate-of-the-art research on the cardiometabolic toxicity of VOCs and to determine howthey affect cardiometabolic disease (CMD) prevalence and severity in exposedpopulations. These studies will be complemented by mode-of-action mechanistic studiesin animals to identify the molecular and cellular mechanisms that contribute to VOCtoxicity. The findings of these studies will continue to contribute to both the discoveryand the validation of sensitive and robust biomarkers that could be used to assess theextent of exposure metabolism and toxicity. Center investigators are creating newtechnologies for detecting VOCs at low environmental levels to enable future exposureassessment activities. Senior Center members educate and train junior investigatorsgraduate students and post-doctoral Fellows in the field of environmental science andpromote relevant community awareness and participation to enhance mutualbidirectional understanding of exposure risk and the health effects of exposure. Thefindings and discoveries of the Center will be transferred to affected communities endusers in public and private sectors and other stakeholders. For future use and analysisall samples of human and animal tissues and all data collected during Centerinvestigations will be stored in a computer-coded biorepository. Collectively expansionand growth of the Center activities will enhance its contribution and lead to rigorousevaluation and better understanding of the effects of these hazardous chemicals onobesity diabetes and cardiovascular disease.

project_terms:
Action Research;Advanced Development;Affect;Animal Experiments;Animal Model;Animals;Area;Atmosphere;Awareness;Biological;Biological Markers;Cardiology;Cardiometabolic Disease;Cardiovascular Diseases;Cause of Death;Chemical Exposure;Chemicals;Chemistry;Communities;Community Outreach;Cost Measures;Critical Pathways;Data;Data Management and Analysis Core;Data Storage and Retrieval;Decision Making;Development;Devices;Diabetes Mellitus;Disease Pathway;Education and Outreach;Ensure;Environment;Environmental Exposure;Environmental Science;Epidemiology;Etiology;Evaluation;Exposure to;Foundations;Funding;Future;Generations;Goals;Growth;Hazardous Chemicals;Hazardous Substances;Hazardous Waste Sites;Health;Heart Diseases;Hepatology;Human;Incidence;Industrialization;Injury;Interdisciplinary Study;Investigation;Knowledge;Mass Spectrum Analysis;Measures;Medical;Membrane;Metabolism;Methods;Molecular;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathway interactions;Population;Postdoctoral Fellow;Predisposition;Prevalence;Private Sector;Procedures;Process;Public Health;Public Sector;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Risk;Sampling;Science;Severities;Site;Superfund;Technology;Tissue Sample;Toxic effect;Toxicology;Training;Training Programs;Universities;Validation;Work;animal tissue;biobank;cardiometabolism;community engagement;computer code;data archive;data sharing;detection method;education research;education resources;experience;exposed human population;fatty liver disease;graduate student;human population study;human tissue;innovation;interest;member;new epidemic;new technology;novel;novel marker;obesity development;outreach program;pollutant;programs;remediation;repository;resilience;response;self assembly;superfund chemical;superfund site;tool;translational medicine;volatile organic compound

public_health_relevance:
This proposal is to establish a Center to support research on the health effects ofhazardous Superfund chemicals. Work in this Center will help in evaluating the healthimpacts of several hazardous chemicals that are present in the environment and inunderstanding how exposure to chemicals could contribute to the risk and developmentof obesity diabetes and heart disease which despite recent medical advances remainthe leading causes of death worldwide.


application_id: 11111889
project_number: 1R21CA292333-01A1
project_title: Guadecitabine-directed immune regulation in targeting prostate cancer
administering_ic: NCI
award_notice_date: 2025-04-07
opportunity_number: PAR-22-216
application_type: 1
activity_code: R21
ic: CA
serial_number: 292333
suffix: A1
program_official: SOMMERS, CONNIE L
project_start_date: 2025-06-01
project_end_date: 2027-05-31
study_section: Special Emphasis Panel[ZCA1 SRB-1 (J1)]
contact_pi_person_id: 8546610
contact_pi: KARAN, DEV
other_pis: Not Applicable
congressional_district: 03
department: UROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Project SummaryImmunotherapy has transformed the treatment landscape for many cancers but its clinical benefit is onlymarginal in prostate cancer patients. Epigenetic changes and altered immune signaling pathways candownregulate antigen presentation resulting in resistance to immunotherapies. There is a significant interestin targeting cancer cells via reversing epigenetic mechanisms to modify the host intrinsic immunity. Epigenetictherapy has the ability to activate tumor-suppressing programs and modulate the tumor microenvironment(TME) by augmenting immune cell infiltration. In this study we used a hypomethylating agent guadecitabine(gDEC) and demonstrated that gDEC leads to the upregulation of epigenetic activating enzymes contributingto the overall prostate cancer phenotype change and anticancer effect independent of apoptosis. We alsoobserved that gDEC induces the level of Class I MHC molecules on the surface of prostate cancer cellsmaking the cancer cells vulnerable to immune cell targets. Based on our strong preliminary data we proposedto test a novel hypothesis that gDEC augments the process of antigen presentation compellingprostate cancer cells susceptible to CD8+ T cells induced by immunotherapy. The rationale for thishypothesis is that gDEC increases the process of antigen presentation with the potential to provokeneoantigens making the tumor cells immunogenic and vulnerable to immune targets. Furthermore thecombined use of an adenovirus-based vaccine expressing prostate cancer-specific antigens (Ad-PS2 bivalentvaccine) induces CD8+ T cell infiltration and eliminates the established tumors. Therefore we aimed todetermine the crosstalk mechanisms between the tumor and immune cells in the prostate TME followingepigenetic remodeling and develop a novel immunotherapy regimen inducing long-lasting antigen-specificantitumor immunity targeting prostate cancer.

project_terms:
Adenoviruses;American men;Antigen Presentation;Antigens;Apoptosis;Automobile Driving;CD8-Positive T-Lymphocytes;Cancer Etiology;Cancer Patient;Cell Physiology;Cells;Cessation of life;Clinical;Combination immunotherapy;Complex;Data;Defect;Development;Enzymes;Epigenetic Process;Epithelium;Genes;Genetic;HLA-A gene;Histocompatibility Antigens Class I;Human;Immune;Immune Evasion;Immune Targeting;Immune signaling;Immunity;Immunocompetent;Immunosuppression;Immunosuppressive Agents;Immunotherapy;Knowledge;Lead;MHC Class I Genes;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mesenchymal;Methylation;Molecular;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Preclinical data;Predisposition;Process;Prostatic Neoplasms;Proteins;Regimen;Regulation;Repression;Resistance;Role;Sampling;Signal Pathway;Site;Suppressor-Effector T-Lymphocytes;Surface of the Prostate;T cell infiltration;T-Lymphocyte;TAP1 gene;TAP2 gene;TFF1 gene;Testing;Translations;Treatment Efficacy;Tumor Immunity;Tumor Suppressor Genes;Upregulation;Vaccines;androgen deprivation therapy;androgen independent prostate cancer;anti-cancer;antigen processing;cancer cell;chemotherapy;effector T cell;epigenetic regulation;epigenetic therapy;immune cell infiltrate;immunogenic;immunoregulation;improved;innovation;interest;mouse model;neoantigens;neoplastic cell;novel;novel therapeutic intervention;programs;prostate cancer cell;prostate cancer cell line;reconstitution;signal processing;therapy resistant;trafficking;treatment response;tumor;tumor microenvironment;tumor-immune system interactions

public_health_relevance:
Project NarrativeDespite considerable progress prostate cancer remains the second leading cause of cancer-related deathsin American men. Immunotherapy has transformed the treatment landscape for many cancers but its clinicalbenefit is only marginal in prostate cancer patients. Therefore we aimed to determine the significance of thehost immunity reconstitution following combination approaches of epigenetics editing and immunotherapytargeting prostate cancer.


application_id: 11111404
project_number: 5R01AI167953-03
project_title: Invasion of the enteric nervous system by neurotropic Listeria monocytogenes
administering_ic: NIAID
award_notice_date: 2025-07-14
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AI
serial_number: 167953
program_official: BAQAR, SHAHIDA
project_start_date: 2023-07-01
project_end_date: 2028-06-30
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 2545336
contact_pi: D'ORAZIO, SARAH E. F.
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:
Listeria monocytogenes (Lm) are Gram-positive facultative intracellular bacteria that cause two types of braininfections in humans: diffuse (meningitis/meningoencephalitis) and focal brainstem (rhombencephalitis).Meningitis occurs in the setting of immune compromise likely due to the failure of the immune system to limitexponential growth of Lm in tissues such as spleen or liver. This leads to high titer bacteremia and either directinvasion of the blood-brain-barrier (BBB) or stealth transport of Lm associated with myeloid-derived cells thatcross the BBB. In contrast rhombencephalitis is an infection of a delayed nature that occurs in young otherwisehealthy immune competent people which suggests that the infection is dependent on bacterially encodedneurovirulence factors. The central hypothesis of this proposal is that the virulence factors which defineneurotropism during rhombencephalitis mediate critical early events in the intestines rather than in the brain.Support for this hypothesis comes from our preliminary data showing that when the neurotropic Lm are injectedintravenously (bypassing the gut phase of the infection) they do not disseminate to the brain. In addition othersshowed that rhombencephalitis isolates did not have an increased ability to survive and replicate in bovineorganotypic brain slices ex vivo relative to other Lm strains. Until recently rhombencephalitis could be studiedonly in cows or sheep due to the lack of a small animal model of Lm brainstem infections. However we recentlyshowed that some clinical isolates of Lm (UKVDL9 and SD4000) could preferentially colonize the brainstems ofmice late in the course of infection without reaching high titer in the blood. Both of the neurotropic strains wereported belong to lineage III the smallest and least characterized group of Lm isolates. The goal of this proposalis to define the factors that promote neurotropism by Lm UKVDL9 and SD4000 during the gut phase of listeriosis.We predict that neurotropic Lm could have an advantage in three different aspects of the intestinal infection;these form the three Specific Aims of the proposal. In Aim 1 we determine if the route used to cross the gutmucosa or inflammatory response induced promotes localization of neurotropic Lm strains in neural bundles inthe intestinal submucosa or within the vagal crypt endings surrounding lymphoid cryptopatches in the gut. InAim 2 we identify the novel Lm surface protein that mediates enhanced invasion of enteric glial cells the celltype that surrounds nerves in the gut. In Aim 3 we test the hypothesis that a truncated actA allele found inneurotropic Lm promotes an altered type of intracellular movement that allows the bacteria to migrate along theentire length of an axon all the way to the brainstem. This work will move the listeriosis field forward by providingthe first real insights into neurotropism during this life-threatening foodborne infection and could also lay thegroundwork for new areas of pathogenesis or microbiome-related research to understand how bacteria interactwith cells of the enteric nervous system.

project_terms:
Actins;Alleles;Animal Model;Area;Axon;Bacteremia;Bacteria;Bacterial Adhesins;Blood;Blood - brain barrier anatomy;Body System;Brain;Brain Stem;Bypass;Cattle;Cell Nucleus;Cells;Clinical;Coculture Techniques;Cranial Nerves;Data;Death Rate;Diffuse;Elderly;Endowment;Enteral;Enteric Nervous System;Event;Failure;Follow-Up Studies;Food Contamination;Goals;Growth;Gut Mucosa;Human;Immune;Immune system;Immunocompetent;In Vitro;Individual;Infection;Inflammatory;Inflammatory Response;Intestines;Intravenous;Invaded;Kinetics;Lamina Propria;Length;Life;Listeria;Listeria monocytogenes;Listeriosis;Liver;Lymphoid;Mediating;Membrane Proteins;Meningitis;Meningoencephalitis;Microscopic;Monitor;Motility;Movement;Mus;Mutagenesis;Myelogenous;Myenteric Plexus;Nature;Nerve;Nervous System;Neuroglia;Neurons;Neurotropism;Oral;Pathogenesis;Pattern;Persons;Phase;Process;Proline-Rich Domain;Proteins;Reporting;Research;Role;Route;Sheep;Slice;Speed;Spleen;Submucosa;Submucous Plexus;System;Tail;Testing;Time;Tissues;Vagus nerve structure;Variant;Virulence Factors;Work;blood-brain barrier crossing;cell type;enteric infection;food consumption;foodborne;foodborne illness;foodborne infection;in vivo;insight;intestinal epithelium;live cell imaging;microbiome;microbiota;migration;mouse model;mutant;neonate;nerve supply;neural;neurotropic;neurovirulence;novel;pathogen;transmission process

public_health_relevance:
Ingestion of food contaminated by Listeria monocytogenes bacteria causes two different types of braininfection in humans. One type (meningitis) happens primarily in individuals with compromised immunesystems (for example neonates and the elderly); the other type (rhombencephalitis) occurs in otherwisehealthy people. The goal of this research is to identify the bacterial factors which allow Listeria to invadecranial nerves in the gut and spread directly to the brainstem resulting in rhombencephalitis.


application_id: 11111394
project_number: 5R01NS126228-03
project_title: The role of macrophage metabolism and age in recovery from spinal cord injury
administering_ic: NINDS
award_notice_date: 2025-07-01
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: NS
serial_number: 126228
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2023-06-01
project_end_date: 2028-05-31
study_section: Special Emphasis Panel[ZRG1-CN-T(90)S]
contact_pi_person_id: 8201969
contact_pi: GENSEL, JOHN C
other_pis: PATEL, SAMIRKUMAR
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/ABSTRACTThe average age at the time of spinal cord injury (SCI) has increased to 50.5 years old in the US. Observationsfrom several independent laboratories demonstrate that inflammation specifically sustained pro-inflammatorymacrophage activation contributes to age-related SCI deficits. In addition it was recently discovered that theefficacy of immunomodulatory SCI therapies is age-dependent. There is an urgent need to understand theage-dependent mechanisms of sustained pro-inflammatory macrophage activation in SCI. The purpose of thisproposal is to investigate the role of macrophage bioenergetics in age-dependent inflammation and SCIpathophysiology. The central hypothesis is that age-dependent impairments in macrophage metabolism drivepro-inflammatory macrophage activation and contribute to secondary injury after SCI. The premise is that thepyruvate dehydrogenase (PDH) pathway is a key regulator of pro- or anti-inflammatory macrophage activationas a connecting link between glycolysis (pro-inflammatory) or oxidative phosphorylation (OXPHOS i.e. TCA orKrebs cycle activity; anti-inflammatory). PDH kinase (PDK) regulates PDH thereby serving as the gatekeeperfor OXPHOS. The hypothesis to be tested is that PDK inhibition will drive metabolic processes (i.e. increasedOXPHOS) required for reparative macrophage activation and improved SCI recovery by PDK. Accordinglythree independent Aims are designed to selectively target macrophage metabolism mechanistically usingchimerization with PDK knockout mice and therapeutically using a newly generated liposomal drugformulation of dichloroacetate (DCA) a PDK inhibitor. 4 and 14-month-old mice will undergo T9 contusion SCIto model the current SCI demographic. Aim 1 will identify PDH as a bottleneck for SCI macrophagemetabolism using a newly optimized purification approach that allows for isolation of macrophages after SCIand assessment of extracellular acidification (ECAR i.e. glycolysis) and oxygen consumption (OCR i.e.OXPHOS) rates using the Seahorse bioanalyzer. Aim 2 will identify metabolic targets for macrophagedysfunction after SCI using state-of-the-art techniques including single-cell RNA-sequencing and in vivo StableIsotope-Resolved Metabolomics to determine the metabolic profiles of resident microglia and peripherallyderived macrophages. Aim 3 will identify PDK inhibition as a therapeutic target to treat SCI through evaluationof anatomic and functional recovery. Completion of the proposed work will identify ways to harness thereparative functions of CNS macrophages and improve clinical practice by refining translational treatmentstrategies including age as a potential influence in SCI treatment and recovery. Understanding the extent towhich metabolic activity regulates macrophage function will provide insight into age-dependent CNSinflammation thereby advancing the fields of neurotrauma neuroscience and aging. Macrophage metabolismis a contributing factor in a host of inflammatory conditions including cardiovascular disease diabetes canceretc. and the completion of the proposed aims will advance the study of human health on multiple fronts.

project_terms:
5 year old;Acetyl Coenzyme A;Age;Aging;Anatomy;Animal Model;Anti-Inflammatory Agents;Automobile Driving;Bioenergetics;Cardiovascular Diseases;Catalogs;Chronic;Citric Acid Cycle;Clinical;Data;Diabetes Mellitus;Dichloroacetate;Disease Progression;Dose;Drug Formulations;Evaluation;Fostering;Functional disorder;Gatekeeping;Genetic;Genetic Transcription;Genus Hippocampus;Gliosis;Glucose;Glycolysis;Health;Health Care Costs;Human;Impairment;In Vitro;Incidence;Inflammation;Inflammatory;Injury;Knockout Mice;Knowledge;Label;Laboratories;Link;Liposomes;Locomotor Recovery;Macrophage;Macrophage Activation;Malignant Neoplasms;Measures;Metabolic;Metabolic Pathway;Metabolic dysfunction;Metabolism;Microglia;Mission;Modeling;Mus;Myeloid Cells;Nervous System Trauma;Neurosciences;Older Population;Outcome;Oxidative Phosphorylation;Oxygen Consumption;PDH kinase;Paralysed;Pathologic;Pathology;Pathway interactions;Patients;Peripheral;Pharmaceutical Preparations;Population;Public Health;Publishing;Pyruvate;Reaction;Recovery;Recovery of Function;Reporting;Research;Role;Secondary to;Sensory;Spinal Cord Contusions;Spinal cord injury;Techniques;Testing;Therapeutic;Therapeutic Effect;Time;Tissues;Translating;United States National Institutes of Health;Work;age related;age-related disease;aged;axonal sprouting;clinical practice;clinically relevant;design;disability;experimental study;extracellular;immunomodulatory therapies;immunoregulation;improved;in vivo;inhibitor;injury recovery;innovation;insight;juvenile animal;kinase inhibitor;liposomal formulation;metabolic profile;metabolomics;neuroinflammation;neuronal survival;novel;old mice;pharmacologic;pyruvate dehydrogenase;repair function;response;single-cell RNA sequencing;stable isotope;therapeutic evaluation;therapeutic target;tissue repair;tool;translational impact;treatment strategy

public_health_relevance:
PROJECT NARRATIVEThe proposed research is relevant to public health because the injured spinal cord does not heal properlyresulting in chronic paralysis and expensive health care costs for patients with spinal cord injuries. There arefew therapies for treating spinal cord injury and although there are increased incidences of injury in olderindividuals age is not considered in most research. The proposed research will examine age-relatedinflammatory mechanisms of spinal cord injury progression using a clinically relevant drug and is thereforerelevant to the part of the NIH mission that pertains to developing fundamental knowledge and applying thatknowledge to foster innovative research strategies to reduce the burden of human disabilities.


application_id: 11110440
project_number: 5R01AI184710-02
administering_ic: NIAID
award_notice_date: 2025-05-22
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AI
serial_number: 184710
program_official: MO, ANNIE X Y
project_start_date: 2024-06-07
project_end_date: 2029-05-31
study_section: Special Emphasis Panel[ZRG1-MCST-M(81)S]
contact_pi_person_id: 6620313
contact_pi: GUY, RODNEY KIPLIN
other_pis: DERISI, JOSEPH L.
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: 2025-06-01
project_title:
Interactions between drug combinations and resistance acquisition risk for antimalarial ATP4 inhibitors

project_abstract:
ABSTRACTThe overall goals of this proposal are to develop an understanding of the factors driving the efficacy of potentialclinical combinations of a new class of fast acting antimalarial the ATP4 inhibitors (ATP4i) includingpharmacology enforcing speed of action and total cidality and the selection of new ATP4i resistant strains of P.falciparum that are competent to propagate in vivo and thus would provide clinically relevant ATP4i resistance.The key goal is to understand how specific drug partners could potentially prevent development of ATP4iresistant parasites. The project centers on the ATP4i SJ733 which has recently successfully completed Phase2a trials and provides rapid pharmacodynamics in humans for both P. falciparum and P. vivax malarias. Thebasic approach will be examining patterns of efficacy and resistance acquisition in both in vitro and in vivomodels. This approach allows understanding how ATP4i inhibitors unique host-mediated clearance mechanism the removal of infected treated erythrocytes by macrophages and the spleen  leads to disparities betweenpredicting resistance risk using in vitro methods and the actual clinical risk. Drug combinations to be examinedinclude: pyronaridine lumefantrine piperaquine artesunate tafenoquine and the triple combination artemether-lumefantrine. The health relatedness of this project is the potential to develop new ATP4i based combinationantimalarial drugs that possess intrinsically low risk for resistance development and could replace the ACTs. Wehave previously developed and carried out all the required in vitro and in vivo pharmacological modelinggenomics and genetic methods for testing candidate resistance-conferring mutations. In Aim 1 we will carryout in vitro experiments using combination drug exposure patterns matched to what would be seen in patientsto both examine total cidality of the combinations and the frequency and nature of resistance-conferringmutations selected in cultured parasites. In Aim 2 we will carry out in vivo experiments using combination drugsdosed so to match blood drug exposure patterns seen in patients to both examine total cidality of thecombinations and the frequency and nature of resistance-conferring mutations selected during infections inhumanized mice. In Aim 3 we will characterize genomic changes in parasites selected by both approachesidentify candidate resistance-conferring changes and generate knock-in strains of P. falciparum to test thefunction of candidate changes. Overall this innovative project will teach us how ATP4i drug combinationsreinforce the fast-acting pharmacodynamics of the class how resistance develops to ATP4i and how thegenomic changes in the parasite interact with the host-driven clearance mechanism to define which mutants arecompetent for growth in vivo. Ultimately this should allow designing the optimal drug combination to best protectthe ATP4i from resistance acquisition and allow development of a drug to replace the ACTs.

project_terms:
Address;Affect;Africa;Anti-malarial drug resistance;Anti-malarials;Artemisinins;Automobile Driving;Blood;Cessation of life;Clinic;Clinical;Clinical Trials;Collaborations;Combined Modality Therapy;Development;Disease;Disparity;Dose;Drug Combinations;Drug Exposure;Drug resistance;Educational process of instructing;Erythrocytes;Excision;Frequencies;Future;Genetic;Genomics;Goals;Growth;Health;Human;In Vitro;Individual;Infection;Knock-in;Laboratories;Macrophage;Malaria;Mediating;Medicine;Methods;Modeling;Mus;Mutation;Nature;Parasite resistance;Parasites;Patients;Pattern;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Phase;Plasma;Plasmodium;Plasmodium falciparum;Plasmodium vivax;Probability;Regimen;Research;Resistance;Resistance development;Risk;Role;Schedule;Signal Transduction;Southeastern Asia;Speed;Spleen;Testing;Time;Variant;Vivax Malaria;acquired drug resistance;artemether;artesunate;atovaquone;benflumetol;candidate identification;clinical development;clinical risk;clinically relevant;clinically significant;combat;cost;design;drug action;experimental study;fitness;humanized mouse;improved;in vivo;in vivo Model;inhibitor;inhibitor therapy;innovation;mutant;novel;novel therapeutics;pharmacologic;pressure;prevent;pyronaridine;resistance mechanism;resistance mutation;resistant strain;risk minimization;risk mitigation;targeted treatment;treatment duration

public_health_relevance:
Project NarrativeMalaria a disease caused by Plasmodia parasites afflicts approximately 240 million individuals and killsup to 630000 each year. A significant problem with fielding effective antimalarial medicines is that themalaria parasites become resistant to treatment over time causing drugs to stop working. We are usingour understanding of the mechanism of action of a new class of antimalarial drugs the ATP4 inhibitorsto direct selection of the best medicines from other classes to combine with ATP4 inhibitors to minimizedrug resistance arising and lengthen the time they can be effectively used to treat malaria.


application_id: 11110379
project_number: 5R01AA030487-04
administering_ic: NIAAA
award_notice_date: 2025-09-03
opportunity_number: RFA-AA-21-016
application_type: 5
activity_code: R01
ic: AA
serial_number: 030487
program_official: FREEMAN, ROBERT
project_start_date: 2022-08-15
project_end_date: 2027-05-31
study_section: ZAA1-DD(17)V
contact_pi_person_id: 12488104
contact_pi: LAUCKNER, CAROLYN
other_pis: KERSHAW, TRACE S
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: 2025-06-01
project_title:
Evaluation of a Combined Motivational Interviewing and Ecological Momentary Intervention to Reduce Risky Alcohol Use among Individuals Vulnerable to HIV/AIDS

project_abstract:
Among emerging adults at high risk for HIV hazardous alcohol use can increase the risk of engaging in HIV risk behaviors. One method of reducing hazardous alcohol use is motivational interviewing which has been effective among various populations in prior literature and the investigators pilot research. Technology can help to extend the impact of this approach by delivering messaging to prevent risk behaviors in real time (i.e. outside of intervention sessions). This study will conduct a 3-arm randomized controlled trial that assesses the efficacy of two interventions compared to a control: 1) A 4-week motivational interviewing intervention (TRAC) delivered remotely via cell phones and 2) TRAC combined with an ecological momentary intervention that delivers messages reinforcing drinking reduction strategies discussed during TRAC sessions when individuals visit risky locations (TRAC-ER). All participants will also monitor alcohol use and sexual behavior via daily surveys and twice-daily mobile breathalyzer readings. TRAC-ER will use an app that uses GPS tracking to determine when individuals visit risky locations. Participants will receive messages upon arrival at these locations reminding them of strategies to address drinking triggers and will complete surveys and breathalyzers when they leave to determine what alcohol and/or risk behaviors they engaged in. If they reported drinking they receive harm reduction messaging to encourage them to avoid subsequent risk behavior. Breathalyzer results and daily self-reports will be used to assess the primary outcomes of drinking days drinks/drinking day binge drinking episodes and HIV risk behaviors and additional assessments over 8 months will evaluate long-term outcomes. Participants will be recruited from Kentucky and Connecticut through community-based recruitment and health clinics that provide HIV/STI prevention services.

project_terms:
AIDS prevention;Address;Adherence;Alcohol abuse;Alcohol consumption;Alcohols;Area;Behavior;Behavioral;Biological;Cancer Survivor;Cellular Phone;Clinic;Communities;Connecticut;Data;Effectiveness;Eligibility Determination;Evaluation;Event;Goals;HIV;HIV diagnosis;HIV risk;HIV/AIDS;HIV/STD;Harm Reduction;Health;Individual;Intervention;Kentucky;Literature;Location;Methods;Motivation;Outcome;Participant;Patient Self-Report;Persons;Population;Randomized Controlled Trials;Reading;Reporting;Research;Research Personnel;Risk;Risk Behaviors;Self Efficacy;Sex Behavior;Surveys;Technology;Testing;Time;Unsafe Sex;Visit;Vulnerable Populations;aged;alcohol behavior;alcohol monitoring;alcohol use disorder;arm;binge drinking;comparison group;comparison intervention;drinking;ecological momentary intervention;efficacy evaluation;emerging adult;evidence base;experience;hazardous drinking;high risk;high risk drinking;high risk population;innovation;intervention effect;literacy;mobile application;motivational enhancement therapy;older adult;pre-exposure prophylaxis;precision medicine;prevent;prevention service;primary endpoint;primary outcome;recruit;reduced alcohol use;remote delivery;secondary endpoint;secondary outcome;sex;substance use;transmission process;trend;young adult

public_health_relevance:
:Emerging adults at risk for HIV are more likely to report hazardous drinking and to have alcohol use disorders compared to those who are not at risk. This is concerning as alcohol use contributes to HIV risk. Through a randomized controlled trial the proposed research will evaluate an enhanced motivational interviewing intervention that utilizes smartphones and mobile breathalyzers to provide real-time messaging that addresses triggers for drinking when individuals visit locations associated with risky alcohol use.


application_id: 11110340
project_number: 5R01CA266579-04
project_title: Targeting Polo-Like Kinase 1 in Prostate Cancer to Enhance Therapeutic Efficacy
administering_ic: NCI
award_notice_date: 2025-06-18
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 266579
program_official: XU, WANPING
project_start_date: 2022-07-01
project_end_date: 2027-06-30
study_section: Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2]
contact_pi_person_id: 10992448
contact_pi: LI, ZHIGUO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Title: Targeting Polo-like kinase 1 in prostate cancer to enhance therapeutic efficacyAbstractProstate cancer (PCa) is the second most common cause of cancer death in men in the US. Over the pastseveral decades androgen deprivation therapy has been the primary therapeutic option for patients withadvanced PCa; however the majority of patients developed into a poor prognosis stage of castration-resistantprostate cancer (CRPC) which eventually led to mortality. And the current therapeutic agents for CRPCpatients only extend survival by around 2.5 - 5 months. Therefore novel and effective therapeutic strategies forCRPC patients are urgently needed. The long-term goals of this study are to identify druggable signalingpathways that offer more effective treatment options for patients with CRPC. The objective is to identify the roleof Plk1/p62/Nrf2 signaling pathway in CRPC and to exploit the potentially therapeutic strategies that could bebenefit the CRPC patients. The central hypothesis is that Nrf2 is activated by a noncanonical mechanisminvolving p62 phosphorylation by Plk1 in CRPC. Our hypothesis will be tested by pursuing Three Specific Aims:(1) to determine the novel role of Plk1 as regulator of cellular response to oxidative stress. (2) examine the roleof Plk1/p62/Nrf2 axis in tumor growth in mouse models. And (3) whether inhibition of Plk1/p62/Nrf2 signalingpathway enhance the efficacy of CRPC therapy. The expected results will reveal a novel molecular mechanismto show how Plk1 contributes to PCa progress and will open up new avenues for application of Plk1 inhibitorsas a therapeutic option. The team with expertise in Plk1 in mouse models Plk1 in cancer cell biology PCapathology GU oncology and biostatistics will be able to finish the proposed research in a timely manner.

project_terms:
Alleles;American men;Androgens;Apoptosis;Autophagocytosis;Biometry;Breeding;Cancer Etiology;Cancer Patient;Cell Survival;Cells;Cellular biology;Cessation of life;Clinic;Clinical Research;Creativeness;Data;Disease;Enterobacteria phage P1 Cre recombinase;Fostering;Genetically Engineered Mouse;Goals;Health;Immune checkpoint inhibitor;Immunocompetent;Immunosuppression;Immunotherapy;Infiltration;Investigation;Lymphocyte;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Mediating;Membrane;Mission;Molecular;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Oncology;Outcome;Oxidative Stress;PDL1 inhibitors;PDL1 pathway;PLK1 gene;Pathology;Patient-Focused Outcomes;Patients;Phosphorylation;Phosphotransferases;Play;Prognosis;Proliferating;Prostate Cancer therapy;Public Health;Reactive Oxygen Species;Refractory;Regulation;Research;Residual state;Role;Signal Pathway;Signal Transduction;Survival Rate;Testing;Therapeutic;Therapeutic Agents;Therapeutic Effect;Treatment Efficacy;Tumor Escape;Tumor Immunity;Tumor-infiltrating immune cells;Upregulation;Work;advanced prostate cancer;androgen deprivation therapy;androgen independent prostate cancer;anti-PD-L1 therapy;cancer cell;cell growth;comparative efficacy;design;effective therapy;immune cell infiltrate;improved;inhibitor;innovation;mortality;mouse model;neoplastic cell;novel;novel strategies;novel therapeutic intervention;nuclear factor-erythroid 2;pharmacologic;programmed cell death ligand 1;programs;promoter;prostate cancer cell;receptor;response;synergism;targeted treatment;therapeutically effective;tumor;tumor growth;tumor microenvironment;tumor xenograft;tumor-immune system interactions

public_health_relevance:
NarrativeThe proposed research is relevant to public health because it focuses on a novel therapeutic strategy forcastration-resistant prostate cancer. These studies will establish new avenues of investigation to developimproved therapeutics to treat this deadly disease and to greatly improve patient outcome. Thus theproposed research is relevant to NCI's mission of fostering creative discoveries and innovativeresearch strategies for protecting and improving health and reducing the burdens associated with cancer.


application_id: 11109847
project_number: 1R21CA288604-01A1
project_title: Mitochondrial regulation of chemotherapy-induced reactive myelopoiesis and pro-metastatic effects
administering_ic: NCI
award_notice_date: 2025-03-25
opportunity_number: PAR-22-216
application_type: 1
activity_code: R21
ic: CA
serial_number: 288604
suffix: A1
program_official: O'HAYRE, MORGAN
project_start_date: 2025-04-01
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZCA1 SRB-F (J1)]
contact_pi_person_id: 9855558
contact_pi: DING, CHUANLIN
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
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:
Recent studies and our preliminary data highlight the importance of myelopoiesis in the chemotherapyinduced accumulation of immunosuppressive myeloid cells. Growing evidence also demonstrates theability of hematopoietic stem and progenitor cells (HSPCs) to sense inflammation ultimately regulatingHSPC proliferation and differentiation via metabolic alterations. Its known that mitochondrial oxidativephosphorylation (OXPHOS) results in an increase of reactive oxygen species (ROS) production in HSPCs.However our understanding of inflammation metabolic alterations of HSPCs and monocyte developmentis still limited. Current antioxidant strategies are not clinically effective. Finding novel targets could providebetter therapeutic efficacy for combination therapy with chemotherapy. Mitochondria are the main sourceof ROS and are highly dynamic through the fission and fusion events and dynamin-related protein 1 (Drp1)is an essential mediator of mitochondrial fission that elicits excessive ROS production. Importantlytargeting of excessive mitochondrial fission can regulate hematopoiesis via the mechanisms beyond ROS.The objective of this project is to determine whether mitochondrial ROS and Drp1 mediated HSPCmitochondria fission control chemotherapy induced reactive myelopoiesis and pro-metastatic effect. Wehypothesize that chemotherapy induces reactive myelopoiesis by enhanced ROS production and Drp1-mediated mitochondrial fission in HSPCs which drive the expansion of pro-metastatic monocytes. Furthertargeting of mtROS or Drp1 reduces chemotherapy-induced metastases by regulating reactivemyelopoiesis and monocyte phenotype. We will test our hypothesis by completing the following two specificaims: (1) Determine chemotherapy induced mitochondrial metabolism in HSPCs and phenotypic changesof monocytes and (2) Determine whether targeting of Drp1 dependent mitochondrial fission reduceschemotherapy induced pro-metastatic effect. The proposed study is significant because it will reveal anovel mechanism by which chemotherapy induces HSPC mitochondrial fission leading reactivemyelopoiesis and pro-metastatic monocyte development. The discovery of role for mitochondrial fission inHSPCs after chemotherapy will stimulate new approach to improve anti-tumor efficacy of conventionalchemotherapy.

project_terms:
Address;Antioxidants;Bone Marrow;Cells;Clinical;Combined Modality Therapy;Cytotoxic agent;Data;Development;Dose;Doxorubicin;Dynamin;Event;Exhibits;Exploratory/Developmental Grant;Glycolysis;Goals;Hematopoiesis;Hematopoietic stem cells;Heterogeneity;Immune response;Immunosuppression;Inflammation;Lung;Macrophage;Measures;Mediating;Mediator;Metabolic;Metabolism;Metastasis Induction;Metastatic Neoplasm to the Lung;Mitochondria;Mus;Myeloid Cells;Myeloid-derived suppressor cells;Myelopoiesis;Neoplasm Metastasis;Oxidative Phosphorylation;Paclitaxel;Phenotype;Phosphorylation;Prevention approach;Primary Neoplasm;Production;Proteins;Proto-Oncogene Protein c-kit;Public Health;RNA Sequences;Reactive Oxygen Species;Regulation;Role;Source;Structure;Structure of parenchyma of lung;Testing;Therapeutic;Time;Treatment Efficacy;cancer therapy;chemotherapy;combination cancer therapy;cytotoxic;gemcitabine;improved;inhibitor;insight;knock-down;metabolomics;mitochondrial metabolism;monocyte;neoplastic cell;novel;novel strategies;response;stem cell differentiation;stem cell proliferation;treatment response;tumor;tumor microenvironment

public_health_relevance:
NARRATIVE:This proposal addresses roles of mitochondrial ROS and Drp1 dependent mitochondrial fission inchemotherapy-induced reactive myelopoiesis and the pro-tumor monocyte development. This proposal alsoaddresses whether targeting of mitochondrial ROS or Drp1 reduces chemotherapy-induced pro-metastaticeffect. The objective of this proposal is consistent with the goals of the NCI R21 program and will have asignificant impact on public health by providing approach for prevention of tumor metastasis.


