# projects

application_id: 10308681
project_number: 5R01HL141103-04
administering_ic: NHLBI
award_notice_date: 2021-11-05
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: HL
serial_number: 141103
program_official: OH, YOUNGSUK
project_start_date: 2019-01-15
project_end_date: 2023-10-31
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: GUO, ZHENHENG
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-11-01
project_title:
Targeting timing of food intake as a novel strategy against disruption of blood pressure circadian rhythm in diabetes

project_abstract:
The normal blood pressure (BP) circadian rhythm is essential to human health as morning BPsurge is associated with increased incidence of life-threatening cardiovascular events. Moreover disruptionof BP circadian rhythm which occurs in up to 75% of diabetic patients is emerging as an index for futuretarget organ injury and poor cardiovascular outcomes. However the mechanism by which BP circadianrhythm is disrupted in diabetes is largely unknown and an effective strategy to restore the disrupted BPcircadian rhythm in diabetes has not yet been identified. Our preliminary studies found that by limiting thetime of food available to the active period (ATRF) provided striking protection of the diabetic db/db micefrom the severe disruption of BP circadian rhythm. Moreover BMAL1 an obligatory clock gene is requiredfor and glucagon-like peptide-1 (GLP-1) receptor activation mimics the protection of BP circadian rhythm byATRF. These intriguing findings suggest that ATRF can serve as a novel strategy to promote normal BPcircadian rhythms thus significantly improving the cardiovascular prognosis of diabetic patients. Thecurrent proposal will examine this new exciting possibility by testing the specific hypothesis that active time-restricted feeding (ATRF) or GLP-1 activation restores normal smooth muscle and renal BMAL1 andsympathetic oscillations thus protects diabetic mice from disruptions of blood pressure circadian rhythm.The three specific aims are 1). Determine the mechanism by which BMAL1 is dysregulated in diabetes andrestored by ATRF. 2). Test the hypothesis that ATRF protects BP circadian rhythm via smooth muscle andrenal BMAL1 in diabetes. 3). Define ATRF as a novel chrononutritional therapy and targeting GLP-1 as anew pharmacological therapy to protect BP circadian rhythm in diabetes. We will monitor the circadianrhythms of BP food intake BMAL1 regulation vascular smooth muscle function and signaling renalfunction and sympathetic regulation under ad libitum and ATRF feeding regimens. The various mousemodels will be used are diabetic db/db mice db/db-per2Luc mice high-fat diet fed mice smooth muscle andrenal BMAL1 knockout mice.

project_terms:
ARNTL gene;Affect;Agonist;Blood Pressure;Calories;Cardiovascular Diseases;Cardiovascular system;Circadian Rhythms;Data;Diabetes Mellitus;Diabetic Angiopathies;Diabetic mouse;Eating;Event;Excretory function;Food;Functional disorder;Future;GLP-I receptor;Genes;Glucagon;Goals;Health;High Fat Diet;Human;Incidence;Intake;Kidney;Knockout Mice;Life;Light;Link;Liver;Macronutrients Nutrition;Metabolism;Monitor;Mus;Muscle function;Norepinephrine;Nuclear;Obesity;Organ;Outcome;Peptides;Pharmacology;Prevalence;Prognosis;Receptor Activation;Regimen;Regulation;Renal function;Reporting;Rho-associated kinase;Role;Severities;Signal Transduction;Smooth Muscle;Smooth Muscle Myocytes;Sympathetic Nervous System;Testing;Time;Time-restricted feeding;Type 2 diabetic;Variant;Vascular Smooth Muscle;circadian;db/db mouse;diabetic;diabetic patient;fasudil;feeding;gender difference;glucagon-like peptide 1;improved;indexing;inhibitor;mouse model;neurotensin mimic 1;novel;novel strategies;novel therapeutic intervention;organ injury;pre-clinical;prevent;protective effect;urinary

public_health_relevance:
Normal blood pressure has regular circadian rhythm which is disrupted in up to 75% diabeticpatients in association with detrimental cardiovascular outcomes. We found that the bloodpressure circadian rhythm is effectively protected if the diabetic mice were only allowed accessto food during their active time (eat at the right time). The proposed study will investigate themechanisms underlying this protection and test the potential of limiting feeding to active time asa novel therapeutic strategy to improve the prognosis in diabetic patients.


application_id: 10308496
project_number: 5R01DK124626-02
project_title: Mechanisms for activation of beige adipose tissue in humans
administering_ic: NIDDK
award_notice_date: 2021-11-22
opportunity_number: PA-18-330
application_type: 5
activity_code: R01
ic: DK
serial_number: 124626
program_official: LAUGHLIN, MAREN R
project_start_date: 2020-12-01
project_end_date: 2025-11-30
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
We have been studying subcutaneous white adipose tissue (SC WAT) beiging in response to mirabegronwhich is a 3 adrenergic receptor (3AR) agonist. 3ARs are found in adipocytes and smooth muscle andmirabegron is an FDA approved drug for overactive bladder. Treatment of obese insulin resistant humans fortwelve weeks with mirabegron consistently induced SC WAT beiging and this led to improved oral glucosetolerance and a lower HbA1c. The mechanism for improved glucose homeostasis involved both a smallimprovement in insulin sensitivity and a significant improvement in -cell function (insulin secretion) along withan increase in muscle oxidative type 1 fibers; however there was no weight loss or induction of brown fat.Since pancreatic -cells and muscle do not express the 3AR the beneficial effects of mirabegron in thesecells likely occurred by an indirect mechanism. The physiological effects of mirabegron are likely mediated in part by the induction of beige adipose whichrepresents a metabolic sink for glucose and lipids and which may alter adipose remodeling. In addition thechanges in adipose tissue and other organs may result in secondary effects that target other tissues. Specific Aim 1. To examine the effects of the 3 agonist mirabegron on glucose metabolism we willcomprehensively analyze glucose tolerance insulin sensitivity and -cell function in prediabetic subjects in a4-month placebo-controlled randomized trial. We will assess changes in adipose tissue including beiginginflammation fibrosis and insulin-stimulated glucose uptake by adipocytes. We will also fully characterizegene expression in SC WAT by RNA-seq to identify potential mechanisms such as altered adipokine profiles. Specific Aim 2. We hypothesize that mirabegron causes cells that express the 3AR to change the levelsof secreted factors that affect peripheral cell types such as -cells and muscle. We will use biochemical andpharmacological approaches to identify the mechanism by which conditioned medium from mirabegron-treatedadipocytes increases PGC1 expression in muscle in vitro. We will utilize unbiased approaches to identifychanges in lipids metabolites and exosome miRNA composition in the adipocyte conditioned media. We willuse these approaches to identify molecules altered in plasma by mirabegron treatment that are responsible forthe improvement in -cell and muscle function. Clinical relevance: Mirabegron treatment has positive effects on glucose tolerance due to improvementsin insulin sensitivity and -cell function. This may be exploited to prevent conversion of prediabetes todiabetes or used as a therapeutic in diabetics. This application will also increase our understanding of themechanism(s) by which mirabegron acts which may reveal new therapeutic targets

project_terms:
Adipocytes;Adipose tissue;Adrenergic Agonists;Adrenergic Receptor;Affect;Agonist;Antidiabetic Drugs;Beta Cell;Biochemical;Bladder;Body Weight decreased;Brown Fat;Cell physiology;Cells;Chronic;Conditioned Culture Media;Consumption;Development;Diabetes Mellitus;Elderly;Epidemic;FDA approved;Fatty acid glycerol esters;Fiber;Fibrosis;Gene Expression;Glucose;Glycosylated hemoglobin A;Health;Homeostasis;Human;In Vitro;Inflammation;Insulin;Insulin Resistance;Lipids;Lipolysis;Mammals;Measures;Mediating;Metabolic;Metabolic syndrome;Methods;MicroRNAs;Mus;Muscle;Muscle Cells;Muscle function;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Organ;Overactive Bladder;Participant;Peripheral;Pharmaceutical Preparations;Pharmacology;Physiological;Placebo Control;Plasma;Play;Prediabetes syndrome;Property;Proteins;Research;Research Project Grants;Rodent;Role;Skeletal Muscle;Smooth Muscle;Structure of beta Cell of islet;Therapeutic;Thinness;Tissues;Volatile Fatty Acids;adipokines;adult obesity;bile acid metabolism;blood glucose regulation;cell type;clinically relevant;combat;design;diabetic;exosome;fighting;glucose metabolism;glucose tolerance;glucose uptake;human study;improved;improved functioning;insulin secretion;insulin sensitivity;interest;mRNA Expression;new therapeutic target;novel strategies;obesity treatment;oral glucose tolerance;overtreatment;prevent;randomized trial;response;subcutaneous;transcriptome sequencing;uncoupling protein 1

public_health_relevance:
This research grant is designed to determine whether chronic treatment with mirabegron a 3adrenergic receptor agonist approved for treatment of over active bladder improves metabolichomeostasis in prediabetic obese research participants. We will also investigate theunderlying mechanisms for improved -cell function and insulin sensitivity by mirabegrontreatment which we recently demonstrated. There is a tremendous need for new approachesto fight the obesity and type 2 diabetes epidemic and this research is thus highly relevant tohuman health.


application_id: 10308384
project_number: 5R01DE028296-03
project_title: Redox Regulation of Gingival Inflammation
administering_ic: NIDCR
award_notice_date: 2021-11-19
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DE
serial_number: 028296
program_official: CHANDER, PREETHI
project_start_date: 2019-12-09
project_end_date: 2022-01-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 11377419
contact_pi: BAGAITKAR, JUHI
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary AbstractPI: BagaitkarPeriodontal diseases are highly common infectious diseases. Chronic inflammation in periodontitis results in theprogressive destruction of hard and soft tissues and enhances susceptibility to other systemic disease. The hostfactors that regulate the magnitude nature and persistence of inflammatory responses in the oral areincompletely understood. We have previously shown that reactive oxygen species (ROS) generated by theactivation of leukocyte NADPH oxidase enzyme complex plays a critical role in dampening hyperinflammatoryresponses. Oxidase deficiency in mice resulted in profound inflammation characterized by dysregulatedneutrophil and macrophages responses and resolution delays. These data support a somewhat counterintuitiverole for ROS in limiting host inflammation. Whether oxidants modulate inflammatory pathways in the oral cavityis unclear. Our central hypothesis is that the NADPH oxidase derived-ROS independent of their antimicrobialfunctions play key roles in redox modulation of neutrophil and macrophage effector functions in vitro and in vivo.Further we hypothesize that while excessive amounts of ROS are associated with the pathophysiology ofperiodontal diseases low-level localized ROS responses are immuno-regulatory. These hypotheses will betested in two specific aims. 1) Determine the role of NADPH oxidase in the regulation of PMN effector functionsin acute responses in the gingiva. 2) Determine the role of NADPH oxidase in the modulation of macrophagefunction and resolution of gingival inflammation. The use of conditional knockout mice that lack NADPH oxidaseactivity selectively in neutrophils or macrophages will enable us to specifically determine the role of oxidants ina cell intrinsic manner in vivo. The data generated by these studies will shed key mechanistic insights in ourunderstanding of immune pathways relevant in gingival inflammation and their regulation by oxidants. Furtherour studies are also highly relevant in understanding the immunopathology of chronic granulomatous disease alife-threatening immunodeficiency caused by inherited mutations in NADPH oxidase subunit genes.

project_terms:
Acute;Alleles;Alveolar Bone Loss;Autoimmune Diseases;Cells;Chronic;Chronic Granulomatous Disease;Clinical Research;Communicable Diseases;Complex;Data;Diffusion;Disease;Effector Cell;Enzymes;Etiology;Family;Functional disorder;Generations;Genes;Genetic;Genetic Transcription;Gingiva;Immune;Immune response;Immunologic Deficiency Syndromes;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Inherited;Integration Host Factors;Knockout Mice;Leukocytes;Life;Ligature;Literature;Mediating;Multienzyme Complexes;Mus;Mutation;NADPH Oxidase;Nature;Oral;Oral cavity;Oral mucous membrane structure;Outcome;Oxidants;Oxidases;Oxidation-Reduction;Oxygen;Pathogenesis;Pathway interactions;Periodontal Diseases;Periodontitis;Play;Predisposition;Production;Publishing;Reactive Oxygen Species;Regulation;Resolution;Risk;Role;Source;Superoxides;Systemic disease;Testing;Tissues;Tooth structure;Work;antimicrobial;base;conditional knockout;cytokine;dysbiosis;immunopathology;immunoregulation;in vivo;inhibitor;insight;leukocyte activation;macrophage;neutrophil;novel;oral microbiome;recruit;response;soft tissue

public_health_relevance:
PROJECT NARRATIVEPI: BagaitkarThe NADPH oxidase enzyme complex generates reactive oxygen species (ROS) that are essential in anti-microbial defense. A large body of literature now supports a role for NADPH oxidase derived ROS in themodulation of host inflammatory pathways via redox regulation of immune cell effector functions. We aim toelucidate how ROS modulates neutrophil and macrophage responses in the oral mucosa. Insights gained fromthese studies would enable us to better understand the chronic inflammation in periodontitis.


application_id: 10307846
project_number: 1R01ES032176-01A1
administering_ic: NIEHS
award_notice_date: 2021-09-06
opportunity_number: RFA-ES-18-007
application_type: 1
activity_code: R01
ic: ES
serial_number: 032176
suffix: A1
program_official: DZIERLENGA, ANIKA LIN
project_start_date: 2021-09-06
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZES1 ARL-D (R0)]
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: ANDRES, ALINE ;EVERSON, TODD M
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:
Growth and metabolic programming from prenatal PFAS exposure: examining the roles of placental functional genomics and protection by maternal exercise

project_abstract:
PROJECT SUMMARY Rates of childhood obesity have more than tripled over the last 40 years with 18.5% of children andadolescents classified as obese. Endocrine-disrupting chemicals particularly environmentally ubiquitousobesogens such as per- and polyfluoroalkyl substances (PFAS) are thought to contribute to the rapid increasesin obesity. Indeed prenatal PFAS exposures have been shown to contribute to gender-specific obesitydevelopment in children. Interestingly PFAS exposures that occur during pregnancy can cross the placentaleading to direct in utero exposure and PFAS have been detected in placental tissues. In addition to supportingfetal growth the placenta is likely involved in longer term persistent effects in the offspring. Howeverinterrelationships between prenatal PFAS impacts on the placenta and postnatal growth and metabolic healthare understudied. Additionally a lifestyle intervention including dietary training physical activity and behavioralmodifications has been shown to attenuate the association between higher PFAS to higher body weight.However similar studies have not been performed in the context of prenatal exposure and childrens healthoutcomes. Thus there are key gaps in our understanding of the impacts and preventive opportunities regardingprenatal PFAS exposure: whether the timing of exposure and/or tissue-specific concentrations are important;whether molecular activities of the placental are disrupted by PFAS; and whether physical activity duringpregnancy may attenuate these effects. For this proposal we have assembled a newly formed collaborativeteam of investigators with unique expertise in childrens growth and metabolic health (mPI Andres Aim 1)environmental health and placental functional genomics (mPI Everson Aim 2) and physical activity interventions(mPI Pearson Aim 3) to address these knowledge gaps. Using an existing longitudinal cohort we aim to quantifyPFAS in maternal serum at each trimester as well as in umbilical cord serum and placental tissues to determinetheir associations with birth weight placental functional genomics as well as pediatric obesity. Additionallybecause PFAS are pervasive and thus exposure avoidance can be difficult we will also explore the role ofmaternal exercise in decreasing maternal PFAS burden during the pregnancy period as part of an ongoingexercise randomized control trial during pregnancy. We hypothesize that 1) prenatal PFAS burden willsignificantly affect birth weight as well as child growth and adiposity accretion; 2) prenatal PFAS exposure willinfluence placental epigenomic regulation with impacts on transcription and metabolic features; and 3) exerciseduring pregnancy will decrease PFAS burden in maternal and umbilical serum. The proposed studies will offerinnovative new insights to understanding the role of PFAS compounds as obesogens during humandevelopment their impact on placental function which could lead to novel targets for intervention or preventionand determine whether exercise mitigates the PFAS exposure risk.

project_terms:
2 year old;Address;Adolescent;Affect;Attenuated;Behavior Therapy;Birth;Birth Weight;Body Composition;Body Weight;Cell physiology;Child;Child Health;Clinical;Cohort Studies;DNA Methylation;Data;Development;Disease;Endocrine Disruptors;Environmental Health;Environmental Pollution;Epigenetic Process;Exercise;Fatty acid glycerol esters;Fetal Growth;Functional disorder;Gender;Gene Expression;Generations;Genetic Transcription;Genomics;Growth;Health;Human Development;Intervention;Intervention Studies;Knowledge;Lead;Longitudinal cohort;Maternal-Fetal Exchange;Measures;Mesenchymal Stem Cells;Metabolic;Metabolism;MicroRNAs;Molecular;Neonatal;Nutrient;Obesity;Organ;Outcome;Physical activity;Placenta;Pregnancy;Prevention;Preventive;Randomized;Regulation;Research;Research Personnel;Research Project Grants;Risk;Role;Sampling;Serum;Testing;Time;Tissues;Training;Translating;Umbilical cord structure;Weight Gain;cohort;control trial;cost;dietary;epigenetic regulation;epigenome;epigenomics;exercise intervention;functional genomics;high reward;high risk;improved;in utero;innovation;insight;intrauterine environment;lifestyle intervention;lipid biosynthesis;maternal serum;metabolomics;novel;obesity development;obesity in children;obesogen;offspring;postnatal;prenatal;prenatal exposure;prenatal influence;protective effect;response;transcriptomics;wasting

public_health_relevance:
PROJECT NARRATIVEOur ViCTER project will bring together a transdisciplinary group of investigators to perform a novel assessmentof the influences of prenatal per- and polyfluoroalkyl substances (PFAS) exposures on childrens health. Wepropose to measure PFAS concentrations at multiple time points throughout pregnancy and at birth then testfor associations with postnatal growth and adiposity. Additionally we will examine the role of the placenta bystudying placental functional genomics and assess the potential protective effects of maternal exercise duringpregnancy.


application_id: 10307828
project_number: 3R01AG061898-03S1
administering_ic: NIA
award_notice_date: 2021-01-27
opportunity_number: PA-20-272
application_type: 3
activity_code: R01
ic: AG
serial_number: 061898
suffix: S1
program_official: CLARKE, AKANNI YAO
project_start_date: 2019-02-01
project_end_date: 2023-11-30
study_section: Special Emphasis Panel[ZRG1(55)-R]
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: WATTERSON, DANIEL MARTIN
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_title:
First-in-human SAD & MAD trials for MW151 a novel Alzheimer's disease drug candidate that attenuates proinflammatory cytokine dysregulation

project_abstract:
PROJECT SUMMARY/ ABSTRACTThis administrative supplement application to R01 AG061898 requests costs to perform activities that arewithin the scope of the R01 project but were unforeseen at the time of award of the grant. The R01 project isto conduct phase 1 clinical studies of MW01-2-151SRM (=MW151) a novel brain-penetrant orallybioavailable small molecule therapeutic candidate for Alzheimers disease (AD). MW151 targets a particularform of dysregulated inflammation injurious proinflammatory cytokine overproduction in the brain that is a keycontributor to synaptic dysfunction neurodegeneration and cognitive decline in diverse neurodegenerativediseases. Thus this project is advancing clinical development of a promising drug candidate that could havedisease-modifying effects not only in AD but also in a number of other CNS disorders where proinflammatorycytokine dysregulation is part of the pathophysiology progression mechanism. Because of the urgent need todevelop disease-modifying therapeutic strategies for AD it is critical to complete the phase 1 safety trials andcontinue to move MW151 forward in development. This administrative supplement is requested because of twomajor unforeseen circumstances. First the conduct of the phase 1a clinical trial was substantially delayedbecause of COVID-19 restrictions on human studies imposed in March 2020 at the Duke clinical site. Thisdelay has resulted in the necessity for additional drug storage time and longer-term stability testing that werenot planned for. Second the FDA has recently issued a new guidance document in September 2020 related tocontrol of nitrosamine impurities in drugs that we need to address in the MW151 development program.Therefore we will pursue two specific aims in the supplement.Aim 1: Management of MW151 drug substance and drug product. We will maintain MW151 drugsubstance and reference standard storage perform additional re-tests and do QC and stability tests on thedrug substance and the drug product over a longer time frame than originally planned. The plasma samples forMW151 PK measurements will also be stored for longer than anticipated before analysis so we will need toadd two additional stability time points to the validated bioanalytical method.Aim 2: Nitrosamine assessment. Because of the increasing number of approved drugs that have beenrecalled or put on clinical hold by the FDA because of nitrosamine contamination the FDA recently issued aguidance document for immediate implementation. Therefore MW151 API will be subjected to a nitrosaminerisk assessment. Depending on the level of risk determined the presence or absence of nitrosamine(s) will bemeasured with a validated high resolution high sensitivity LC-mass spectrometry method. If a nitrosaminecontaminant is present at levels above the FDA-recommended Acceptable Intake Limits then future studieswill develop strategies for changes in the manufacturing process to reduce or prevent nitrosamine impuritiesbefore MW151 is brought into phase 2 clinical trials.

project_terms:
Address;Administrative Supplement;Adult;Alzheimer's Disease;Alzheimer's disease therapy;Animals;Applications Grants;Attenuated;Award;Bioavailable;Biological Sciences;Brain;COVID-19;COVID-19 pandemic;Carcinogens;Central Nervous System Diseases;Clinical;Clinical Research;Clinical Trials;Coenzyme A;Communication;Complex;Consumption;Development;Disease;Drug Kinetics;Drug Storage;Due Process;Functional disorder;Funding;Future;Government Agencies;Grant;Human;Impaired cognition;Inflammation;Intake;Lead;Length;Life;Liquid Chromatography;Mass Spectrum Analysis;Measurement;Measures;Methods;Nerve Degeneration;Neurodegenerative Disorders;Nitrosamines;Oral;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Phase I Clinical Trials;Phase II Clinical Trials;Phase Ia Clinical Trial;Placebos;Plasma;Probability;Process;Program Development;Public Health;Reference Standards;Reporting;Resolution;Risk;Risk Assessment;Safety;Sampling;Suspensions;Synapses;Testing;Therapeutic;Time;Update;analytical method;base;capsule;clinical development;clinical research site;cost;cytokine;dose information;drug candidate;first-in-human;genotoxicity;manufacturing process;novel;pandemic disease;phase I trial;prevent;response;small molecule;small molecule therapeutics;stability testing;success;therapeutic candidate;volunteer

public_health_relevance:
NARRATIVESuccess in the proposed supplement activities will allow us to complete the first-in-human phase 1 clinical trialin healthy adult volunteers and provide safety and dosing information required to progress to the next stage ofdevelopment for MW151. MW151 is a promising brain-penetrant small molecule drug candidate that targetsdysregulated inflammation in the brain and has the potential to be a first-in-class disease modifying therapy forAlzheimer's disease.


application_id: 10307577
project_number: 5R01HL135158-05
project_title: Effect of early life stress on obesity-induced hypertension in mice
administering_ic: NHLBI
award_notice_date: 2021-11-20
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 135158
program_official: MCDONALD, CHERYL
project_start_date: 2017-12-01
project_end_date: 2023-11-30
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 10353675
contact_pi: LORIA, ANALIA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTObesity promotes hypertension a major risk factor for cardiovascular disease. Epidemiological studies havelinked early life stress as a modifiable risk factor for increased body mass index and blood pressure. Using anadvantageous mouse model of early life stress that combines postnatal maternal separation and earlyweaning (MSEW) with a high fat diet we have identified two potential adipose tissue-derived targetsimplicated in the pathways by which these mice display exacerbated obesity-induced hypertension.Experimental studies have demonstrated that adipose afferent reflex (AAR) is enhanced in diet-inducedobesity models. Specifically the acute stimulation of adipose tissue afferent nerve fibers (e.g. capsaicin leptin)elevates blood pressure renal nerve activity and plasma catecholamines. Adipose tissue also expressescomponents of the renin-angiotensin system (RAS). Notably it has been shown that adipose tissue-specificabrogation of the sole RAS precursor angiotensinogen (AGT) effectively prevents high fat diet-inducedincreases in blood pressure. Our preliminary findings support for the novel central hypothesis postnatalMSEW aggravates obesity-induced HT in adult life by stimulating AAR reflex-mediated sympatheticactivation and adipose tissue-derived AGT secretion. We will test key predictions in two multilevel specificaims: (1) To test the hypothesis that MSEW heightens obesity-induced hypertension by stimulating adiposetissue excitatory signals to increase AAR reflex. We will assess the effects of MSEW on AAR reflex in acuteand chronic in vivo experiments using a novel state of the art technique in order to determine the adiposetissue-brain axis effects on blood pressure; and (2) To test the hypothesis that MSEW exacerbates obesity-induced hypertension by increasing AGT secretion in adipose tissue. We will generate an adipose tissue-specific tamoxifen-inducible AGT knockout mouse expose the mice to MSEW and wean them on a high fatdiet. The AGT deletion will be induced at three time points from early postnatal life to adulthood in order toassess its effects on programming progression and reversion of hypertension. The outcomes of these studiesmay provide novel early life stress-programmed adipose tissue targets with impact on blood pressure control.

project_terms:
Acute;Adipose tissue;Adult;Affect;Afferent Neurons;American;Angiotensin II;Angiotensinogen;Autonomic ganglion;Baroreflex;Biological Assay;Birth;Blood Pressure;Body mass index;Capsaicin;Cardiovascular Diseases;Catecholamines;Child;Chronic;Dose;Exposure to;Feedback;Female;Gene Expression;Generations;Glomerular Filtration Rate;Glucocorticoids;Health;High Fat Diet;Homeostasis;Hormones;Hypertension;Hypothalamic structure;Immediate-Early Genes;Kidney;Knockout Mice;Leptin;Life;Link;Longevity;Mediating;Mediator of activation protein;Metabolic;Microinjections;Modeling;Morbidity - disease rate;Mus;Myocardial Ischemia;Nerve;Nerve Fibers;Neuraxis;Neurons;Nociceptors;Norepinephrine;Obesity;Organ;Outcome Study;Pathway interactions;Personal Satisfaction;Plasma;Procedures;Reflex action;Renal Hypertension;Renin-Angiotensin System;Resiniferatoxin;Risk Factors;Role;Scheme;Sensory;Signal Transduction;Source;Stimulus;Sympathetic Nervous System;Tamoxifen;Techniques;Testing;Therapeutic Intervention;Time;Tissues;Visceral;Weaning;abuse neglect;afferent nerve;analog;base;blood pressure control;blood pressure elevation;blood pressure reduction;blood pressure regulation;brain tissue;cardiovascular risk factor;chromatin immunoprecipitation;comorbidity;diet-induced obesity;early life stress;epidemiologic data;epidemiology study;experimental study;hypertension prevention;in vivo;indexing;kidney dysfunction;leptin receptor;male;maternal obesity;maternal separation;modifiable risk;molecular marker;mortality;mouse model;neglect;neonate;neurotransmission;next generation;novel;paraventricular nucleus;postnatal;prevent;promoter;response;somatosensory;stressor;urinary

public_health_relevance:
PROJECT NARRATIVEEarly life stress (ELS) has been established as an independent risk factor for cardiovascular disease bypromoting adiposity and high blood pressure; however the causative mechanisms remain unknown. We willuse an advantageous paradigm involving postnatal maternal separation and early weaning (MSEW) a modelof ELS to decipher the role of adipose tissue-brain axis on heightening obesity-induced hypertension. Theoutcomes of these studies may provide novel early life stress-programmed adipose tissue targets with impacton blood pressure control.


application_id: 10307569
project_number: 5R01ES030380-03
project_title: Radon on the RADAR
administering_ic: NIEHS
award_notice_date: 2021-11-19
opportunity_number: PA-18-260
application_type: 5
activity_code: R01
ic: ES
serial_number: 030380
program_official: O'FALLON, LIAM
project_start_date: 2020-02-20
project_end_date: 2024-11-30
study_section: Community Influences on Health Behavior Study Section[CIHB]
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN J
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Kentucky's high radon potential and high smoking rates create the perfect storm for theoverrepresentation of lung cancer cases. Our transdisciplinary community-academic team-led projectRadon on the RADAR (Residents Acting to Detect and Alleviate Radon) will address community concernsabout lung cancer by identifying geological and atmospheric conditions that increase radon intrusion intohomes translating this knowledge into greater residential awareness of risk enabling home radon testingand report back and growing access to affordable and adequate radon mitigation. We will team geologistswith citizen scientists to determine how new radon detection technology (i.e. Airthings) compares totraditional charcoal kits and outdoor soil radon measurements over a range of atmospheric and geologicalconditions to close a critical knowledge gap in our understanding of radon risk. The study will buildcapacity in environmental health by: (a) training citizens in rigorous data collection and interpretation offindings; (b) engaging these citizen scientists in creating and promoting library loan programs to increaseradon testing; and (c) creating sustainable environmental health action plans to alleviate radon exposurein rural communities. Our overall hypothesis is that by increasing knowledge on how geological andatmospheric conditions can impact radon partnering with citizen scientists to use new radon detectiontechnology and translate the data and by growing access to low-cost radon mitigation we will reduceradon risk. Aim 1 will use a citizen science approach to identify and train 60 community residents in fourKY counties to test for radon and evaluate change in environmental health literacy (EHL) and self-efficacy.Aim 2 will compare indoor home radon values and soil radon values over time controlling for atmosphericconditions seasonality geology topography and smoking in the home. Aim 3 will create and evaluate apilot radon detector library loan program with 400 homeowners in the four counties. Aim 4 will launch theradon detector loan program and examine changes in home testing and accessing geologically basedradon potential maps. Aim 5 will examine the impact of citizen scientist-led radon coalitions on reacheffectiveness adoption implementation maintenance and environmental health literacy. The RADARstudy challenges and expands the current environmental health science paradigm by collaborating withgeologists and integrating their scientific approach. We will impact community concerns about high lungcancer rates by: 1) transforming radon detection and report back using geoscience and new radon gasdetection technology; 2) developing a library-lending approach to increase radon testing; and 3) supportingenvironmental action by creating and sustaining citizen science-led radon coalitions that share newknowledge and engage health advocates radon mitigation professionals policymakers builders anddevelopers to promote improved radon management in rural Kentucky.

project_terms:
Address;Advocate;Awareness;Back;Charcoal;Collaborations;Communities;County;Data;Data Analyses;Data Collection;Detection;Diagnostic Reagent Kits;Disease;Environmental Health;Environmental Risk Factor;Equipment;Feedback;Gases;Geological Survey;Geology;Geoscience;Health;Home;Information Dissemination;Kentucky;Knowledge;Libraries;Low income;Malignant neoplasm of lung;Maps;Marketing;Measurement;Monitor;Outcome;Precipitation;Procedures;Property;Provider;Radar;Radon;Reach Effectiveness Adoption Implementation and Maintenance;Reporting;Risk;Rural;Rural Community;Sampling;Self Efficacy;Smoking;Soil;Technology;Temperature;Testing;Time;Tobacco smoke;Training;Translating;atmospheric conditions;base;cancer risk;citizen science;cost;design;detector;digital;environmental tobacco smoke exposure;health literacy;home test;improved;information seeking behavior;interest;member;novel;programs;testing access;time use;usability;web site

public_health_relevance:
PROJECT NARRATIVEThe public is concerned about the high rates of lung cancer from environmental exposure to tobacco smokeand radon. We will identify geological and atmospheric conditions that increase radon intrusion into homestranslate this knowledge into increased residential awareness of lung cancer risk facilitate home radon testingand report back and increase access to affordable and adequate radon mitigation. By bringing residents andtraditional (e.g. public libraries) and non-traditional (e.g. low interest loan providers) organizations to the tableto reduce radon exposure the way communities address environmental health issues will be transformed.


application_id: 10307532
project_number: 5R01CA221867-05
project_title: Nucleus Accumbens-Associated Protein-1 in Melanoma Immunotherapy
administering_ic: NCI
award_notice_date: 2021-11-03
opportunity_number: PAR-16-228
application_type: 5
activity_code: R01
ic: CA
serial_number: 221867
program_official: KUO, LILLIAN S
project_start_date: 2018-07-03
project_end_date: 2023-11-30
study_section: Special Emphasis Panel[ZRG1-OTC-Y(55)R]
contact_pi_person_id: 7598539
contact_pi: YANG, JIN-MING
other_pis: SONG, JIANXUN JIM
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTAs melanoma mostly expresses tumor-specific neo-antigens (Ags) immunotherapy such as adoptive celltransfer-based therapy (ACT) is considered a promising treatment option for this notoriously deadly disease.Nevertheless due to various factors that may weaken therapeutic immunity the clinical outcomes and benefitsof this remedy remain less satisfactory. Importantly accumulating evidence suggests that the metabolic statusof both immune cells and tumor cells has a significant impact on the potency of ACT and that metabolicreprogramming may represent a viable target for reinforcing immunotherapy. Nucleus accumbens-associatedprotein-1 (NAC1) is a transcription co-regulator belonging to the BTB/POZ gene family and is highly expressedin several types of cancer including melanoma. Published studies including our own have shown that NAC1not only bestows oncogenic potential but also undermines therapeutic outcomes through its transcription-dependent or -independent functions. More recently we discovered that NAC1 can promote glycolysis throughits interaction with HIF-1a and is critically required for development survival and function of T cells as well astumor cells. We also found that NAC1 negatively affects the tumoral expression of major histocompatibilitycomplexes (MHCs); the alteration of NAC1 gene expression occurs during differentiation of the pluripotentstem cell (PSC)-derived T cells and this alteration is accompanied by changes in the expressions of a numberof other genes. Based on these intriguing findings we hypothesize that NAC1-mediated metabolicreprogramming suppresses anti-tumor immunity; targeting NAC1 would hasten death or reduce resilience ofboth tumor and suppressor immune cells and modulate the expression of tumor Ags checkpoint moleculesand the related proteins thereby relieving immune-suppression and reinforcing the efficacy of ACT againstmelanoma. To test these hypotheses the current multiple PI application proposes the following highlyinteractive specific aims: (1) To determine the novel role of NAC1 in T cells; (2) To determine the role oftumoral NAC1 in melanoma immune escape; and (3) To determine the impact of targeting NAC1 in ACTagainst melanoma. This multiple PI project combines the Yang laboratorys strength in cancer biology with theSong laboratorys expertise in tumor immunology. We have already established the mouse and human PSC-derived antigen-specific CD8+ T lymphocytes and the murine syngeneic and humanized (NOD-scid IL2rgnull)mouse melanoma models for the proposed studies and are well poised to accomplish the above aims.Completion of this project will not only uncover NAC1 as a unique molecular determinant of tumor-specificimmune responses and shed new light on the importance of NAC1 in cancer pathobiology but also providenovel therapeutic opportunities to enhance ACT against melanoma through the NAC1-targeted strategy.

project_terms:
Adoptive Cell Transfers;Affect;Antigens;Apoptosis;Autophagocytosis;Biological Models;CD8-Positive T-Lymphocytes;CTLA4 gene;Cancer Biology;Cells;Cessation of life;Clinical;Cytotoxic T-Lymphocytes;Development;Disease;Eragrostis;FASN gene;Fibrinogen;Gene Expression;Gene Family;Genes;Genetic Transcription;Glycolysis;Goals;Immune;Immune checkpoint inhibitor;Immune response;Immunity;Immunology;Immunosuppression;Immunosuppressive Agents;Immunotherapy;In Vitro;Laboratories;Light;Literature;Major Histocompatibility Complex;Malignant Neoplasms;Mediating;Melanoma Cell;Memory;Metabolic;Metabolism;Metastatic Melanoma;Modeling;Molecular;Mus;Myeloid-derived suppressor cells;Neoplasms;Nucleus Accumbens;Oncogenic;Outcome;Patients;Physiological;Play;Pluripotent Stem Cells;Proteins;Publishing;Refractory;Regulation;Regulatory T-Lymphocyte;Role;Skin Cancer;Small Interfering RNA;T memory cell;T-Cell Development;T-Lymphocyte;Testing;Therapeutic;Tumor Antigens;Tumor Immunity;Tumor Suppressor Proteins;Tumor-associated macrophages;Tumor-infiltrating immune cells;Yang;base;cancer recurrence;cancer type;cytokine;cytotoxic CD8 T cells;design;effector T cell;gene product;human pluripotent stem cell;immunogenicity;improved;improved outcome;in vivo Model;innovation;melanoma;nanoliposome;negative affect;neoantigens;neoplastic cell;novel;novel strategies;novel therapeutics;nutrition;programmed cell death ligand 1;programmed cell death protein 1;resilience;response;therapy outcome;tumor;tumor immunology;tumor microenvironment;tumor-immune system interactions

public_health_relevance:
PROJECT NARRATIVEMelanoma one of the most aggressive and fatal neoplasms is responsible for over 80% of skincancer-related deaths. By determining the role and importance of NAC1 a cancer recurrence-associated gene product and a transcription co-regulator in regulating antitumor immunity we proposeto design and develop a novel and effective strategy to reinforce immunotherapy for patients with thisdevastating disease. Thus this proposal is immediately relevant to Cancer Moonshot and mayultimately have a large impact in improving melanoma treatment.


application_id: 10307413
project_number: 7R01AG068331-02
administering_ic: NIA
award_notice_date: 2021-04-21
opportunity_number: PA-18-590
application_type: 7
activity_code: R01
ic: AG
serial_number: 068331
program_official: YAO, ALISON Q
project_start_date: 2020-09-15
project_end_date: 2025-05-31
study_section: Molecular Neurogenetics Study Section[MNG]
contact_pi_person_id: 9202423
contact_pi: EBBERT, MARK T W
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-06-01
project_title:
Using long-range technologies as a multi-omic approach to understand Alzheimers disease in brain tissue

project_abstract:
PROJECT SUMMARY/ABSTRACTOur long-term goal is to help develop a meaningful therapeutic and pre-symptomatic diagnosticfor Alzheimers disease because while a disease-altering therapeutic is essential it will not besufficient without a diagnostic that identifies disease before symptoms onset. We seek tocontribute to these long-term goals by helping identify specific molecular modifications andtherefore specific mechanisms driving disease using long-range optical DNA mapping andsequencing technologies. Unfortunately most Alzheimers disease genes are only implicatedthrough common non-functional variants and it is still unclear how most Alzheimers diseasegenes are involved in disease. Likewise individual RNA isoforms in diseased brains for topAlzheimers disease genes and their involvement in disease are poorly understood. Functionalvariants and RNA sequencing at the isoform level in diseased brain tissue will provide specificmechanisms to target for therapeutics and diagnostics. Large short-read sequencing efforts arealready ongoing to identify small functional variants involved in Alzheimers disease but structuralDNA variantsmany of which directly affect downstream RNA and proteinsalso causeneurodegenerative diseases. We hypothesize that undiscovered SVs and aberrant RNA isoformsplay a direct role in Alzheimers disease. A thorough study in diseased brain using long-rangeDNA and RNA technologies will complement current short-read efforts providing importantdisease insights.

project_terms:
Affect;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease diagnostic;Alzheimer's disease risk;Automobile Driving;Biology;Brain;Brain Diseases;Clinic;Complement;Complex;DNA;DNA Structure;DNA mapping;DNA sequencing;Data;Data Set;Detection;Development;Diagnostic;Disease;Genes;Goals;Grant;Individual;Intervention;Methods;Modification;Molecular;Mutation;Nerve Degeneration;Neurodegenerative Disorders;Nucleotides;Optics;Phenotype;Play;Prognosis;Protein Isoforms;Proteins;RNA;RNA Splicing;Research Personnel;Role;Sampling;Symptoms;Technology;The Sun;Therapeutic;Validation;Variant;Work;advanced disease;brain health;brain tissue;cohort;design;differential expression;disease diagnosis;frontal lobe;gain of function;genome-wide;insight;mind control;multiple omics;programs;targeted treatment;transcriptome sequencing

public_health_relevance:
PROJECT NARRATIVEOur overarching scientific premise is that Alzheimers disease interventions and pre-symptomatic disease diagnostics remain elusive in part because we still do not understandexactly how top genes are driving disease. Our group seeks to help develop a pre-symptomaticdisease diagnostic and a meaningful therapy by identifying specific molecular modifications andtherefore specific mechanisms driving disease using long-range optical DNA mapping andsequencing technologies.


application_id: 10307112
project_number: 5R01NS103785-04
project_title: Cell-Specific Actions of IL-1 / IL-1R1 Signaling Following Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2021-12-14
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: NS
serial_number: 103785
program_official: AWWAD, HIBAH OMAR
project_start_date: 2018-12-15
project_end_date: 2023-11-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
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:
ABSTRACT Management of neuroinflammation is a promising target for improving patient outcomes following atraumatic brain injury (TBI) and substantial evidence suggests therapies targeting the interleukin-1 receptor(IL-1R1) pathway may control neuroinflammation. Despite the promise there have been limited attempts tomove anti-interleukin-1 (IL-1) drugs forward for TBI neuroprotection. We hold that a critical reason for the lackof progress on this promising target is the incomplete understanding of the mechanistic underpinnings of IL-1signaling after a TBI. It is well-recognized that the clinical picture of TBI is a spectrum of different primary injurymechanisms and injury severities and that it is necessary to understand the secondary injury mechanism asthey relate to the primary injury. Over 75% of TBIs are classified as mild. While not all TBIs lead toneurodegeneration a mild TBI can result in progressive brain atrophy and persistent cognitive dysfunction andis a known risk factor for the development of Alzheimers disease and related dementias. The currentknowledge of IL-1 / IL-1R1 signaling after a TBI is almost exclusively following a moderate-to-severe injury.Using our novel genetic mouse models that allow for cell-type regulation of IL-1R1 signaling and our model ofmild TBI caused by a closed head injury (CHI) we will address this fundamental gap in our knowledge bytesting the role of IL-1R1 following a mild TBI and for the first time define a cellular mechanism for thepathological effects of IL-1R1 following a mild TBI. Importantly our exciting preliminary data has uncovered acritical role for the brain endothelium in regulating neuroinflammation which is dependent on IL-1R1. Ourpreliminary results have led us to propose the overall hypothesis: Secondary neuronal injury following amild TBI is driven by neuroinflammation and vascular dysfunction which can be reduced throughsuppression of IL-1R1. The actions of IL-1R1 following a mild TBI will require the involvement ofendothelial cells. We will test our hypothesis in the following aims: Aim 1: Assess the role of endothelial IL-1R1 signaling in the neuroinflammatory feedforward loop. Aim 2: Define the role of endothelial IL-1R1 signaling in the vascular response to a CHI. Aim 3: Delineate the role of endothelial IL-1R1 signaling on synaptic plasticity and spatial learning and memory following a CHI. Successful completion of these studies will increase our understanding of the role of IL-1R1 after a mildTBI and define the role of the brain endothelium in the neuroinflammatory response to a mild TBI. Our resultswill fill a critical knowledge gap concerning how best to target neuroinflammation to achieve neuroprotectionafter a mild TBI and potential for other disease associated with neuroinflammation (i.e. Alzheimers disease).

project_terms:
Acute;Address;Alzheimer's Disease;Alzheimer's disease related dementia;Attenuated;Blood Vessels;Brain;Cells;Central Nervous System Diseases;Chronic;Clinical;Closed head injuries;Data;Development;Disease;Electrophysiology (science);Endothelial Cells;Endothelium;Extravasation;FDA approved;Failure;Functional disorder;Generations;Genetic;Goals;Immunomodulators;Immunosuppressive Agents;Impaired cognition;Impairment;Inflammation;Inflammatory;Injury;Interleukin Suppression;Interleukin-1;Interleukin-1 Receptors;Knockout Mice;Knowledge;Lead;Learning;LoxP-flanked allele;Memory;Modeling;Molecular;Mus;Nature;Nerve Degeneration;Neurodegenerative Disorders;Neuronal Injury;Outcome;Pathologic;Pathway interactions;Patient-Focused Outcomes;Pharmaceutical Preparations;Public Health;Radial;Receptor Signaling;Regulation;Residual state;Risk Factors;Role;Severities;Signal Transduction;Synapses;Synaptic plasticity;Testing;Time;Traumatic Brain Injury;Vascular Diseases;Vascular remodeling;Vertebral column;arm;blood-brain barrier permeabilization;brain endothelial cell;cell type;central nervous system injury;cerebral atrophy;density;improved;mild traumatic brain injury;mouse model;neuroinflammation;neuroprotection;novel;response;restoration;severe injury;targeted treatment;water maze

public_health_relevance:
PROJECT NARRATIVEEmerging evidence suggests that selective modulation of neuroinflammation is a promising avenue forimproving patient outcomes following a traumatic brain injury (TBI). We have recently demonstrated thatinterleukin-1 receptor (IL-1R1) pathway may control neuroinflammation at the level of the blood vesselproviding evidence of an underappreciated mechanism of how the brain becomes inflamed after a TBI. In thisproject we propose to determine the role of endothelial IL-1R1 after experimental mild TBI with the goal ofproviding the knowledge necessary to enable the development of selective modulators of neuroinflammationfor TBI.


application_id: 10307016
project_number: 3R01AG019223-14S1
project_title: Neutral sphingomyelinase-2 and glucocorticoid receptor
administering_ic: NIA
award_notice_date: 2021-03-09
opportunity_number: PA-20-222
application_type: 3
activity_code: R01
ic: AG
serial_number: 019223
suffix: S1
program_official: OROSZ, ANDRAS
project_start_date: 2002-08-01
project_end_date: 2023-05-31
contact_pi_person_id: 6730250
contact_pi: NIKOLOVA-KARAKASHIAN, MARIANA N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract from Prime AwardSome of the leading causes of death among the elderly are a number of chronic conditions associated withpersistent low-grade inflammation in which IL-1 has a central role. One of the paths by which low-gradeinflammation contributes to aging-associated diseases is by interfering with the ability of the host to maintainhomeostasis. The experiments from the previous funding period provided evidence for a novel pathway bywhich inflammation may deteriorate a major regulatory mechanism. Specifically we found that IL-1 increasesthe levels of glucocorticoid receptor an effect especially potent in aged animals leading to an augmentedresponse to glucocorticoids. This proposal investigates the mechanisms and impact of IL-1 control ofglucocorticoid -dependent functions in the elderly. The proposed studies will do that in the context of fatty livera condition of paramount health importance for public health which is frequent in the elderly and in somecases may progress to non-alcoholic fatty liver disease. In aim 1 a series of in vitro studies will identify themechanisms for IL-1-induced increases in GR levels and delineate some of the functional consequences inhepatocytes. A candidate approach paralleled by an unbiased genome wide analyses using ChipSeq andmRNA arrays will determine the degree of IL-1 impact on GR-dependent transcriptional regulation of geneexpression in the liver. Specific aim 2 is dedicated to investigating the impact IL-1 has on GR responses invivo using a diet-induced mouse model of steatosis and metabolic syndrome. The magnitude of IL-1 responsein hepatocytes will be modulated in vivo or in vitro by targeting a key component of its signaling cascadenSMase2. The consequences on lipogenesis gluconeogenesis and insulin sensitivity will be main readouts.Glucocorticoid hypersensitivity underlies many aging-associated disease. The chronic used of glucocorticoidsfor the treatment of inflammation is associated with significant side effects particularly in the elderly. Thereforeby uncovering the mechanisms that regulate glucocorticoid response in the liver during aging the proposedstudies have the potential to discover both basic mechanisms of aging as well as novel approaches tomanage unwanted side effects of chronic use of glucocorticoids.

project_terms:
Affinity;Aging;Agonist;Alzheimer's Disease;Animals;Award;Cause of Death;Cell Aging;Cell physiology;Cells;Ceramides;ChIP-seq;Chronic;Clinical;Complex;Diet;Disease;Dose;Drug Prescriptions;Elderly;Enzymes;FOXO1A gene;Fatty Liver;Funding;Gene Delivery;Gene Expression Regulation;Genes;Genetic;Glucocorticoid Receptor;Glucocorticoids;Gluconeogenesis;Goals;Grant;Health;Hepatic;Hepatocyte;Histologic;Homeostasis;Hypersensitivity;IGFBP1 gene;IRAK1 gene;In Vitro;Incidence;Infection;Inflammation;Inflammation Mediators;Inflammatory;Insulin Signaling Pathway;Interleukin-1 beta;Lead;Link;Liver;MAPK8 gene;Medical;Messenger RNA;Metabolic syndrome;Minor;Morbidity - disease rate;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Organ;Organism;Oxidation-Reduction;Pain;Pathway interactions;Pattern;Pharmacology;Phosphorylation;Play;Population;Process;Progress Reports;Protein Phosphatase 2A Regulatory Subunit PR53;Public Health;Rattus;Receptor Signaling;Regulation;Research;Role;Series;Signal Transduction;Sphingomyelinase;Stress;Testing;Transcriptional Regulation;Trauma;Ubiquitination;Work;adenoviral-mediated;aged;experimental study;genome-wide;genome-wide analysis;in vivo;in vivo evaluation;insulin sensitivity;lipid biosynthesis;mouse model;non-alcoholic fatty liver disease;novel;novel strategies;response;senescence;side effect;stressor;transcription factor;transcriptome sequencing

public_health_relevance:
Project Narrative from Prime AwardSome of the leading causes of death among the elderly are a number of chronic conditions associated withpersistent low-grade inflammation. Uncovering new aging-specific factors that influence the onset ofinflammation is of uttermost significance for the over health and medical treatment of the elderly. The proposedstudies are concentrated on steatosis the hepatic manifestation of metabolic syndrome which is a commondisease of the aged.


application_id: 10306968
project_number: 1R01CA264652-01
project_title: Plk1 as a prognostic biomarker for prostate cancer
administering_ic: NCI
award_notice_date: 2021-06-24
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: CA
serial_number: 264652
program_official: JOHNSON, RONALD L
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_terms:
Affect;Androgen Receptor;Androgens;BRCA mutations;Biochemical;Cancer Patient;Castration;Cell Culture System;Cells;Chromatin;Clinic;Clinical;Clinical Research;Clinical Trials;Complex;DNA Damage;DNA Repair;DNA Repair Gene;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 of activation protein;Meiotic Recombination;Mission;Mitotic;Mus;Mutation;Outcome;PLK1 gene;Patient-Focused Outcomes;Patients;Phosphorylation;Phosphotransferases;Poly(ADP-ribose) Polymerases;Prognostic Marker;Proteins;Public Health;Receptor Signaling;Recovery;Research;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Testing;Therapeutic;Tumor Subtype;Withdrawal;Work;abiraterone;ataxia telangiectasia mutated protein;base;brca gene;cancer cell;castration resistant prostate cancer;clinically relevant;comparative efficacy;cytotoxic;design;efficacy evaluation;genetic approach;improved;inhibitor/antagonist;innovation;mouse model;novel;novel strategies;overexpression;patient population;predictive marker;premature;prostate cancer cell;prostate cancer progression;response;success;tumor


application_id: 10306092
project_number: 1R21AI155824-01A1
project_title: Dissemination of intracellular and extracellular Listeria from the gut
administering_ic: NIAID
award_notice_date: 2021-06-03
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AI
serial_number: 155824
suffix: A1
program_official: BAQAR, SHAHIDA
project_start_date: 2021-06-04
project_end_date: 2023-05-31
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
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
project_abstract:
Foodborne transmission of the facultative intracellular bacterial pathogen Listeria monocytogenes (Lm)results in human disease that ranges in severity from mild gastroenteritis to life-threatening septicemia ormeningoencephalitis. The host and bacterial factors that determine disease severity are not well definedand our understanding of the intestinal phase of listeriosis in particular is severely limited. To address thisknowledge gap we developed a mouse model of foodborne Lm infection that closely mimics all phases ofthe human disease. In preliminary studies we found that the majority of Lm in the gut were extracellularand that Lm was not able to replicate in many of the mononuclear phagocyte subsets present in the intestinallamina propria. This was an unexpected result because intracellular growth and spread from cell-to-cellwithout encountering the extracellular milieu are generally regarded as the primary virulence strategies forLm. The overall hypothesis of this proposal is that foodborne Lm can use one of three distinct pathways todisseminate from the intestinal lamina propria to the mesenteric lymph nodes (MLN): 1) Lm hitch a rideattached to migratory inflammatory Ly6Chi monocytes which they cannot efficiently invade; 2) Lm invadeconventional dendritic cells (cDC) which serve as a Trojan horse to deliver non-replicating but intracellularbacteria to the MLN; and 3) extracellular Lm traffic free-flowing through lymphatic vessels to the subcapsularsinus of the MLN. We propose that these three pathways are likely to be redundant during in vivo infectionbut may be influenced by the route used by Lm to invade the intestinal epithelium. In Aim 1 the role of cell-associated vs. free-flowing extracellular bacteria in promoting dissemination to the MLN that drain either theileum or the colon will be determined. In Aim 2 we will determine how the dissemination pathway used byLm affects the ability of the bacteria to survive and replicate in the MLN and to promote further systemicspread. These exploratory studies will advance the field by defining the mechanisms used by Lm to avoidclearance in the MLN a critical bottleneck to avoid systemic spread of orally acquired pathogens.

project_terms:
Address;Affect;Anatomy;Antibodies;Antibody Therapy;Antigens;Area;Bacteria;Binding;Blood;Body part;Brain;Bypass;CCL21 gene;Cardiovascular system;Cells;Colon;Confocal Microscopy;Cytosol;Data;Death Rate;Dendritic Cells;Disease;Disease Outbreaks;E-Cadherin;Elderly;Enterocytes;Epithelial;Epithelial Cells;Equus caballus;Feces;Food;Food Contamination;Food Supply;Foundations;Gastroenteritis;Gastrointestinal tract structure;Goals;Growth;Gut Mucosa;Hospitalization;Human;Immune;Immune system;In Vitro;Incidence;Individual;Infection;Inflammatory;Ingestion;Intestines;Intravenous;Invaded;Knowledge;Lamina Propria;Lead;Life;Listeria;Listeria monocytogenes;Listeriosis;Lymph Node Subcapsular Sinus;M cell;Macrophage Colony-Stimulating Factor;Mediating;Membrane Proteins;Meningoencephalitis;Microscopic;Minor;Modeling;Mononuclear;Oral;Output;PTPRC gene;Pathway interactions;Phagocytes;Phase;Process;Resistance;Role;Route;Sepsis;Septicemia;Severities;Severity of illness;Small Intestines;Symptoms;Systemic infection;T-Lymphocyte;Therapeutic Intervention;Time;Vascular Endothelial Growth Factor Receptor-3;Virulence;Work;adaptive immunity;base;cell type;draining lymph node;enteric infection;experience;extracellular;foodborne;foodborne infection;human disease;ileum;in vivo;intestinal epithelium;lymphatic vessel;macrophage;mesenteric lymph node;migration;monocyte;mortality;mouse model;mutant;neonate;pathogen;pathogenic bacteria;podoplanin;prevent;transmission process;uptake

public_health_relevance:
Ingestion of food that is contaminated with the bacterium Listeria monocytogenes causes a wide spectrumof disease in humans ranging from mild gastroenteritis to life-threatening infections of the blood and brain.The goal of this proposal is to understand how the bacteria are able to spread from the gastrointestinal tractto other parts of the body. A better understanding of this process could lead to new strategies to prevent themore severe systemic forms of the infection which can have a 25-30% death rate in susceptible individualssuch as neonates and the elderly.


application_id: 10305413
project_number: 1R01HG011598-01A1
project_title: Utility of Genomic Sequencing in Community Care Contexts
administering_ic: NHGRI
award_notice_date: 2021-09-22
opportunity_number: PAR-20-254
application_type: 1
activity_code: R01
ic: HG
serial_number: 011598
suffix: A1
program_official: STERLING, RENE
project_start_date: 2021-09-22
project_end_date: 2025-06-30
study_section: Special Emphasis Panel[ZRG1 SEIR-S (80)]
contact_pi_person_id: 10692185
contact_pi: BROTHERS, KYLE BERTRAM
other_pis: COOPER, GREGORY MICHAEL
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Address;Advisory Committees;Area;Behavior;Behavior Therapy;Caregivers;Caring;Child;Child Care;Childhood;Clinical;Communities;Complex;Diagnosis;Dimensions;Disease;Evaluation;Face;Family;Focus Groups;Future;Genetic;Genetic Diseases;Genomics;Health;Health Personnel;Healthcare;Impairment;Intervention;Interview;Language;Measures;Medical;Mental Health;Musculoskeletal;National Human Genome Research Institute;Occupational Therapist;Occupational Therapy;Operative Surgical Procedures;Parents;Pathologist;Pharmacology;Physical therapy;Preventive service;Professional Practice;Psyche structure;Quality of life;Research;Resources;Schools;Sensory;Services;Shapes;Site;Source;Special Education;Speech;Speech Therapy;Speech-Language Pathology;Structure;Support Groups;Technology;Testing;Therapeutic;Translating;Underserved Population;base;care systems;clinical application;clinical care;clinical diagnostics;clinical research site;cohort;community based service;community setting;exome sequencing;experience;falls;family support;genetic testing;genome sequencing;improved functioning;physical therapist;policy implication;rural underserved;social implication;social media;teacher


application_id: 10304343
project_number: 2RF1NS088555-07A1
project_title: B Cells Directly Alter Adaptive Plasticity to Support Functional Recovery After Stroke
administering_ic: NINDS
award_notice_date: 2021-07-08
opportunity_number: PA-20-185
application_type: 2
activity_code: RF1
ic: NS
serial_number: 088555
suffix: A1
program_official: BOSETTI, FRANCESCA
project_start_date: 2015-02-01
project_end_date: 2024-06-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9562586
contact_pi: STOWE, ANN MARIE
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
The central hypothesis of this R01 renewal focuses on a subset of B cells that provide neurotrophic support to counter cognitive impairment and improve motor function after ischemic stroke a key risk factor for the development of vascular contributions to cognitive impairment and dementia (VCID). These neurotrophic B cells secrete brain-derived neurotrophic factor (BDNF) and may be critical to countering the development of VCID. Unfortunately the patient population most at risk for stroke and VCID aged individuals have impaired B cell development and secretion of growth factors that could limit protection from post-stroke depression and dementia. Sex is also a factor as elderly women with post-stroke dementia have the lowest levels of circulating BDNF though no prior studies have directly linked a loss of neurotrophic immune cell populations and the development of VCID. Based on our pilot data we will test: if a subset of post-stroke B cells (i.e. B cellsBDNF+) upregulate BDNF after encountering glutamate; if B cellsBDNF+ limit the development of VCID and support motor recovery; and if B cell-derived BDNF is impaired in aged females. We will use 4 mos. (young) and 16 mos. (aged) female and male mice to test if B cellsBDNF+ support neuronal function plasticity motor and multi-domain cognitive recovery post-stroke. Aim 1 will test if after stroke (1A) glutamate binds to B cells to increase BDNF production and drive recovery-linked intracellular Ca2+ signaling that is sex- and age-dependent. We will (1B) use B cellsNtrk2tm1Ddg/J in vitro totest if the BDNF receptor TrkB is required for BDNF production and in vitro neuroprotection. Aim 2 will test if B cellsBDNF+ support remote plasticity as well as cognitive and motor recovery in a primary motor cortex (M1) photothrombosis stroke model. Inducible depletion of (2A) all B cells or (2B) specific B cell-derived BDNF in young and aged female hCD20TamCre/ BDNFfl/fl mice and littermate controls will occur either acute (day 0) or delayed (beginning day 7 post-stroke). Primary outcomes will include 1) preservation of Pavlovian stimulus-reinforcer learning on an automated touchscreen task 2) improved forelimb precision reaching and 3) peri-infarct and contralesional M1 plasticity. Aim 3 will test if B cell-derived BDNF augments long-term cognitive and motor recovery. Aged C57BL/6J female mice will receive tMCAo or sham surgery and adoptive transfer of B cells that (3A) overexpress BDNF or (3B) lack BDNF the latter derived from hCD20TamCre/BDNFfl/fl donor mice beginning day 7 post-stroke. Primary outcomes will include 1) ameliorated hippocampal-specific cognitive deficits tested via touchscreen pattern separation 2) improved precision skilled reaching and 3) regional ipsi- and contralesional diapedesis of B cells as determined via whole brain serial two-photon tomography that correlates to within-animal magnitude of brain circuit-specific cognitive function and motor recovery. These studies will confirm an age-dependent loss of a novel subset of B cells B cellsBDNF+ in females that develop VCID. They will also confirm that therapeutically targeting B cells can counter post-stroke dementia and motor deficits a potential treatment supporting plasticity-based recovery after any CNS injury or disease.

project_terms:
Acute;Adult;Affect;Age;Anatomy;Animals;Anxiety;Area;Automobile Driving;Award;B-Cell Development;B-Lymphocyte Subsets;B-Lymphocytes;Binding;Brain;Brain region;Brain-Derived Neurotrophic Factor;Cell Survival;Cell surface;Cells;Central Nervous System Diseases;Cognitive deficits;Data;Dementia;Development;Elderly woman;FDA approved;Female;Forelimb;Genetic Polymorphism;Genetic Transcription;Glutamates;Growth Factor;Health;Hippocampus (Brain);Immune;Immune system;Impaired cognition;Impairment;In Vitro;Individual;Infarction;Interleukin-10;Ischemic Stroke;Learning;Leukocytes;Link;Mediating;Memory;Middle Cerebral Artery Occlusion;Modeling;Motor;Motor Activity;Motor Cortex;Mus;N-Methyl-D-Aspartate Receptors;Neuronal Plasticity;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 2;Pattern;Population;Production;Publishing;Recovery;Recovery of Function;Research;Risk Factors;Role;Signal Transduction;Stimulus;Stroke;Support System;Synaptic Transmission;Tamoxifen;Techniques;Testing;Therapeutic;Up-Regulation;adoptive B cell transfer;age related;aged;base;central nervous system injury;cognitive function;cognitive recovery;dentate gyrus;disability;excitotoxicity;extracellular;functional plasticity;improved;in vitro testing;learning strategy;male;migration;motor deficit;motor function improvement;motor recovery;neuroinflammation;neuronal survival;neuroprotection;neurotrophic factor;novel;overexpression;patient population;post stroke;post stroke dementia;post stroke depression;preservation;primary outcome;reinforcer;response;rituximab;sex;sham surgery;stroke model;stroke recovery;stroke risk;synaptogenesis;therapeutic target;tomography;touchscreen;two-photon;vascular cognitive impairment and dementia


application_id: 10303743
project_number: 1R21AG070659-01A1
administering_ic: NIA
award_notice_date: 2021-08-09
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AG
serial_number: 070659
suffix: A1
program_official: MILLER, MARILYN
project_start_date: 2021-09-01
project_end_date: 2023-05-31
study_section: Biostatistical Methods and Research Design Study Section[BMRD]
contact_pi_person_id: 14549909
contact_pi: ZHENG, QI
other_pis: Not Applicable
congressional_district: 03
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Global significance test based on quantile regression with applications to genomic studies of Alzheimers disease

project_abstract:
Project Summary/AbstractAlzheimer's disease (AD) is one of the leading causes of death for the elderly with no current cure. Genomicsstudies such as mapping expression quantitative trait loci (eQTL) and differential gene expressions play acritical role in understanding the biological mechanisms of AD and developing potential therapeutic treatments.In genomics studies there has been growing awareness that the covariates (e.g. quantitative gene expression)may have changing effects on the distribution of responses (e.g. disease phenotypes) reecting a heterogeneouscovariates-response association. Those heterogeneous associations shed insight on scientic discoveries andentail signicant implications but are often neglected by most existing analysis procedures conned to a narrowaspect of the response distribution (e.g. standard linear regression focusing on the mean or quantile regressionat a single quantile level). Thus the development of valid and efcient hypothesis tests to detect heterogeneousassociations is of great value to genomics studies of complex diseases such as AD. This proposal aims to develop several quantile regression-based global signicance tests which utilize allinformation across a well-chosen region of quantile levels and provide researchers with evaluations of the overallimpacts of covariates on the response. Inspired by our preliminary data analysis on the two studies of aging anddementia namely Religious Orders Study (ROS) and Memory and Aging Project (MAP) we will rst proposea global signicance test to thoroughly evaluate covariates' impact across all quantile levels of the responsevariable (Aim 1). Then motivated by high-dimensional genomics data of AD in ROS/MAP we will further developtwo global signicance tests for high-dimensional responses and covariates data respectively (Aim 2). Moreoverwe will apply the proposed tests in Aims 1-2 to the genomics data generated by ROS/MAP to identify eQTL anddifferentially expressed genes that can be used to prioritize risk genes of AD for identifying developing potentialtreatments (Aim 3). We will also provide a user-friendly R package to implement the proposed tests. The innovation of our proposal is three-fold. (i) By evaluating the impacts of covariates on responses acrossthe entire quantile domain the proposed global signicance tests have a superior power to identify heterogeneouscovariates-response associations compared to alternative methods. (ii) As the proposed tests neither impose anystringent model assumption nor require additional splines smoothing or re-sampling or shrinkage estimation theycan be broadly implemented in large-scale genomics data. (iii) Our proposed test in Aim 2 will serve as a usefultool for detecting heterogeneous associations between covariates and multiple responses. The successful completion of this project will facilitate detecting heterogeneous associations and thesubsequent scientic discoveries in AD genomics studies for developing treatments. Moreover our tests canbe applied to a broad scope of biomedical elds resulting in a fruitful avenue for promoting public health.

project_terms:
Affect;Age-Years;Aging;Alzheimer's Disease;Awareness;Biological;Biomedical Research;Brain Diseases;Cause of Death;Cohort Studies;Complex;Confounding Factors (Epidemiology);Data;Data Analyses;Dementia;Development;Dimensions;Disease;Disease regression;Elderly;Etiology;Evaluation;Foundations;Gene Expression;Gene Expression Profiling;Genes;Genetic Predisposition to Disease;Genomics;Goals;Heritability;Joints;Light;Linear Regressions;Memory;Methods;Modeling;Neurodegenerative Disorders;Pattern;Phenotype;Play;Probability;Procedures;Public Health;Quantitative Trait Loci;Research Personnel;Role;Sampling;Single Nucleotide Polymorphism;Standardization;Testing;Therapeutic;Tissue-Specific Gene Expression;United States;base;biological research;differential expression;disease phenotype;flexibility;follow-up;genome-wide;genomic data;genomic tools;high dimensionality;improved;innovation;insight;multidimensional data;neglect;novel;religious order study;research and development;response;risk variant;statistics;theories;tool;user-friendly

public_health_relevance:
NarrativeThe novel global signicance test methods developed out of this proposal will provide useful statistical toolsfor testing heterogeneous covariates-response associations in broad biomedical researches. Our methods forhandling data with high-dimensional responses and covariates will make our global tests especially useful forgenomic studies of complex diseases that deal with thousands of genes and millions of SNPs. The ndings out ofour application genomic studies about Alzheimer's disease will not only validate our test methods but also curatea list of risk genes that are potentially important for developing therapeutic treatment.


application_id: 10303334
project_number: 1F99CA264165-01
project_title: Aberrant Glycogen Modulates Metabolism in Ewings Sarcoma
administering_ic: NCI
award_notice_date: 2021-08-23
opportunity_number: RFA-CA-20-048
application_type: 1
activity_code: F99
ic: CA
serial_number: 264165
program_official: ELJANNE, MARIAM
project_start_date: 2021-09-01
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZCA1 SRB-H (M1)]
contact_pi_person_id: 16250663
contact_pi: YOUNG, LYNDSAY E A
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Ewing's sarcoma (ES) is the second most common pediatric bone malignancy affecting ~10000 childrenadolescents and young adults worldwide each year. Approximately half of all patients with Ewing's sarcomawill develop either recurrent or metastatic disease with less than 20% of such patients surviving long-term. Thestandard of care for ES patients includes multi-agent chemotherapy to treat documented or potential metastaticdisease coupled with surgery and/or irradiation to treat the primary tumor. Although some incrementaladvances have been made in the last three decades through intensification of conventional chemotherapyagents more significant improvements will likely depend on the identification of novel treatment strategies.Two hallmark clinical features of ES are: 1) the accumulation of intracellular glycogen deposits that arePeriodic acid-Schiff positive (PAS+) during pathological analysis and 2) the EWS-FLI1 fusion oncogene.Contribution of EWS-FLI1 to tumorigenesis and epigenetics is well defined but little is known about the biologyand pathology of ES glycogen accumulation nor has ES glycogen metabolism been explored as an anti-EStarget. The aims presented in this proposal are designed to interrogate the role of glycogen metabolism inpromoting tumorigenesis in ES and extend my career in cancer metabolism. My preliminary data demonstrateglycogen in ES models has aberrant architecture with long chains increased branching pattern and highphosphate content. Thus this glycogen is more similar to pathogenic polyglucosan bodies (i.e. ES-PGBs) anddisrupts normal cellular processes. Excitingly I have demonstrated that targeting ES-PGBs using a glycogensynthase inhibitor reduces in vivo tumor growth. I will expand on these findings in Aim 1 by demonstrating ES-PGBs alter cellular energy homeostasis utilizing high-throughput metabolomics profiling and innovativebiochemical assays in vitro and in vivo. These results will advance our understanding of glycogen metabolismin ES and have broad implications for designing new therapeutic options for ES patients. In Aim 2 I plan toextend my predoctoral training in cellular metabolism of a rare cancer to my postdoctoral training in theemerging field of cancer metabolism's role in epigenetic regulation. I have received excellent training in thefield of glycogen metabolism in cancer and I believe this foundation will help answer key outstanding questionsin the utilization of key metabolites to control gene expression and protein function. Cumulatively this proposalprovides time in both my predoctoral and postdoctoral training to learn skills necessary to achieve my goal ofan independent investigator in cancer metabolism.

project_terms:
5'-AMP-activated protein kinase;Adolescent;Adolescent and Young Adult;Affect;Age;Aggressive behavior;Architecture;Biochemical;Biological;Biology;Bone Tissue;CRISPR/Cas technology;Cell physiology;Cellular Metabolic Process;Child;Childhood;Clinical;Comprehension;Coupled;Cyclic AMP-Dependent Protein Kinases;Cytoplasmic Granules;Data;Deposition;Diagnosis;Disease;EWS-FLI1 fusion protein;Enzymes;Epigenetic Process;Event;Ewings sarcoma;Foundations;Gene Expression;Gene Proteins;Genetic;Glucose;Glycogen;Glycogen (Starch) Synthase;Goals;Histones;Homeostasis;In Vitro;Incidence;Knock-out;Learning Skill;Malignant Childhood Neoplasm;Malignant Neoplasms;Metabolic;Metabolism;Metastatic Ewing's Sarcoma;Modeling;Modification;Nude Mice;Oncogenes;Operative Surgical Procedures;Pathogenicity;Pathologic;Pathology;Patients;Pattern;Periodic acid Schiff stain method;Phosphorylation;Positioning Attribute;Primary Neoplasm;Proliferating;Protein Kinase;Proteins;Recurrence;Research;Research Personnel;Resolution;Role;Sampling;Structure;Survival Rate;Techniques;Therapeutic;Time;Training;Translating;Work;Xenograft Model;base;bone;cancer cell;career;chemotherapy;design;epigenetic regulation;glucose metabolism;glycogen metabolism;histone modification;in vitro Assay;in vivo;inhibitor/antagonist;innovation;inorganic phosphate;insight;irradiation;lipid metabolism;macrophage;metabolomics;multidisciplinary;novel;novel therapeutic intervention;novel therapeutics;personalized medicine;polyglucosan;post-doctoral training;pre-doctoral;protein function;rare cancer;soft tissue;stable isotope;standard of care;therapeutic target;treatment strategy;tumor;tumor growth;tumor metabolism;tumorigenesis

public_health_relevance:
Project Narrative The focus of my work is to determine the role of glycogen in Ewing's sarcoma tumorigenesis andidentify these accumulations as a novel therapeutic intervention. This proposal is built on our pastdiscoveries understanding aberrant glycogen in disease through profiling cell metabolismproliferation and tumorigenesis. Completion of this work will yield a better comprehension betweenglycogen and these events and will allow us to translate our insights into disease mechanismsdiagnoses and treatments.


application_id: 10303293
project_number: 1R21DK127295-01A1
administering_ic: NIDDK
award_notice_date: 2021-06-23
opportunity_number: PAR-19-222
application_type: 1
activity_code: R21
ic: DK
serial_number: 127295
suffix: A1
program_official: SERRANO, KATRINA JANE
project_start_date: 2021-06-23
project_end_date: 2024-05-31
study_section: Special Emphasis Panel[ZRG1 DKUS-H (54)]
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_title:
Hyaluronan as a mediator of intrauterine growth restriction-induced islet dysfunction in type 2 diabetes

project_abstract:
PROJECT SUMMARYType 2 diabetes (T2D) burden rests disproportionately on ethnic minorities and economically distressedAppalachian communities. These populations also have high rates of low birth weight (LBW) which itself is anindependent risk factor for T2D. One major cause of LBW is uteroplacental insufficiency and subsequentintrauterine growth restriction (IUGR). We model uteroplacental insufficiency in late gestation pregnant rats byligating the uterine arteries. The growth-restricted offspring display diminished glucose-stimulated insulinsecretion (GSIS) reduced islet capillary density and decreased -cell proliferation. We recently sequenced theIUGR islet transcriptome at 2 weeks of age revealing increased expression of Hyaluronan Synthase 2 (Has2)which makes the extracellular matrix glycosaminoglycan hyaluronan (HA) and Cd44 the principal HA receptor.HA has size-dependent opposing effects on angiogenesis and inflammation with native high molecular weight(HMW) HA being inhibitory and its enzymatic or oxidative fragmentation to LMW-HA being activating. Previousstudies show increased HA in serum and adipose tissue of humans with T2D and attenuating HA levels or CD44activity improves insulin sensitivity. Studies have yet to quantify islet HA in T2D despite evidence that HA andHA-binding proteins are normal islet components and HA levels are altered in T2D. To determine whether HAcontributes to IUGR-mediated islet dysfunction we will determine HA abundance size and cell type-specificinteractions. There is a paucity of research regarding effects of HA on -cell function. However HA modulatesactin cytoskeleton dynamics via regulation of monomeric G-proteins in a variety of cell types which if occurringin -cells can have profound effects on GSIS. Taken together I hypothesize that HA abundance and sizedistribution are altered in IUGR islets and HA size-specifically modulates GSIS in vitro. The goal ofSpecific Aim 1 is to determine whether IUGR alters abundance size distribution and cell type-specific bindingof HA in islets. The goal of Specific Aim 2 is to determine whether HA size-specifically alters GSIS in vitro viamodulation of monomeric G-proteins and associated actin dynamics. In a move toward an interventionalapproach we will examine whether pharmacological modulation of HA content normalizes GSIS in IUGR isletsex vivo. Successful completion of the proposed studies will fill a key knowledge gap regarding changes in islet-associated HA in T2D and provide strong evidence that HA negatively impacts -cell function. These data willprovide rationale and demonstrate feasibility for my future R01 grant application investigating an etiological rolefor HA in IUGR-mediated T2D.

project_terms:
Accounting;Actins;Address;Adipose tissue;Adult;Affect;Age;Age-Months;American;Animal Model;Appalachian Region;Applications Grants;Arteries;Attenuated;B Cell Proliferation;Beta Cell;Binding;Blood capillaries;CD44 Antigens;CD44 gene;Cell Culture Techniques;Cell physiology;Cells;Clinical Research;Communities;Cytoskeleton;Data;Distress;Endothelial Cells;Enzyme-Linked Immunosorbent Assay;Etiology;Extracellular Matrix;F-Actin;Family;Fetal Growth Retardation;Fetus;Flow Cytometry;Functional disorder;Future;GTP-Binding Proteins;Genes;Glucose;Glycosaminoglycans;Goals;Growth;HAS2 gene;HMMR gene;Human;Hyaluronan;Hyaluronidase;Immunohistochemistry;Impairment;In Vitro;Incidence;Individual;Inflammation;Insulin;Insulin Resistance;Intervention;Islet Cell;Knowledge;Leukocytes;Low Birth Weight Infant;Mediating;Mediator of activation protein;Modeling;Molecular;Molecular Weight;Monomeric GTP-Binding Proteins;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;PTPRC gene;Peripheral;Pharmacology;Population;Potassium;Prediabetes syndrome;Pregnancy;Primary Cell Cultures;Rattus;Regulation;Reporting;Research;Rest;Risk;Risk Factors;Role;Serum;Signal Pathway;Testing;Tissues;Uterus;Vulnerable Populations;angiogenesis;cell type;density;epidemiology study;ethnic minority population;gel electrophoresis;human tissue;improved;insulin secretion;insulin sensitivity;islet;offspring;pregnant;protein activation;response;rho;transcriptome

public_health_relevance:
PROJECT NARRATIVELow birth weight is an independent risk factor for type 2 diabetes in adulthood. Populations that have high ratesof low birth weight are the same populations with disproportionate incidence of type 2 diabetes. Using a well-characterized animal model and cell cultures studies the proposed research shows that fetal growth restrictiondysregulates an extracellular matrix molecular hyaluronan in islets which disrupts insulin secretion.


application_id: 10303283
project_number: 1R03NS120081-01A1
project_title: Method for Detection and Quantification of CLN3 Protein
administering_ic: NINDS
award_notice_date: 2021-06-28
opportunity_number: PA-20-200
application_type: 1
activity_code: R03
ic: NS
serial_number: 120081
suffix: A1
program_official: MORRIS, JILL A
project_start_date: 2021-07-01
project_end_date: 2024-06-30
study_section: Molecular Neurogenetics Study Section[MNG]
contact_pi_person_id: 8688832
contact_pi: WANG, QINGJUN
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project Summary/Abstract CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis or juvenile Batten disease; OMIM #204200) is afatal neurodegenerative disease. This autosomal recessive disease is caused by mutations in a single geneCeroid Lipofuscinosis Neuronal 3 (CLN3). The majority of patients are homozygous for a 1 kb deletion mutationin CLN3. Despite two decades of extensive research on CLN3 disease after discovery of the CLN3 gene thereis still no cure; and even the function of CLN3 protein and etiology and pathogenesis of the disease are still ill-defined. Research on CLN3 disease and development of therapeutics are greatly hindered by lack of a workingantibody for detecting either wild type (WT) or disease-causing mutant CLN3 proteins. For example it is unknownif WT and mutant CLN3 protein levels and subcellular distributions correlate with disease severity; and theeffectiveness of CLN3 gene therapy cannot be fully evaluated without monitoring CLN3 protein levels in patients.Therefore there is a greatly unmet need for detection and quantification of WT and mutant CLN3 proteins. Herewe propose to develop a mass spectrometry-based method to reliably detect WT and mutant CLN3 proteins andquantify their absolute levels. Our preliminary studies provide compelling proof-of-concept evidence that we havebuilt the framework of such a method that is capable of detection and quantification of endogenous WT CLN3protein in human and mouse cell lines as well as mouse brain. In Aim 1 we will further develop this method todetect and quantify WT (1A) and mutant (1B) CLN3 proteins in vitro with applications on human and mouse celllines human primary fibroblasts with and without CLN3 disease and neurons differentiated from both isogeniccontrol and CLN3 mutant human induced pluripotent stem (iPS) cells. In Aim 2 we will expand this method todetect and quantify WT and mutant CLN3 protein in vivo with applications on human and mouse tissues (2A)as well as 1 kb deletion mutant mice (Cln3exon7/8) that undergo AAV9-mediated CLN3 gene therapy (2B).Successful completion of this project will provide an essential tool that removes the bottleneck of CLN3 diseaseresearch and therapeutic development.

project_terms:
Adolescent;Arginine;Biological Assay;Blindness;Brain;C-terminal;CLN3 gene;Calibration;Cell Extracts;Cells;Cessation of life;Child;Childhood;Cognitive;Coupled;Deletion Mutation;Detection;Disease;Drug or chemical Tissue Distribution;Effectiveness;Etiology;Exons;Failure;Fibroblasts;Gene Delivery;Genes;Genetic;Human;In Vitro;Injections;Intrathecal Injections;Kentucky;Label;Letters;Liquid Chromatography;Location;Lysine;Mass Spectrum Analysis;Measures;Mediating;Methods;Mitochondrial Proton-Translocating ATPases;Monitor;Motor;Mouse Cell Line;Mus;Mutant Strains Mice;Mutate;Mutation;Names;Nature;Neurodegenerative Disorders;Neuronal Ceroid-Lipofuscinosis;Neurons;Nonsense-Mediated Decay;Online Mendelian Inheritance In Man;Pathogenesis;Patients;Peptides;Pre-Clinical Model;Proteins;Proteome;Proteomics;Protocols documentation;Research;Rotarod Performance Test;Seizures;Severity of illness;Small Interfering RNA;Specificity;Spielmeyer-Vogt Disease;Stable Isotope Labeling;Study Subject;Time;Tissue Harvesting;Tissues;Treatment Efficacy;Trypsin;United States National Institutes of Health;Universities;Viral;Wild Type Mouse;Work;antibody detection;base;biobank;detection limit;detection method;experience;gene therapy;gene therapy clinical trial;immunoreactivity;in vivo;induced pluripotent stem cell;ionization;juvenile neuronal ceroid lipofuscinosis;knock-down;laboratory cat;mouse model;mutant;neuron development;novel;pre-clinical;premature;research and development;response;tandem mass spectrometry;therapeutic development;tissue processing;tool

public_health_relevance:
Project Narrative CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis or juvenile Batten disease) is a fatalneurodegenerative disease in children without a cure. One major bottleneck in understanding the disease anddeveloping treatments is the lack of a valid and reliable assay to detect and quantify CLN3 protein the soleprotein mutated in CLN3 disease. The current proposal will develop an essential assay to remove this keyroadblock in CLN3 disease research and therapeutic development.


application_id: 10302311
project_number: 5R01CA214638-05
project_title: A redox-mediated mechanism of UVB-induced metabolic switch in skin carcinogenesis
administering_ic: NCI
award_notice_date: 2021-12-02
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 214638
program_official: JOHNSON, RONALD L
project_start_date: 2017-12-18
project_end_date: 2023-12-31
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
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:
More than 1.2 million new cases of non-melanoma skin cancer including squamous cell carcinoma andbasal cell carcinoma are diagnosed annually in the United States and the lifetime risk for skin cancerexceeds the lifetime risk for all other cancers combined. Ultraviolet (UV) radiation is considered as themain cause of non-melanoma skin cancer. The current paradigm for prevention against UVB-inducedskin cancer is application of general antioxidant products which is inadequate because it is based onincomplete understanding of the role of oxidative stress in cancer development. The overall goal of thisresearch is to gain an in-depth understanding of the mechanism by which superoxide radical/anion (O2-) in mitochondria contributes to metabolic switch during UVB carcinogenesis and to test the conceptthat a targeted antioxidant approach can prevent skin cancer. Our preliminary data demonstrate thatthe expression of manganese containing superoxide dismutase (MnSOD) is suppressed inhistologically normal skin at preneoplastic stage which results in increased superoxide production andincreased synthesis of uncoupling proteins (UCPs). Furthermore knockdown of UCPs suppresseslactate production and increases ATP levels. Thus adaptation to increased superoxide production byinduction of UCPs is likely the critical step leading to the Warburg effect. We also have found thatexposure to UVB causes nitration and inactivation of MnSOD and activation of prosurvival autophagyresponses. Co-immunoprecipitation of nitrated MnSOD identified members of the Chaperone-MediatedAutophagy (CMA) pathway which supports the role of CMA in selective degradation of nitrated proteins.Based on these novel findings we propose that O2- is a critical driver of metabolic alteration in UVBcarcinogenesis that promotes cancer development and progression. Specific Aim 1 will test thehypothesis that O2- triggers an uncoupling protein (UCP)-dependent metabolic switch. Specific Aim 2will test the hypothesis that MnSOD is a critically important target of UVB-induced peroxynitrite (OONO-) that leads to activation of autophagy responses. Specific Aim 3 will test the concept that UVB-inducedO2- and OONO- are critical mediators that promote UV carcinogenesis. We will use molecular geneticapproach coupled with proteomics to identify UCP transcriptomes and stable-isotope-resolvedmetabolomics to identify pathways leading to preneoplastic metabolic alterations. We will use well-characterized mimetics of MnSOD to test the concept that mechanistically targeted antioxidants canprevent UV carcinogenesis. The relationship between UV radiation and energy metabolism remainsunknown. The results from this study will close that knowledge gap and will provide valuable insightsinto the metabolic vulnerabilities that are amenable to cancer prevention.

project_terms:
Affinity;Anions;Antioxidants;Autophagocytosis;Basal cell carcinoma;Bioenergetics;Chemistry;Chemoprevention;Co-Immunoprecipitations;Consumption;Coupled;Data;Development;Diagnosis;Energy Metabolism;Epithelial Cells;Event;Exposure to;Genetic Enhancer Element;Genetic Transcription;Glucose;Glycolysis;Goals;Histologic;Human;Intervention;Kinetics;Knowledge;Luciferases;Malignant Epithelial Cell;Malignant Neoplasms;Manganese;Mediating;Mediator of activation protein;Metabolic;Metabolism;Mitochondria;Modeling;Molecular;Molecular Biology;Molecular Chaperones;Molecular Genetics;Normal tissue morphology;Ontology;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Peroxonitrite;Prevention;Production;Proteins;Proteomics;Reporter Genes;Research;Risk;Role;Skin;Skin Cancer;Skin Carcinogenesis;Skin Carcinoma;Squamous cell carcinoma;Superoxide Dismutase;Superoxides;Testing;Tissues;Transgenic Mice;UV carcinogenesis;UV induced;UVB carcinogenesis;UVB induced;Ultraviolet B Radiation;Ultraviolet Rays;United States;Validation;Warburg Effect;base;cancer prevention;carcinogenesis;design;genetic approach;insight;knock-down;lifetime risk;member;metabolomics;mimetics;nitration;novel;prevent;promoter;prototype;response;skin cancer prevention;stable isotope;transcriptome;tumor

public_health_relevance:
The overall goal of this research is to gain a comprehensive understanding of the mechanism by whichsuperoxide radical/anion (O2-) in mitochondria contributes to metabolic switch during UVBcarcinogenesis and to obtain valuable in-depth insights into the metabolic vulnerabilities that areamenable to cancer prevention. The results achieved from this study will have the potential tofundamentally change the practice of chemoprevention of UV-induced skin cancer.


application_id: 10301362
project_number: 5R03AI151878-02
project_title: Novel therapeutic approaches for treatment of drug-resistant Gram-positive infections
administering_ic: NIAID
award_notice_date: 2021-10-20
opportunity_number: PA-19-052
application_type: 5
activity_code: R03
ic: AI
serial_number: 151878
program_official: XU, ZUOYU
project_start_date: 2020-11-12
project_end_date: 2023-10-31
study_section: Special Emphasis Panel[ZRG1-IDM-Y(82)S]
contact_pi_person_id: 11365624
contact_pi: KOROTKOV, KONSTANTIN V
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Emergence of hospital-associated drug-resistant bacterial infections represents one ofthe major challenges for the US healthcare system. There is an urgent need fordevelopment of new and more effective anti-bacterial agents targeting previouslyunexplored cellular processes. The goal of this proposal is to find a novel class ofbiological drugs active against Staphylococcus aureus and pathogenic Enterococci. Thebacterial cell wall biogenesis is an established drug target for many existing and novelantibacterial agents. In recent years lipoteichoic acid biosynthesis pathways emergedas an attractive target for development of new therapeutics. Published data indicate thatlipoteichoic acid is required for the growth and survival of Gram-positive bacteria in thehost. The experiments in this proposal are designed to generate single domain camelidantibodies (nanobodies) that bind and inactivate extracellular domains of enzymesinvolved in synthesis and modification of lipoteichoic acid. Upon successful completionof this project we will obtain a number of nanobodies active against S. aureus andEnterococci that would be further validated in in vivo studies. The strategies developedin the proposed study will be also applicable to other medically relevant bacterialpathogens.

project_terms:
Acinetobacter baumannii;Affinity;Alpaca;Anabolism;Animals;Anti-Bacterial Agents;Antibiotic Resistance;Antibiotics;Antibodies;Bacteria;Bacterial Infections;Bacterial Physiology;Binding;Biogenesis;Biological;Camels;Cell Wall;Cell division;Cell membrane;Cell physiology;Cells;Complex;Core Protein;Data;Development;Drug Controls;Drug Targeting;Drug resistance;ESKAPE pathogens;Enterobacter;Enterococcus;Enterococcus faecalis;Enterococcus faecium;Enzymes;Extracellular Domain;Future;Genetic study;Genus staphylococcus;Glycerol;Goals;Gram-Positive Bacteria;Gram-Positive Bacterial Infections;Growth;Healthcare Systems;Hospitals;Immune Evasion;Immunization;Immunize;Immunoglobulin Fragments;In Vitro;Infection;Ions;Kentucky;Klebsiella pneumoniae;Libraries;Link;Llama;Measures;Medical;Methicillin Resistance;Modeling;Modification;Outcomes Research;Pathogenicity;Pathway interactions;Peptidoglycan;Permeability;Phage Display;Pharmaceutical Preparations;Phosphatidylglycerols;Play;Polysaccharides;Problem Solving;Process;Property;Proteins;Pseudomonas aeruginosa;Publishing;Resistance development;Role;Specificity;Staphylococcus aureus;Staphylococcus aureus infection;Teichoic Acids;Testing;Thick;Transferase;Tunicamycin;Universities;Vancomycin Resistance;Vertebral column;Virulence;antigen binding;antimicrobial peptide;cell envelope;cold temperature;design;drug resistant bacteria;experience;experimental study;human pathogen;in vivo;inorganic phosphate;insight;lipoteichoic acid;member;methicillin resistant Staphylococcus aureus;nanobodies;novel;novel therapeutic intervention;novel therapeutics;pathogen;pathogenic bacteria;targeted agent;targeted treatment

public_health_relevance:
The proposed studies aim to generate novel biological probes that could be used totarget cell wall biogenesis processes in the important human pathogens Staphylococcusaureus Enterococcus faecalis and Enterococcus faecium. The outcomes of this research areexpected to have a positive impact on the development of highly targeted therapeutics to controldrug-resistant Gram-positive bacterial infections.


application_id: 10301234
project_number: 7R01CA207401-05
project_title: Increasing HPV vaccine uptake in community-based pediatric practices
administering_ic: NCI
award_notice_date: 2021-02-01
opportunity_number: PA-13-302
application_type: 7
activity_code: R01
ic: CA
serial_number: 207401
program_official: WEAVER, SALLIE JAYNE
project_start_date: 2016-12-20
project_end_date: 2023-11-30
study_section: Special Emphasis Panel[ZRG1-HDM-J(02)]
contact_pi_person_id: 8310976
contact_pi: HULL, PAMELA CARMEN
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 SUMMARYThe human papillomavirus (HPV) vaccine offers the unprecedented opportunity to prevent nearly all cervicaland anal cancers and a high proportion of vaginal oropharyngeal vulvar and penile cancers where HPV is theetiologic agent. HPV vaccination is recommended for all children ages 11-12 with catch up for females to age26 and males to age 21. However despite clear and indisputable value in cancer prevention uptake andcompletion of the HPV vaccine series has lagged far behind the goal of 80%. Provider recommendation is thestrongest determinant of HPV vaccination but slow translation of guidelines for preventive services such asimmunizations into practice is a known challenge. Practice Facilitation (PF) is a multicomponent qualityimprovement intervention approach that has well-established efficacy in which external support and resourcesare provided to build the internal capacity of practices to improve quality of care and patient outcomes. Ourcentral goal is to identify the optimal approach to implementing an evidence-based intervention for the uptakeand completion of HPV vaccine among adolescents receiving care in the community guided byimplementation science theory. AIM 1: Determine the clinical effectiveness and cost-effectiveness of twomodalities for delivering a multi-component PF intervention to increase HPV vaccination initiation andcompletion in community-based pediatric practices. We will compare the traditional in-person Coach PFmodality to a lower-resource Web-Based PF modality. The primary patient outcome is HPV vaccination. Wewill also examine and compare the sustainability of practice changes on vaccination rates and the effects overtime for each intervention modality. H1: Both interventions will result in significant increases in HPV vaccinationfrom baseline over time. H2: Increases in the rate of HPV vaccination will be higher and sustained for a longerperiod of time in the Coach PF Arm as compared with the Web-Based PF Arm. H3: The Web-Based PF Armwill be more cost-effective than the Coach PF Arm. AIM 2. Understand mechanisms of why the PF interventionmay work better for some pediatric practices than others for HPV vaccination. We will examine theory-baseddeterminants at the organizational provider and patient levels that may mediate (explain) or moderate(change) the effects of the PF intervention on vaccination outcomes. H4: Adoption of changes (processvariables) and patient factors will mediate effects of the intervention on HPV vaccination outcomes. H5:Organizational factors provider attitudes and intervention characteristics will moderate intervention effects onHPV vaccination outcomes. The findings will inform organizations about which PF modality to use among theirconstituent practices to improve HPV vaccination rates with potential for future national dissemination.

project_terms:
13 year old;21 year old;Address;Adolescent;Adoption;Age;Attitude;Caring;Characteristics;Child;Childhood;Clinic;Clinical effectiveness;Communities;Computer software;Data;Data Collection;Dose;Effectiveness;Electronic Health Record;Etiology;Evidence based intervention;Female;Future;Goals;Guideline Adherence;Guidelines;HPV-High Risk;Health Personnel;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Immune response;Immunization;Incidence;Intervention;Knowledge;Link;Malignant Vaginal Neoplasm;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;Malignant neoplasm of penis;Malignant neoplasm of vulva;Measures;Mediating;Modality;Online Systems;Parents;Patient-Focused Outcomes;Patients;Persons;Preventive service;Primary Health Care;Process;Provider;Quality of Care;Randomized;Recommendation;Resources;Role;Series;System;Technology;Tennessee;Testing;Time;Translations;Vaccination;Vaccines;Visit;Visualization;Work;arm;base;cancer prevention;care outcomes;cervical and anal cancer;control trial;cost;cost effective;cost effectiveness;human mortality;implementation research;implementation science;improved;innovation;intervention effect;male;malignant oropharynx neoplasm;online resource;post intervention;prevent;primary care setting;provider adherence;relative cost;theories;trial design;uptake;vaccination outcome;vaccine acceptance

public_health_relevance:
RelevanceIncreasing HPV vaccine uptake will eventually lower incidence and mortality from HPV-associated cancers. Primary care settings represent a crucial priority for developing andtesting interventions to increase HPV vaccine uptake given the important role ofprovider recommendations.


application_id: 10298646
project_number: 1R01DE030100-01A1
administering_ic: NIDCR
award_notice_date: 2021-07-01
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: DE
serial_number: 030100
suffix: A1
program_official: WANG, LU
project_start_date: 2021-07-01
project_end_date: 2025-06-30
study_section: Clinical Data Management and Analysis Study Section[CDMA]
contact_pi_person_id: 10376668
contact_pi: CLARKSON, MELISSA
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adult;Anatomy;Animal Model;Clinical;Clinical Data;Clinical Medicine;Clinical Research;Collection;Communication;Complement;Complex;Computer software;Computers;Correlation Studies;Custom;Data Set;Developmental Anatomy;Documentation;Education;Environment;Evaluation;Face;Future;Genotype;Head;Human;Informatics;Libraries;Measurement;Medical Education;Medical Illustration;Medical Research;Medicine;Methods;Morphology;Nature;Online Systems;Ontology;Patient Care;Patients;Phenotype;Physical Anthropology;Play;Population;Positioning Attribute;Production;Research;Role;Severities;Site;Standardization;Terminology;Text;Time;Variant;Visual;Work;base;clinical application;clinical practice;congenital anomaly;craniofacial;design;malformation;multidisciplinary;next generation;orofacial cleft;preservation;prototype;real world application;skills;tool;tool development;vector;web-based tool


application_id: 10298483
project_number: 1R01DK126777-01A1
project_title: ABIN1 dysfunction in Lupus Nephritis
administering_ic: NIDDK
award_notice_date: 2021-09-02
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: DK
serial_number: 126777
suffix: A1
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
project_terms:
Address;African American;Alleles;Animal Experiments;Animals;Autoimmunity;B-Lymphocytes;Binding Proteins;Biological Response Modifiers;Blood;Bone Marrow;CXCL10 gene;Cell Maturation;Cell physiology;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;Inflammation Mediators;Inflammatory;Interleukin-6;Investigation;Kidney;Kidney Failure;Knowledge;Lupus Nephritis;Mature T-Lymphocyte;Mediating;Molecular;Mus;Mutation;Nature;Outcome;Pathologic;Patients;Peripheral;Physiological;Play;Polyubiquitin;Precision therapeutics;Predisposition;Production;Prognosis;Proteins;Proteinuria;Publishing;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 autoantibody;caucasian American;cell type;chemokine;cohort;cytokine;diagnostic biomarker;disorder risk;experimental study;genetic variant;high risk;inhibitor/antagonist;insight;monocyte;neutrophil;novel diagnostics;personalized diagnostics;podocyte;protein function;racial disparity;risk variant;therapeutic target


application_id: 10298039
project_number: 2R01HL124015-06
project_title: Latexin function in the maintenance and regeneration of the hematopoietic system
administering_ic: NHLBI
award_notice_date: 2021-06-16
opportunity_number: PA-20-185
application_type: 2
activity_code: R01
ic: HL
serial_number: 124015
program_official: BAI, C BRIAN
project_start_date: 2016-01-01
project_end_date: 2025-07-31
study_section: Basic Biology of Blood, Heart and Vasculature Study Section [BBHV]
contact_pi_person_id: 9839693
contact_pi: LIANG, YING
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe hematopoietic system is very sensitive to a variety of stresses. Radiation therapy commonly results in notonly acute hematopoietic suppression but also long-term bone marrow (BM) injury with increased risk of BMfailure or malignancy. Accumulation of damages during aging process is another type of stress on HSCs.Enhancing HSC survival and maintaining their genomic integrity upon stress are crucial for preservation of HSCself-renewal function and for protection against stress-induced BM injury. However the underlying molecularmechanisms are not well defined. No effective treatment has been developed to prevent or treat stress-inducedHSC damages and related pathological consequences. The primary goal of this project is to identify novelpharmaceutical compounds and transcriptional mechanism that target a HSC stress regulatory protein latexin(Lxn) and to uncover the mechanisms that Lxn suppression results in radiation protection and HSC rejuvenation.We have identified a novel Lxn inhibitor small compound and found that it significantly increases survival byprotecting HSCs via a newly identified canonical mechanism of carboxypeptidase A inhibition upon radiation.Lxn deletion also mitigates aging-related functional decline of HSCs. We hypothesize that pharmaceutical andtranscriptional suppression of Lxn protects HSCs and blood system from stress (radiation and aging)-inducedfunctional decline via the upregulation of canonical CPA3 pathway. Aim 1 is to determine the molecularmechanisms by which Lxn inactivation protects against radiation-induced BM injury via up-regulation of canonicalCPA3 pathway. Aim 2 is to identify the mechanism of action of Lxn lead inhibitor in radiation protection ofhematopoietic system. Aim 3 is to define the role of Lxn suppression in rejuvenating old HSCs. Findings willadvance our knowledge of novel mechanisms how Lxn regulates stress hematopoiesis. Results will provide acompelling starting point and lay grounds for the novel drug discovery by targeting Lxn which will benefit patientssubject to radiation treatment and old people with dysfunctional HSC and immune aging.

project_terms:
Acute;Aging;Amino Acids;Angiotensin II;Apoptosis;BCL2 gene;Binding;Binding Proteins;Blood;Blood Cells;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;Cancer Patient;Carboxypeptidase;Carboxypeptidase A;Cellular Stress;Development;Dose;Elderly;Fluorouracil;Funding;Genes;Genetic;Genetic Transcription;Goals;HMGB2 Protein;HMGB2 gene;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Hematopoietic System;Hematopoietic stem cells;Hemorrhage;Homing;Ice;Immune;In Vitro;Infection;Injury;Intervention;Knockout Mice;Knowledge;Lead;Legal patent;Life;Lymphoid;Maintenance;Malignant - descriptor;Malignant Neoplasms;Measures;Mediating;Molecular;Mus;Myelogenous;Myelosuppression;NF-kappa B;Natural regeneration;Output;PC3.1 antigen;Pancytopenia;Pathologic;Pathway interactions;Patients;Pharmacologic Substance;Pharmacy (field);Physiological;Process;Protein Subunits;Quality of life;Radiation;Radiation Protection;Radiation therapy;Regenerative capacity;Regulation;Regulator Genes;Rejuvenation;Reporting;Ribosomal Proteins;Risk;Role;Signal Transduction;Stress;System;Therapeutic;Time;Transplantation;Up-Regulation;Work;base;cancer therapy;cell injury;cell regeneration;drug discovery;effective therapy;functional decline;genetic regulatory protein;genome integrity;hematopoietic stem cell aging;hematopoietic stem cell self-renewal;in vivo;inhibitor/antagonist;irradiation;knock-down;novel;novel therapeutics;overexpression;preconditioning;preservation;prevent;radiation response;self-renewal;senescence;stem cell survival;stem cells

public_health_relevance:
PROJECT NARRATIVEMitigation and protection of bone marrow cells particularly hematopoietic (blood forming) stem cells fromradiation and aging-induced acute and permanent injury is critical for the quality of life of cancer patients receivingradiotherapy and for the elderly. This study will investigate pharmaceutic and genetic inhibition of hematopoieticstress regulatory gene latexin in radiation protection and stem cell rejuvenation.


application_id: 10296752
project_number: 1R01AI148241-01A1
project_title: Iron independent role for yersiniabactin in Yersinia pestis
administering_ic: NIAID
award_notice_date: 2021-06-04
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AI
serial_number: 148241
suffix: A1
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2021-06-04
project_end_date: 2026-05-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
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_terms:
3-Dimensional;Affinity;Attenuated;Bacteria;Binding;Bubonic Plague;Cells;Characteristics;Chemicals;Crystallography;Data;Defect;Development;Drug Targeting;Foundations;Goals;Gram-Negative Bacteria;Hemochromatosis;Human;Immune response;In Vitro;Infection;Iron;Kinetics;Lead;Leukocyte L1 Antigen Complex;Leukocytes;Mammals;Mediating;Membrane;Metals;Modeling;Molecular;Mus;Mutagenesis;Nutritional Immunity;Plague;Pneumonic Plague;Predisposition;Prevention;Proteins;Pump;Research Personnel;Role;Siderophores;Solid;Specificity;Structure;System;Testing;Therapeutic;Time;Transition Elements;Virulence;Virulence Factors;Work;Yersinia pestis;Zinc;combat;design;efflux pump;fitness;human disease;improved;inhibitor/antagonist;innovation;mouse model;mutant;neutrophil;novel;novel therapeutic intervention;novel therapeutics;pathogen;pathogenic bacteria;permease;receptor;response;therapeutic candidate;therapeutic target;transposon sequencing;yersiniabactin


application_id: 10294787
project_number: 1R01CA256893-01A1
project_title: Enhancing the efficacy of androgen signaling inhibitors in prostate cancer
administering_ic: NCI
award_notice_date: 2021-06-11
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: CA
serial_number: 256893
suffix: A1
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
project_terms:
Acetates;Affect;Androgen Antagonists;Androgen Receptor;Androgens;Autocrine Communication;Biochemical;Bioinformatics;Cancer Patient;Castration;Cells;Clinic;Clinical;Coculture Techniques;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;Pharmacology;Pharmacotherapy;Play;Protein Family;Public Health;RNA analysis;Receptor Activation;Receptor Signaling;Research;Resistance;Resistance development;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;base;castration resistant prostate cancer;clinical translation;clinically relevant;docetaxel;gain of function;hormone therapy;improved;inhibitor/antagonist;innovation;loss of function;mouse model;new therapeutic target;novel;novel strategies;patient derived xenograft model;planar cell polarity;prostate cancer cell;prostate cancer progression;receptor;response;therapeutic target;transcriptome;transcriptome sequencing;tumor;tumor microenvironment


application_id: 10292931
project_number: 5F31AG069372-02
project_title: Assessing impaired neuroinflammation associated with Apolipoprotein E4
administering_ic: NIA
award_notice_date: 2021-07-12
opportunity_number: PA-19-195
application_type: 5
activity_code: F31
ic: AG
serial_number: 069372
program_official: OPANASHUK, LISA A
project_start_date: 2020-09-01
project_end_date: 2022-01-29
study_section: Special Emphasis Panel[ZRG1-F01A-F(20)L]
contact_pi_person_id: 15605929
contact_pi: KLOSKE, COURTNEY MARIE
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT:Alzheimers Disease (AD) remains the leading cause of dementia worldwide and 6th leading cause of death inthe United States. While the majority of AD cases have no clear genetic cause a few genetic risk factors fordeveloping AD have been identified. One of the most significant genetic risk factors is Apolipoprotein E (ApoE).Of the three identified ApoE isoforms ApoE4 confers an increased risk of AD ApoE3 is believed to be thecontrol phenotype and ApoE2 has been shown to be protective for AD. Interestingly ApoE has been shownto interact with a surface receptor on microglia triggering receptor expressed on myeloid cells 2 (TREM2) whichhas also been shown to confer an increased risk of AD. Recent studies suggest this interaction drives microglialgene expression and function toward an activated microglial state in the presence of neurodegenerationsuggesting a role for ApoE in the inflammatory response seen in AD. While the AD field has established ApoEand TREM2 as risk factors for AD the mechanistic insights into these risk factors remain murky at best.Preliminary results for this project using autopsy tissue from the University of Kentucky Alzheimers DiseaseCenter Brain Bank suggests ApoE3 patients with AD have a neuroinflammatory response differing from thatseen in ApoE3 patients without AD suggesting that the ApoE3 isoform is responding to AD pathology. Incontrast ApoE4 patients with AD tend to be in a state of neuroinflammation similar to that found in ApoE3patients without AD suggesting they cannot respond to the AD pathology. This project aims to determine theimpact of ApoE isoforms on the inflammatory cascade in both mouse and human models. We hypothesizethat the ApoE4 isoform impairs a beneficial neuroinflammatory response in AD and has a weakened interactionwith TREM2. To delve into the differences highlighted by the preliminary data two approaches will be used todetermine the impact of the ApoE isoform dependent mechanism. First we will continue investigating theneuroinflammatory profile of AD autopsy brains by determining microglial morphology in ApoE3/3 and ApoE4/4patients with AD to compare activation states of the microglia. We will also perform NanoString Digital SpatialProfiling to look at proteins surrounding AD hallmarks and microglia. These approaches will allow for a deeperunderstanding of how these changes seen from the preliminary data associate with the pathology. Our secondapproach will use animal models to target TREM2 and investigate the impact ApoE isoforms have on TREM2activation. We will target TREM2 activation using phosphatidylserine and a TREM2 agonizing antibody to allowfor a more comprehensive view of the impact ApoE isoforms have on TREM2 activation. This project overallaims to investigate the importance of ApoE isoforms on neuroinflammation to in an ApoE isoform specificmanner. Cumulatively this proposal provides adequate time and with excellent facilities to acquire training innecessary laboratory techniques data analysis scientific communication manuscript writing and mentoring toprovide a strong foundation to achieve my goal of an independent investigator in neuroinflammation.

project_terms:
Affect;Alleles;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease pathology;Alzheimer's disease patient;Alzheimer's disease risk;Animal Model;Animals;Antibodies;Apolipoprotein E;Apoptosis;Apoptotic;Autopsy;Bioinformatics;Brain;Breeding;Cause of Death;Cholesterol;Communication;Communication Research;Data;Data Analyses;Dementia;Distant;Foundations;Gene Expression;Genes;Genetic;Goals;Histologic;Human;Immunohistochemistry;Impairment;Inflammatory;Inflammatory Response;Injections;Investigation;Kentucky;Laboratories;Late Onset Alzheimer Disease;Link;Lipoproteins;Manuscripts;Mentors;Microglia;Morphology;Nerve Degeneration;Neurofibrillary Tangles;Operative Surgical Procedures;Pathogenesis;Pathology;Pathway interactions;Patients;Phenotype;Phosphatidylserines;Play;Protein Analysis;Protein Isoforms;Proteins;RNA;Research;Research Ethics;Research Personnel;Rest;Risk Factors;Role;Sampling;Stains;Surface;TREM2 gene;Techniques;Testing;Time;Tissues;Training;United States;Universities;Variant;Writing;animal tissue;apolipoprotein E-3;apolipoprotein E-4;brain tissue;digital;drug discovery;gene function;genetic risk factor;human model;human tissue;inflammatory marker;insight;mouse model;nano-string;neuroinflammation;protein biomarkers;protein expression;receptor;response;tau Proteins

public_health_relevance:
Project NarrativeApolipoprotein E4 (ApoE) is the largest known genetic risk factor for late onset Alzheimers disease (AD). Whileits role in AD remains unclear it has recently been shown to impact the inflammatory response seen in the ADbrain. This proposal will investigate the impact of ApoE on the inflammatory response that occurs in AD throughinvestigation of both human autopsy brain tissue and by targeting specific inflammatory pathways in ApoE mousemodels providing crucial information for the treatment of AD.


application_id: 10292454
project_number: 5R01AI143690-03
project_title: Biogenesis and Function of Streptococcus Pyogenes Cell Wall
administering_ic: NIAID
award_notice_date: 2021-11-23
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AI
serial_number: 143690
program_official: GU, XIN-XING
project_start_date: 2019-11-25
project_end_date: 2024-10-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 8869391
contact_pi: KOROTKOVA, NATALIA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Group A streptococcus (GAS Streptococcus pyogenes) is a leading bacterial pathogen of thehuman pharynx and skin. In recent years a striking resurgence in severe invasive GASinfections has been observed worldwide. GAS infections account for more than 650000 casesof severe invasive disease annually. The invasive GAS infections necrotizing fasciitis cellulitisand erysipelas with concomitant scarlet fever and streptococcal toxic syndrome are difficult totreat with antibiotics and a GAS vaccine is urgently needed to combat this neglected disease. Amajor component of the GAS cell wall is the Group A Carbohydrate (GAC) covalently linked topeptidoglycan consisting of a polyrhamnose backbone with N-acetylglucosamine (GlcNAc)side-chains. GAC is an attractive vaccine candidate due to its conserved expression in all GASserotypes and the absence of its constitutive component rhamnose in humans. Our geneticbiochemical and structural studies identified two novel modifications of GAC glycans: glycerolphosphate modification of GAC and de-N-acetylation of the GAC linkage unit. The goal of thisproposal is to characterize the mechanisms of GAC biosynthesis and modification andelucidate the roles of cell wall modifications in antimicrobial resistance mechanisms and GASpathogenesis. To help answer these questions we will employ a variety of genetic biochemicalanalytical and structural approaches. The function of cell wall modifications in GASpathogenesis will be studied in ex vivo and in vivo models of GAS infection. The proposedstudies provide a platform for design of a safe and effective vaccine against this importanthuman pathogen and should have broad application to other streptococci which express similarcell wall polysaccharides. Since the enzymes of the GAC biosynthesis pathway are attractivedrug targets the proposed studies will have important implications for drug design.

project_terms:
Acetylation;Anabolism;Analytical Chemistry;Antibiotic Therapy;Antibiotics;Antimicrobial Cationic Peptides;Antimicrobial Resistance;Bacterial Physiology;Binding;Biochemical;Biogenesis;Biological;Biological Assay;Carbohydrates;Cations;Cell Wall;Cell membrane;Cell physiology;Cells;Cellulitis;Charge;Chemicals;Communicable Diseases;Control Groups;Data;Deacetylase;Dental;Development;Diagnostic;Disease;Drug Design;Drug Targeting;Electrostatics;Enzymatic Biochemistry;Enzymes;Epitopes;Erysipelas;Freeze Substitution;Gene Cluster;Genetic;Glycerol;Goals;Histones;Homologous Gene;Human;Infection;Knowledge;Link;Mass Spectrum Analysis;Methods;Modeling;Modification;Molecular;Molecular Genetics;Molecular Structure;Muramidase;Necrotizing fasciitis;Outcome;Outcome Study;Outcomes Research;Pathogenesis;Pathway interactions;Peptidoglycan;Permeability;Pharyngeal structure;Phospholipase A2;Polymers;Polysaccharides;Predisposition;Proteins;Publishing;Rhamnose;Role;Scarlet Fever;Serotyping;Serum;Side;Skin;Streptococcal Infections;Streptococcal Vaccines;Streptococcus;Streptococcus mutans;Streptococcus pyogenes;Structure;Surface;Syndrome;Techniques;Testing;Therapeutic Intervention;Thick;Vaccine Antigen;Vaccine Design;Vaccines;Vertebral column;Work;analog;antimicrobial;antimicrobial peptide;carbohydrate biosynthesis;cell envelope;combat;density;design;drug development;extracellular;human pathogen;improved;in vivo;in vivo Model;inorganic phosphate;insight;molecular size;mortality;mouse model;mutant;neglect;neutrophil;novel;pathogen;pathogenic bacteria;resistance mechanism;targeted treatment;vaccine candidate

public_health_relevance:
The proposed studies investigate structure biosynthesis pathway and function of cellwall in the important human pathogen Streptococcus pyogenes. The outcomes of this researchare expected to have a positive impact on the development of highly targeted therapeutics tocontrol S. pyogenes infections.!


application_id: 10290070
project_number: 1R03CA256230-01A1
administering_ic: NCI
award_notice_date: 2021-07-05
opportunity_number: PAR-20-052
application_type: 1
activity_code: R03
ic: CA
serial_number: 256230
suffix: A1
program_official: SHARMAN, ANU
project_start_date: 2021-07-05
project_end_date: 2023-06-30
study_section: Special Emphasis Panel[ZCA1 TCRB-Q (M3)]
contact_pi_person_id: 11597020
contact_pi: FONG, KA-WING
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:
E2F family transcription factors are directly regulated by TRIM28 to promote castration-resistance in prostate cancer

project_abstract:
Prostate cancer (PCa) is the second-leading cause of cancer-related death in American men.Androgen deprivation therapies that target the androgen receptor (AR) are the mainstay treatmentfor metastatic PCa. New generation anti-androgen enzalutamide (Enz) significantly increasesPCa patient survival. However resistance to Enz develops rapidly. Importantly castration-resistant prostate cancer (CRPC) is driven primarily by aberrant activation of the AR in the milieuof low androgen. The AR exerts its tumorigenic roles mainly through genomic regulation of targetgene expression. This genomic action is tightly regulated by a number of cofactors and one ofwhich is TRIM24. We recently reported that TRIM28 is an upstream regulator of TRIM24 proteinstability in CRPC where both TRIM24 and TRIM28 expression is highly elevated. MechanisticallyTRIM28 stabilizes TRIM24 by preventing TRIM24 from SPOP-driven ubiquitination anddegradation and thereby TRIM24 is able to reactivate AR signaling in CRPC. To explore theTRIM28-mediated downstream signaling genome-wide transcriptome analysis revealed thatTRIM28 engaged in various oncogenic pathway including cell cycle and DNA replication. Byinterrogating cell cycle signature genes we showed that TRIM28 induces E2F1 E2F2 and E2F3gene expression in PCa. In addition TRIM28 ChIP-seq revealed that TRIM28 directly binds topromoter region of transcription factor E2F1-E2F3 which play a pivotal role in activatingtranscription of the genes required for cell cycle progression. Further deregulated expression oractivity of the E2F family has often been detected in many human cancers which leads touncontrolled cell proliferation. In this proposal we hypothesize that E2F transcription factor is acritical downstream target of TRIM28 and clinically-available E2F small molecules inhibitorLY101-4B may suppress CRPC progression. To test this hypothesis three specific aims areproposed. In Aim1 we will first validate the direct regulation of E2F1-E2F3 gene expression byTRIM28 with the use of genomic approaches. Aim2 will examine clinical expression of E2F andevaluate the efficacy of E2F inhibitor in CRPC cell lines and xenografts.

project_terms:
American;Androgen Antagonists;Androgen Receptor;Androgens;Antibodies;Binding;Biological Assay;CRISPR/Cas technology;Cancer Cell Growth;Cancer Etiology;Cancer Patient;Castration;Cell Cycle;Cell Cycle Progression;Cell Extracts;Cell Line;Cell Proliferation;Cells;Cessation of life;ChIP-seq;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;DNA Binding;DNA biosynthesis;E2F transcription factors;Family;Gene Expression;Generations;Genetic Transcription;Genomic approach;Genomics;Growth;Harvest;Human;Immunohistochemistry;LNCaP;Luciferases;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metastatic Prostate Cancer;Oncogenic;Pathway interactions;Patients;Play;Promoter Regions;Proteins;RNA;Receptor Signaling;Regulation;Reporter;Reporting;Resistance;Role;Running;Signal Transduction;Specimen;Testing;Tissue Microarray;Transactivation;Transcriptional Activation;Ubiquitination;Western Blotting;Xenograft procedure;advanced prostate cancer;androgen deprivation therapy;androgen sensitive;biobank;castration resistant prostate cancer;cell growth;cofactor;cohort;efficacy evaluation;experimental study;genetic signature;genome-wide;inhibitor/antagonist;knock-down;men;mutant;prevent;promoter;prostate cancer cell;prostate cancer cell line;prostate cancer progression;small hairpin RNA;small molecule inhibitor;targeted treatment;therapeutic target;transcription factor;transcriptome;tumor growth;tumor xenograft;tumorigenic

public_health_relevance:
TRIM28 is a transcription factor which was recently found to be aberrantly upregulated inadvanced prostate cancer. In this proposal we will characterize E2F as a crucial downstreamtarget of TRIM28 and targeting TRIM28-E2F axis may suppress castration resistant prostatecancer progression.


application_id: 10288039
project_number: 1R21ES033323-01
project_title: Cardiovascular Benefits of Inhaled Biogenic Volatile Organic Compounds
administering_ic: NIEHS
award_notice_date: 2021-07-30
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: ES
serial_number: 033323
program_official: SCHUG, THADDEUS
project_start_date: 2021-08-01
project_end_date: 2023-07-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV 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 PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Program Director/Principal Investigator (Last First Middle): Conklin Daniel J. Ph.D.ABSTRACTExtensive epidemiological evidence suggests that exposure to vegetation and residential proximity togreenspaces lowers the risk of all-cause mortality cardiovascular disease anxiety depression and aggression.Although it has been suggested that urban greenspaces exert their beneficial effects by removing air pollutantsand promoting physical activity plants emit biogenic volatile organic chemicals (BVOCs) which by elicitingbeneficial cardiovascular and neurological effects could mediate the salutary effects of vegetation. Vegetation isa major underappreciated domain of the natural environment that has received limited interest. Exposure togreenspace within the natural environment has been linked to improvements in cardiovascular health. Wepropose that plant-derived BVOCs including pinenes limonene and citronellol stimulate distinct signalingpathways in part by activating the transient receptor potential ankyrin-1 (TRPA1) channel on cardiovasculartargets. In endothelial cells for example activation of TRPA1 releases nitric oxide that lowers blood pressureimproves cardiovascular function and tamps down inflammation and thrombosis leading to an overall decreasein cardiovascular disease risk. Completion of this project will rigorously establish beneficial cardiovascular effectsof inhaled BVOCs that are prevalent in human environments. Moreover our studies will provide a first test ofhypothesis that beneficial effects of inhaled BVOCs are mediated in part by TRPA1. These preclinical studiesmay also lead to the development of biomarkers of exposure to greenness which likely will be useful in clinicalevaluation of the potential therapeutic use of greenness (e.g. planting trees) to decrease CVD risk in humanpopulations.PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

project_terms:
ANK1 gene;Acute;Adult;Affect;Aggressive behavior;Air;Air Pollutants;Anti-Inflammatory Agents;Antiinflammatory Effect;Anxiety;Attention;Blood Pressure;Blood Vessels;Cardiac;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Cell physiology;Cells;Chemical Exposure;Chrysanthemum;Cypress;Data;Doctor of Philosophy;Endothelial Cells;Endothelium;Environment;Environmental Risk Factor;Epidemiology;Eucalyptol;Exposure to;Female;Frequencies;Future;Green space;Health;Heart Rate;Human;Inflammation;Inflammatory;Inhalation;Intravenous;Juniper;Knowledge;Lead;Life Style;Link;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Mental Depression;Metabolism;Molecular;Monoterpenes;Mus;National Institute of Environmental Health Sciences;Neurologic Effect;Nitric Oxide;Oral;Pathway interactions;Pharmacology;Physical activity;Physiological;Plants;Population;Principal Investigator;Production;Radio;Rattus;Risk;Role;Screening procedure;Shapes;Signal Pathway;Signal Transduction;Sleep;Stress;TRPA channel;Telemetry;Testing;Therapeutic Uses;Thrombosis;Time;Trees;United States;Vasodilation;Work;aerosolized;anti-cancer;biomarker development;blood pressure reduction;cardioprotection;cardiovascular disorder risk;cardiovascular effects;cardiovascular health;dosimetry;heart rate variability;hemodynamics;improved;in vitro Assay;interest;lifestyle factors;limonene;linalool;male;mortality;normotensive;preclinical study;prevent;programs;receptor;research clinical testing;urinary;volatile organic compound

public_health_relevance:
Program Director/Principal Investigator (Last First Middle): Conklin Daniel J. Ph.D.NarrativeWe propose that plant-derived biogenic volatile organic chemicals (BVOCs) including pinenes limonene andcitronellol stimulate distinct signaling pathways in part by activating the transient receptor potential ankyrin-1(TRPA1) channel on cardiovascular targets. In endothelial cells for example activation of TRPA1 releases nitricoxide that lowers blood pressure improves cardiovascular function and tamps down inflammation andthrombosis leading to an overall decrease in cardiovascular disease risk. Completion of this project will verifybeneficial cardiovascular effects of inhaled BVOCs and also lead to the development of biomarkers of exposureto greenness.PHS 398/2590 (Rev. 06/09) Page Continuation Format Page


application_id: 10287757
project_number: 1R03CA262720-01
project_title: Fatty acid synthase in regulation of UDP-GlcNAc synthesis in colorectal cancer
administering_ic: NCI
award_notice_date: 2021-06-24
opportunity_number: PAR-20-052
application_type: 1
activity_code: R03
ic: CA
serial_number: 262720
program_official: WILLIS, KRISTINE AMALEE
project_start_date: 2021-07-01
project_end_date: 2023-06-30
study_section: Special Emphasis Panel[ZCA1 TCRB-V (M1)]
contact_pi_person_id: 10755133
contact_pi: ZAYTSEVA, YEKATERINA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYAltered metabolism is rapidly emerging as a target for therapeutic intervention in cancer. An increased rate oflipid synthesis in cancer has been recognized as an important aspect of rewired metabolism in transformedcells. Fatty acid synthase (FASN) a key enzyme of lipid synthesis is actively investigated in pre-clinicalstudies and clinical trials as a therapeutic target for cancer. Altered glycosylation also a universal feature ofcancer is associated with cancer progression reduced immune response and resistance to drug treatments.The hexosamine biosynthesis pathway (HBP) generates a nucleotide sugar uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) a key substrate for protein glycosylation. However the mechanisms of howupregulation of de novo lipid synthesis can contribute to synthesis of UDP-GlcNAc and the effect of FASN-targeted therapy on hexasomine biosynthesis are not yet understood. We developed colorectal cancer (CRC)mouse models with heterozygous and homozygous deletion of FASN in intestine and colon and found thatdeletion of FASN is associated with a significant decrease in tumor number and an increase in mouse survival.The RNA-seq data and metabolic analysis of tumors show that FASN selectively regulates the levels ofenzymes and metabolites within the HBP. Consistantly we found that expression of FASN alters synthesis ofUDP-GlcNAc in human CRC cells and correlates with UDP-GlcNAc level in human CRC tissues. Furthermorewe show that FASN alters O-linked and N-linked protein glycosylation. Therefore we hypothesize thatupregulation of FASN during tumorigenesis enhances synthesis of UDP-GlcNAc via rewiring the metabolicnetwork in CRC cells. In Aim 1 using stable isotope labeling and ultrahigh-resolution mass-spectrometry andnuclear magnetic resonance we will delineate FASN-mediated metabolic changes in polar metabolites ofmultiple pathways that supply metabolic subunits to UDP-GlcNAc in vivo. In Aim 2 we will determine the effectof pharmacological inhibition of FASN on synthesis of UDP-GlcNA in human CRC organoids and establishedthe link between expression of FASN and enzymes within the HBP in human CRC tissues. Knowledge of howFASN regulates UDP-GlcNAc synthesis will have a significant translational impact by contributing to betterunderstanding of the mechanisms of metabolic adoptations in cancer cells and identifying new targetableliabilities that would lead to development of more effective therapeutic strategies for CRC. Completion of thesestudies will also help us advance our ongoing research to better understand how lipid synthesis regulates thelandscape of glycosylation in CRC and contribution of these metabolic pathways to CRC progression andmetastasis.

project_terms:
Acetyl Coenzyme A;Acyl Coenzyme A;Adopted;Amino Sugars;Anabolism;Biochemical Pathway;Cancer Etiology;Cell Proliferation;Cessation of life;Characteristics;Clinical Trials;Colon;Colorectal Cancer;Data;Development;Disease;Disease-Free Survival;Drug resistance;Enzymes;Fatty Acids;Fatty-acid synthase;Funding;Gene Expression;Genes;Genetic;Glucose;Glutamine;Glycolysis;Growth;Hexosamines;Human;Immune response;Intestines;Knowledge;Lead;Link;Lipids;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Membrane;Metabolic;Metabolic Pathway;Metabolism;Mus;Neoplasm Metastasis;Nitrogen;Nuclear Magnetic Resonance;Organoids;Pathway interactions;Pharmacology;Pharmacotherapy;Phase II Clinical Trials;Post-Translational Protein Processing;Process;Production;Prognosis;Protein Glycosylation;Regulation;Research;Resolution;Role;Signal Transduction;Solid;Stable Isotope Labeling;Testing;Therapeutic;Therapeutic Intervention;Tissues;United States;Up-Regulation;Uridine Diphosphate N-Acetylglucosamine;Woman;anti-cancer;cancer cell;cell transformation;colorectal cancer progression;glycosylation;improved;in vivo;inhibitor/antagonist;link protein;lipid biosynthesis;long chain fatty acid;men;mouse model;neoplastic cell;novel;novel therapeutic intervention;overexpression;oxidation;preclinical study;sugar nucleotide;targeted treatment;therapeutic target;therapeutically effective;transcriptome sequencing;translational impact;tumor;tumor progression;tumorigenesis;uptake

public_health_relevance:
PROJECT NARRATIVE Colorectal cancer is the 2nd most common cause of cancer death among men and women in the UnitesStates. We have proposed to investigate a novel mechanism of how an increase in lipid synthesis rewiresthe metabolic network to enhance synthesis of uridine diphosphate N-acetylglucosamine a substrate forglycosylation. The completion of this study we will determine novel metabolic vulnerabilities in fatty acidsynthase-driven colorectal cancer and further guide the development of novel therapeutic strategies to treatcolorectal cancer and potentially other solid cancers.


application_id: 10287080
project_number: 1R21ES033327-01
project_title: Cr(VI)-Induced DNA Damage Contributes to Brain Aging
administering_ic: NIEHS
award_notice_date: 2021-09-16
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: ES
serial_number: 033327
program_official: HOLLANDER, JONATHAN
project_start_date: 2021-09-17
project_end_date: 2023-08-31
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 12632642
contact_pi: WISE, JOHNNY
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYToday our societies are challenged with the health burdens of environmental pollution and a rapidly agingpopulation. Global lifespan is 30 years longer than it was 100 years ago and 1 in 5 Americans will be geriatricby the year 2030. Given this prolonged aging combined with environmental exposures we urgently need tounderstand how environmental pollution affects an aged body differently from a younger body and howenvironmental pollution contributes to aging phenotypes. Most of our understanding of toxic effects of chemicalscome from human research focused on young to middle aged people or from animal studies using young tomiddle aged rodents. Very few studies have considered toxicity of environmental pollutants in an aged body orpopulation and we simply do not understand the impacts on an aged population. Traditionally the brain wasconsidered composed of mostly post-mitotic neurons and hence genotoxic agents were considered less of athreat. Now we know the opposite is true  most of the brains cells the glia are mitotic and play critical rolesin protecting and supporting neuronal health. Recent studies show these glial cells can exhibit increasedaneuploidy and chromosome instability with aging and early in neurodegenerative diseases. Hence there is acritical need to understand how genotoxic chemicals affect brain health and contribute to premature aging.Hexavalent chromium [Cr(VI)] is a major environmental health concern that can induce aging phenotypes andhas the best defined clastogenic mechanism of metals. Cr(VI) also causes brain damage that may be linked toa variety of neurological symptoms. We propose to investigate the role of Cr(VI) in this aging paradigm usingyoung vs middle-aged vs geriatric rats exposed to Cr(VI) for 90 days via drinking water. We hypothesize agedanimals will be more susceptible to Cr(VI)-induced neurotoxicity and that Cr(VI)-induces brain aging bycausing aneuploidy and chromosome instability resulting in glial senescence. We will test our hypothesiswith two aims. Aim 1 will identify brain regions and cell populations vulnerable to Cr(VI) toxicity across ages. Thisaim will allow us to compare Cr(VI) neurotoxicity across ages and endpoints for premature or advanced aging.Aim 2 will determine the role of aneuploidy and chromosome instability in Cr(VI) neurotoxicity and brain aging.Our study will provide essential detailed insights into Cr(VI) neurotoxicity considering age- sex- region- andcell type-specific effects. Our study will further consider mechanistically how genotoxicity contributes to brainaging with in vivo and in vitro techniques. Outcomes will provide key and novel insights for understanding Cr(VI)srole in the aging process identifying cellular and regional targets in the brain and how an aged brain is affectedby toxicants differently. This study will also characterize a new model system for further study of neurotoxicityand aging for Cr(VI) or other metals and will contribute to improvements in Cr(VI) risk assessment andmanagement that are not currently possible because of limitations due to the absence of these data.

project_terms:
Address;Affect;Age;Aging;American;Aneuploid Cells;Aneuploidy;Animal Model;Animals;Astrocytes;Attention;Biological Aging;Biological Models;Biological Process;Blood - brain barrier anatomy;Blood Vessels;Brain;Brain Diseases;Brain Injuries;Brain region;Cell Aging;Cells;Cerebellum;Cerebrovascular system;Chemicals;Chromosomal Instability;Chronic;Cultured Cells;DNA Damage;DNA Double Strand Break;Data;Dementia;Double Strand Break Repair;Elderly;Endothelial Cells;Environment;Environmental Exposure;Environmental Health;Environmental Pollutants;Environmental Pollution;Etiology;Exhibits;Exposure to;Extravasation;Face;Functional disorder;Health;Heavy Metals;Hemorrhage;High Fat Diet;Hippocampus (Brain);Homeostasis;Human;Hypothalamic structure;Immunohistochemistry;In Vitro;Individual;Inductively Coupled Plasma Mass Spectrometry;Industrialization;Knowledge;Learning;Link;Literature;Longevity;Malignant Neoplasms;Memory impairment;Metabolic Diseases;Metals;Microglia;Mitotic;Motor Neuron Disease;Mutagens;Nerve Degeneration;Neurodegenerative Disorders;Neuroglia;Neurologic;Neurologic Symptoms;Neurons;Onset of illness;Outcome;Pericytes;Phenotype;Play;Poison;Population;Premature aging syndrome;Process;Rattus;Reporting;Research;Risk;Risk Assessment;Risk Management;Rodent;Role;Route;Societies;Techniques;Testing;Tissues;Toxic Environmental Substances;Toxic effect;Toxicology;Vulnerable Populations;White Matter Disease;age group;age related;age related neurodegeneration;aged;aging brain;aging population;brain cell;brain health;cell type;chromium hexavalent ion;drinking water;gene environment interaction;genotoxicity;human disease;improved;in vivo;insight;lifestyle factors;metal poisoning;middle age;neurodegenerative phenotype;neuroinflammation;neuropathology;neurotoxic;neurotoxicity;neurovascular;neurovascular unit;novel;oxidative damage;premature;senescence;sex;toxicant

public_health_relevance:
PROJECT NARRATIVEThis project aims to determine how chronic exposure to hexavalent chromium (Cr[VI]) will induce neurotoxicityand premature brain aging in young middle-aged and geriatric rats. We propose the geriatric rats will be moresusceptible to damaging effects of Cr(VI) and we propose a novel clastogenic mechanism for Cr(VI)-inducedaging. Subsequent studies will further evaluate this proposed mechanism consider Cr(VI) exposure with otherlifestyle factors (e.g. high fat diet) and possible gene-environment interactions contributing to premature aging.


application_id: 10286202
project_number: 1R15GM143662-01
project_title: Inteins: Expanding Biological Roles and Biotechnological Applications
administering_ic: NIGMS
award_notice_date: 2021-08-31
opportunity_number: PAR-18-714
application_type: 1
activity_code: R15
ic: GM
serial_number: 143662
program_official: RIGAS, MARC
project_start_date: 2021-09-01
project_end_date: 2025-08-31
study_section: Macromolecular Structure and Function B Study Section[MSFB]
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 given inteins are absent in humans and located within essential genes of severalpathogens understanding the environmental factors that regulate protein splicing inform possible antimicrobialdevelopment.We propose the following two aims building upon recent discoveries as well as expanding into new arenas.Aim 1 will for the first time investigate the role inteins play as nascent chains broadly determining whethersplicing is possible prior to release from the ribosome as well as examining possible stress responsestrategies of bacterial and fungal pathogens. Aim 2 seeks to develop two novel intein-based technologies.First a general strategy to improve expression of misfolding-prone proteins in bacteria and second a zinc-controlled self-removing protein purification tag for use in both bacterial and mammalian systems. Throughthese Aims this work will enhance our understanding of the roles these exciting and understudied elementsplay in nature their role in pathogen stress response and will lead to new intein-based technologies for proteinengineering.

project_terms:
Active Sites;Archaea;Area;Attenuated;Bacteria;Behavior;Biochemical;Biological;Biomedical Research;Biomedical Technology;Biotechnology;Chemistry;Communities;Cryptococcus neoformans;DNA biosynthesis;Development;Drug Targeting;Elements;Engineering;Environment;Environmental Risk Factor;Essential Genes;Exteins;Genes;Genetic;Goals;Human;In Vitro;Investigation;Measures;Mediating;Methods;Mobile Genetic Elements;Molecular;Monitor;Mycobacterium leprae;Mycobacterium tuberculosis;Nature;Organism;Oxidative Stress;Parasites;Peptides;Play;Post-Translational Regulation;Process;Protein Engineering;Protein Splicing;Proteins;RNA Splicing;Reaction;Recombinant Proteins;Regulation;Regulatory Element;Ribosomes;Role;Signal Transduction;Stress;System;Techniques;Technology;Time;Translating;Translations;Work;Zinc;antimicrobial;applied biomedical research;attenuation;base;biological adaptation to stress;experimental study;high risk;human pathogen;improved;in vivo;inhibitor/antagonist;intein;microbial;mycobacterial;novel;pathogen;pathogenic bacteria;pathogenic fungus;pathogenic microbe;polypeptide;protein activation;protein expression;protein folding;protein purification;recombinational repair;response;sensor;tool

public_health_relevance:
PROJECT NARRATIVEInteins or intervening proteins are mobile genetic elements found within essential proteins of severaldevastating human pathogens including Mycobacterium tuberculosis. Due to their unique ability to rearrangepeptide bonds inteins are also important tools in biotechnology. The overall goals of this application are todiscover novel mechanisms by which inteins act as environmental stress sensors and to develop new intein-derived applications for protein engineering.


application_id: 10285469
project_number: 3R35NS116824-01S1
project_title: Brain Glycogen - Metabolism Mechanisms and Therapeutic Potential
administering_ic: NINDS
award_notice_date: 2021-02-10
opportunity_number: PA-20-222
application_type: 3
activity_code: R35
ic: NS
serial_number: 116824
suffix: S1
program_official: LEENDERS, MIRIAM
project_start_date: 2021-03-01
project_end_date: 2028-04-30
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Brain metabolism is a fundamental aspect of biology and human disease. The brain critically depends onglucose consuming large quantities as the biochemical fuel for cognition memory and behavior. Fundamentalaspects of brain metabolism have been extensively studied but recent evidence regarding the key role ofglucose and glycogen metabolism in neurological diseases has recently opened up new avenues of research.The neurological disease where aberrant glucose metabolism has been investigated in-depth is Lafora disease(LD). LD is an autosomal recessive fatal glycogen storage disease (GSD) that equally affects both sexes.Symptoms emerge in adolescence with drug-resistant epilepsy ataxia neurodegeneration and a rapid declineinto a vegetative state before death. Results from several labs using multiple models have demonstrated thataberrant intracellular glycogen-like aggregates known as polyglucosan bodies (PGBs) are the cause of LD.Strikingly we and others have identified PGBs in multiple neurological diseases and we hypothesize thatPGBs are a driving force in disease progression for brain-impacted GSDs and that PGBs also play acritical role in Alzheimer's disease (AD). We have made foundational discoveries regarding glucose hypometabolism in LD defined how PGBsimpact cellular processes developed cutting-edge tools to determine the underlying cellular mechanisms andestablished therapeutic platforms to inhibit and/or eliminate PGBs. Defining the mechanisms of glycogenmetabolism in LD provides insights into how PGBs form and impact brain homeostasis. Thus LD offers aunique window into both normal brain glucose metabolism and broader disease implications when thismetabolism is perturbed. This supplement will allow Mr. Trey Coburn to further hone his skills in neuroscience. His results will assistin determining the role of PGBs in AD. He will look at perturbations in signaling at the molecular levelelucidate changes in cellular physiology and establish novel therapeutic modalities at the organismal level.

project_terms:
Adolescence;Affect;Alzheimer's Disease;Ataxia;Behavior;Biochemical;Biology;Brain;Carbohydrates;Cell physiology;Cellular Metabolic Process;Cessation of life;Cognition;Complex;Comprehension;Consumption;Diagnosis;Disease;Disease Progression;Event;Foundations;Glucose;Glycogen;Glycogen Storage Disease;Homeostasis;Intractable Epilepsy;Knowledge;Lafora Disease;Memory;Metabolism;Modality;Modeling;Molecular;Nerve Degeneration;Neurosciences;Play;Research;Role;Signal Transduction;Symptoms;Therapeutic;Translating;Vegetative States;Work;brain metabolism;driving force;glucose metabolism;glycogen metabolism;human disease;insight;nervous system disorder;novel therapeutics;polyglucosan;sex;skills;tool

public_health_relevance:
The focus of our work is to determine how carbohydrate aggregates impact multiple neurological diseasesand to translate this knowledge into therapies. Our proposal is built on our past discoveries and usescomplementary approaches to advance our understanding of the intertwined events of cell metabolismneurodegeneration and neurological disease. Completion of this work will yield a better comprehension ofthese complex events and will allow us to translate our insights into disease mechanisms diagnoses andtreatments.


application_id: 10285052
project_number: 271201600028C-P00009-9999-4
administering_ic: NIDA
project_start_date: 2016-09-18
project_end_date: 2021-09-17
contact_pi_person_id: 77868586
contact_pi: MURTY, RAM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 943117366
primary_uei: DNJBTJ3XBQM6
duns_number: 943117366
uei: DNJBTJ3XBQM6
fips: US
organization_id: 3514301
organization_name: MURTY PHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405091016
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_title:
DEVELOPMENT&MANUFACTURE OF PHARMACEUTICAL PRODUCTS FOR THE TREATMENT OF SUBSTANCE ABUSE DISORDERS. NIDA REF. NO. N01DA-16-8926; POP: 09/18/2016 - 09/1

project_abstract:
To carry out the development and manufacture of pharmaceutical preparations to be used in the medications development program of the National Institute on Drug Abuse (NIDA) for treating substance use disorders.

project_terms:
Development;Disease;National Institute of Drug Abuse;Pharmaceutical Preparations;Pharmacologic Substance;Placebos;Program Development;Substance Use Disorder;substance abuse treatment


application_id: 10285036
project_number: 7K07CA218247-04
project_title: Human Papillomavirus-Specific Biomarkers for the Prediction of Oropharyngeal Cancer Recurrence
administering_ic: NCI
award_notice_date: 2021-05-05
opportunity_number: PA-18-590
application_type: 7
activity_code: K07
ic: CA
serial_number: 218247
program_official: BIAN, YANSONG
project_start_date: 2020-10-16
project_end_date: 2022-03-31
study_section: Career Development Study Section (J)[NCI-J]
contact_pi_person_id: 14510566
contact_pi: KUHS, KRYSTLE A.
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThis Career Development Award (CDA) is designed to provide Dr. Krystle A. Lang Kuhs with the necessary skills andmentorship to develop an independent research program focused on head and neck cancer prevention. The goals of herfuture research program are to improve patient outcomes by using molecular markers to: a) detect head and neck cancersearlier (secondary prevention); b) improve pre-treatment risk stratification to personalize therapy based on prognosis(tertiary prevention) and; c) detect recurrences earlier when highly-curative salvage surgery is still an option (quaternaryprevention). This is the natural next-step in Dr. Lang Kuhs career given that it builds upon her strengthens in cancerprevention basic science epidemiology oncogenic infections and biomarker development. However to achieve hercareer goals Dr. Lang Kuhs will need to address 3 main gaps in her training: 1) clinical epidemiology (patient populationexperience and clinical cohort building); 2) biomedical informatics (use of electronic health record [EHR] data); and 3)advanced biostatistics (risk prediction modeling). This training will be obtained through coursework seminars experientiallearning hands on training and mentorship. Dr. Lang Kuhs will be mentored by leading experts in molecular epidemiologyand cohort development (Dr. Wei Zheng) head and neck cancer immunology (Dr. Young Kim) and head and neck cancersurvivorship (Dr. Barbara Murphy). The research portion of this CDA will focus on human papillomavirus-drivenoropharyngeal cancer (HPV-OPC) a type of rapidly increasing head and neck cancer. While treatment of HPV-OPC is oftencurative it is associated with severe morbidity. Clinical trials are underway to investigate whether de-escalation oftreatment for HPV-OPC can decrease morbidity while still preserving high survival rates. However the most significantbarrier for the adoption of de-escalated treatment is the inability to identify patients at highest risk for recurrence. Theobjective of this research is to examine the potential utility of using HPV-specific biomarkers to identify patients at highestrisk for recurrence. This research will utilize banked biospecimens and EHR data to create a clinical cohort of HPV-OPCpatients to: 1) examine the association between HPV viral variants within OPC tumors and recurrence; 2) examine theassociation between pre-treatment HPV16 E6 seropositivity and E6 oncogene expression and risk recurrence; and 3)develop and refine protocols for expanded prospective collection of clinical data and biospecimens from OPC patients.The mentored training hands on experience and results gained from this CDA will position Dr. Lang Kuhs to successfullycompete for funding to establish an independent research program focused on developing biomarkers for the preventionof head and neck cancer.

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

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


application_id: 10284936
project_number: 5F31NS116935-02
project_title: The effects of activity on propriospinal neuron morphology and connectivity
administering_ic: NINDS
award_notice_date: 2021-12-02
opportunity_number: PA-19-195
application_type: 5
activity_code: F31
ic: NS
serial_number: 116935
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2020-12-01
project_end_date: 2023-09-30
study_section: Special Emphasis Panel[ZRG1-F01A-F(20)L]
contact_pi_person_id: 16080666
contact_pi: BROWN, BRANDON LEE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary. The majority of human spinal cord injuries (SCI) are anatomically incomplete potentiallyleaving propriospinal pathways which may relay information past the injury epicenter intact. Following SCI inrodents descending motor tracts sprout and increasingly contact descending propriospinal neurons (DPNs)forming detour circuits to relay signals caudal to the injury. However no studies have evaluated the potentialfor ascending PNs to form bottom-up detour circuits post-SCI. We previously found that silencing longascending PNs (LAPNs) which directly connect the lumbar and cervical spinal enlargements disruptedcoordination at each limb girdle. Surprisingly silencing this anatomically intact pathway post-SCI improvedlocomotor function. Thus it is critical to evaluate LAPN plasticity and determine how this plasticity might berefined by therapeutic interventions. To do so LAPN somatic and dendritic morphology will be characterizedusing a dual-viral system to specifically label LAPNs. We will also use a multi-viral system with a highlymodified rabies virus to identify the sources of direct synaptic input to LAPNs. Increased physical activity andrehabilitative training are known to improve locomotor function and anatomical outcomes post-SCI. To evaluatethe impact of physical activity and rehabilitative training on LAPN plasticity and locomotor function post-SCIwe will alter activity levels by housing animals in tiny cages or in large cages to restrict or facilitate activity.Animals in large cages will also receive rehabilitative training which mimics clinical rehabilitation. Furtherunderstanding SCI-induced neuroplasticity and how physical activity and rehabilitative training impact thisplasticity will further our understanding of SCI pathology and provide new therapeutic targets. Working closelywith my mentors we have developed a training plan that will broaden my scientific skills facilitate independentscientific thought and cultivate skills needed to be a productive postdoctoral fellow. The Kentucky Spinal CordInjury Research Center provides clinical and scientific expertise in SCI and related fields and has a history ofsuccessfully preparing trainees for current and next stages in their careers.Hypothesis. Pre-SCI we hypothesize that DPNs reticulospinals and sensory afferents will provide input toLAPNs. Post-SCI we anticipate 1) LAPN dendrite orientation change 2) LAPNs will be increasingly contactedby sensory afferents to form bottom-up detour circuits and 3) increased activity plus rehabilitative training post-SCI will improve locomotor function impact dendrite reorganization and refine detour circuits.Aim 1. Characterize the somatic and dendritic morphology of LAPNs and identify the sources of directsynaptic input onto LAPNs.Aim 2. Evaluate the effects of activity and rehabilitative training on locomotor function LAPN morphology andthe sources of direct synaptic inputs to LAPNs after T10 contusive spinal cord injury.

project_terms:
Anatomy;Animal Housing;Animal Model;Animals;Area;Axon;Behavior;Behavioral;Behavioral Assay;Breathing;Cells;Cervical;Chest;Clinical;Data;Dendrites;Dependovirus;Ensure;Enterobacteria phage P1 Cre recombinase;Forelimb;GTP-Binding Proteins;Gait;Genes;Genetic Transcription;Growth and Development function;Hindlimb;Human;Injections;Injury;Kentucky;Label;Lateral;Lentivirus;Limb structure;Locomotion;Locomotor Recovery;Mentors;Messenger RNA;Morphology;Motor;Muscle;Nervous system structure;Neuraxis;Neuronal Plasticity;Neurons;Ontology;Outcome;Output;Pathology;Pathway interactions;Pattern;Periodicity;Physical Rehabilitation;Physical activity;Positioning Attribute;Postdoctoral Fellow;Presynaptic Terminals;Rabies;Rabies virus;Recording of previous events;Recovery of Function;Regulation;Rehabilitation therapy;Research;Rodent;Role;Sensory;Signal Transduction;Source;Specificity;Spinal;Spinal Cord Contusions;Spinal Ganglia;Spinal cord injury;Synapses;System;Therapeutic Intervention;Training;Transcriptional Regulation;Vertebrates;Viral;base;career;central pattern generator;improved;kinematics;neuronal excitability;neuroregulation;new therapeutic target;receptor;reconstruction;skills;transcriptome sequencing;white matter

public_health_relevance:
This project aims to evaluate spinal cord injury (SCI)-induced neuroplasticity and how rehabilitative trainingalters this plasticity. By characterizing the morphology of and inputs to long ascending propriospinal neurons(LAPNs) before SCI we will be able to assess SCI induced changes to LAPN morphology determine the roleof LAPNs in forming de novo spinal circuits post-SCI and determine the potential for rehabilitative training torefine these newly formed spinal circuits. Elucidating this will enhance our understanding of SCI pathology andprovide new targets for neuromodulatory and rehabilitative therapies.


application_id: 10279103
project_number: 1R01DE030939-01
project_title: A T.fosythia-derived protease inhibitor in periodontal health and disease
administering_ic: NIDCR
award_notice_date: 2021-07-08
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: DE
serial_number: 030939
program_official: MCNEALY, TAMARA L
project_start_date: 2021-07-12
project_end_date: 2026-06-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
other_pis: BAGAITKAR, JUHI
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Active Sites;Affect;Alveolar Bone Loss;Animal Model;Anti-Bacterial Agents;Automobile Driving;Bacteria;Binding Sites;Biological Response Modifiers;Blood coagulation;Caspase;Cathepsin G;Cathepsin L;Cell surface;Cells;Chronic;Clinical;Communities;Complex;Cysteine;Data;Dental Plaque;Disease;Elastases;Enzymes;Event;Extracellular Matrix;Extracellular Matrix Proteins;Forsythia;Genetic Engineering;Gingiva;Goals;Gram-Negative Anaerobic Bacteria;Growth Factor;Health;Human;Immune;Infection;Inflammation;Inflammatory;Knowledge;Light;Lipoprotein (a);Lung;Lys-gingipain;Modeling;Morbidity - disease rate;Mus;Names;Nature;Nutrient;Oral;Organism;Outcome;Pathogenesis;Pathogenicity;Peptide Hydrolases;Periodontal Diseases;Periodontal Pocket;Periodontitis;Periodontium;Play;Porphyromonas gingivalis;Prevention;Prevotella intermedia;Process;Prokaryotic Cells;Protease Inhibitor;Reaction;Recombinants;Research;Resolution;Role;Serine Protease;Serine Proteinase Inhibitors;Serpins;Side;Signal Transduction;Site;Specificity;Structure;Testing;Thrombus;Tissues;Treponema denticola;Virulence;Virulence Factors;Yin-Yang;base;chronic inflammatory disease;co-infection;controlled release;design;dysbiosis;fascinate;gingipain;in vivo Model;inhibitor/antagonist;member;mortality;mutant;neutrophil;novel;pathobiont;pathogen;periodontopathogen;receptor;scaffold;subcutaneous;subgingival biofilm;subgingival microbiome


application_id: 10278375
project_number: 1R01DC019687-01
project_title: Connexin Function and Mechanisms of Cx26 Deficiency Induced Hearing Loss
administering_ic: NIDCD
award_notice_date: 2021-07-19
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: DC
serial_number: 019687
program_official: WATSON, BRACIE
project_start_date: 2021-07-19
project_end_date: 2026-05-31
study_section: Special Emphasis Panel[ZRG1 IFCN-E (02)]
contact_pi_person_id: 8536073
contact_pi: ZHAO, HONG-BO
other_pis: Not Applicable
congressional_district: 06
department: OTOLARYNGOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Summary Mutations of gap junction gene Cx26 (GJB2) cause the most of hereditary deafness ranging from profoundcongenital deafness at birth to mild late-onset hearing loss in childhood. Mouse models show that Cx26deficiency can induce cochlear developmental disorders hair cell degeneration endocochlear potential (EP)reduction and active cochlear amplification declining. We further found that the cochlear developmentaldisorder rather than hair cell degeneration is a primary cause for congenital deafness whereas late-onsethearing loss is associated with reduction of outer hair cell (OHC) electromotility even hair cells have noconnexin expression. We also evidenced that K+-recycling hypothesis is not the deafness mechanism of Cx26deficiency. However detailed mechanisms of these pathological changes induced by Cx26 deficiency remainunclear. Moreover little is known about pathological changes in the human cochlea. Recently gene therapywith viral-expression of Cx26 in the cochlea was failed to restore hearing. The main reason is lack of requiredknowledge of Cx26 function in the cochlea and deafness mechanisms by Cx26 deficiency. In this proposal we will continually investigate Cx26 function and cellular and molecular mechanisms ofCx26 deficiency-induced congenital deafness and late-onset hearing loss. Cx26 deficiency causes thecochlear developmental disorder indicating that gap junction (GJ) channels as an intercellular communicationconduit are crucial for the cochlear development. Many factors such as promoters transcription factors andmiRNAs can regulate gene expressions during development. However none of these regulators is permeableto GJ channels except miRNAs. miRNAs can regulate gene expression broadly and have a critical role in theorgan development. Deficiency of miRNAs can cause cochlear developmental disorders. In this study we willfirst test whether Cx26 deficiency can disrupt miRNA expression and intercellular communication in thecochlea to affect cochlear development in the congenital deafness. Secondly we will define how Cx26deficiency decline OHC electromotility leading to late-onset hearing loss which patients are good candidatesfor administration of preventive and therapeutic interventions due to normal hearing in their earlier life.Recently connexin non-channel function has been emerged. Besides forming GJ channels connexins canparticipate in cell cytoskeleton formation. We will test whether Cx26 deficiency can impair cytoskeletonformation in the OHCs supporting cells thereby changing OHC-loading (membrane tension) and decliningOHC electromotility and active cochlear amplification. Finally we will use backward-mutation screeningapproach to screen Cx26 mutations in the archival human temporal bones from patients with nonsyndromichearing loss whose pathological changes in the cochlea have been diagnosed to identify mutation-inducedpathological changes in the human cochlea. Apparently these studies will reveal detailed deafnessmechanisms by Cx26 deficiency. Such information is urgently required for developing efficient therapies.

project_terms:
Affect;Archives;Basilar Membrane;Birth;Caliber;Cells;Child;Childhood;Clinical;Cochlea;Connexins;Cytoskeleton;Development;Diagnosis;GJB2 gene;Gap Junctions;Gene Expression;Genes;Hair Cells;Human;Impairment;In Situ;Incidence;Induced Mutation;Knowledge;Laboratories;Lead;Life;Mechanics;Membrane;MicroRNAs;Molecular;Mus;Mutation;National Institute on Deafness and Other Communication Disorders;Nucleotides;Outer Hair Cells;Pathologic;Pathology;Patients;Permeability;Pillar Cell;Recycling;Role;Supporting Cell;Temporal bone structure;Testing;Therapeutic Intervention;Viral;congenital deafness;deafness;developmental disease;gap junction channel;gene therapy;genetic deafness;hearing impairment;hearing restoration;hereditary hearing loss;intercellular communication;mouse model;mutation screening;normal hearing;novel;organ growth;preventive intervention;promoter;public health relevance;transcription factor

public_health_relevance:
Public Health Relevance Statement: Connexin 26 mutations can induce a high incidence of hearing loss responsible for >50% ofcases of nonsyndromic hearing loss in children. In this proposal we will investigate detailedcellular and molecular mechanisms underlying Cx26 deficiency induced hearing loss inparticular mutation-induced pathological changes in the human cochlea. These studies can beexpected to have great impact on the understanding underlying deafness mechanisms and areurgently required for developing efficient therapeutic interventions to this most commonhereditary hearing loss.


application_id: 10276657
project_number: 1R01HL158779-01
project_title: Low Density Neutrophils Link Inflammation and Coagulopathy in COVID-19
administering_ic: NHLBI
award_notice_date: 2022-09-22
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 158779
program_official: AGRAWAL, NITIN
project_start_date: 2022-09-23
project_end_date: 2026-08-31
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: HUANG, JIAPENG ;URIARTE, SILVIA M
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
arra_indicator: N
project_terms:
2019-nCoV;Acute Lung Injury;Acute Respiratory Distress Syndrome;Alpha Granule;Antibodies;Apoptosis;Bilateral;Blood Circulation;Blood Coagulation Disorders;Blood capillaries;Blood specimen;Bronchoalveolar Lavage Fluid;COVID-19;COVID-19 patient;COVID-19 severity;COVID-19/ARDS;Cells;Chemotaxis;Chimeric Proteins;Clinical;Coagulation Process;Custom;Cytoplasmic Granules;Data;Diffuse;Disease;Disease Outcome;Disease Progression;Economics;Endothelial Cells;Exocytosis;Exocytosis Inhibition;FCGR3B gene;Fibrin fragment D;Fibrinogen;Functional disorder;Gene Expression;Hemorrhage;Histologic;Hypoxia;Immune;Impairment;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Interleukin-6;Life;Link;Lower respiratory tract structure;Lung;Lymphocyte;Measures;Mediating;Modeling;Neutrophil Infiltration;Outcome;Patients;Pattern;Perfusion;Phagocytosis;Plasma;Platelet Activation;Platelet Count measurement;Play;Pneumonia;Population;Predisposing Factor;Proteome;Proteomics;Pulmonary Inflammation;Reactive Oxygen Species;Respiratory Burst;Role;SARS-CoV-2 negative;Sampling;Severity of illness;Structure of parenchyma of lung;Surface;T-Lymphocyte;TNF gene;Therapeutic;Therapeutic Intervention;Thrombus;Time;Venous;Viral;antimicrobial;base;cell injury;cytokine;cytokine release syndrome;cytotoxic;density;design;exhaustion;experience;extracellular;immune activation;immunoregulation;immunothrombosis;in vivo;inhibitor;insight;lung injury;mouse model;neutrophil;novel;novel marker;novel therapeutic intervention;pandemic disease;pathogen;pathogenic virus;peripheral blood;prevent;response;therapeutic target;therapeutically effective;transcriptome sequencing;transcriptomics;treatment effect;ventilation


application_id: 10275603
project_number: 1U01DA051377-01A1
project_title: Development of Agents for Synthetic Opioid Overdose
administering_ic: NIDA
award_notice_date: 2021-08-17
opportunity_number: PAR-19-039
application_type: 1
activity_code: U01
ic: DA
serial_number: 051377
suffix: A1
program_official: VEMURI, KIRAN R V
project_start_date: 2021-09-01
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZRG1 MDCN-B (50)]
contact_pi_person_id: 7842243
contact_pi: PRISINZANO, THOMAS EDWARD
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Fentanyl is a synthetic opioid that is approximately 100 times stronger than morphine and is used for thetreatment of pain as well as an adjuvant for anesthesia. It is also considered an incapacitating agent a chemicalthat produces a disabling condition that persists for hours to days after exposure has occurred such as in anunexpected chemical attack. As an opioid fentanyl depresses the central nervous system and respiratoryfunctions and can be lethal by respiratory depression. Due to its high potency ingestion of just a few milligramsof fentanyl or other synthetic opioid can be deadly to an opioid nave individual. Furthermore first responders ata chemical attack site who come in contact with free base fentanyl analogues are at significant risk for life-threatening toxicities.Currently there are three opioid antagonists available on the market that have potential to reverse the effects offentanyl namely naloxone naltrexone and nalmefene. The most commonly used is naloxone which is approvedfor administration by a variety of routes including intravenous intramuscular subcutaneous and intranasal.However recent reports suggest that higher doses or repeated dosing of naloxone (due to recurrence ofrespiratory depression) may be required to reverse fentanyl-induced respiratory depression. This highlights thepressing need for a more potent and longer acting opioid antagonist to combat fentanyl-induced respiratorydepression.Previous studies and our own preliminary results indicate that structural modification of naltrexone can increaseits potency and duration of action. Our central hypothesis is that structural modification of naltrexone will lead tonovel opioid receptor antagonists with the potential to treat overdose by fentanyl and related analogues inindividuals at high risk of exposure. The specific aims of this proposal are (1) identify opioid antagonists withenhanced pharmacodynamic and pharmacokinetic properties; (2) determine and optimize the in vivo activity ofopioid antagonists in mice and for their effectiveness in reversing the effects of fentanyl in preclinical models ofantinociception iteratively with Aim 1; and (3) determine and optimize the in vivo activity of opioid antagonists inrats and for their effectiveness in reversing the effects of fentanyl and selected analogues in preclinical modelsof opioid-induced locomotor and respiratory depression iteratively with Aim 1. The design synthesis evaluationof these molecules will have a broad impact on development of new pharmacologic probes that are designed tointeract with high potency and long duration at opioid receptors. This information will facilitate the identificationof safe and effective therapeutics that would rescue individuals after an acute and unexpected exposure tofentanyl and related analogues.

project_terms:
Acute;Adjuvant;Anesthesia procedures;Antidotes;Centers for Disease Control and Prevention (U.S.);Cessation of life;Chemical Warfare;Chemicals;Chemistry;Country;Development;Dose;Effectiveness;Evaluation;Event;Exposure to;FDA approved;Fentanyl;Gases;Generations;Goals;Half-Life;Hospitalization;Hostage;Hour;In Vitro;Individual;Ingestion;Inhalation Anesthetics;Intramuscular;Intravenous;Laboratories;Lead;Life;Metabolic;Military Personnel;Modification;Morphine;Moscow;Mus;Naloxone;Naltrexone;Neuraxis;Neuropharmacology;Opioid;Opioid Antagonist;Opioid Receptor;Pain management;Pharmaceutical Preparations;Pharmacology;Pre-Clinical Model;Property;Rapid screening;Rattus;Recurrence;Reporting;Research;Research Personnel;Respiratory physiology;Risk;Route;Safety;Series;Serum;Site;Structure;Survivors;Testing;Therapeutic;Time;Toxic effect;Ventilatory Depression;Work;aerosolized;analog;base;carfentanil;combat;design;experience;experimental study;fentanyl overdose;first responder;follow-up;high risk;improved;in vivo;incapacitating agents;mass casualty;milligram;mouse model;nalmefene;noradrenergic;novel;opioid overdose;overdose death;pharmacokinetics and pharmacodynamics;subcutaneous;synthetic opioid;therapeutically effective;water solubility

public_health_relevance:
Project NarrativeOur central hypothesis is that structural modification of naltrexone will lead to novel opioid receptor antagonistswith the potential to treat overdose by fentanyl and related analogues in individuals at high risk of exposure. Thedesign synthesis evaluation of these molecules will have a broad impact on development of new pharmacologicprobes that are designed to interact with high potency and long duration at opioid receptors. This information willfacilitate the identification of safe and effective therapeutics that would rescue individuals after an acute andunexpected exposure to fentanyl and related analogues.


application_id: 10274783
project_number: 3R01DA044311-05S1
project_title: Dynamic Signaling of NRG3-ErbB4 in the Hippocampus Mediates Nicotine Withdrawal Phenotypes
administering_ic: NIDA
award_notice_date: 2021-02-10
opportunity_number: PA-20-222
application_type: 3
activity_code: R01
ic: DA
serial_number: 044311
suffix: S1
program_official: LOSSIE, AMY C
project_start_date: 2018-04-01
project_end_date: 2023-01-31
study_section: Molecular Neuropharmacology and Signaling Study Section[MNPS]
contact_pi_person_id: 10484112
contact_pi: TURNER, JILL R.
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACTNearly 80% of smokers attempting to quit fail. While there is increased appreciation for geneticcontributions to this statistic the molecular mechanism(s) underlying this remain a critical gap in ourknowledge. We have previously shown that multiple single-nucleotide polymorphisms (SNPs) across theNeuregulin 3 (NRG3) gene significantly associate with smoking cessation outcomes in two independentcohorts of smokers.104 We now have new evidence that SNPs previously identified to increase NRG3expression are significantly associated with nicotine withdrawal phenotypes in smokers. Our published murineexperiments104 demonstrate that this increased NRG3 expression may be responsible for affective nicotinewithdrawal (WD) phenotypes in particular: (1) chronic nicotine and 24hWD increase mRNA and proteinexpression of NRG3 and it's receptor ErbB4 in the ventral hippocampus (2) genetic interruption of NRG3signaling blocks expression of nicotine WD anxiety-like phenotypes in the Novelty-induced Hypophagia Test amodel shown to be dependent upon ventral hippocampal function and (3) inhibition of ErbB4 the NRG3receptor by Afatinib reduced anxiety-like behaviors during WD in this same behavioral model. While this ispersuasive evidence for the role of ventral hippocampal NRG3 signaling in modulating affective nicotine WDphenotypes little is known regarding the precise mechanisms through which NRG3 and nicotine interact.Therefore the overall goal of this proposal is to systematically investigate the cell-specific role of the NRG3-ErbB4 signaling in the ventral hippocampus during nicotine treatment and withdrawal. To accomplish this weare posing three central questions: 1) Is NRG3-ErbB4 signaling between pyramidal cells and interneurons inthe hippocampus necessary for expression of nicotine WD-induced anxiety? 2) Does the location of nicotinicreceptors and NRG3/ErB4 dictate chronic nicotine and 24hWD effects on cellular cascades and glutamatergicinput? and (3) How does nicotine-mediated NRG3-ErbB4 signaling regulate the activity of CCK+ and PV+cells to influence the dynamic properties of the hippocampal circuit? Our approach is significant because itcombines collective genetic information from both human and animal studies to generate atranslational high-impact hypothesis examining the functional role of this signaling pathway within thespecific cell-types of the hippocampus during nicotine and withdrawal. Completion of these studies willexpand understanding of the complex interplay between genetics circuit function and behavior in order todevelop better more specific smoking cessation aids.

project_terms:
Abstinence;Affective;Animals;Anxiety;Awareness;Axon;Behavior;Behavioral;Behavioral Model;Binding;Biochemical;Biological Assay;Calcium;Cells;Cholecystokinin;Chronic;Cleaved cell;Complex;Dimerization;Drug Exposure;ERBB2 gene;ErbB4 gene;FRAP1 gene;Family;Genes;Genetic;Genetic Transcription;Glutamates;Goals;Heterodimerization;Hippocampus (Brain);Homo;Homodimerization;Human;In Vitro;Individual;Interneurons;Interruption;Knowledge;Laboratories;Ligation;Location;MAPK3 gene;Mediating;Microscopy;Modeling;Molecular;Morphine;Mus;NRG3 gene;Nicotine;Nicotine Dependence;Nicotine Withdrawal;Nicotinic Receptors;Opiate Addiction;Opioid;Outcome;Oxycodone;Parvalbumins;Pathway interactions;Pattern;Phenotype;Phosphorylation;Population;Property;Protein Isoforms;Proteins;Proto-Oncogene Proteins c-akt;Publishing;Pyramidal Cells;Receptor Activation;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Reporting;Risk;Role;Saline;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Single Nucleotide Polymorphism;Site;Slice;Smoker;Smoking;Specificity;Surgeon;Synapses;Testing;Therapeutic;Therapeutic Intervention;Tissues;Tobacco smoking behavior;United States;Variant;Viral;Western Blotting;Withdrawal;Withdrawal Symptom;anxiety-like behavior;beta-site APP cleaving enzyme 1;cell type;cohort;density;drug relapse;drug reward;drug withdrawal;genetic information;hippocampal pyramidal neuron;improved;interest;mRNA Expression;mu opioid receptors;new therapeutic target;nicotine treatment;novel;opioid withdrawal;preclinical study;preventable death;prospective;protein expression;receptor;receptor expression;smoking cessation;synergism;transcriptomics;withdrawal-induced anxiety

public_health_relevance:
PROJECT NARRATIVETobacco smoking is still the leading cause of preventable death in the United States 50 years after theSurgeon General's Report on Smoking. While the majority of smokers would like to quit and are aware of therisks of smoking most are unable to do so with currently available therapeutics. This proposal aims toelucidate the roles of a novel signaling pathway (NRG3-ErbB4) during nicotine and withdrawal in hopes ofdeveloping better therapeutics for nicotine dependence by specifically targeting anxiety-related WD symptoms.


application_id: 10273379
project_number: 1R21DC019602-01
project_title: Hearing Healthcare Assessment in Rural Communities (HHARC)
administering_ic: NIDCD
award_notice_date: 2021-08-04
opportunity_number: RFA-DC-19-001
application_type: 1
activity_code: R21
ic: DC
serial_number: 019602
program_official: KING, KELLY ANNE
project_start_date: 2021-08-04
project_end_date: 2023-07-31
study_section: Special Emphasis Panel[ZDC1 SRB-R (39)]
contact_pi_person_id: 11512687
contact_pi: BUSH, MATTHEW LEE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Administrator;Adult;Affect;Appalachian Region;Area;Chronic;Communication impairment;Communities;Country;County;Depressed mood;Development;Diagnosis;Diagnostic;Disease;Education;Elderly;Employment;Enabling Factors;Enrollment;Environmental Risk Factor;Epidemiology;Evaluation;Face;Geographic state;Goals;Health;Health Personnel;Health Services Accessibility;Healthcare;Healthcare Systems;Hearing;Hearing Tests;Intervention;Kentucky;Lead;Life;Measurable;Medical;Methods;Morbidity - disease rate;Occupational;Outcome;Patients;Phase;Population;Positioning Attribute;Precede-Proceed Model;Predisposing Factor;Prevalence;Prevention;Primary Health Care;Protocols documentation;Provider;Public Health;Reinforcing Factor;Research;Resources;Rural;Rural Appalachia;Rural Community;Rural Health Centers;Testing;Time;United States;Vulnerable Populations;Well in self;barrier to care;base;care delivery;experience;health care availability;health care delivery;health care service;health care service utilization;hearing impairment;hearing loss treatment;improved;innovation;medical specialties;medically underserved;mortality;novel;practice-based research network;preference;prevent;primary care services;programs;rural area;rural patients;rural underserved;screening;social;therapy development;treatment comparison;underserved community;urban setting;virtual;young adult


application_id: 10273171
project_number: 1R21CA261844-01
administering_ic: NCI
award_notice_date: 2021-09-14
opportunity_number: RFA-CA-20-028
application_type: 1
activity_code: R21
ic: CA
serial_number: 261844
program_official: BERRIGAN, DAVID
project_start_date: 2021-09-14
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZCA1 SRB-T (M1)]
contact_pi_person_id: 12488104
contact_pi: LAUCKNER, CAROLYN
other_pis: MCLOUTH, LAURIE
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-09-14
project_title:
Pilot test of an mHealth Intervention for Reducing Alcohol Use among Rural Adolescent and Young Adult Cancer Survivors

project_abstract:
ABSTRACTAdolescent and young adult (AYA) survivors of cancer have poorer health than their peers who have not beendiagnosed with cancer and are more likely to die from non-cancer related causes. Researchers have called forhealth promotion interventions to improve outcomes and reduce risk behaviors among this population;however one key risk factoralcohol consumptionhas been largely unstudied. Most AYA survivors arecurrent drinkers and over a third report engaging in binge drinking. Survivors living in rural areas may be evenmore at risk as they have limited access to health and psychological care and many youth in these areasreport more frequent alcohol consumption than their urban counterparts. Given that alcohol use is associatedwith increased risk of cancer recurrence poorer survival and other comorbidities it is important to exploreinterventions for reducing this behavior among rural AYA survivors. The proposed research will test a mobilehealth (mHealth) intervention for reducing alcohol use called TRAC: Tracking and Reducing AlcoholConsumption. This intervention which is currently being implemented among a sample of people living withHIV/AIDS is based on principles of motivational interviewing. It utilizes weekly phone conversations with aninterventionist over an 8-week period and twice-daily self-monitoring of alcohol consumption using mobilesurveys and Bluetooth breathalyzers. The intervention has strong potential for acceptability among rural AYAsgiven this populations high digital literacy and will also reduce barriers to care experienced by those in ruralareas who often have to travel long distances to see providers in-person. Through key informant interviewsthe TRAC intervention will be adapted and refined for rural AYA survivors. Then it will be tested through a pilotrandomized controlled trial with a monitoring and education comparison group. This pilot trial will assessintervention retention adherence and acceptability and provide preliminary data regarding impact on alcoholuse. Overall the proposed research will yield valuable feasibility data to inform a definitive randomizedcontrolled trial of this intervention to test efficacy among a larger sample of rural AYA survivors. If TRAC isshown to be successful in this population it could be implemented in rural cancer clinics across the countryand reduce risky alcohol consumption among the over 2 million AYAs in the United States.

project_terms:
AIDS/HIV problem;Address;Adherence;Adolescent and Young Adult;Advocate;Aftercare;Alcohol consumption;Alcohols;Area;Behavior;Bluetooth;Cancer Center;Cancer Survivor;Cancer Survivorship;Caring;Cellular Phone;Clinic;Clinical Trials;Communities;Counseling;Country;Data;Development;Diagnosis;Education;Enrollment;Evidence based intervention;Frequencies;Health;Health Promotion;High Prevalence;Incidence;Intervention;Intervention Trial;Interview;Kentucky;Literature;Malignant Neoplasms;Mental Health;Meta-Analysis;Monitor;Moods;Oncology;Outcome;Ownership;Persons;Physical activity;Population;Primary Health Care;Procedures;Provider;Randomized Controlled Trials;Reporting;Research;Research Personnel;Risk;Risk Behaviors;Risk Factors;Rural;Sampling;Services;Sleep;Structure;Surveys;Survivors;Technology;Telephone;Testing;Transportation;Travel;United States;Veterans;Visit;Youth;acceptability and feasibility;aged;alcohol behavior;alcohol intervention;alcohol monitoring;barrier to care;base;binge drinker;binge drinking;cancer recurrence;cancer risk;comorbidity;comparison group;digital;digital health;drinking;efficacy testing;experience;feasibility testing;follow-up;health literacy;improved outcome;informant;innovation;literacy;mHealth;mortality;motivational enhancement therapy;nutrition;peer;physical conditioning;pilot trial;psychologic;reduced alcohol use;rural area;rural dwellers;social stigma;substance use;survivorship;tool;underage drinking

public_health_relevance:
PROJECT NARRATIVEMost adolescent and young adult (AYA) survivors of cancer engage in alcohol consumption with manyexceeding recommended moderate drinking limitsa concerning behavior given alcohols association withpoorer health outcomes. Rural AYA cancer survivors are especially vulnerable as rural AYAs drink at higherlevels than their urban counterparts and often have limited access to health and psychological care. Theproposed research will aim to reduce alcohol use among this population by adapting and pilot testing an 8-week smartphone-based alcohol reduction intervention (TRAC) which pairs weekly counseling sessions withmobile monitoring of alcohol behaviors.


application_id: 10272821
project_number: 261201800013I-0-759102000001-1
project_title: NCI SEER-LINKED PEDIATRIC WHOLE SLIDE IMAGING (POP: 8/17/2020 - 8/16/2021)
administering_ic: NCI
project_start_date: 2020-08-17
project_end_date: 2021-08-16
contact_pi_person_id: 77812978
contact_pi: TUCKER, THOMAS
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
funding_mechanism: R and D Contracts
project_abstract:
Project Abstract: The development of high-quality digital scanners has made it possible to produce detailed images of hematoxylin and eosin (H&E) slides from cancer patient histological material. Emerging new informatics technologies also make it possible to develop machine learned models to extract additional important features from the digitized slides such as tumor infiltrating lymphocytes delineating tumor regions and identifying nuclear segmentation. The Kentucky Cancer Registrys Virtual Tissue Repository (VTR) has experience obtaining the H&E slides for specific patient populations from pathology labs across the state having these slides digitized submitting the anonymized digitized images to the National Cancer Institute (NCI) for research and returning the original slides to the contributing pathology labs.

project_terms:
Cancer Patient;Cancer Surveillance Research Program;Childhood;Computer software;Development;Diagnosis;Goals;Hematoxylin and Eosin Staining Method;Histologic;Image;Informatics;Kentucky;Logistics;Machine Learning;Malignant Childhood Neoplasm;Metadata;Modeling;National Cancer Institute;Nuclear;Operative Surgical Procedures;Pathology;Research Institute;Resources;Slide;Technology;Testing;Tissue Banks;Tumor-Infiltrating Lymphocytes;cancer diagnosis;digital;experience;microscopic imaging;neoplasm registry;patient population;tumor;virtual;whole slide imaging


application_id: 10272657
project_number: 3P42ES007380-23S1
administering_ic: NIEHS
award_notice_date: 2021-02-04
opportunity_number: PA-18-591
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S1
program_official: HENRY, HEATHER F
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1(SF)
contact_pi_person_id: 8776790
contact_pi: PENNELL, KELLY G
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
UK NIEHS SRP Project # 3 Supplement Relating to Extending Halo-organic Capture/Remediation Technology to Corona Virus Membrane Mask and Enclosed Space Air Filter Development

project_abstract:
Abstract: Through our NIEHS-SRP research we have advanced materials (membranes to adsorptive andrecognition-based polymers) development for degradation and capture/sensing of toxic organics from water.Membranes and polymers-based technologies are also used in air filtration area to remove particles andaerosols. Learning from nanoparticles and virus to organic separations from water media we propose toadvance the aqueous treatment technology and science to create advanced mask and enclosed space airfiltration platform to capture coronavirus particles in a transformative way. By expanding on our current specificaims the overall goal will be to bring interaction-based capture and recognition with highly efficient airbornecoronavirus removal with easy breathability and air filtration properties. The transfer of smart materialsdevelopment knowledge from water remediation area to airborne virus removal area will bring in immensebenefit to society and human health. Virus nanoparticles (micro aerosols) build-up in enclosed air space iscritical factor in viral transmission. For the enclosed space air filter unique regenerative mechanisms will bedeveloped. This supplement will allow us to add virus capture/deactivation functionality so that our on-goinghalo-organic capture/destruction technology will also be effective against coronavirus (COVID-19)environmental pollutant. Our work will involve pseudotype virus particles and we will also concentrate on theouter surface S-protein and functionalized synthetic nanoparticles.

project_terms:
2019-nCoV;Address;Adhesives;Adsorption;Aerosols;Affinity;Air;Anti-Bacterial Agents;Appearance;Area;Binding;Biochemistry;Biomedical Research;Breathing;COVID-19;Cations;Confined Spaces;Coronavirus;Data Collection;Dental crowns;Development;Drops;Electrostatics;Engineering;Environmental Pollutants;Excision;Exhibits;Exposure to;Frequencies;Gel;Generations;Glycoproteins;Goals;Health;Heating;Human;Humidity;Hydration status;Hydrogels;Hydrogen Bonding;Immobilization;Knowledge;Lead;Learning;Literature;Magnetism;Masks;Membrane;Membrane Proteins;Metals;Methods;Modification;Molecular;Morphology;Mucins;Nanostructures;National Institute of Environmental Health Sciences;Natural regeneration;Nature;Nutritional Science;Oxides;Permeability;Phase;Polymers;Property;Proteins;Public Health;Reactive Oxygen Species;Reporting;Research;Risk;Science;Signal Recognition Particle;Societies;Source;Sulfhydryl Compounds;Surface;Swelling;System;Technology;Thick;Variant;Virion;Virus;Virus Inactivation;Water;Work;aerosolized;air filter;air filtration;aqueous;base;crosslink;design;food science;graphene;hazard;iron oxide;magnetic field;materials science;monomer;nanocomposite;nanoparticle;novel;particle;physical property;pollutant;polyvinylidene fluoride;pressure;programs;regenerative;remediation;superfund site;symposium;transmission process;viral transmission

public_health_relevance:
PROJECT NARRATIVEThe persistence of toxic pollutants at Superfund sites and coronavirus transmission issues poses a majorenvironmental public health problem and a serious need for environmental solutions to reduce risk. Ourresearch is expected to lead to advanced air filtration technologies for remediation of SARS COV-2 and otherairborne viruses learning from current NIEHS halo-organic remediation science. By extending lessons andtechnology from water remediation to humid air filtration and molecular pollutants to virus nanoparticle captureit will be possible to bring significant advancements to society and human health.


application_id: 10271869
project_number: 2P20GM121327-06
administering_ic: NIGMS
award_notice_date: 2022-02-15
opportunity_number: PAR-19-312
application_type: 2
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C2)]
subproject_number: 6637
contact_pi_person_id: 14584136
contact_pi: ZHU, CAIGANG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-01-01
project_title:
An intra-vital metabolic microscope to reveal the mechanisms of radiation resistance in  head and neck carcinomas

project_abstract:
PROJECT SUMMARYGiven the clinical importance of radio-resistance in head and neck squamous cell cancer (HNSCC)understanding how radio-resistant tumors rewire their metabolic pathways and vascular network to escaperadiotherapy (RT) is critical towards developing strategies to eliminate residual tumor cells and/or preventsubsequent recurrence. Currently no techniques are available to provide a systems level approach to image themajor axes of metabolism and the associated vasculature at a spatial resolution that can elucidate the modulationof cancer cell metabolism or vascular reprogramming in vivo. Our technological goal is to create innovativesolutions in microscopy automated algorithms and experimental strategies to image tumor metabolism vascularfunction and architecture at a spatial resolution that allows for visualization of primary tumors residual diseaseand recurrence following RT to facilitate the understanding of tumor biology and function assessment ofrecurrence risk and design of therapies to mitigate residual disease and/or recurrence altogether in pre-clinicalmodels. Our technological approach fills an important gap that exists between in vitro cell studies and whole-body imaging and is complementary to metabolomics and immunohistochemistry. The Specific Aims of thisproposal are to develop a portable multi-parametric microscope that combines structured illumination microscopyand dark field microscopy in a re-emission geometry to image key metabolic and vascular endpointssimultaneously (Specific Aim 1); and use the technology with in vivo HNSCC orthotropic models to test thenovel hypothesis that RT-induced hypoxia-inducible factors (HIF-1 and HIF-2) expression and subsequentchanges in metabolism/vasculature underlie HNSCC radio-resistance (Specific Aim 2). This proposal will setthe foundation for translating our technology to patient-derived xenograft models that have been shown tofaithfully recapitulate many of the micro-environmental features of patient tumors allowing us to move ourtechnique forward towards translational pharmaceutical research.

project_terms:
Algorithms;Animal Model;Architecture;Bioenergetics;Biological;Biomedical Research;Blood Vessels;Cancer Biology;Cancer Center;Cancer Model;Cancer Patient;Cells;Characteristics;Citric Acid Cycle;Clinical;Complement;Dark-Field Microscope;Development;Esters;Foundations;Geometry;Glycolysis;Goals;Head and Neck Squamous Cell Carcinoma;Hypoxia;Hypoxia Inducible Factor;Image;Immunohistochemistry;In Vitro;Kentucky;Label;Lighting;Lipids;Measures;Membrane Potentials;Metabolic;Metabolic Pathway;Metabolism;Microscope;Microscopy;Modeling;Monitor;Optics;Outcome;Patients;Pharmacologic Substance;Pre-Clinical Model;Primary Neoplasm;Process;Radiation Tolerance;Radiation therapy;Radiobiology;Reactive Oxygen Species;Recurrence;Research;Residual Tumors;Resistance development;Resolution;Risk;Role;SLC2A1 gene;Structure;System;Targeted Radiotherapy;Techniques;Technology;Testing;Time;Tissues;Translating;Tumor Angiogenesis;Tumor Biology;Tumor Volume;Universities;Visualization;Warburg Effect;angiogenesis;automated algorithm;cancer cell;cancer imaging;cancer stem cell;design;glucose uptake;high resolution imaging;image processing;imaging capabilities;improved outcome;in vivo;in vivo imaging;innovation;insight;lens;metabolic imaging;metabolic phenotype;metabolomics;mitochondrial membrane;mitochondrial metabolism;neoplastic cell;new technology;novel;novel strategies;optical imaging;overexpression;patient derived xenograft model;portability;pre-clinical;prevent;radiation resistance;radioresistant;stable isotope;stem-like cell;targeted treatment;tetramethylrhodamine;therapy design;therapy resistant;tissue oxygenation;tool;translational cancer research;trend;tumor;tumor metabolism;whole body imaging


application_id: 10271868
project_number: 2P20GM121327-06
project_title: Circulating tumor cell-neutrophil clusters in breast cancer metastasis
administering_ic: NIGMS
award_notice_date: 2022-02-15
opportunity_number: PAR-19-312
application_type: 2
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C2)]
subproject_number: 6636
contact_pi_person_id: 12106844
contact_pi: LIU, XIA X
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 SUMMARYMetastasis causes a majority of breast cancer (BCa)-related deaths. Among all types of BCas triple-negativebreast cancers (TNBCs) are more aggressive and have a poorer prognosis. To metastasize cancer cells mustenter into the circulatory system. These circulating tumor cells (CTCs) are considered the seeds of metastasis.Recently both our preliminary data and other studies have shown that neutrophils can interact with asubpopulation of CTCs (named CTC-neutrophil clusters) to facilitate metastasis. However the features ofneutrophil-associated CTCs and how CTC-associated neutrophils facilitate metastasis has yet to be determined.The overall objective of this proposal is to identify and characterize neutrophil-associated CTCs and how theinteraction promotes metastasis with the hope of developing a novel therapeutic strategy to inhibit metastasisby blocking CTC-neutrophil cluster formation. We found that the intercellular adhesion molecule 1 (ICAM-1)which is well-known to bind to Mac-1 on neutrophils is overexpressed in lung metastases and knockdown ofICAM-1 inhibits TNBC metastasis. In addition ICAM-1+ TNBC cells produce high level of soluble urokinaseplasminogen activator receptor (uPAR). Since uPAR is a potent chemoattractant for recruitment of neutrophilsand facilitates Mac-1-mediated adhesion we hypothesize that ICAM-1+ CTCs are prone to associate withneutrophil by increasing suPAR production to enhance their metastatic ability. Furthermore our preliminaryfindings indicate that Mac-1 expression is upregulated in circulating neutrophils from tumor-bearing mice. Sinceboth phospholipase A2 and arachidonate 5-lipoxygenase the key enzymes in arachidonic acid (AA) metabolismcan upregulate Mac-1 expression we also hypothesize that enhanced AA metabolism in circulating neutrophilsis required for their interaction with CTCs to promote metastasis. We propose 2 Specific Aims: 1) to determinethe molecular mechanisms by which ICAM-1 promotes BCa metastasis particularly whether uPAR facilitatesICAM-1 and Mac-1 mediated CTC and neutrophil interaction using both mouse and human TNBC models; 2) todissect the role of AA metabolism in the pro-metastatic activity of circulating neutrophils using blood samplesfrom both TNBC mouse models and BCa patients. The results from this proposal will not only reveal newmechanisms of metastasis but also have significant implications for understanding how AA metabolismregulates pro-metastatic function of neutrophils which will pave the way for the design of next-generationneutrophil-based immunotherapy.

project_terms:
Adhesions;Arachidonate 5-Lipoxygenase;Arachidonic Acids;Binding;Biological Assay;Blood Circulation;Blood specimen;Brain;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer cell line;Breast cancer metastasis;Cancer Center;Cardiovascular system;Cell Communication;Cells;Centers of Research Excellence;Cessation of life;Chemotactic Factors;Chemotaxis;Data;Development;Diagnosis;Dinoprostone;Disease;Distant;Endothelial Cells;Enzymes;Exhibits;Goals;Human;Immune;Immunotherapy;In Vitro;Intercellular adhesion molecule 1;Kentucky;Lung;Macrophage-1 Antigen;Malignant Neoplasms;Mediating;Metabolic Pathway;Metabolism;Metastatic Neoplasm to the Lung;Molecular;Mus;Names;Neoplasm Circulating Cells;Neoplasm Metastasis;Neutrophil Infiltration;Nonmetastatic;Organ;Phenotype;Phospholipase A2;Play;Production;Prognosis;Property;Prostaglandin-Endoperoxide Synthase;Role;Seeds;Site;Testing;Therapeutic;Tissues;Universities;Urokinase Plasminogen Activator Receptor;Western Blotting;base;cancer cell;design;healthy volunteer;improved;in vivo;innovation;intravital imaging;knock-down;lung colonization;malignant breast neoplasm;metastatic process;mouse model;neutrophil;next generation;novel;novel therapeutic intervention;overexpression;recruit;single-cell RNA sequencing;stem cells;targeted treatment;triple-negative invasive breast carcinoma;tumor;tumor metabolism;tumorigenic;uptake


application_id: 10271867
project_number: 2P20GM121327-06
project_title: Imaging Core
administering_ic: NIGMS
award_notice_date: 2022-02-15
opportunity_number: PAR-19-312
application_type: 2
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C2)]
subproject_number: 6635
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Aging;Animal Disease Models;Area;Award;Bioinformatics;Bioluminescence;Biomedical Research;Biometry;Cancer Center;Centers of Research Excellence;Clinical;Complex;Computer software;Consult;Consultations;Data;Development;Disease Progression;Distant;Equipment;Evaluation;Extramural Activities;Faculty;Floor;Fluorescence;Goals;Human Resources;Image;Imaging Device;Imaging Techniques;Individual;Infrastructure;Institutes;Kentucky;Laboratories;Laboratory Research;Link;Malignant Neoplasms;Medicine;Metabolic;Metabolism;Methodology;Methods;Microscope;Mission;Monitor;Mus;Neoplasm Metastasis;Organ;Pathology;Phase;Pilot Projects;Positioning Attribute;Proteins;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Role;Sampling;Scientist;Services;Site;Slide;System;Tissues;Training;Transfection;Universities;Work;advanced analytics;analytical tool;animal facility;anticancer research;cancer therapy;cell motility;cost effective;design;digital;experimental study;flexibility;imaging capabilities;imaging modality;imaging study;imaging system;in vivo;in vivo imaging;in vivo imaging system;instrument;metabolomics;microscopic imaging;multidisciplinary;novel;optical imaging;programs;skills;success;treatment response;tumor initiation;tumor metabolism;tumorigenesis


application_id: 10271866
project_number: 2P20GM121327-06
project_title: Metabolism Core
administering_ic: NIGMS
award_notice_date: 2022-02-15
opportunity_number: PAR-19-312
application_type: 2
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C2)]
subproject_number: 6634
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Algorithms;Behavior;Biochemical;Biochemistry;Bioinformatics Shared Resource;Biological;Biology;Biomass;Biometry;Cancer Center;Carbon;Cells;Centers of Research Excellence;Chromatography;Classification;Collaborations;Consult;Culture Media;Data;Data Analyses;Databases;Development;Dinucleoside Phosphates;Disease;Electrophoresis;Experimental Designs;Fourier Transform;Genomics;Goals;Human Resources;Inductively Coupled Plasma Mass Spectrometry;Informatics;Infusion procedures;Isotope Labeling;Isotopes;Kentucky;Liquid Chromatography;Literature;Logistic Regressions;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic;Metabolic Pathway;Metabolism;Methods;Mus;Nuclear Magnetic Resonance;Operative Surgical Procedures;Organism;Output;Oxidation-Reduction;Pathway Analysis;Phase;Preparation;Principal Investigator;Procedures;Process;Protein Analysis;Protein Array;Proteins;Research Personnel;Resolution;Retrieval;Sampling;Schedule;Services;Source;Standardization;Statistical Data Interpretation;System;Techniques;Technology;Time;Tissue Harvesting;Tissues;Tracer;Universities;Update;Validation;advanced analytics;analytical method;base;cell growth;data acquisition;data reduction;design;experimental study;high throughput analysis;medical specialties;metabolic abnormality assessment;metabolome;metabolomics;stable isotope;tumor metabolism;ultra high resolution;web site


application_id: 10271865
project_number: 2P20GM121327-06
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2022-02-15
opportunity_number: PAR-19-312
application_type: 2
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C2)]
subproject_number: 6633
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe University of Kentucky (UK) Center for Cancer and Metabolism (CCM) is a unique multidisciplinary Centerof Biomedical Research Excellence (COBRE) embedding a strategically developed sustainable centerinfrastructure that cultivates cutting-edge research focused on the role of metabolic dysregulation in cancerdevelopment and progression. The Administrative Core provides critical scientific and administrative leadershipto advance the goals of the CCM: to develop and sustain a thematically focused multidisciplinary centerinfrastructure dedicated to defining the role of altered metabolism in the development and treatment of cancerand to use this innovative center structure to develop promising early-stage investigators with enhanced cancerresearch skills. The goal of the Administrative Core is to increase the scientific productivity of the centers facultyby delivering efficient administrative services across scientific projects and cores as well as pilot projects throughan organizational / leadership framework that supports flexible team-based mentoring and provides for clearaccountability. The Administrative Core is the central coordinating hub responsible for integrating highlycomplementary disciplinary strengths at UK in cancer metabolism and informatics and leveraging sophisticatedmetabolomics tools and advanced cancer imaging capabilities in support of data-intensive research focused oncancer metabolism. The core has primary responsibility for facilitating the CCMs scientific vision operating onprinciples grounded in transformational leadership and shared administrative oversight. Administrative Corefunctions are operationalized through the following 3 specific aims: 1) to provide overall operational managementof the center; 2) to facilitate research training mentoring and career development activities to develop early-stage investigators in cancer and metabolism and expand research in this area through pilot projects; and 3) toconduct overall planning and evaluation of CCM activities and resources. The core implements all administrativeactivities of the CCM: oversees daily center activities; manages program communications fiscal processesmeeting organization and advisory committee input; facilitates and expedites interactions among projects andcores; manages the pilot project program; and leads program and project evaluation efforts. The core overseesa total of 4 projects 2 scientific cores a biostatistics and bioinformatics support component that is integratedinto each project and 4 pilot projects each year. In addition the core ensures highly effective well-planned team-based mentorship including basic and clinical perspectives and external expertise for early-stage investigators.The core supports CCM investigators through their career development milestones including tenure andpromotion stages. In implementing these activities effectively the Administrative Core contributes substantiallyto development of a sustainable biomedical research infrastructure dedicated to advancing a cancer metabolismmultidisciplinary theme.

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


application_id: 10271864
project_number: 2P20GM121327-06
project_title: University of Kentucky Center for Cancer Metabolism
administering_ic: NIGMS
award_notice_date: 2022-02-15
opportunity_number: PAR-19-312
application_type: 2
activity_code: P20
ic: GM
serial_number: 121327
program_official: REVILLEZA, MARIA JAMELA R
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C2)]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: ST CLAIR, DARET K
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Applications Grants;Area;Basic Science;Biochemistry;Bioinformatics;Biology;Biometry;Cancer Center;Cell Survival;Centers of Research Excellence;Clinical;Clinical Trials;Collaborations;Core Facility;Coupled;Data;Development;Disease;Distant Metastasis;Drug resistance;Early Diagnosis;Educational workshop;Environment;Epigenetic Process;Equipment;Extramural Activities;Faculty;Fees;Fostering;Foundations;Funding;Goals;Grant;Growth;Health;Image;Incidence;Infrastructure;Interdisciplinary Study;Intervention;Kentucky;Lead;Link;Malignant Neoplasms;Mediator of activation protein;Mentors;Metabolic;Metabolic Diseases;Metabolism;Methodology;NCI Center for Cancer Research;Neoplasm Metastasis;Obesity;Outcome;Oxidation-Reduction;Phase;Pilot Projects;Positioning Attribute;Protein Array;Quality of life;Recurrence;Research;Research Personnel;Research Project Grants;Research Support;Role;Scientist;Seeds;Services;Signal Transduction;System;Therapeutic;Training;Translational Research;Translations;United States National Institutes of Health;Universities;Vital capacity;animal imaging;anticancer research;base;cancer cell;cancer imaging;cancer initiation;cancer prevention;cancer therapy;career;cohesion;defined contribution;early detection biomarkers;editorial;improved;in vivo;innovation;metabolic imaging;metabolomics;mortality;multidisciplinary;new technology;next generation;novel;prevent;programs;recruit;skills;success;symposium;synergism;therapeutic target;therapy resistant;tool;tumor;tumor initiation;tumor metabolism;tumorigenesis


application_id: 10271240
project_number: 5F31HL151111-02
project_title: Bronchiolar Dysplasia in COPD is Governed by Loss of Polycomb Repressive Complex 2
administering_ic: NHLBI
award_notice_date: 2021-03-03
opportunity_number: PA-19-196
application_type: 5
activity_code: F31
ic: HL
serial_number: 151111
program_official: WHITE, MARQUITTA JONISSE
project_start_date: 2020-03-15
project_end_date: 2021-10-14
study_section: Special Emphasis Panel[ZRG1-F10A-R(20)L]
contact_pi_person_id: 11938641
contact_pi: BYRD, ARIA
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 SUMMARYFuture Research QuestionsAs a graduate student in the Toxicology and Cancer Biology Department of University of Kentucky I seek tounderstand the complex molecular processes that drive development of lung diseases. The goal of mydissertation research is to determine how the role of Polycomb Repressive Complex 2 (PRC2) directs properlung stem cell fate and how this process is dysregulated in lung disease. My central hypothesis is that PRC2normally represses basal and goblet cell fates in bronchiolar epithelium and that loss of PRC2-mediatedrepression of these lineages leads to phenotypes observed in bronchiolar epithelium of Chronic ObstructivePulmonary disease (COPD) including basal cell and goblet cell metaplasia.Background and MethodologyPolycomb Repressive Complex 2 (PRC2) modulates gene expression through histone modification. Recentunpublished data from the Brainson lab suggests that PRC2 activity is dysregulated in chronic obstructivepulmonary disease (COPD). These findings fit with others in the field that demonstrated loss of PRC2 indeveloping lung causes aberrant expression of basal cell markers including KRT5 and p63 in distal lung airwaysin mice. Together these data suggest that improper PRC2 activity is important for cell development fate andfunction. They also warrant further investigation into PRC2's role in disease development and propagationparticularly those involving lung functions.MethodologyThe Aims of my proposal are to: 1) Elucidate the cellular changes in bronchiolar epithelial cells observed in invitro and in vivo after genetic modulation of the PRC2 complex and 2) Confirm that loss of proper PRC2 genesilencing leads to expansion of basal cell and goblet cell fates in human bronchiolar epithelial cells. For Aim 1I am knocking out one or two alleles of Ezh2 the gene encoding the enzyme for PRC2 in adult mouse lung forfour months and challenging the mice with ovalbumin to induce goblet cell metaplasia. My hypothesis that lossof PRC2 will prevent cells from resolving allergic response will be tested by lung histology. In parallel I will uselung organoid cultures and single cell RNA-sequencing to examine lung cell fates when PRC2 is dysregulatedin mouse lung cells. For Aim 2 I will use an EZH2 inhibitor short hairpin RNAs against PRC2 components andcigarette smoke extract on human bronchial epithelial cells in air-liquid interphase cultures to examine howperturbation of PRC2 changes lung cell fate decisions. I will also establish new cultures from COPD patientsand finally explore the transcriptional changes in these cultures and how PRC2 influences these changes bychromatin immunoprecipitation experiments.Career PotentialMy ultimate goal is to influence national and global health policy by effectively investigating the physiologicalchanges that are currently taking and have taken place as a result of environmental changes. My personalinterest in stem cell biology and epigenetic manipulation coincides with Dr. Brainson's objective to elucidate lungstem cell fate and annotate the epigenome of diseased versus normal human and mouse lung epithelium.

project_terms:
Ablation;Adult;Air;Alleles;Allergens;Area;Back;Basal Cell;Basal Cell Hyperplasia;Cancer Biology;Cell Differentiation process;Cells;Chromatin;Chronic Bronchitis;Chronic Obstructive Airway Disease;Coal;Complex;DNA;Data;Deposition;Development;Disease;Distal;Doxycycline;Dust;Dysplasia;EZH2 gene;Embryo;Environmental Risk Factor;Enzymes;Epigenetic Process;Epithelial;Epithelial Cells;Future;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Silencing;Genetic;Genetic Transcription;Genetically Engineered Mouse;Goals;Goblet Cells;Health Policy;Histology;Histone H3;Histones;Human;In Vitro;Infiltration;Inflammatory;Interphase;Investigation;Kentucky;Knock-out;Laboratories;Liquid substance;Lung;Lung diseases;Lysine;MUC5AC gene;Measures;Mediating;Mentors;Metaplastic Cell;Methodology;Methods;Molecular;Mucous body substance;Mus;Organoids;Ovalbumin;Oxidative Stress;Patients;Phenotype;Physiological;Polycomb;Process;Progressive Disease;Repression;Research;Respiration;Reverse Transcriptase Polymerase Chain Reaction;Role;Smoker;Smoking;Stains;Structure of parenchyma of lung;Testing;Toxicology;Universities;allergic response;bronchial epithelium;career;chromatin immunoprecipitation;cigarette smoke;design;effective therapy;environmental change;epigenome;experimental study;exposure to cigarette smoke;gene repression;global health;graduate student;histone modification;in vivo;inhibitor/antagonist;interest;knock-down;lung development;mouse model;novel;prevent;pulmonary function;respiratory;response;single-cell RNA sequencing;small hairpin RNA;stem cell biology;stem cell fate;treatment strategy

public_health_relevance:
NARRATIVEChronic obstructive pulmonary disease (COPD) is a progressive disease with no effective treatments and oftenthe disease persists well after the initial drivers such as coal dust or smoking are eliminated. My researchfocuses on understanding how DNA organization is altered in the lung cells of COPD patients. If my hypothesisabout how normal DNA organization is changed in lung cells of COPD patients is supported by our data thisresearch may suggest novel treatments strategies to reverse these changes during COPD.


application_id: 10268972
project_number: 5R01DA048892-02
project_title: DAT- Integrated Outpatient Treatment of Opioid Use Disorder and Injection-Related Infections
administering_ic: NIDA
award_notice_date: 2021-08-03
opportunity_number: PA-19-055
application_type: 5
activity_code: R01
ic: DA
serial_number: 048892
program_official: DUFFY, SARAH Q
project_start_date: 2020-09-30
project_end_date: 2024-08-31
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 14788426
contact_pi: FANUCCHI, LAURA
other_pis: LOFWALL, MICHELLE RENEE
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTDAT18-06: Hospitalizations for complications of opioid use disorder (OUD) like infectious endocarditis (IE) andother severe injection-related infections (SIRI) have increased dramatically along with the opioid epidemic.Persons with OUD hospitalized with SIRI often remain inpatient to complete prolonged intravenous (IV)antibiotic courses due to several assumptions such as 1) if outpatient patients will inject illicit drugs into the IVcatheter and will fail to complete prescribed antibiotic regimens and 2) if inpatient patients will not inject drugsbecause of the increased supervision and will complete the antibiotic regimen. No evidence supports theseassumptions and unfortunately the inpatient stay is not only very costly to the healthcare system butinfrequently includes comprehensive OUD treatment. In contrast outpatient parenteral antibiotic therapy(OPAT) via a peripherally-inserted central catheter (PICC) is the standard of care for continuing IV medicationsfor patients without injection drug use (IDU) once medically stable and is commonly used in treatmentinfections requiring prolonged IV antibiotics. OPAT is cost-effective associated with improved patientsatisfaction and with decreased risks of hospital-acquired infections. Development of innovative outpatientclinical models is urgently needed to improve the management and transition plan of persons with OUD andSIRI given the costs and risks associated with prolonged hospitalizations. We conducted a successful pilotproof-of-concept randomized study to establish the safety and feasibility of discharging inpatients with OUDand SIRI to complete IV antibiotics in an innovative integrated outpatient model combining BUP treatmentwith OPAT. This 12-week outpatient randomized parallel-group study builds on our preliminary work todemonstrate efficacy of the integrated outpatient care model (B-OPAT: BUP treatment with OPAT). Patientswith OUD and SIRI will be randomized (1:1) to either B-OPAT (n=45) or treatment-as-usual (TAU) (n=45) andcompared on the primary outcome of the proportion of urine samples negative for illicit opioids and on criticalsecondary outcomes including completion of recommended IV antibiotic therapy self-reported number of daysof illicit opioid abstinence and retention in outpatient treatment. The study will also incorporate acomprehensive economic evaluation of the integrated outpatient care model as well as a qualitativeinvestigation to inform future implementation and dissemination. These results will demonstrate the efficacyand cost effectiveness of an integrated outpatient care model to provide outpatient treatment of OUD and SIRIafter hospitalization.

project_terms:
Abstinence;Address;Adoption;Alcohol consumption;Ambulatory Care;Antibiotic Therapy;Antibiotics;Buprenorphine;Catheters;Client satisfaction;Clinical;Counseling;Criminal Justice;Development;Dissemination and Implementation;Dose;Drug usage;Effectiveness of Interventions;Endocarditis;Enrollment;Evidence based treatment;Future;Health Care Costs;Health Care Sector;Health Services;Healthcare Systems;Home;Hospitalization;Hospitals;Illicit Drugs;Infection;Injections;Inpatients;Intervention;Interview;Intravenous;Investigation;Length of Stay;Medical;Medical Care Team;Methadone;Modeling;National Institute of Drug Abuse;Nosocomial Infections;Observational Study;Outcome;Outpatients;Participant;Patient Self-Report;Patient-Focused Outcomes;Patients;Peripheral;Persons;Pharmaceutical Preparations;Phase;Pilot Projects;Population;Productivity;Provider;Quality-Adjusted Life Years;Randomized;Randomized Clinical Trials;Reach Effectiveness Adoption Implementation and Maintenance;Regimen;Research;Resources;Risk;Running;Sampling;Schedule;Self Administration;Supervision;Testing;Time;Tobacco Use Disorder;Urine;Work;addiction;buprenorphine treatment;clinical practice;cost;cost effective;cost effectiveness;economic evaluation;effectiveness outcome;health care model;health care service organization;health care settings;health economics;illicit drug use;illicit opioid;improved;injection drug use;innovation;opioid epidemic;opioid use;opioid use disorder;primary outcome;response;safety and feasibility;secondary outcome;standard of care;treatment as usual

public_health_relevance:
PROJECT NARRATIVEHospitalizations for severe injection-related infections have increased along with the opioid epidemic andsome of these infections require prolonged courses of intravenous (IV) antibiotic therapy. There are currentlyno outpatient care models that incorporate evidence-based treatment of opioid use disorder withbuprenorphine with management of IV antibiotics. Demonstration of a successful integrated outpatient modelincorporating buprenorphine treatment and outpatient parenteral antibiotic therapy may change current clinicalpractice improve patient outcomes and be cost-effective.


application_id: 10268619
project_number: 1R01AG073122-01
project_title: Immunoproteasome inhibitors for the treatment of Alzheimers disease
administering_ic: NIA
award_notice_date: 2021-07-29
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AG
serial_number: 073122
program_official: GROTHAUS, PAUL G
project_start_date: 2021-08-01
project_end_date: 2026-04-30
study_section: Drug Discovery for the Nervous System Study Section[DDNS]
contact_pi_person_id: 8152159
contact_pi: KIM, KYUNG BO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryWith the failure of nearly all clinical trials for AD drugs in the pipeline to date identification of a new class of drugcandidates has become imperative to bring about effective AD therapies. A major obstacle is the lack ofpromising new drug targets unrelated to the events leading to the accumulation of the amyloid-beta (A) and tau-protein. We recently reported that linear peptide epoxyketones targeting the immunoproteasome (iP) aninducible variant of the 20S constitutive proteasome (cP) may represent a new class of AD drugs that canameliorate cognitive deficits independently of A or tau accumulation. While displaying promising efficacyhowever the prospect of these linear peptide epoxyketones for clinical use in AD appears limited at this timedue to potential issues of having a poor brain accessibility in vivo metabolic instability and short circulation time(largely attributable to the ABCB1-mediated drug efflux at the BBB and enzymatic hydrolysis by peptidases andepoxide hydrolases). Yet the family of peptide epoxyketones (short peptides with C-terminal -epoxyketonewarhead) remain attractive drug candidates considering their pharmacological advantages conferred by theirproven target specificity for the proteasomes and long-term safety in the clinic.Our current findings reveal that some of the peptide epoxyketone family members containing a macrocycle havethe ability to resist the ABCB1-mediated efflux and metabolic stability superior to their linear counterparts andthe potential to be a meaningful new treatment for patients with AD. Our objective in this application is to identifyand characterize one of these macrocyclic compounds best suited for brain iP inhibition in vivo and proceed tothe next phase of drug development. To do this in aim 1 we will prepare the current sets of promising macrocyclicpeptide epoxyketones with different structural features that displayed comparable target inhibition and biologicalactivity in vitro and in cellulo on a gram scale. In aim 2 we will characterize in vivo properties of each macrocyclicpeptide epoxyketone to identify a lead drug candidate. In aim 3 we will verify in vivo efficacy and the proposedmechanism of action of the lead drug candidate [iP inhibition  (NLRP3 inflammasome)  suppression ofmicroglial IL-1 release  blockade of astrocytes transformation (to A1 subtype)  neuronal survival] using twomouse models of AD (APP/PS1 and PS19 tau transgenic mice). By completing the proposed study we will haveidentified a lead candidate with the best attributes for IND enabling studies and novel mode of action. Theseresults are expected to have an important positive impact by examining the validity of the previously untappediP-targeting approach for AD therapy and potentially offering a new direction for AD drug discovery.

project_terms:
ABCB1 gene;APP-PS1;Affect;Alkenes;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Astrocytes;Biological;Blood Circulation;Brain;C-terminal;Clinic;Clinical;Clinical Trials;Cognitive deficits;Data;Development;Dose;Drug Efflux;Drug Targeting;Drug or chemical Tissue Distribution;Ensure;Epoxide hydrolase;Epoxy Compounds;Event;Excretory function;Failure;Family;Family member;Human;Hydrolysis;In Vitro;Inflammasome;Interleukin-1 alpha;Lead;Macrocyclic Compounds;Mediating;Metabolic;Metabolism;Mus;Organ;Pathway interactions;Patients;Peptide Hydrolases;Peptides;Permeability;Pharmaceutical Preparations;Pharmacology;Phase;Property;Reaction;Reporting;Safety;Specificity;Structure;Therapeutic;Time;Toxic effect;Transgenic Mice;Variant;abeta accumulation;analog;base;brain tissue;chemical stability;clinical candidate;clinical development;comparative;drug candidate;drug development;drug discovery;drug disposition;expectation;in vitro activity;in vivo;inhibitor/antagonist;lead candidate;mouse model;multicatalytic endopeptidase complex;neuronal survival;new therapeutic target;novel;novel drug class;pharmacokinetics and pharmacodynamics;preclinical study;reduce symptoms;success;tau Proteins;tau aggregation

public_health_relevance:
Project Narrative:Given the prospect to develop effective AD therapies via current therapeutic strategies seems limited at thispoint in this application we propose to develop a new class of AD drugs that target previously unrecognizedpathways in AD drug development. We expect to identify a lead AD drug to stop or slow down the progressionof AD in a manner independent of A or tau aggregation that needs to be further investigated in clinical trials.Successful completion of our study will have an important positive impact because currently available drugs onlyoffer temporary relief from the symptoms of AD.


application_id: 10268179
project_number: 5R01AA027990-02
project_title: Estradiol Effects on Behavioral and Reward Sensitivity to Alcohol across the Menstrual Cycle
administering_ic: NIAAA
award_notice_date: 2021-09-20
opportunity_number: PA-19-055
application_type: 5
activity_code: R01
ic: AA
serial_number: 027990
program_official: AKBAR, MOHAMMED
project_start_date: 2020-09-25
project_end_date: 2025-08-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
other_pis: MARTEL, MICHELLE M
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Adverse effects;Affect;Alcohol abuse;Alcohol consumption;Alcohols;Animal Experimentation;Area;Behavior;Behavioral;Behavioral Mechanisms;Clinical assessments;Consumption;Data;Data Reporting;Dose;Estradiol;Estrogens;Exhibits;Female;Grain;Health;Heavy Drinking;Hormonal;Hormones;Impulsivity;Intervention;Investigation;Laboratories;Link;Liver Cirrhosis;Longitudinal Studies;Maintenance;Measures;Menstrual cycle;Neurobiology;Oral Contraceptives;Organ;Ovarian hormone;Ovulation;Ovulation Prediction;Patient Self-Report;Pattern;Periodicity;Phase;Physiological;Placebos;Play;Progesterone;Puberty;Public Health;Recording of previous events;Relapse;Research;Rewards;Risk;Risk-Taking;Role;Saliva;Sampling;Sex Behavior;Sex Differences;Substance abuse problem;Testing;Theoretical model;Visit;Woman;Work;alcohol abuse therapy;alcohol craving;alcohol effect;alcohol sensitivity;alcohol use disorder;binge drinking;craving;disorder later incidence prevention;drinking behavior;men;neurobehavioral;personalized intervention;proliferative phase Menstrual cycle;reproductive;sexual assault;theories;university student;young adult;young woman


application_id: 10267035
project_number: 5R44NS108804-03
project_title: Mimicking synuclein toxicity in plant cells to identify novel neuroprotective leads
administering_ic: NINDS
award_notice_date: 2021-08-13
opportunity_number: PA-19-272
application_type: 5
activity_code: R44
ic: NS
serial_number: 108804
program_official: TRZCINSKI, NATALIE KATHERINE
project_start_date: 2018-09-01
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZRG1-ETTN-A(13)B]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractA general mechanism for neurodegeneration including Parkinson's disease and Alzheimer's dementia is thebreakdown and subsequent aggregation of misfolded neuronal proteins. In the synucleinopathies for exampleneurotoxicity is associated with the cleavage of mis-folded alpha-synuclein (ASYN) probably mainly byasparagine endopeptidase (AEP) [Zhang et al 2017]. This generates neurotoxic peptides that then aggregatewith ASYN in lysosomes forming the Lewy inclusion bodies associated with neurodegeneration. A very similarmechanism exists in plant cells in which plant AEP breaks down misfolded proteins to produce vacuolaraggregates associated with programmed cell death (PCD) [Hatsugai et al 2015]. However plants do notcontain ASYN so in order to mimic ASYN toxicity plant cells were transformed to express the misfolding-prone A53T variant of human ASYN (phase I). Thymoquinone was then used to trigger plant PCD [Hassanienet al 2013] and the plant cells expressing ASYN-A53T were shown to be significantly more susceptible to thistoxicity than controls. In phase II a mutant population of these transgenic (ASYN) plant cells will be selected forsurvival under this procedure. This is an example of target-directed evolution in which mutants that surviveselection should evolve toward increased biosynthesis of metabolites that inhibit AEP and/or ASYN toxicity.Individual mutant plant cell clones with ASYN-protective activity will be identified by screening extracts ofresistant cultures and micro-analytical methods [Kelley et al 2019] will then be used to identify activemetabolites as leads. Lobelia cardinalis cell cultures were used in phase I because we had previouslytransformed these with the human dopamine transporter gene to mimic MPP+-induced dopaminergicneurotoxicity [Brown et al 2016]. In phase II we will also use the medicinal plant Polygonum multiflorum whichcontains a stilbene that inhibits ASYN toxicity [Zhang et al 2018]. Phase II aims to identify novel leads thatengage the AEP and ASYN targets and to test the most promising of these in cellular and animal models ofsynucleinopathy. Leads will be developed with the University of Kentucky Parkinson's Disease ResearchCenter and a pharmaceutical partner. Identification of leads that engage these targets will also support target-directed evolution in mutant plant cells as a commercial platform for drug discovery.

project_terms:
1-Methyl-4-phenylpyridinium;Agrobacterium;Alzheimer's Disease;Anabolism;Animal Model;Apoptosis;Asparagine;Biotechnology;Cell Culture Techniques;Cell model;Cells;Chemicals;Cleaved cell;Clone Cells;Complementary DNA;Development;Directed Molecular Evolution;Endopeptidases;Enzymes;Exposure to;Foundations;Genes;Human;In Vitro;Inclusion Bodies;Individual;Kentucky;Lead;Lobelia;Lysosomes;Materials Testing;Mediating;Medicinal Plants;Methods;Modification;Molecular;Mutagenesis;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Neurotoxins;Parkinson Disease;Pathologic;Peptide Hydrolases;Peptides;Pharmacologic Substance;Phase;Plant Roots;Plants;Polygonum;Population;Procedures;Process;Proteins;Research;Resistance;Risk;Stilbenes;Substance Use Disorder;Technology Transfer;Testing;Therapeutic;Toxic effect;Transgenic Organisms;United States National Institutes of Health;Universities;Variant;aged;alpha synuclein;analytical method;asparaginylendopeptidase;base;commercialization;cytotoxic;dopamine transporter;drug discovery;expectation;gain of function mutation;inhibitor/antagonist;misfolded protein;mutant;neurotoxic;neurotoxicity;novel;novel therapeutics;programs;screening;substance use treatment;synuclein;synucleinopathy

public_health_relevance:
Project narrativeSeveral human neurodegenerative diseases including familial Parkinson's disease share a mechanism inwhich the enzymatic modification and subsequent aggregation of a nerve cell protein called alpha-synucleinkills nerve cells. Plant root cells contain a similar enzyme but they do not contain alpha-synuclein. By creatingplant cells expressing human alpha-synuclein the applicants will be able to seek novel plant metabolites thatinhibit this neurotoxic process and that will lead to novel drugs to treat these devastating neurodegenerativediseases.


application_id: 10266377
project_number: 1U18TR003787-01
project_title: A Handheld Microchip for GC analysis of breath to screen for COVID-19
administering_ic: NCATS
award_notice_date: 2020-12-21
opportunity_number: RFA-OD-20-017
application_type: 1
activity_code: U18
ic: TR
serial_number: 003787
program_official: CROUCHER, LEAH TOLOSA
project_start_date: 2020-12-21
project_end_date: 2024-01-31
study_section: Special Emphasis Panel[ZTR1 DPI-9 (01)]
contact_pi_person_id: 10807170
contact_pi: FU, XIAO-AN
other_pis: NANTZ, MICHAEL H
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary The COVID-19 pandemic has caused unprecedented societal suffering and economic disruption. In theUnited States more than six million people have contracted COVID-19 and more than one hundred ninetythousand patients have died of this disease to date. Although current COVID-19 diagnostic testing technologiesare critical for slowing the spread of the virus and preventing future outbreaks they are not practical for field use.Current diagnostic tests are cumbersome to perform because they use aqueous solutions require multiple stepsand hours-to-days to obtain results. Since the US began to reopen the economy in May there has been asignificant increase in the number of COVID-19 cases. Therefore there is an urgent need to develop a diagnosticapproach that is non-invasive portable and can rapidly provide test results. The overall goal of the project is to develop a mobile breath analysis technology for rapid screening forCOVID-19 using a handheld breath collection tool and a portable GC with a photoionization detector (PID). Thehandheld tool will be a closed system for trapping select volatile organic compounds (VOCs) on a microfabricatedchip. The captured VOCs will be eluted with ethanol and then analyzed using a commercially available portableGC-PID instrument. Artificial intelligence (AI) and machine learning algorithms will be applied to recognize theVOC pattern that correlates with COVID-19 infection. The central innovation is the microfabricated chip thatcaptures carbonyl compounds in exhaled breath and thus serves as a preconcentrator which enables analysisof carbonyl VOCs by the portable GC-PID. The hypothesis is that the carbonyl metabolome in exhaled breath isdirectly related to the bodys reaction to the novel coronavirus infection and changes in the carbonyl VOCcomposition in exhaled breath relative to healthy controls can be used to detect both symptomatic andasymptomatic COVID-19 patients. Three specific aims are proposed to fulfill the overall goal. Aim 1 is to build a disposable handheld breathanalyzer tool for concentrating carbonyl VOCs. Aim 2 is to identify VOC patterns in the breath of COVID-19patients by machine learning algorithms. Aim 3 is to integrate portable GC technology with the breath samplingtool for COVID-19 screening guided by an AI system. The University of Louisville is uniquely suited to rapidlytransition the microchip technology to field use because of the PI and Co-PIs experience in breath analysis andtranslational research and the project teams experience in virology infectious diseases biostatistics andartificial intelligence as well as the state-of-the-art facilities that include a MicroNano Technology CenterBiosafety Level 3 Regional Biocontainment Lab and an NIH-funded REACH program.

project_terms:
2019-nCoV;Acute;Address;Artificial Intelligence;Biochemical Process;Biometry;Breath Tests;COVID-19;COVID-19 detection;COVID-19 diagnostic;COVID-19 pandemic;COVID-19 patient;COVID-19 screening;COVID-19 test;Cancer Detection;Clinic;Collaborations;Collection;Communicable Diseases;Contracts;Coronavirus Infections;Detection;Device or Instrument Development;Devices;Diagnosis;Diagnostic;Diagnostic tests;Disease;Disease Outbreaks;Economics;Epithelial Cells;Ethanol;Exhalation;Expert Systems;Foundations;Funding;Future;Goals;Hour;Human;Influenza;Institutes;Institution;Laboratories;Machine Learning;Malignant neoplasm of lung;Mass Fragmentography;Medical Device;Modeling;Monitor;Nasal Epithelium;Oxidative Stress;Patients;Pattern;Process;Production;Protocols documentation;Rapid screening;Reaction;Reagent;Research Project Grants;Role;SARS-CoV-2 infection;Sampling;Sensitivity and Specificity;Signal Transduction;Silicon;Sterilization;System;Technology;Test Result;Testing;Training;Translational Research;Tuberculosis;United States;United States National Institutes of Health;Universities;Vial device;Viral;Viral Respiratory Tract Infection;Virulent;Virus;Virus Diseases;adduct;aqueous;asymptomatic COVID-19;biosafety level 3 facility;bronchial epithelium;carbonyl compound;detection sensitivity;detector;experience;innovation;instrument;machine learning algorithm;metabolome;microchip;mobile computing;novel coronavirus;photoionization;point of care;portability;prevent;programs;prototype;reagent testing;symptomatic COVID-19;tool;virology;volatile organic compound

public_health_relevance:
8. Project Narrative This project will develop a mobile breath analysis technology for rapid screening for COVID-19 using ahandheld breath collection tool and a portable GC with a photoionization detector (PID). Artificial intelligence andmachine learning algorithms will be used to analyze the detected signals of volatile organic compounds (VOCs)in exhaled breath by the portable GC for detection of COVID-19 patients. UofL is uniquely suited to develop thisapproach because of the PIs expertise in breath analysis for detection of Tuberculosis and lung cancer and theteams experience in virology infectious diseases biostatistics and artificial intelligence.


application_id: 10266030
project_number: 5R01DA049333-02
administering_ic: NIDA
award_notice_date: 2021-06-18
opportunity_number: PAR-18-747
application_type: 5
activity_code: R01
ic: DA
serial_number: 049333
program_official: DUNSTON, SHEBA KING
project_start_date: 2020-09-30
project_end_date: 2025-07-31
study_section: Health Disparities and Equity Promotion Study Section[HDEP]
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: 2021-08-01
project_terms:
Address;Adult;African American;Age;Area;Attention;Buprenorphine;Cessation of life;Characteristics;Child Rearing;Communities;Complex;Comprehension;Criminal Justice;Data;Data Sources;Dimensions;Discrimination;Dose;Drug usage;Employment;Epidemic;Ethnic Origin;Evolution;Female;Future;Gender;Generations;Goals;Healthcare Systems;Heroin;Intervention;Interview;Kentucky;Libraries;Link;Longevity;Mediating;Mental Health;Methadone;Methods;Morbidity - disease rate;National Institute of Drug Abuse;Outcome;Overdose;Pain;Participant;Patients;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Policies;Population;Public Health;Race;Reporting;Research;Research Personnel;Research Project Grants;Risk;Sampling;Stress;Structure;Surveys;Techniques;Testing;Treatment outcome;Underrepresented Populations;Underserved Population;base;cohort;design;distrust;drug testing;evidence base;experience;health care availability;health communication;illicit drug use;improved;insight;low socioeconomic status;male;men;misuse of prescription only drugs;mortality risk;older women;opioid epidemic;opioid overdose;opioid use;opioid user;physical conditioning;pill;prescription opioid;prescription opioid misuse;recruit;response;social;synthetic opioid;theories;treatment services;trend;young woman


application_id: 10265090
project_number: 3P30ES026529-04S1
project_title: Center for Appalachian Research in Environmental Sciences
administering_ic: NIEHS
award_notice_date: 2020-09-17
opportunity_number: PA-18-591
application_type: 3
activity_code: P30
ic: ES
serial_number: 026529
suffix: S1
program_official: THOMPSON, CLAUDIA L
project_start_date: 2017-05-01
project_end_date: 2022-03-31
study_section: Environmental Health Sciences Review Committee[EHS(P3)-1]
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN J
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY  OverallThe University of Kentucky Center for Appalachian Research in Environmental Sciences (UK-CARES) willestablish an Environmental Health Sciences Core Center to enhance research capacity focused on majorenvironmental health impacts to air and water quality that have been implicated in environmentally induceddisease. This Center will provide advanced infrastructure and leading expertise dedicated career developmentand mentorship and community-engaged interactions to facilitate innovative discovery and new understandingsof environmental factors in disease initiation progression and outcomes and their community impacts. Thecentral hypothesis is that toxic environmental agents are contributors to the disproportionately high incidence ofchronic diseases e.g. cancers cardiopulmonary disease and metabolic disorders in Appalachian Kentuckyand that the impacts of early exposure are especially harmful. UK-CARES draws on a strong and diverse baseof environmental health science and community-engaged research to build environmental health researchcapacity to meet the needs of communities in three Area Development Districts in southeastern Kentucky: BigSandy Kentucky River and Cumberland Valley. Center members bring notable strengths in environmentalhealth across four Research Interest Groups: Cardiopulmonary Diseases Metabolic Disorders Cancer andChild Health and Early Life Exposures. To achieve the Centers goal UK-CARES will: 1) establish a richresearch environment and a framework for transdisciplinary leadership and integrated infrastructure to facilitatecollaboration and efficient use of resources for research expansion and development of new scientific directions;2) build research capacity in environmental health sciences by providing an outstanding intellectual environmentand advanced infrastructure to support innovation and community engagement; 3) recruit new talent andfacilitate career development of investigators whose research addresses critical issues in environmentallyinduced disease through mentorship and structured career training activities; 4) develop multi-directional andmutually beneficial communications and interactions with community residents policymakers and publichealth/healthcare professionals to identify environmental concerns of target communities as a stimulus to newresearch; and 5) bridge the gap between discovery of novel research findings and population-level awarenessand practice via community-focused science communication training. An Integrative Health Sciences FacilityCore Analytical Core and Community Outreach and Engagement Core are integral to this effort and willcatalyze multi-directional translation across the whole spectrum of research; provide advanced analyticalsupport in metabolomics computational biology analytical chemistry biospecimen management andbioinformatics; and bridge Center and community priorities. Complementary activities in career development ofscientists who are interested in tackling challenging environmental health questions and pilot project funding willsupport developing research and evolving scientific directions.

project_terms:
Address;Air;Analytical Chemistry;Appalachian Region;Area;Arsenic;Asthma;Atherosclerosis;Awareness;Bioinformatics;Chemicals;Child Health;Chromium;Chronic Disease;Chronic Obstructive Airway Disease;Clinical;Collaborations;Colorectal Cancer;Communication;Communities;Community Outreach;Complex;Computational Biology;Core Facility;Development;Diabetes Mellitus;Disease;Ecology;Environment;Environmental Health;Environmental Risk Factor;Exposure to;Fostering;Foundations;Funding;Genetic Predisposition to Disease;Goals;Health;Health Professional;Health Sciences;Healthcare;Heart;Heart Diseases;Heavy Metals;Human;Incidence;Individual;Infrastructure;Integrative Medicine;Interest Group;Kentucky;Leadership;Longevity;Malignant Neoplasms;Malignant neoplasm of lung;Medical;Medical center;Mentorship;Metabolic Diseases;Mining;National Institute of Environmental Health Sciences;Nickel;Obesity;Outcome;Particulate;Pilot Projects;Population;Positioning Attribute;Public Health;Pulmonary Heart Disease;Radon;Research;Research Personnel;Resources;Rivers;Rural;Science;Scientist;Stimulus;Structure;Talents;Toxic Environmental Substances;Toxicology;Training;Training Activity;Translations;Universities;Vision;Water;advanced analytics;base;career;career development;early life exposure;health science research;innovation;interest;member;metabolomics;neonate;novel;population health;programs;recruit;socioeconomic disadvantage;water quality

public_health_relevance:
PROJECT NARRATIVE  OverallThe University of Kentucky Center for Appalachian Research in Environmental Sciences (UK-CARES) willenhance programmatic and scientific capacity toward the goal of facilitating innovative discovery and newunderstandings of environmental factors in disease initiation progression and outcomes and their communityimpacts. Further the Center will foster career development of environmental scientists interested in tacklingchallenging environmental health questions facing the southeastern Kentucky region. UK-CARES will achievethis goal by providing advanced infrastructure and expertise training and mentorship and community-engagedinteractions.


application_id: 10264811
project_number: 5R21DA049130-02
project_title: Glutamergic Mechanisms in Opioid and Cocaine Co-Use
administering_ic: NIDA
award_notice_date: 2021-08-03
opportunity_number: PAR-18-084
application_type: 5
activity_code: R21
ic: DA
serial_number: 049130
program_official: ANANTHAN, SUBRAMANIAM
project_start_date: 2020-09-30
project_end_date: 2022-08-31
study_section: Special Emphasis Panel[ZRG1-BBBP-X(03)M]
contact_pi_person_id: 9706320
contact_pi: GIPSON-REICHARDT, CASSANDRA D
other_pis: STOOPS, WILLIAM WALTON
congressional_district: 06
department: FAMILY MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acetylcysteine;Animals;Attenuated;Biological Markers;Brain;Chemosensitization;Chronic;Clinical;Cocaine;Cues;Dendritic Spines;Dependence;Development;Disease;Dose;Drug Controls;Drug Use Disorder;Drug usage;Food;Glutamate Transporter;Glutamates;Heroin;Homosynaptic Depression;Human;Individual;Intake;Intervention;Intravenous;Knowledge;Laboratories;Magnetic Resonance Spectroscopy;Maintenance;Measures;Methods;Modeling;Motivation;N-Methylaspartate;Neurons;Nucleus Accumbens;Opioid;Opioid agonist;Oral;Oxycodone;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Phase;Phased Innovation Awards;Physical Dependence;Physiological;Placebos;Proteins;Protocols documentation;Proxy;Public Health;Randomized;Reporting;Self Administration;Specific qualifier value;Stimulus;Synapses;Synaptic plasticity;System;Time;United States;Up-Regulation;Withdrawal;Work;cocaine exposure;cocaine self-administration;cocaine use;comorbidity;comparison group;experience;glutamatergic signaling;improved outcome;incentive salience;meetings;motivated behavior;multiple drug use;neurobiological mechanism;neuromechanism;novel;novel therapeutics;opioid use;opioid use disorder;opioid withdrawal;overdose risk;polysubstance abuse;pre-clinical;protein expression;relating to nervous system;sex


application_id: 10263610
project_number: 3P42ES007380-22S1
project_title: NUTRITION AND SUPERFUND CHEMICAL TOXICITY
administering_ic: NIEHS
award_notice_date: 2020-09-16
opportunity_number: PA-18-591
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S1
program_official: HENRY, HEATHER F
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D(SF)
contact_pi_person_id: 8776790
contact_pi: PENNELL, KELLY G
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Age;Aging;Appalachian Region;Awareness;Binding;Biochemical;Biological;Biological Markers;Biological Models;Biological Monitoring;Biomedical Engineering;Biomedical Research;Biomimetics;Chemicals;Communication Research;Communities;Complex;Consumption;Data;Data Analyses;Detection;Diet;Diet and Nutrition;Diffusion;Disease;Disease Outcome;Ecology;Economically Deprived Population;Engineering;Environment;Environmental Engineering technology;Environmental Health;Environmental Pollutants;Environmental Pollution;Evaluation;Exercise;Exposure to;Fiber;Fostering;Funding;Future;Goals;Hazardous Substances;Health;Human;Industry;Intake;Interdisciplinary Study;Intervention;Iron;Kentucky;Life;Life Style;Link;Membrane;Metals;Methods;Molecular;Nanostructures;National Institute of Environmental Health Sciences;Nutrient;Outcome;Oxides;Pathway interactions;Physical activity;Physiological;Plants;Policies;Policy Maker;Polychlorinated Biphenyls;Predisposition;Pregnancy;Prevention;Prevention strategy;Primary Prevention;Problem Sets;Recommendation;Research;Research Project Grants;Research Training;Resources;Risk;Risk Assessment;Risk Management;Science;Scientist;Services;Site;Superfund;System;Techniques;Technology;Tetrachloroethylene;Toxic effect;Toxicant exposure;Training;Translational Research;Trichloroethylene;Universities;Vulnerable Populations;base;chemical stability;chronic inflammatory disease;community intervention;community involvement;data management;disadvantaged population;disorder prevention;disorder risk;environmental chemical;environmental chemistry;experience;exposure pathway;graphene;healthy lifestyle;improved;innovation;insight;interdisciplinary approach;lifestyle intervention;metabolic profile;metabolomics;next generation;novel;nutrition;organic contaminant;pollutant;polyphenol;prevent;programs;remediation;social;superfund chemical;superfund site;tool


application_id: 10261966
project_number: 1P30AG072946-01
project_title: Core E: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2021-07-30
opportunity_number: RFA-AG-21-019
application_type: 1
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-G (M1)]
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_terms:
Address;African American;Aging;Agreement;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimer's disease related dementia;Americas;Autopsy;Awareness;Biological Markers;Brain;Brothers;Caring;Catchment Area;Censuses;Centers for Disease Control and Prevention (U.S.);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;Fostering;Foundations;Genetic;Goals;Grant;Health Promotion;Healthcare;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;base;checkup examination;clinical examination;cohort;community engagement;dementia risk;demographics;education research;effectiveness evaluation;efficacy evaluation;ethnic minority population;health disparity;health literacy;improved;innovation;meetings;mixed dementia;neuropathology;outreach;outreach program;programs;racial and ethnic;racial minority;recruit;research study;response;success;volunteer;willingness


application_id: 10261964
project_number: 1P30AG072946-01
project_title: Core C: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2021-07-30
opportunity_number: RFA-AG-21-019
application_type: 1
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-G (M1)]
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_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;Consult;Data;Data Analyses;Data Collection;Dementia;Development;Elderly;Elements;Enrollment;Environment;Epidemiology;Etiology;Evaluation;Event;Experimental Designs;Extramural Activities;Faculty;Funding;Generations;Genetic;Gerontology;Health Services Research;Information Systems;Interruption;Kentucky;Leadership;Life;Literature;Manuscripts;Methodology;Mission;Neuroepidemiology;Observational Study;Online Systems;Participant;Pathology;Pilot Projects;Procedures;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;Ursidae Family;Vision;base;central database;clinical biomarkers;cohort;dashboard;data dictionary;data management;data warehouse;direct application;doctoral student;education research;electronic data capture system;improved;innovation;interest;meetings;member;mixed dementia;neuropathology;novel;outreach;programs;recruit;statistics;student training;success;user-friendly;web app;web site


application_id: 10261963
project_number: 1P30AG072946-01
project_title: Core B: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2021-07-30
opportunity_number: RFA-AG-21-019
application_type: 1
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-G (M1)]
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_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;Ensure;Environment;Etiology;Family;Fostering;Foundations;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;base;clinical biomarkers;clinical phenotype;cohort;design;driving force;high risk;innovation;multidisciplinary;normal aging;novel;novel therapeutic intervention;parity;pre-clinical;preclinical study;research clinical testing;success;therapeutic development


application_id: 10261962
project_number: 1P30AG072946-01
project_title: Core A: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2021-07-30
opportunity_number: RFA-AG-21-019
application_type: 1
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-G (M1)]
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_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;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;cognitive development;cohort;comorbidity;disease heterogeneity;effective therapy;innovation;meetings;multidisciplinary;novel therapeutics;pre-clinical;prevent;programs;success;training opportunity;treatment strategy;volunteer


application_id: 10261533
project_number: 5R00CA225633-04
administering_ic: NCI
award_notice_date: 2021-08-19
opportunity_number: PA-18-398
application_type: 5
activity_code: R00
ic: CA
serial_number: 225633
program_official: AMIN, ANOWARUL
project_start_date: 2020-09-11
project_end_date: 2023-08-31
study_section: NSS
contact_pi_person_id: 14359954
contact_pi: GUO, HOUFU
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: 2021-09-01
project_title:
Determining structural features of a collagen lysyl hydroxylase that promotes lung cancer metastasis

project_abstract:
Project Summary/Abstract:Candidate: Dr. Guo has received broad training in biochemistry and structural biology. He is a postdoctoralfellow at MD Anderson Cancer Center seeking to understand how collagen lysyl hydroxylase (LH) structuralfeatures regulate lung cancer metastasis. Dr. Guo is a highly productive investigator with 18 peer-reviewedpapers (6 of which as first or co-first author). As recognition of his achievements he received numerousawards during his doctoral and postdoctoral training.Career Development/Training: Dr. Guo's mentors at MD Anderson include Dr. Jonathan Kurie a physician-scientist with expertise in lung cancer biology and mouse modeling of human lung cancer and Dr. John Tainera renowned protein crystallographer studying macromolecular assemblies to inform drug design. AdditionallyDr. Guo will receive training from Dr. Mitsuo Yamauchi (UNC-Chapel Hill) a collagen biochemist who wasamong the first to elucidate how collagens are modified by LHs. These investigators have designed a trainingprogram centered on their key scientific disciplines that will strengthen Dr. Guo's abilities in their respectivefields and provide the skills needed for a smooth transition to independence.Research: Our group has shown that high expression of LH2 drives lung cancer metastasis and induces acollagen cross-link switch in tumor stroma. LH2 is a therapeutic target of interest but selective LH inhibitorsare not available a deficiency due in part to a lack of structural insight into LH2. The objective of my proposalis to elucidate LH2 structural features that promote lung cancer metastasis. In my preliminary results Idescribe new methods to produce human LH2 protein and assay its activity and the structure of the catalyticdomain of a viral LH homologue which revealed a homodimer stabilized by Fe+2-binding. I found that the twoactive sites flank a deep surface cleft on the dimer interface suggesting that dimerization creates a collagen-binding site and that basic residues adjacent to the active site are positioned to form salt bridges withtelopeptidyl acidic residues on collagen. From these findings I hypothesize that LH2 has telopeptidyl-LHactivity owing to unique features that allow it to form Fe2+-stabilized dimeric structures that interact withtelopeptidyl lysines on collagen. I will test this hypothesis by determining how LH dimer assemblies arestabilized by Fe2+-binding and interact with telopeptidyl lysine residues to regulate collagen cross-link formationand lung tumorigenesis.In sum my proposal will address the clinical problem of lung cancer metastasis. The novelty rests inpreliminary results that provide the first structural insights into a collagen LH hypotheses that challenge currentparadigms and technologies that facilitate quantification of LH enzymatic activity and evaluation of candidatemetastasis drivers.

project_terms:
2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine;Acanthamoeba;Achievement;Active Sites;Address;Aldehydes;Alleles;Arginine;Aspartate;Award;Binding;Binding Sites;Biochemical;Biochemistry;Biological Assay;Biology;C-terminal;Cancer Biology;Cancer Center;Cartilage;Catalytic Domain;Charge;Clinical;Collagen;Complex;Crystallization;Crystallography;Development;Dimerization;Discipline;Disease;Drug Design;Enzymes;Epithelial;Epithelial Cells;Evaluation;Family member;Foundations;Future;Gelatinase B;Glutamates;Growth;Homologous Gene;Human;Hydrophobicity;Hydroxylysine;KRAS2 gene;Laboratories;Leucine;Lung;Lung Adenocarcinoma;Lung Neoplasms;Lysine;Malignant neoplasm of lung;Mentors;Metastatic Neoplasm to the Lung;Methods;Mus;Mutation;N-terminal;Neoplasm Metastasis;Paper;Peer Review;Physicians;Positioning Attribute;Postdoctoral Fellow;Proline;Proteins;Reporting;Research;Research Personnel;Rest;Scientist;Sodium Chloride;Structure;Sum;Surface;Technology;Testing;Training;Training Programs;Tumor Tissue;Tumor-infiltrating immune cells;Tyrosine;Viral;bone;career development;clinical application;crosslink;design;dimer;human model;inhibitor/antagonist;insight;interest;lung tumorigenesis;macromolecular assembly;malignant breast neoplasm;mouse model;mutant;novel;post-doctoral training;prognostic value;protein structure;sarcoma;skills;structural biology;therapeutic target;tumor;tumor growth;tumorigenesis

public_health_relevance:
Project NarrativeBuilding on evidence from my mentors laboratory that the collagen modifying enzyme lysyl hydroxylase 2(LH2) induces a collagen cross-link switch in tumor stroma and thereby drives lung adenocarcinomametastasis I have generated a crystal structure of an informative viral homologue of LH2. The structuralfeatures of that enzyme are the basis for my hypothesis that LH2 has a novel dimerization interface and basicresidues adjacent to the active site that confer its unique collagen telopeptidyl LH activity. Testing thishypothesis will inform LH2 biology and may have broad clinical applicability because LH has been implicated inthe metastatic activity of multiple tumor types and the development of fibrotic diseases.


application_id: 10261452
project_number: 5R01AG068331-03
administering_ic: NIA
award_notice_date: 2022-06-07
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AG
serial_number: 068331
program_official: YAO, ALISON Q
project_start_date: 2020-09-15
project_end_date: 2025-05-31
study_section: Molecular Neurogenetics Study Section[MNG]
contact_pi_person_id: 9202423
contact_pi: EBBERT, MARK T W
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-06-01
project_terms:
Affect;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease diagnostic;Alzheimer's disease risk;Automobile Driving;Biology;Brain;Brain Diseases;Clinic;Complement;Complex;DNA;DNA mapping;DNA sequencing;Data;Data Set;Detection;Development;Diagnostic;Disease;Genes;Goals;Grant;Individual;Intervention;Methods;Modification;Molecular;Mutation;Nerve Degeneration;Neurodegenerative Disorders;Nucleotides;Optics;Phenotype;Play;Prognosis;Protein Isoforms;Proteins;RNA;RNA Splicing;Research Personnel;Role;Sampling;Symptoms;Technology;The Sun;Therapeutic;Validation;Variant;Work;advanced disease;brain health;brain tissue;cohort;design;differential expression;disease diagnosis;disease diagnostic;frontal lobe;gain of function;genome-wide;insight;mind control;multiple omics;programs;targeted treatment;transcriptome sequencing


application_id: 10261369
project_number: 5K01AA025305-04
administering_ic: NIAAA
award_notice_date: 2021-07-26
opportunity_number: PA-14-044
application_type: 5
activity_code: K01
ic: AA
serial_number: 025305
program_official: FREEMAN, ROBERT
project_start_date: 2018-08-15
project_end_date: 2023-02-28
study_section: ZAA1-GG(02)
contact_pi_person_id: 12488104
contact_pi: LAUCKNER, CAROLYN
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
budget_start_date: 2021-08-01
project_title:
A Telemedicine and mHealth Intervention for Reducing Alcohol Consumption among People Living with HIV/AIDS.

project_abstract:
Project Summary/AbstractWith advances in treatment people living with HIV/AIDS (PLWHA) have greatly improved survival rates andmedical outcomes. However despite the increased availability of highly-active antiretroviral therapy manyPLWHA fail to take their medication as directed. This reduces their chances of achieving viral suppression andis thus a crucial component of the HIV/AIDS treatment cascade. To improve the outcomes of PLWHA andaddress the low levels of viral suppression observed nationwide it is essential to examine factors that are likelyto decrease medication adherence. One such factor is alcohol consumption which has been shown to have asignificant and large effect on whether or not individuals follow their medication regimen.The primary objective of this research is to develop and test an alcohol reduction intervention for PLWHA.Based on collaborators previous research and prior literature this eight-week intervention titled Tracking andReducing Alcohol Consumption (TRAC) will be delivered entirely using technology. Counselors will meet withpatients using videoconferencing in partnership with the Georgia Department of Public Healths TelehealthNetwork as well as via phone-based conversations. This technology-based delivery will be highly accessible topatients in both rural and urban areas of Georgia as it requires only two in-person visits to a local healthdepartment office for videoconferencing sessions. As a supplement to the intervention participants will alsoengage in self-monitoring of alcohol consumption and medication adherence through mobile questionnairesand Bluetooth-enabled breathalyzers. The use of mobile breathalyzers represents an innovative application ofmodern technologies and has potential to improve the validity of self-reported alcohol consumption. Overallthe TRAC intervention will be developed and tested in two stages: an open trial (N=10) exploring acceptanceand usability and a small randomized pilot trial (N=60) assessing feasibility and evidence for efficacy in regardto reducing alcohol consumption increasing medication adherence and improving medical outcomes.I aim to receive comprehensive training to support this line of research related to reducing alcohol consumptionamong PLWHA. As part of my training plan five mentors who specialize in HIV/AIDS alcohol interventiondesign telemedicine and advanced data analysis will provide guidance through directed readings regularmeetings and feedback on research design. These mentors are located at the University of Georgia and YaleUniversity. Both universities will provide me with access to extensive intellectual resources and partneringorganizations who can aid in my research including the Georgia Department of Public Health Yales Centerfor Interdisciplinary Research on AIDS and the NIAAA Consortia for HIV/AIDS and Alcohol-Related ResearchTrials. I will also participate in courses and workshops related to clinical data analysis HIV/AIDS research andbehavioral intervention design. This training will provide me with the foundation needed to meet my long-termgoal of conducting an externally-funded program of research in HIV/AIDS and alcohol and drug use.

project_terms:
AIDS/HIV problem;Acquired Immunodeficiency Syndrome;Address;Adherence;Age;Alcohol consumption;Alcohols;Attitude;Behavior Therapy;Behavioral;Bluetooth;Caring;Cellular Phone;Client;Clinic;Clinical;Clinical Data;Cognitive Therapy;Collection;Communication;Counseling;Data;Data Analyses;Databases;Disease;Drug usage;Educational workshop;Effectiveness;Ethnic Origin;Evaluation;Feedback;Foundations;Funding;Gender;General Population;Goals;HIV;Health;Health Insurance Portability and Accountability Act;Highly Active Antiretroviral Therapy;Improve Access;Individual;Interdisciplinary Study;Intervention;Intoxication;Link;Literature;Measures;Medical;Mental Depression;Mentors;Methods;Modernization;Monitor;National Institute on Alcohol Abuse and Alcoholism;Outcome;Outcomes Research;Participant;Patient Self-Report;Patients;Persons;Pharmaceutical Preparations;Prevention;Process;Professional counselor;Public Health;Questionnaires;Race;Randomized;Randomized Controlled Trials;Reading;Recording of previous events;Regimen;Reporting;Research;Research Design;Research Personnel;Resources;Secure;Social support;Survival Rate;Technology;Telemedicine;Telephone;Testing;Time;Training;Transportation;Travel;Universities;Validity of Self Report;Videoconferencing;Viral;Visit;Voice;Waiting Lists;Wireless Technology;alcohol abuse therapy;alcohol availability;alcohol intervention;alcohol monitoring;alcohol related problem;alcohol research;alcohol testing;base;brief intervention;cocaine use;dosage;drinking;efficacy trial;follow-up;heroin use;improved;improved outcome;innovation;intervention effect;intervention participants;mHealth;medication compliance;meetings;member;motivational enhancement therapy;new technology;pilot trial;problem drinker;programs;recruit;reduced alcohol use;response;rural area;skills;telehealth;therapy adherence;therapy design;tool;treatment response;urban area;usability

public_health_relevance:
Project NarrativeWhile advances in medication have led to greatly improved outcomes for people living with HIV/AIDS lessthan one-third of all people living with the disease are adherent enough to their medication to achieve viralsuppression. Alcohol consumption has been shown to have a significant effect on HIV medication adherenceso the proposed research will aim to reduce alcohol use among people living with HIV/AIDS through atechnology-driven intervention. This eight-session intervention will be delivered using a combination ofvideoconferencing smartphones and Bluetooth-enabled breathalyzers for monitoring of alcohol consumptionwith an overall goal of reducing alcohol use mitigating adherence issues and achieving optimal preventionand treatment responses for people living with HIV/AIDS.


application_id: 10261059
project_number: 1R56DK126930-01
administering_ic: NIDDK
award_notice_date: 2020-09-15
opportunity_number: PA-19-056
application_type: 1
activity_code: R56
ic: DK
serial_number: 126930
program_official: SCHULMAN, IVONNE HERNANDEZ
project_start_date: 2020-09-19
project_end_date: 2021-08-31
study_section: Biomedical Computing and Health Informatics Study Section[BCHI]
contact_pi_person_id: 12422704
contact_pi: NEYRA, JAVIER A.
other_pis: NADKARNI, GIRISH NITIN
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-09-19
project_title:
Artificial Intelligence to Predict Outcomes in Patients with Acute Kidney Injury on Continuous Renal Replacement Therapy

project_abstract:
ABSTRACTAcute kidney injury (AKI) affects up to half of critically ill patients admitted to intensive care units (ICU). In patientswith AKI and hemodynamic instability continuous renal replacement therapy (CRRT) is the preferred dialysismodality for solute and volume control. ICU mortality in this vulnerable population is high (~75%) but kidneyrecovery occurs in up to two-thirds of survivors. Fluid overload is a potentially modifiable risk factor associatedwith these outcomes. However there are currently no universally accepted approaches for predicting kidneyrecovery survival or individual response to fluid removal during CRRT. Due to recent advances in computerscience and widespread big data usage deep learning (DL) has emerged as a valuable approach. DL allowsconstruction of risk prediction models using time-series data that incorporate thousands of variables and dynamicchanges in these variables derived from multi-dimensional sources and not only static values of these variables.We propose to develop and validate innovative DL approaches to dynamically predict these outcomes usingmulti-modal data from electronic health records and CRRT machines. We demonstrated superiority of DL modelswithout a-priori variable selection compared to optimized logistic regression (C-Statistic of 0.72 vs. 0.62) forprediction of RRT liberation. We also showed that mortality prediction improved by incorporating changes inclinical data within 6-hour intervals after CRRT initiation. In addition we identified distinctive mortality riskaccording to quintiles of achieved net ultrafiltration rates after adjustment by patients weight duration of CRRTand other clinical parameters: OR 8.0 (95% CI: 2.7-25.1) when the highest quintile (>36 ml/kg/day) wascompared to the lowest quintile (<13 ml/kg/day). We hypothesize that innovative DL approaches integrating time-series data will generate accurate and generalizable risk prediction models that can impact CRRT delivery. Wewill utilize a multi-institutional dataset that encompasses clinical data and CRRT programmatic and therapy data(CRRTnet registry n=1500 patients) for model development and an independent multi-institutional dataset forvalidation (n=1500 patients) to: 1) continuously predict short-term (7-day) and medium-term (28-day) liberationfrom RRT due to kidney recovery; 2) continuously predict 24-hour mortality; and 3) identify and validate sub-phenotypes of patients with AKI on CRRT with differing achieved net ultrafiltration rates. This innovative researchwill assist 1) the development of novel clinical decision support platforms for guiding informed CRRT deliveryand promoting kidney recovery; 2) the identification of sub-phenotypes of patients that can benefit from precision-medicine approaches to fluid removal during CRRT; and 3) the design of interventional studies focusing on fluidremoval during CRRT to impact patient-centered outcomes.

project_terms:
Acute;Acute Renal Failure with Renal Papillary Necrosis;Affect;Algorithms;Artificial Intelligence;Big Data;Clinical;Clinical Data;Clinical Research;Clinical Trials;Clinical Trials Design;Critical Illness;Data;Data Set;Decision Making;Development;Dialysis procedure;Dose;Electronic Health Record;Event;Excision;Fluid overload;Goals;Hospital Mortality;Hour;Intensive Care Units;Intervention;Intervention Studies;Kidney;Liquid substance;Logistic Regressions;Measurement;Measures;Modality;Modeling;Outcome;Patient-Focused Outcomes;Patients;Performance;Phenotype;Population;Predictive Factor;Recovery;Registries;Renal Replacement Therapy;Reproducibility;Research;Resolution;Risk Factors;Series;Source;Statistical Algorithm;Survivors;Time;Ultrafiltration;Validation;Vulnerable Populations;Weight;clinical decision support;clinical decision-making;computer science;deep learning;electronic data;hemodynamics;improved;individual patient;individual response;innovation;model development;modifiable risk;mortality;mortality risk;multimodal data;multimodality;novel;outcome prediction;patient response;precision medicine;predict clinical outcome;risk prediction model;solute;therapy design;time use

public_health_relevance:
PROJECT NARRATIVEContinuous renal replacement therapy (CRRT) is the preferred dialysis treatment for critically ill patients withacute kidney injury and hemodynamic instability yet mortality is high (~75%). Presently there are no universallyaccepted approaches for predicting kidney recovery survival or individual response to fluid removal duringCRRT. We propose to develop and validate innovative deep learning approaches to dynamically predict theseoutcomes which could guide CRRT decision-making including intensification de-escalation and enrich clinicaltrials focusing on fluid removal during CRRT.


application_id: 10260562
project_number: 5R42NS107148-03
project_title: EpiZode: Noninvasive Seizure Screening in Preclinical Models of Epilepsy
administering_ic: NINDS
award_notice_date: 2022-08-18
opportunity_number: PA-19-270
application_type: 5
activity_code: R42
ic: NS
serial_number: 107148
program_official: CAPORELLO, EMILY LAURA
project_start_date: 2018-04-15
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1-ETTN-C(10)B]
contact_pi_person_id: 9484873
contact_pi: SUNDERAM, SRIDHAR
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 964938455
primary_uei: D9DRUX8SM4V9
duns_number: 964938455
uei: D9DRUX8SM4V9
fips: US
organization_id: 10032136
organization_name: SIGNAL SOLUTIONS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
EpiZode: Noninvasive Seizure Screening in Preclinical Models of EpilepsyThere is an urgent need for research into treatment options for epilepsy and other seizure disorders. Animalmodels are increasingly used to understand disease mechanisms and to screen promising therapeuticapproaches. Animal epilepsy model use typically requires expensive and labor-intensive experimentation withinvasive EEG measurements being the preferred method of validation. This severely limits the pace and scale ofinvestigation. In models of acquired epilepsy animals usually undergo treatment to induce status epilepticusa period of unremitting seizurefollowed by a latent period during which the brain rewires itself to generatespontaneously recurring seizures the hallmark of chronic epilepsy. The duration of the latent period and thelikelihood that an animal will develop epilepsy are both uncertain. Animals must be observed for weeks toconfirm epilepsy before they are ready for experimentation. During this latent period seizures are commonlydocumented by visual observation or video review which are tedious and prone to error. A commercial systemfor automated noninvasive seizure detection would therefore be invaluable to epilepsy researchers.Signal Solutions LLC has developed piezoelectric sensor technologies for noninvasive high-throughputbehavioral monitoring in rodents. This is being used by sleep/circadian researchers around the world anddiscriminates sleep from wakefulness with >90% accuracy. The Sunderam Lab at the University of Kentuckyhas further demonstrated that these piezo sensors can distinguish REM and NREM stages of sleep in mice.To address the needs of epilepsy researchers we performed a Phase I STTR study to: 1. Test the feasibility ofepilepsy onset detection in rodents using noninvasive piezo film sensors; 2. Validate piezo detections againstsimultaneous EEG recordings in rodents with epilepsy; and 3. Test the feasibility of using smaller profile piezosensors and an infrared imager for seizure screening and verification. The study successfully confirmed thefeasibility of these aims.In this Phase II STTR proposal we will further develop methods for accurate noninvasive seizure screening inrodent models through the following objectives: 1. Develop algorithms for detection of both overt and subtleseizures using small form factor piezo sensors; 2. Send a prototype system out for beta testing on differentanimal models and refine the system based on feedback; 3. Develop and validate novel sensor configurationsalgorithms for accurate seizure detection and attribution in group-housed epileptic animals.The envisioned product is a turnkey system for convenient noninvasive seizure screening in small animalmodels of epilepsy in custom or commercial cages that minimizes the need for invasive and resource-intensiveEEG analysis. Potential customers include academic research labs as well as labs in the pharmaceutical sectorengaged in high-volume screening of antiepileptic drugs.

project_terms:
Acute;Address;Aftercare;Algorithms;Animal Experimentation;Animal Model;Animals;Antiepileptic Agents;Behavior;Behavior monitoring;Behavioral;Brain;Chronic;Circadian Rhythms;Communities;Computer software;Convulsants;Custom;Detection;Development;Disease;Drug Screening;Electrodes;Electroencephalography;Epilepsy;Epileptogenesis;Essential Tremor;Evaluation;Family;Feedback;Film;Floor;Frontal Lobe Epilepsy;Funding;Genes;Genetic Models;Government;Harmaline;Industrialization;Investigation;Kentucky;Knock-out;Laboratory Animals;Lafora Disease;Measurement;Measures;Methods;Modeling;Monitor;Mus;Outcome;Persons;Pharmacologic Substance;Phase;Post-Traumatic Epilepsy;Pre-Clinical Model;Rattus;Research;Research Personnel;Resources;Rodent;Rodent Model;SCN8A gene;Sampling;Seizures;Signal Transduction;Sleep;Sleep Stages;Small Business Technology Transfer Research;Status Epilepticus;System;Technology;Temporal Lobe Epilepsy;Testing;Therapeutic;Time;Tonic - clonic seizures;Tremor;United States National Institutes of Health;Universities;Validation;Video Recording;Visual;Wakefulness;acquired epilepsy;base;circadian;dravet syndrome;drug development;feasibility testing;imager;interest;kainate;natural hypothermia;non rapid eye movement;non-invasive monitor;novel;perinatal stroke;pressure;prototype;relating to nervous system;respiratory;screening;sensor;sensor technology;social;source localization;success;trait;treatment effect;voltage

public_health_relevance:
The development of drugs and other treatments for epilepsy depends heavily on laboratory animal studies inwhich their effect on seizures is measured. Seizures are rare and unpredictable and monitoring animals forseizures in person or from video recordings is tedious; the alternative is to record brain signals which requiresinvasive and expensive recordings using electrodes. A new noninvasive technology is proposed for detectingseizures in lab animals used for epilepsy research.


application_id: 10259881
project_number: 5R01HL149164-02
project_title: Length-dependent activation in human myocardium
administering_ic: NHLBI
award_notice_date: 2021-08-11
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 149164
program_official: ADHIKARI, BISHOW B
project_start_date: 2020-09-15
project_end_date: 2024-07-31
study_section: Clinical and Integrative Cardiovascular Sciences Study Section[CICS]
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH S
other_pis: TANNER, BERTRAND C.W.
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:
ABSTRACTThis translational project uses human biospecimens procured from organ donors and patients undergoingcardiac transplant to advance understanding of a cellular-level mechanism that underpins the Frank-Starlingrelationship. Specifically the project focuses on length-dependent activation defined as the increased maximumforce and Ca2+ sensitivity of contraction induced by myocardial stretch. The mechanisms that underlie length-dependent activation remain unclear but may involve thick-filament regulation and transitions between the newlydiscovered OFF and ON states of myosin.Co-PI Campbell has spent a decade building a biobank that now contains >10000 myocardial specimens from>360 patients. Pilot experiments performed by Co-PI Tanner with these samples show that length-dependentchanges in Ca2+ sensitivity are eliminated in myocardium from patients who have non-ischemic heart failure butpreserved in myocardium from organ donors and patients who have ischemic heart failure. New computermodeling predicts that these functional effects reflect destabilization of the myosin OFF state in patients whohave non-ischemic heart failure. This hypothesis is supported by additional experiments that used fluorescentpolarization techniques to assess OFF/ON dynamics in the thick filaments of human myocardium. Further pilotstudies tested the effects of peptides targeted to the thick filament. Peptides that stabilize the OFF state reducedthe Ca2+ sensitivity of contraction at long sarcomere length while destabilizing peptides enhanced Ca2+ sensitivityat short length. The length-dependence of these effects was predicted by our computer modeling.The project builds on these data from human biospecimens and integrates the skills and resources of fivecardiovascular researchers a statistician and a physician-scientist who specializes in advanced heart failure.The Aims explore the global hypothesis that length-dependent activation is reduced in patients who have non-ischemic heart failure because their cardiac thick filaments are biased towards the ON state.Aim 1: Test the hypothesis that length-dependent changes in Ca2+ sensitivity are reduced in myocardium from patients who have non-ischemic heart failure.Aim 2: Test the hypothesis that the OFF state of the thick filament is destabilized in myocardium from patients who have non-ischemic heart failure.Aim 3: Target OFF/ON transitions to manipulate the Ca2+ sensitivity of human myocardium.

project_terms:
American;Biochemical;Biological Assay;Biophysics;Calcium;Cardiac;Cardiomyopathies;Cardiovascular system;Computer Models;Data;Data Set;Dependence;Development;Disease;Electrophoresis;Genetic;Genomics;Head;Heart Transplantation;Heart failure;Histologic;Histology;Human;Impairment;Infarction;Kentucky;Length;Levosimendan;Mus;Muscle Cells;Muscle Contraction;Mutation;Myocardial;Myocardial Ischemia;Myocardium;Myosin ATPase;Organ Donor;Organ Transplantation;Patients;Penetrance;Peptides;Pharmacologic Substance;Phenotype;Physicians;Physiologic pulse;Pilot Projects;Preparation;Property;Regulation;Research;Research Personnel;Resources;Sampling;Sarcomeres;Scientist;Specimen;Stretching;Structure;Sturnus vulgaris;Techniques;Testing;Thick Filament;Transplant Recipients;Transplantation;Universities;base;biobank;biophysical techniques;design;experimental study;gel electrophoresis;genomic data;human data;predictive modeling;preservation;skills

public_health_relevance:
NARRATIVEThis project analyzes samples of cardiac muscle procured from organ donors and patients who have heartfailure. Experiments will test how the muscle contraction changes as the samples are stretched and whether thecontraction can be modulated with specially designed molecules. The results of this project will accelerate thedevelopment of better therapies for patients who have different types of heart failure.


application_id: 10259668
project_number: 5UH3NS116238-02
administering_ic: NINDS
award_notice_date: 2022-08-15
opportunity_number: RFA-NS-18-023
application_type: 5
activity_code: UH3
ic: NS
serial_number: 116238
program_official: GROSS, BROOKS ANDREW
project_start_date: 2020-09-15
project_end_date: 2023-09-29
study_section: ZNS1-SRB-S(03)
contact_pi_person_id: 11410337
contact_pi: ANGELI, CLAUDIA
other_pis: BOAKYE, MAXWELL
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-07-01
project_title:
Inter-System Closed-Loop Control of Locomotor and Bladder Function in Individuals with Acute Spinal Cord Injury

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

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

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


application_id: 10259308
project_number: 1R43HL158430-01
administering_ic: NHLBI
award_notice_date: 2021-03-19
opportunity_number: PA-20-260
application_type: 1
activity_code: R43
ic: HL
serial_number: 158430
program_official: FENTON, KATHLEEN NELLE
project_start_date: 2021-04-01
project_end_date: 2023-09-30
study_section: Special Emphasis Panel[ZRG1 CVRS-C (10)]
contact_pi_person_id: 11058700
contact_pi: TOPAZ, STEPHEN R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 832402486
primary_uei: RK1ZDCXE3LJ7
duns_number: 832402486
uei: RK1ZDCXE3LJ7
fips: US
organization_id: 10024870
organization_name: W-Z BIOTECH, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-04-01
project_title:
Development of a Minimally Invasive Single Cannulation Compact Single Port Pulsatile Ventricular Assist Device (sppVAD) for Total LV Support

project_abstract:
Cardiogenic shock (CS) is a serious condition of reduced cardiac output (CO) with a mortality as high as40-50%. In severe CS end organ hypoperfusion from low CO causes multi-organ failure and elevated leftventricle (LV) preload increases LV wall stress. For severe CS venoarterial extracorporeal membraneoxygenation is most often used and is fastest way to reestablish circulation but it fails to unload LV in > 50% ofthese patients. Percutaneous mechanical circulatory support (MCS) devices are used in severe CS but maynot fully stabilize circulation. Non-percutaneous MCS devices supply total cardiac support but require openchest surgery for installation. Our goal is to develop a compact single port pulsatile ventricular assist device(sppVAD) for total LV support that employs a minimally invasive single cannulation technique for implantation.Compared to a continuous flow LVAD our sppVAD system may further unload the LV when synchronized withthe native heart for counterpulsation. Our enabling technologies that form the sppVAD system are a valvedsingle lumen cannula (VSLC) and a valveless single port diaphragm displacement pump (spDDP). Ourinnovative sppVAD system features: 1) Minimally invasive trans-apical to aorta installation by one VSLCcannulation through small left thoracotomy; 2) Smaller spDDP without inlet/outlet valves and large dead space;3) Lower blood resistance due to shorter pathway through LV via the VSLC that serves as both inlet and outletcannula; 4) Dependable total LV unloading; 5) Potential LV internal/stroke work decrease with counterpulsationpumping. W-Z Biotech made an initial prototype of sppVAD system which had 3.1 L/min pumping flow against80 mm Hg afterload in mock loop testing. Our objective in this Phase I SBIR is to develop/fabricate newworking prototype of sppVAD system (VSLC and spDDP) and to test sppVAD system prototype in mock loopand severe CS sheep model. Specific Aim 1: To develop/fabricate/bench test new working prototype ofsppVAD system (VSLC and spDDP). The 22 Fr VSLC main body will be memory alloy wire reinforcedpolyurethane (PU). Two one-way inlet valves on VSLC wall will be in LV for blood withdrawal. Two one-wayoutlet valves on VSLC wall near tip and a one-way outlet valve on VSLC tip will be in ascending aorta for blooddelivery. The spDDP will have rigid PU housing a soft flexible PU diaphragm membrane and a 50 mL pumpvolume. Only one 3/8 blood port will be made on spDDP for direct connection to VSLC. This sppVAD systemwill be tested in a bench mock loop. Specific Aim 2: To test sppVAD system prototype in a severe CSsheep model. Our severe CS sheep model will be used to test our sppVAD system prototype for ease ofinsertion/deployment LV unloading performance counterpulsation capacity and 6 hr reliability (n=5). ThesppVAD system prototype design/fabrication/in vitro testing will be done at W-Z Biotech while the in vivoanimal studies will be done at University of Kentucky. Upon project completion the commercialized sppVADsystem will provide total LV support to severe CS patients via only a minimally invasive single cannulation.

project_terms:
Alloys;Animals;Aorta;Apical;Biotechnology;Blood;Blood Circulation;Cannulas;Cannulations;Carbon Dioxide;Cardiac;Cardiac Output;Cardiogenic Shock;Clinical;Complex;Counterpulsation;Data;Development;Devices;Engineering;Excision;Extracorporeal Membrane Oxygenation;Goals;Heart;Heart Transplantation;Hour;Housing;Kentucky;Laboratory Animal Production and Facilities;Left;Left ventricular structure;Low Cardiac Output;Lung;Mechanics;Membrane;Memory;Multiple Organ Failure;Myocardial Infarction;Organ;Pathway interactions;Patients;Performance;Perfusion;Phase;Polyurethanes;Publications;Pump;Recovery;Research;Resistance;Respiratory Diaphragm;Safety;Scientist;Self-Help Devices;Small Business Innovation Research Grant;Stress;Stroke;Surgeon;System;Techniques;Technology;Testing;Thinness;Thoracic Surgical Procedures;Thoracotomy;Universities;Withdrawal;Work;artificial lung;ascending aorta;blood pump;design;experience;flexibility;hypoperfusion;implantation;improved outcome;in vitro testing;in vivo;innovation;invention;minimally invasive;mortality;multidisciplinary;myocardial injury;novel;prevent;prototype;research and development;sheep model;simulation;ventricular assist device

public_health_relevance:
We are proposing to develop a compact single port pulsatile ventricular assist device (sppVAD) for totalleft ventricle (LV) support that employs a minimally invasive single cannulation technique for implantation. Ourenabling technologies that form the sppVAD system are a valved single lumen cannula (VSLC) and a valvelesssingle port diaphragm displacement pump (spDDP). Our sppVAD system will provide total LV support via onlya minimally invasive single cannulation to bridge the severe cardiogenic shock patient to recovery furthertreatment long-term LVAD or heart transplantation potentially improving outcomes.


application_id: 10257468
project_number: 3P30CA177558-08S5
project_title: University of Kentucky Markey Cancer Center - Cancer Center Support Grant
administering_ic: NCI
award_notice_date: 2020-09-10
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S5
program_official: ROBERSON, SONYA
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Achievement;Address;Appalachian Region;Area;Award;Basic Science;Behavioral Research;Bioinformatics;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Cancer Research Project;Catchment Area;Cell Separation;Cellular biology;Centers of Research Excellence;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Communities;Community Healthcare;Community Networks;Community Outreach;Community Physician;Comprehensive Cancer Center;County;Coupled;Data Sources;Development;Disease;Distress;Early Diagnosis;Ecology;Education;Education and Outreach;Environmental Risk Factor;Epigenetic Process;Faculty Recruitment;Fellowship;Flow Cytometry;Foundations;Funding;Genetic;Genomic Instability;Genomics;Health Professional;Healthcare;Immunotherapy;Incidence;Individual;Informatics;Infrastructure;Institution;Intervention;Intervention Studies;Intervention Trial;Investments;Kentucky;Malignant Neoplasms;Mediator of activation protein;Mentors;Metabolic;Metabolism;Methods;Minority;Minority Graduate Student;Mission;Molecular;Mutation;NCI Center for Cancer Research;National Cancer Institute;Natural Products;Obesity;Obesity associated cancer;Oncology;Outcome;Oxidation-Reduction;Pathology;Patients;Phenotype;Population;Population Research;Population Sciences;Positioning Attribute;Prevention;Prevention therapy;Preventive;Program Development;Publications;Publishing;Quality of life;Radon;Registries;Research;Research Personnel;Resistance;Resource Sharing;Resources;Risk Factors;Role;SEER Program;Science;Scientist;Screening for cancer;Services;Signal Transduction;Site;Strategic Planning;Target Populations;Therapeutic;Training;Transcend;Translating;Translational Research;Translations;Underserved Population;Universities;anticancer research;authority;base;bench to bedside;biomedical informatics;cancer care;cancer genomics;cancer health disparity;cancer prevention;cancer research center director;cancer site;cancer survival;cancer therapy;career development;clinical development;clinical translation;cohort;college;community based participatory research;cost;drug discovery;early phase clinical trial;genetic epidemiology;health assessment;health disparity;high school;higher education;improved;innovation;instrumentation;inter-institutional;medically underserved;meetings;member;metabolomics;mortality;multidisciplinary;next generation;novel anticancer drug;outreach;personalized diagnostics;personalized intervention;population health;precision medicine;precision medicine clinical trials;programs;prospective;recruit;repository;response;screening;standard of care;synergism;targeted treatment;treatment response;tumor;tumor metabolism;undergraduate student


application_id: 10256613
project_number: 1R43CA261417-01
administering_ic: NCI
award_notice_date: 2021-03-24
opportunity_number: PAR-18-801
application_type: 1
activity_code: R43
ic: CA
serial_number: 261417
program_official: ZHAO, MING
project_start_date: 2021-04-01
project_end_date: 2023-06-30
study_section: Special Emphasis Panel[ZRG1 SBIB-T (10)]
contact_pi_person_id: 10810394
contact_pi: MOLLOY, JANELLE ARLENE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 093718777
primary_uei: L8D1CH5FK9X3
duns_number: 093718777
uei: L8D1CH5FK9X3
fips: US
organization_id: 10052089
organization_name: WILD DOG PHYSICS, LLC
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403568039
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-04-01
project_title:
Enabling remote medical physics services for medical accelerator quality assurance through a novel table-top imaging device

project_abstract:
Project Summary / Abstract Radiation therapy is an effective component of the treatment strategy for patients suffering from smoking-related cancers. Advanced techniques such as intensity modulated radiation therapy (IMRT) improve outcomesrelative to conventional approaches. Access to this modern treatment modality is limited in Eastern KentuckyAppalachia and other geographically isolated populations throughout low- and middle-income countries. Thebroad long-term objective of this research is improving the accessibility and safety of advanced radiationtechniques for patients low-resource settings globally. Quality assurance (QA) programs are required to ensuresafe and accurate treatment. The complexity of QA devices is such that their use requires highly specializedhuman resources (i.e. medical physicists) who must be physically present to collect and analyze data. Providersin these low-resource settings struggle to recruit the necessary staff. This can prevent such clinics from providingIMRT to their patients even when they own accelerators that are IMRT-capable. Medical Physics Innovations (MPI) proposes to design and construct a user-friendly affordable QAdevice that will make high quality QA and precision RT treatments in these low-resource settings more accessibleand safe. This proposal will establish feasibility via two specific aims: 1) Build and test the 3 primarysubcomponents of an integrated device and 2) Construct and test a clinical prototype. The consolidation ofmultiple device functions combined with the ease of use and measurement precision enable a paradigm shift ifhow medical physics services and quality assurance are rendered. Sparse but efficient daily QA protocols willbe replaced with comprehensive data collection and automated analysis at no additional cost in time orstaffing. High precision radiation treatments can be safely brought to rural and underserved areas with safetyefficiency and precision improved in any center using the innovation.

project_terms:
Address;Adoption;Advocate;Appalachian Region;Caliber;Clinic;Clinical;Collection;Data;Data Collection;Dependence;Devices;Dose;Elderly;Ensure;Film;Future;Generations;Geography;Human Resources;Hybrids;Image;Imaging Device;Improve Access;Incidence;Industry Standard;Intensity-Modulated Radiotherapy;International;Kentucky;Light;Linear Accelerator Radiotherapy Systems;Measurement;Measures;Medical;Medical center;Modality;Modernization;Monitor;Optics;Output;Patients;Peer Review;Performance;Phase;Physics;Population;Positioning Attribute;Process;Protocols documentation;Provider;Public Health;Quality Control;Radiation;Radiation therapy;Radio;Radiosurgery;Reporting;Research;Resources;Risk;Rural Community;Safety;Series;Services;Side;Smoking;Surface;System;Techniques;Testing;Time;Tissues;Travel;Universities;Vulnerable Populations;Work;X-Ray Computed Tomography;aged;automated analysis;cost;data acquisition;design;design and construction;dosimetry;health care availability;health care disparity;image guided radiation therapy;improved;improved outcome;innovation;low and middle-income countries;non-compliance;nonmetropolitan area;novel;optical polarization;peer support;phase 2 study;prevent;programs;prototype;public health relevance;quality assurance;recruit;rural area;rural setting;rural underserved;sensor;smoking-related cancer;success;treatment strategy;underserved area;user-friendly

public_health_relevance:
Project Narrative  Public Health Relevance The proposed work has the potential to improve public health by developing a commercial device thatwill improve access to and safety of advanced radiation therapy treatments especially in low-resource settings.By markedly improving efficiency in the collection of routine quality assurance measurements access tohealthcare and treatment safety can be improved while costs can be decreased.


application_id: 10256079
project_number: 5R01NR019456-02
administering_ic: NINR
award_notice_date: 2021-06-14
opportunity_number: RFA-NR-20-001
application_type: 5
activity_code: R01
ic: NR
serial_number: 019456
program_official: PRICE, AMANDA ALISE
project_start_date: 2020-09-07
project_end_date: 2025-06-30
study_section: ZNR1-REV-W(23)
contact_pi_person_id: 9701191
contact_pi: MUDD, GIA
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-07-01
project_terms:
Address;Adult;Affect;Age;Behavior;Behavioral;Biological;Blood Pressure;Body mass index;Cardiovascular Diseases;Cause of Death;Collaborations;Communities;Complement;Controlled Study;Data;Diabetes Mellitus;Education;Ethnic Origin;Ethnic group;Face;Family;Family member;Feedback;Geography;Glycosylated hemoglobin A;Health;Health Resources;Health behavior;Heart;Heart Diseases;Heart Rate;High Prevalence;Hispanics;Hyperglycemia;Hypertension;Individual;Intervention;Kentucky;Life Style Modification;Lipids;Mediating;Modeling;Modification;Non-Insulin-Dependent Diabetes Mellitus;Not Hispanic or Latino;Nutritional;Obesity;Outcome;Participant;Pattern;Physical activity;Population;Poverty;Prediabetes syndrome;Prevalence;Public Health;Race;Randomized;Randomized Controlled Trials;Research;Research Design;Resources;Risk;Risk Factors;Risk Management;Risk Reduction;Rural;Rural Community;Rural Population;Self Care;Social support;Testing;Tobacco use;Unhealthy Diet;Urban Community;Urban Population;Weight maintenance regimen;active control;base;behavior change;behavioral outcome;burden of illness;cardiovascular disorder risk;community based participatory research;comorbidity;comparison intervention;diabetes risk;disorder risk;efficacy testing;experience;family support;good diet;group intervention;health disparity;health inequalities;healthy lifestyle;high risk;hypercholesterolemia;improved;indexing;intervention effect;lifestyle intervention;lifetime risk;member;mortality;physical inactivity;post intervention;racial and ethnic disparities;rural Hispanic;rural dwellers;rural families;rural residence;smoking prevalence;social;socioeconomics


application_id: 10255561
project_number: 1R44DA053848-01
project_title: Digital Therapeutic Development of Virtual Cognitive-Affective Training for Opioid Use Disorder
administering_ic: NIDA
award_notice_date: 2021-05-13
opportunity_number: RFA-DA-19-019
application_type: 1
activity_code: R44
ic: DA
serial_number: 053848
program_official: ANGELONE, LEONARDO MARIA
project_start_date: 2021-05-15
project_end_date: 2022-08-14
study_section: Special Emphasis Panel[ZDA1 GXM-A (03)]
contact_pi_person_id: 7594377
contact_pi: WEISBERG, RISA B
other_pis: Not Applicable
congressional_district: 02
department: Unavailable
primary_duns: 080772307
primary_uei: PYRCCX2DHMJ7
duns_number: 080772307
uei: PYRCCX2DHMJ7
fips: US
organization_id: 10047086
organization_name: BEHAVR, LLC
organization_city: ELIZABETHTOWN
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 427014430
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abstinence;Adherence;Affect;Affective;American;Area Under Curve;Back;Behavior Therapy;Behavioral;Biochemical;Biometry;Brain;Buprenorphine;COVID-19 pandemic;Clinic;Clinical;Clinical Research;Cloud Computing;Cognitive;Computerized Medical Record;Custom;Data;Development;Dropout;Ecological momentary assessment;Educational Intervention;Electronic Health Record;Environment;Epidemic;Fast Healthcare Interoperability Resources;Feedback;Funding;Goals;Health Services Accessibility;Human;Human Resources;Individual;Ingestion;Intervention;Light;Link;Machine Learning;Measurement;Measures;Medical Device;National Institute of Drug Abuse;Opioid;Outcome;Participant;Patients;Pharmaceutical Preparations;Phase;Plant Roots;Process;Protocols documentation;Psychophysiology;Randomized Controlled Trials;Records;Recovery;Regulatory Pathway;Relapse;Research Design;Resources;Rewards;Risk;Safety;Self Efficacy;Services;Signal Transduction;Small Business Innovation Research Grant;Specific qualifier value;Sum;System;Techniques;Teleconferences;Testing;Therapeutic Effect;Training;Translating;Treatment outcome;United States;United States Food and Drug Administration;Viral;addiction;affective neuroscience;arm;barrier to care;biobehavior;chronic pain;clinical efficacy;commercialization;craving;cue reactivity;design;digital treatment;effective intervention;efficacy study;electronic data;evidence base;experience;implementation barriers;improved;innovation;meetings;mindfulness;neurophysiology;novel;opioid epidemic;opioid misuse;opioid treatment program;opioid use;opioid use disorder;patient engagement;patient safety;phase 1 study;prescription opioid;prevent;programs;promoter;prototype;response;reward processing;satisfaction;skills;success;therapeutic development;therapy development;treatment as usual;treatment program;treatment risk;treatment strategy;usability;virtual;virtual machine;virtual reality;virtual reality system


application_id: 10254858
project_number: 3R01DK124112-01S1
administering_ic: NIDDK
award_notice_date: 2020-09-11
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: DK
serial_number: 124112
suffix: S1
program_official: SADUSKY, ANNA BURKART
project_start_date: 2020-01-01
project_end_date: 2023-12-31
contact_pi_person_id: 6769757
contact_pi: SISKIND, LEAH J
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-01-01
project_title:
The role of neutral ceramidase in acute kidney injury and its progression to chronic kidney disease.

project_abstract:
Summary:The long-term goal of this proposal is to develop novel therapeutics for a serious unmet medical need namelyacute kidney injury (AKI) and its progression to chronic kidney disease (CKD) for which there are no treatmentsother than supportive care. The mechanisms of kidney injury and its progression to CKD are largely unknownand this proposal aims to fill some of these knowledge gaps. The short-term goal of this proposal is to validatea novel target for treating AKI and its progression to CKD for future drug development. This target is neutralceramidase (NCD) an enzyme involved in metabolism of the sphingolipid ceramide. The proposal is based ona strong foundation of supporting preliminary data that indicates that mice lacking NCD are protected in modelsof AKI and CKD and in vitro data indicating that deletion or inhibition of NCD increases autophagy and protectscells from a variety of cellular stresses. Thus this proposal will test the hypothesis that deletion or inhibition ofNCD confers protection from AKI and injury-induced CKD via upregulation of autophagy. We will test thishypothesis with three interrelated but independent specific aims that will (1) determine the mechanism ofprotection of kidney cells in vitro from cellular stress when NCD is deleted or inhibited; (2) determine the role ofNCD in AKI; and (3) determine the role of NCD in kidney injury progression to CKD. Data obtained in this proposalwill provide many scientific and translational advances that are essential for achieving our long-term goal ofdeveloping therapeutics for this unmet medical need.

project_terms:
Acute Renal Failure with Renal Papillary Necrosis;Autophagocytosis;Cells;Cellular Stress;Ceramidase;Ceramides;Chronic Kidney Failure;Data;Development;Enzymes;FDA approved;Foundations;Future;Goals;In Vitro;Injury to Kidney;Knowledge;Medical;Metabolism;Modeling;Mus;Recording of previous events;Risk;Role;Sphingolipids;Supportive care;Testing;Therapeutic;Up-Regulation;base;drug development;kidney cell;novel;novel therapeutics

public_health_relevance:
Acute kidney injury is an unmet medical need with no FDA approved treatments other than supportive care. Inaddition a history of prior kidney injury is a major risk for development of chronic kidney disease. The overallgoal of this proposal is to determine the role of neutral ceramidase in acute kidney injury and its progressionto chronic kidney disease.


application_id: 10254314
project_number: 5R21AI155008-02
project_title: The Dual Reporter Sensor Cell (DRSC) Assay: An Enhanced Tool for Measuring the Viral Reservoir
administering_ic: NIAID
award_notice_date: 2021-08-03
opportunity_number: PA-19-053
application_type: 5
activity_code: R21
ic: AI
serial_number: 155008
program_official: LAWRENCE, DIANE M
project_start_date: 2020-09-04
project_end_date: 2023-08-31
study_section: HIV Molecular Virology, Cell Biology, and Drug Development Study Section[HVCD]
contact_pi_person_id: 10311819
contact_pi: BERRY, SCOTT M
other_pis: SHERER, NATHAN M
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 latent viral reservoir is a major barrier to eradicating HIV infection. Unfortunately very few tools are availableto quantify the reservoir and monitor the effectiveness of prospective therapies that aim to reduce it. The currentgold standard assay the quantitative viral outgrowth assay (QVOA) has enabled landmark scientific studiesbut lacks the simplicity and robustness required for large-scale clinical implementation. Other options include anumber of nucleic acid-based assays but these are thought to overestimate the quantity of latent HIV that isactually replication-competent. Thus there exists an unmet need for next-generation reservoir assaytechnologies that are capable of analyzing the HIV proviral reservoir in a straightforward and precise manner.The cornerstone of our proposed assay is a novel dual reporter sensor cell (DRSC) line that contains twoindependent HIV infection-linked reporter systems both of which must be triggered to designate a true positiveresult thereby enhancing specificity. Like QVOA our DRSC requires successful spread of HIV infection betweenmultiple cells to trigger a positive signal thereby eliminating many of the false positive events seen with non-livecell assays (e.g. defective HIV DNA will be erroneously quantified in many PCR-based reservoir assay).Importantly preliminary data suggests that the DRSC is significantly faster (2 vs. 7 days) and requires lesssample volume when compared with the QVOA.In the proposed project we further optimize the DRSC via development of two key concepts: First we willevaluate and implement low convection culture environments which will accelerate assay kinetics (and improvesensitivity) via elimination of the convective dilution of secreted factors (including virions) resulting in theconcentration of factors within the vicinity of producing cells. Second we will continue to improve our automatedimaging and image analysis techniques (including real-time imaging processes) facilitating the furtheroptimization of assay performance (e.g. through better selection of assay timing) and streamlining the ultimatetranslation of this technology into broader research and clinical roles (e.g. via integration of image-basedgenotyping into our readout). These two key developments enable a number of advantageous featuresincluding: 1) Reduction in total assay time; 2) The spatial resolution of the DRSCs combined with diffusion-dominant fluid mechanics eliminates the need for limiting dilution endpoints (as with QVOA which requiresmultiple replicates of multiple T cell dilutions to obtain a single endpoint) substantially reducing the amount ofsample volume required; 3) an overall reduction in assay complexity relative to the QVOA. Importantly at theconclusion of this study we will perform a pilot study comparing patient samples with expected high and lowreservoir values using both the DRSC assay and QVOA thus laying the foundation for larger future studies.

project_terms:
APOCEC3G gene;Address;Antiviral Agents;Antiviral Therapy;Behavior;Biological Assay;Blood;CD4 Positive T Lymphocytes;Cell Line;Cells;Cellular Assay;Chemicals;Clinical;Complex;Convection;Cultured Cells;Custom;DNA;Data;Development;Devices;Diffusion;Effectiveness;Environment;Event;Foundations;Future;Genotype;Geometry;Gold;HIV;HIV Genome;HIV Infections;HIV-1;Half-Life;Image;Image Analysis;Infection;Kinetics;Link;Liquid substance;Measurement;Measures;Mechanics;Mediation;Modification;Monitor;Nucleic Acids;Patients;Performance;Phase;Pilot Projects;Plaque Assay;Population;Process;Production;Proteins;Protocols documentation;Reporter;Research;Resolution;Rest;Role;Sampling;Scanning;Signal Transduction;Specificity;System;T-Lymphocyte;Techniques;Technology;Therapeutic;Time;Translations;Universities;Validation;Viral;Viral reservoir;Viremia;Virion;Virus;Virus Latency;Wisconsin;assay development;automated image analysis;base;clinical implementation;improved;latent infection;next generation;novel;phenotypic data;prospective;real-time images;research study;response;sensor;tool

public_health_relevance:
PROJECT NARRATIVEThe latent viral reservoir is a major barrier to eradicating HIV infection. Unfortunately very few tools areavailable to quantify the reservoir and monitor the effectiveness of prospective therapies that aim to reduce it.We propose to develop a novel assay a dual reporter sensor cell (DRSC) line that contains two independentHIV infection- linked reporter systems both of which must be triggered to designate a true positive resultthereby enhancing specificity.


application_id: 10254281
project_number: 5F31AA028423-02
project_title: sEH Inhibition in Alcoholic Liver Disease: A Novel Therapeutic Strategy
administering_ic: NIAAA
award_notice_date: 2021-08-23
opportunity_number: PA-19-195
application_type: 5
activity_code: F31
ic: AA
serial_number: 028423
program_official: RADAEVA, SVETLANA
project_start_date: 2020-09-01
project_end_date: 2023-08-31
study_section: ZAA1-GG(32)
contact_pi_person_id: 15958059
contact_pi: WARNER, JEFFREY B
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryAlcoholic liver disease (ALD) is the most common liver disease and is responsible for nearly half of all deathsfrom diseases affecting this organ. Despite this there remain no FDA-approved treatments for any stage of thedisease highlighting the need for the discovery of new therapies. As an aspiring scientist whose goal is to pursuea career in alcohol-related multi-organ pathology investigating new therapies for ALD treatment would not onlyhelp fill this medical need but also serve as an excellent platform from which to learn how to become a successfulscientist. With the help and supervision of my co-mentors Dr. Kirpich (an expert in basic research on ALD) andDr. McClain (an expert on clinical aspects of the disease) as well as several knowledgeable collaborators I willinvestigate soluble epoxide hydrolase (sEH) inhibition as a novel therapeutic strategy for the treatment of ALDusing pre-clinical mouse models. This approach has been applied to other inflammatory diseases but not toALD a disease shown by previous work in our group to be characterized by a loss of anti-inflammatoryepoxygenated lipids (epoxides) in part due to their rapid degradation by sEH. I have generated substantialpreliminary data with an orally-administered sEH inhibitor in a chronic-binge mouse model of ALD thatrecapitulates human ALD. Through two related but independent specific aims proposed in this application I willfurther assess the efficacy of sEH inhibition and explore its mechanisms of action. Aim 1 will use pharmacologicaland genetic ablation of sEH to further characterize the effects of sEH inhibition in mouse models of ALD. Aim 2will describe the mechanistic effects of individual anti-inflammatory epoxides on changes in hepatocyte andimmune cell health and function to explain changes seen in vivo. To complete this research I will follow a detailedtraining plan laid out for me by my co-mentors and pursue the career goals that I have set for myself. Theseinclude among others continuing my didactic training in areas relevant to my research gaining experience innew laboratory techniques developing effective written and oral communication skills and building aprofessional network of scientists. For example to assess liver injury and changes in cellular function I will learnto read histological liver slides use enzymatic assays set up ELISAs isolate and culture primary hepatocytesand macrophages and learn flow cytometry. The research environment at the University of Louisvilles state-of-the-art Clinical and Translational Research Building is highly productive and staffed with expert faculty andresearch personnel willing to help me learn these techniques and advise me as I pursue my training and careergoals. My academic department the Department of Pharmacology & Toxicology is equally positioned to supportmy training in the classroom and provide many resources (e.g. travel funds career development seminars andnew courses) to ensure my success. Collectively the training and research proposed here will not only fill asignificant need for the development of ALD treatments but will also foster my development from a youngscientist to a successful independent investigator in the field of alcohol-induced organ disease.

project_terms:
ANXA5 gene;Ablation;Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animals;Anti-Inflammatory Agents;Area;Attenuated;Basic Science;Biological;Biological Assay;CXCL1 gene;Cell Death;Cell Line;Cell physiology;Cells;Cellular biology;Cessation of life;Chronic;Clinical;Clinical Research;Data;Development;Disease;Ensure;Environment;Enzyme-Linked Immunosorbent Assay;Epoxide hydrolase;Epoxy Compounds;Ethanol;FDA approved;Fatty Acids;Flow Cytometry;Fostering;Funding;Genetic;Goals;Health;HepG2;Hepatic;Hepatocyte;Histologic;Human;IL6 gene;Immune;Individual;Inflammation;Inflammatory;Interleukin-1 beta;Knock-out;Knockout Mice;Kupffer Cells;Laboratories;Learning;Lipids;Liver;Liver diseases;Medical;Mentors;Modeling;Mus;Neutrophil Infiltration;Oral;Organ;Palmitic Acids;Pathogenesis;Pathology;Patients;Pharmaceutical Preparations;Pharmacology;Pharmacology and Toxicology;Phenotype;Physiological;Polyunsaturated Fatty Acids;Positioning Attribute;Predisposition;Prevention;Production;Propidium Diiodide;Research;Research Personnel;Resolution;Resources;Role;Scientist;Slide;Stains;Supervision;TNF gene;Techniques;Testing;Therapeutic;Training;Translational Research;Translations;Travel;Universities;Work;alcohol exposure;bench to bedside;career;career development;career networking;chronic liver disease;cytokine;efficacy evaluation;experience;experimental study;faculty research;feeding;improved;in vivo;inhibitor/antagonist;lipid mediator;lipidome;lipidomics;liver inflammation;liver injury;macrophage;mouse model;novel therapeutic intervention;novel therapeutics;oral communication;pre-clinical;prevent;recruit;skills;success;treatment strategy

public_health_relevance:
Project NarrativeAlcoholic liver disease (ALD) is responsible for nearly half of liver disease deaths yet there are no FDA-approvedtherapies available for the treatment of any stage of its progression. Discovery of unique changes in the hepaticlipidome reveal soluble epoxide hydrolase (sEH) inhibition as a therapeutic strategy with high potential to lessenliver damage associated with ALD. Full assessment of the efficacy of sEH inhibition through this proposedresearch will allow us to better understand its uses and mechanisms of action and contribute to the translationof this approach from bench to bedside.


application_id: 10252006
project_number: 5K01CA251487-02
project_title: Promoting Cervical Cancer Screening among African American and Sub-Saharan African Immigrant women
administering_ic: NCI
award_notice_date: 2021-08-25
opportunity_number: PAR-18-365
application_type: 5
activity_code: K01
ic: CA
serial_number: 251487
program_official: VAHEDI, SHAHROOZ
project_start_date: 2020-09-02
project_end_date: 2025-08-31
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 14387971
contact_pi: ADEGBOYEGA, ADEBOLA O
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Africa South of the Sahara;African;African American;Awareness;Behavior Therapy;Belief;Cancer Control;Cancer Etiology;Central Asia;Cervical;Cervical Cancer Screening;Cessation of life;Clinic Visits;Clinical Trials Design;Collection;Consent;Cross-Sectional Studies;Data;Death Rate;Developing Countries;Development;Development Plans;Diagnosis;Education;Emotional;Environment;Evidence based intervention;Extramural Activities;Frequencies;Fright;Funding;Future;Geographic Locations;Goals;Health;Health Promotion;Health behavior;Health education;Healthcare Systems;Human Papillomavirus;Human papilloma virus infection;Immigrant;Incidence;Individual;Intervention;Intervention Studies;Irrigation;K-Series Research Career Programs;Kentucky;Knowledge;Lesion;Literature;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mentored Research Scientist Development Award;Mentors;Methods;Minority;Modality;Modeling;Not Hispanic or Latino;Outcome;Outcome Measure;Pattern;Physicians;Population;Population Heterogeneity;Population Study;Preventative vaccination;Prevention;Privatization;Quality of Care;Quasi-experiment;Race;Randomized Clinical Trials;Research;Research Personnel;Research Training;Resources;Role;Sampling;Screening for cancer;Screening procedure;Self Efficacy;Sensitivity and Specificity;South America;Structure;Subgroup;Swab;Testing;Time;Training;Treatment Efficacy;Underserved Population;United States;Universities;Visit;Vulnerable Populations;Woman;aged;anticancer research;behavior change;behavior influence;black men;black subgroup;black women;cancer health disparity;cancer prevention;career;career development;cervical cancer prevention;cost;evidence base;experience;health belief;health care availability;health knowledge;high risk;high risk population;innovation;intervention effect;mortality;peer;prevent;programs;racial and ethnic disparities;recruit;research study;satisfaction;screening;screening participation;skills;social;social cognitive theory;underserved minority;willingness


application_id: 10251386
project_number: 3R21ES031510-01S1
project_title: m6A Epitranscriptomics in Toxicant Associated Steatohepatitis
administering_ic: NIEHS
award_notice_date: 2021-02-15
opportunity_number: PA-20-222
application_type: 3
activity_code: R21
ic: ES
serial_number: 031510
suffix: S1
program_official: TYSON, FREDERICK L
project_start_date: 2021-02-15
project_end_date: 2022-06-30
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: CAVE, MATTHEW C
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:
Project Summary/AbstractExposure to persistent environmental contaminants including polychlorinated biphenyls (PCBs) contributes tometabolic diseases including toxicant-associated steatohepatitis (TASH) a form of nonalcoholic fatty liverdisease (NAFLD). PCBs have been positively associated with TASH hepatocellular cancer altered liverenzymes and mortality in human cohorts. A complete understanding of the mechanisms by which PCBs act asa 1st hit in combination with a high fat Western diet (HFD) as a 2nd hit to increase triglyceride accumulationfibrosis and inflammation in the liver (hallmarks of TASH) remains elusive. Further although liver sexualdimorphism is well-established and sex-specific differences in human health outcomes after PCB exposure havebeen reported there are few mechanistic studies addressing these differences. N(6)-methyladenosine (m6A) isthe most common dynamic modification of transcribed RNAs. The regulation and role of m6A in liverepitranscriptomics and the impact of PCB exposure is unknown. This application addresses RFA-ES-19-002 byinvestigating the role of altered m6A and its writers readers and erasers in TASH in vivo using an establishedPCB exposure model. Preliminary RNA-seq data show that liver from HFD + Aroclor 1260 (PCB) exposed maleC57BL/6J mice have reduced transcript levels of the m6A methyltransferase complex protein Rbm15 and alteredlevels of the m6A readers Ythdf1 and Ythdc1/2. Whether these HFD + Aroclor 1260-induced changes are alsooccur in females and how they affect the m6A epitranscriptome and hepatocyte homeostasis or liver function isunknown. We recently reported increased PCB-induced hepatic inflammation and altered lipid metabolism infemale vs. male mice. The goal of this exploratory study is to determine the impact of PCB +/- HFD exposure invivo on the hepatic m6A epitranscriptome in male and female mice. We will test the hypothesis that altered m6Alevels of specific transcripts play a role in TASH in vivo. Integrated analysis will identify m6A epitranscriptome-mediated changes in signaling pathways regulating TASH pathophysiology. This goal will be achieved by 1)Identification of m6A-mediated transcriptome changes in HFD Aroclor 1260 (a mixture of non-dioxin-like (NDL)PCB subtypes that best mimics the PCB bioaccumulation in human adipose tissue) and HFD + Aroclor 1260 exposed male and female mouse liver; 2) Determination if HFD Aroclor 1260 or HFD + Aroclor 1260 exposurealter the expression of the writers readers and erasers of m6A in mouse liver. Integrated analysis will identifym6A epitranscriptome-mediated changes in signaling pathways regulating TASH pathophysiology that may betargets for therapeutic intervention. In the future knockdown or overexpression of key proteins identified in thisstudy will confirm their role in the observed m6A changes and in downstream signaling.

project_terms:
Address;Adenosine;Adipose tissue;Affect;Alternative Splicing;Animal Model;Antibodies;Aryl Hydrocarbon Receptor;Attenuated;Biological Markers;C57BL/6 Mouse;Cessation of life;Cirrhosis;Data;Diet;Dioxygenases;Disease;Dose;Environmental Exposure;Environmental Pollutants;Environmental Pollution;Enzymes;Epidermal Growth Factor;Euthanasia;Event;Exposure to;Fatty Liver;Fatty acid glycerol esters;Female;Fibrosis;Functional disorder;Future;Genes;Goals;Health;Hepatic;Hepatocyte;High Fat Diet;Histology;Homeostasis;Human;Hypertriglyceridemia;Immunoprecipitation;Inflammation;Knockout Mice;Liver;Liver Extract;Liver diseases;Measures;Mediating;Messenger RNA;Metabolic Diseases;Methyltransferase;MicroRNAs;Modeling;Modification;Mus;Necrosis;Nuclear Receptors;Nutrient;Nutritional;Outcome;Pathology;Pathway Analysis;Play;Polychlorinated Biphenyls;Positioning Attribute;Primary carcinoma of the liver cells;Protein Methyltransferases;Proteins;Proteome;RNA;RNA Splicing;Reader;Receptor Inhibition;Regulation;Reporting;Role;Sampling;Sex Differences;Signal Pathway;Signal Transduction;Steatohepatitis;Stress;Testing;Therapeutic Intervention;Time;Transcript;Translations;Untranslated RNA;Western Blotting;base;bioaccumulation;circulating microRNA;cohort;constitutive androstane receptor;epitranscriptome;epitranscriptomics;human subject;in vivo;knock-down;lipid metabolism;liver function;liver transplantation;mRNA sequencing;male;methyl group;mortality;non-alcoholic fatty liver disease;overexpression;pregnane X receptor;protein complex;protein expression;receptor;response;sex;sexual dimorphism;targeted treatment;toxicant;transcriptome;transcriptome sequencing;virtual;western diet

public_health_relevance:
Environmental pollutants (polychlorinated biphenyls (PCB)) increase toxicant-associated steatohepatitis(TASH) in the context of a high fat diet. Whether PCB-induced modification of the epitranscriptome is involvedin TASH is unknown. The major goal of this exploratory project is to determine if PCBs alter the liverN(6)methyladenosine epitranscriptome in TASH resulting in sex-specific gene changes and disease pathology.


application_id: 10251367
project_number: 5R01AG054559-05
project_title: Emerging Roles of Higher-order Polyamines During Tauopathies
administering_ic: NIA
award_notice_date: 2021-04-05
opportunity_number: PAR-15-358
application_type: 5
activity_code: R01
ic: AG
serial_number: 054559
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2017-04-01
project_end_date: 2025-03-31
study_section: Special Emphasis Panel[ZRG1-MDCN-T(56)R]
contact_pi_person_id: 9300523
contact_pi: LEE, DANIEL CARL
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:
Collectively tauopathies including Alzheimers disease (AD) impact close to 6 million Americans and cost over$200 billion in medical care. They devastate families and cause victims to lose their memory their dignity andfinally their identity. Currently no disease modify agents exist for treating tauopathies and AD andspontaneous recovery is unknown; a diagnosis of tauopathy is a death sentence. Strategies proposed toreduce tau burden include increasing clearance decreasing phosphorylation or nitration reducing aggregationand diminishing inflammation among others. Arginine metabolism is poised at a critical branch-point andserves as a precursor for nitric oxide generation from nitric oxide synthases or polyamine production fromarginase (Arg1). Our data indicates that Arg1 overexpression in a mouse model of tauopathy reduces multipleaspects of the tau phenotype; phospho-tau deposition Gallyas staining hippocampal atrophy high molecularweight tau multimers tau nitration cytokine markers of inflammation inhibitors of autophagy and proteinkinase activation. Many of these effects can also be demonstrated in cell culture. We also show that higher-order polyamines directly block tau aggregation and promote microtubule assembly in solution at physiologicalconcentrations but acetylated polyamines fail to mimic this affect. Several distinct effects of this manipulationcould mediate these remarkable benefits of Arg1 over expression and polyamine metabolism. The goal of thisapplication is to better understand how polyamines contribute to the benefits of reducing the tau phenotypeand identify other potential targets for treating tauopathies and possibly AD. Utilizing gene therapy mousemodels of tauopathy and knockout models we will test four aims. 1) Determine if Increased PolyaminesDiminish Tau Pathology. 2) Determine if Reduced Polyamines Enhance Tau Pathology. 3) Test ifPharmacological Nutritional Modulation of Polyamines Regulates Tau Pathology and 4) Test if the Deletion ofSSAT Reduces Tau Pathology. Success in these aims will increase our knowledge regarding the role ofpolyamines metabolism in regulating the tau phenotype. Our goal is to identify additional therapeutic targetsthat could be regulated by pharmacological agents to arrest or slow the progression of the tau deposition inhumans with neurodegenerative disease.

project_terms:
Acetylation;Affect;Age;Alzheimer's Disease;American;Anabolism;Animal Model;Arginine;Autophagocytosis;Axon;Back;Behavioral;Caring;Catabolism;Cell Culture Techniques;Cells;Cessation of life;Cognition;DL-alpha-Difluoromethylornithine;Data;Dependovirus;Deposition;Diagnosis;Diet;Dietary Administration;Disease;Drug Targeting;Enzymes;Family;Functional disorder;Generations;Goals;Human;Inflammation;Knock-out;Knockout Mice;Knowledge;Learning;Length;Measures;Mediating;Medical;Memory;Metabolism;Microtubules;Modeling;Molecular Weight;Mus;Neurodegenerative Disorders;Neurons;Nitric Oxide;Nitric Oxide Synthase;Nutritional;Ornithine;Ornithine Decarboxylase;Ornithine Decarboxylase Inhibitor;Pathology;Pathway interactions;Pharmaceutical Preparations;Pharmacology;Phenotype;Phosphorylation;Phosphotransferases;Physiological;Polyamine Catabolism;Polyamines;Production;Protein Kinase;Proteins;Recovery;Regulation;Reporting;Role;Spermidine;Spermidine Synthase;Spermine;Spermine Synthase;Stains;Supplementation;System;Tauopathies;Testing;Therapeutic;Transferase;Transgenic Mice;age related;arginase;behavioral outcome;biological adaptation to stress;chronic traumatic encephalopathy;cost;cytokine;gene therapy;hippocampal atrophy;inflammatory marker;inhibitor/antagonist;mouse model;nitration;novel;ornithine decarboxylase antizyme;overexpression;response;success;tau Proteins;tau aggregation;tau-1;therapeutic target;transcription factor

public_health_relevance:
Tauopathies consist of a group of neurodegenerative diseases including Alzheimers disease and currently notherapeutic treatments exist for tauopathies. This study will test various aspects of how polyamines impacts tauand how tau disrupts the polyamine system. We aim to identify novel targets along the polyamine pathway andlearn how dysregulation of this pathway promotes tau neuropathology.


application_id: 10250531
project_number: 5R01AA023190-07
project_title: Mechanisms of Probiotics in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2021-07-27
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AA
serial_number: 023190
program_official: WANG, JOE
project_start_date: 2015-09-15
project_end_date: 2025-07-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
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:
Probiotics have been used to prevent/treat a variety of digestive diseases including alcoholic liver disease (ALD).Live probiotics need to colonize the gut to exert their function. Unfortunately underlying disease states providean unfavorable environment for probiotic bacterial gut colonization which diminishes probiotics function. In lastfew years we showed that LGG culture supernatant (LGGs without live bacteria) was effective in the preventionof ALD in experimental models of acute and chronic alcohol exposure in mice. However how LGG supernatantexerts its therapeutic effects is not fully understood. Exosomes are nanoparticles (NPs) derived from cellendocytosis which act as transmitters between cells. Recent studies show that bacteria both Gram-negativeand Gram-positive produce NPs. The NPs derived from bad bacteria have been demonstrated to bepathogenic. However good bacteria- probiotics-derived NPs have not been studied. Our preliminary studyshowed that administration of LGG-derived exosome-like NPs (LDNPs) effectively reversed ALD in binge-on-chronic alcohol exposure mouse model suggesting that probiotic LGGs may exert its function through LDNPsin ALD. LDNPs administration markedly increased intestinal AhR activity IL-22 regenerating islet-derived 3(Reg3) beta and gamma expression which play a key role in maintaining gut microbiota homeostasis andpreventing bacterial intestinal transcytosis. In addition LDNPs administration significantly increased intestinalepithelial cell (IEC) tight junctions and decreased circulating LPS concentration associated with upregulation ofintestinal Nrf2 signaling which is known for protecting intestinal barrier junctions against oxidative stress-induceddamage by alcohol. Metabolomic analysis revealed that LDNPs contain high levels of microbial metabolites oftryptophan which are AhR ligands indicating LDNPs may activate intestinal AhR signaling. Furthermore wedemonstrated that ginger exosome-like nanoparticles (GDNPs) are preferentially taken up by LGG suggestingthat GDNP may serve as a prebiotic to enhance the effects of LGG. These preliminary studies provide thegroundwork for our central hypothesis that by activating intestinal AhR-Nrf2 signaling LDNPs increase intestinalexpression of Il-22 Reg3 and tight junctions and modulate gut microbiota homeostasis and enhance intestinalbarrier function leading to the suppression of ALD. We will test our hypothesis in following three specific aims:(1) Determine the role of bacteria-derived NPs in ALD; (2) Define the mechanisms of the beneficial effect ofLDNPs in ALD; (3) Determine whether ginger-derived exosome-like nanoparticles (GDNPs) treatment enhancesLDNP production and AhR agonist enrichment that lead to improved effects of LDNPs against ALD. Completionof this study is expected to significantly impact the development of LGG-based probiotic therapeutics in thetreatment of alcohol-associated liver diseases.

project_terms:
Acute;Agonist;Alcohol-Induced Disorders;Alcoholic Liver Diseases;Aryl Hydrocarbon Receptor;Bacteria;Bacterial Translocation;Bilophila wadsworthia;Cells;Chronic;Development;Digestive System Disorders;Disease;Endocytosis;Environment;Epithelial;Epithelial Cells;Experimental Models;Ginger;Goals;Growth;Homeostasis;Intestines;Lactobacillus casei rhamnosus;Lead;Liver diseases;Mediating;Mus;Natural regeneration;Oxidative Stress;Pathogenicity;Pathway interactions;Play;Prevention;Prevention strategy;Probiotics;Production;Receptor Signaling;Role;Signal Transduction;Testing;Therapeutic Effect;Tight Junctions;Tryptophan;Up-Regulation;alcohol abuse therapy;alcohol exposure;aryl hydrocarbon receptor ligand;base;dysbiosis;exosome;gut colonization;gut microbiota;improved;inflammatory disease of the intestine;interleukin-22;intestinal barrier;intestinal epithelium;islet;metabolomics;microbial;mouse model;nanoparticle;novel therapeutic intervention;pathogenic bacteria;prebiotics;prevent;probiotic therapy;protective effect;transcytosis

public_health_relevance:
The goals of this project are to investigate the mechanisms of probiotic Lactobacillus rhamnosus GG actionon alcoholic liver disease. This study will have a major impact on the development of a probiotics-based newtherapeutic strategy for the prevention and treatment of alcoholic liver disease.PHS 398/2590 (Rev. 05/01) Page 1 Continuation Format Page


application_id: 10250367
project_number: 5R01ES026657-05
project_title: Microenvironment and Arsenic Lung Tumorigenesis
administering_ic: NIEHS
award_notice_date: 2022-08-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 026657
program_official: HUMBLE, MICHAEL C
project_start_date: 2017-09-30
project_end_date: 2024-08-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 10212779
contact_pi: CHEN, GANG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract Chronic exposure of environmental arsenic promotes skin bladder liver and lung cancers. Howeverthe mechanism underlying arsenic lung carcinogenesis is unclear. Evidence from animal models and studies incancer patients indicate that the immune system monitors the host body recognizing and reacting againstnewly arising transformed/tumor cells to stop/control tumor formation. The encounter between the immunesystem and transformed/tumor cells initiates a process termed immunoediting that can bring about threeoutcomes: elimination equilibrium or escape of transformed/tumor cells from immune control. Host immunitysuppresses tumor development whereas tumor formation implies the successful escape of transformed/tumorcells from the surveillance of the immune system. Effector T cells particularly cytotoxic T (Tc) cells representa major component of cell-mediated anti-tumor immunity. One of the mechanisms modulating T cell antitumoreffector function involves the activation/inhibition receptors on a T cell membrane. Inhibition of T cell antitumorfunction through the activation of immune checkpoint pathways (e.g. PD-1/PD-L1 pathway) has been shown topromote tumor cell immune escape and tumor formation. In addition previous reports indicate that the aberrantactivation of STAT3 occurs in many human tumors and STAT3-mediated PD-L1 up-regulation impedes T cellantitumor function. Our previous in vitro study showed that the IL-6/STAT3 axis plays a critical role in arsenic-induced transformation in human bronchial epithelial cells. Using a lung tumor mouse model our newpreliminary data show that long-term arsenic exposure increased lung tumor incidence rate and multiplicity ofA/J mice. In addition arsenic exposure dose-dependently activated STAT3 increased the binding of STAT3 tothe promoter of the PD-L1 gene and up-regulated PD-L1 in mouse lungs. Flow cytometry data further indicatedthat arsenic increased PD-1+ T cell numbers and decreased CD8+/CD4+ T cell ratio in the lungs while injectionof PD-1 or PD-L1 antibodies reversed the decreased CD8+/CD4+ ratio. Since PD-1/PD-L1 up-regulation mayinhibit T cell antitumor function and promote escape of transformed cells from host immunosurveillance andeventually lead to tumor formation we hypothesize that arsenic promotes lung tumor formation throughSTAT3/PD-1/PD-L1-mediated inhibition of T cell antitumor function. Three specific aims are proposed:Aim 1: To determine if chronic arsenic exposure inhibits T cell antitumor function and the types of cells inwhich PD-1 or PD-L1 is up-regulated by arsenic in the lungs of A/J mice.Aim 2: To determine if inhibition of the PD-1/PD-L1 pathway ameliorates arsenic-promoted T cell dysfunctionand tumor formation in the lungs of A/J mice.Aim 3: To determine if activation of STAT3 is the mechanism underlying arsenic-enhanced PD-L1 up-regulation T cell dysfunction and tumor formation in the lungs of A/J mice.

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

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


application_id: 10250347
project_number: 5F99AG068525-02
project_title: Young cardiomyocyte phenotype drives enhanced cardiac recovery in spiny mice
administering_ic: NIA
award_notice_date: 2021-08-11
opportunity_number: RFA-AG-20-009
application_type: 5
activity_code: F99
ic: AG
serial_number: 068525
program_official: WILLIAMS, JOHN
project_start_date: 2020-09-01
project_end_date: 2022-08-31
study_section: ZAG1-ZIJ-1(M2)
contact_pi_person_id: 15924998
contact_pi: PENG, HSUAN
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:
Aging is a major risk factor for ischemic heart disease often caused by heart attack (myocardial infarction MI). MI occurs at an alarmingly high rate in the United States (approximately one case every 40 seconds) and is the leading cause of morbidity and mortality in the geriatric population. At present heart failure (HF) represents an unmet need with no approved clinical therapies to repair the damaged myocardium. As the population ages the number of HF patients is projected to increase doubling the annual cost by 2030. Identifying novel and translational mechanisms for robust cardiac repair presents a critical approach to counter aging-associated cardiac diseases and guide the design of future successful therapies.  Acomys (African Spiny mouse) is a mammal closely related to Mus (laboratory mouse). Recently independent groups have reported that Acomys are capable of regenerating injured tissue in multiple organs. Most importantly after MI Acomys demonstrated significant cardiac protection with a higher survival rate than mice. Our preliminary studies revealed that Acomys hearts retained a high frequency of young proliferative phenotype cardiomyocytes (CM). This proposal will further dissect the mechanisms driving the youthful cardiac phenotype and cardiac protection in Acomys. The candidate will study Acomys and Mus side by side to test the central hypothesis that cytoprotective resilience to reactive oxygen species (ROS) preserves young phenotype CM into adulthood and drives enhanced myocardial preservation in Acomys after a heart attack.  In the F99 phase of training the candidate will continue investigating the contribution of Acomys cardiomyocytes in endogenous cardiac repair following MI in both young and aged animals. Specifically the candidate will examine cardiomyocyte proliferation in both species and different age groups after MI. Scar size cardiac function and angiogenesis will also be characterized to determine the extent of recovery. In the K00 phase the candidate will switch focus to identify molecular targets and pathways that allow Acomys to maintain a young heart into adulthood. The proposed work is designed to provide a robust transition training into aging research that will prepare the candidate for an academic career in translational anti-aging cardiac therapy. The proposed work will yield valuable information on endogenous cardiac repair in adult mammals. This knowledge will aid in the discovery of novel therapies and approaches for maintaining cardiac health throughout adulthood.

project_terms:
Acomys;Address;Adult;African;Age;Aging;Animals;Automobile Driving;Calcium;Cardiac;Cardiac Myocytes;Cardiac health;Career Choice;Cell Therapy;Cellular Stress;Cicatrix;Clinical;Clinical Medicine;Diploidy;Elderly;Electrophysiology (science);Exhibits;Fellowship;Flow Cytometry;Frequencies;Future;Goals;Healthcare;Heart;Heart Diseases;Heart failure;Human;Immunohistochemistry;Injury;Knowledge;Laboratories;Laboratory mice;Longevity;Mammals;Methods;Modeling;Molecular;Molecular Target;Mononuclear;Morbidity - disease rate;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Natural regeneration;Neonatal;Organ;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Patients;Phase;Phenotype;Physiologic pulse;Population;Publications;Reactive Oxygen Species;Recovery;Reporting;Research;Research Personnel;Risk Factors;Role;Side;Signal Transduction;Stress;Survival Rate;Testing;Tissues;Training;Translating;United States;Vertebrates;Work;age group;aged;aging population;angiogenesis;anti aging;cardiac repair;career;clinical development;clinically relevant;cost;design;functional decline;healing;heart function;in vivo;injured;injury recovery;insight;ischemic injury;mortality;mouse model;myocardial injury;neonatal mice;new therapeutic target;novel;novel therapeutic intervention;preservation;regeneration model;regenerative;regenerative biology;repaired;resilience;response;skills;small molecule

public_health_relevance:
The proposed research is relevant to aging research and health care in that ischemic heart disease following myocardial infarction (MI) continues to be the leading cause of mortality and morbidity in the aging population with no approved clinical therapies to replace the damaged myocardium. The goal of this proposal is to elucidate cardiac protective mechanisms that enhance recovery after MI using the novel regenerative mammal Acomys as adult mouse model. Our results will identify new therapeutic targets for the future development of clinically relevant cardiac therapies for human patients.


application_id: 10248534
project_number: 5R01ES032189-02
project_title: Exposome and Precision Medicine in NAFLD
administering_ic: NIEHS
award_notice_date: 2021-08-19
opportunity_number: RFA-ES-18-007
application_type: 5
activity_code: R01
ic: ES
serial_number: 032189
program_official: SCHUG, THADDEUS
project_start_date: 2020-08-28
project_end_date: 2023-07-31
study_section: ZES1-JAB-D(VT)
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and it is often associated with obesityand metabolic disruption. NAFLD has a variable clinical course and only some patients develop nonalcoholicsteatohepatitis (NASH) and progressive fibrosis which increase mortality. An environmental contribution toNAFLD has previously been demonstrated by special exposure cohort studies and animal models. Howeverdata gaps prevent the clinical application of this emerging environmental health scientific knowledge to impactthe clinical care of NAFLD patients through a precision medicine approach. This project proposes a new high-impact virtual consortium (the NAFLD-ViCTER) to conduct synergistic multidisciplinary translationalexposomics research in adult NAFLD patients to address these knowledge gaps. It tests the hypothesis thatenvironmental exposures contribute to NAFLD severity natural history and response to therapy via hepatictranscriptional reprogramming resulting in metabolic disruption. The consortium is composed of investigatorswith synergistic expertise and resources from three centers including: Matt Cave (PI University of Louisville)Naga Chalasani (Co-I Indiana University) and Dean Jones (Co-I Emory University). The specific aims are: 1)To determine the environmental exposures associated with adult NAFLD severity in a cross-sectional study. Thisanalytical cross-sectional study with internal comparisons utilizes previously collected archived de-identifiedmaterials from adult patients with NAFLD characterized by vibration-controlled transient elastography andhistology. Untargeted high-resolution exposomics (HRE) will be performed in plasma. Sex differences will beinvestigated. Exposome-wide association studies (EWAS) vs. NAFLD severity biomarkers will be performed. 2)To elucidate the mechanisms by which environmental exposures increase the severity of NAFLD. This analyticalcross-sectional study utilizes materials from Aim 1 along with previously determined genotyping and hepaticmRNA-SEQ data. Untargeted high-resolution metabolomics (HRM) will be performed in plasma. MWAS andtranscriptome wide association studies (TWAS) will be performed vs. (i) NAFLD severity biomarkers and (ii) theexposures associated with NAFLD severity using data-driven integrative and pathway analyses. Gene:environment interactions will be examined. 3) To determine the environmental chemicals associated with NASHhistologic progression and response to therapy in a longitudinal study. Archived de-identified data and plasmaspecimens from a previously-published multi-center placebo-controlled clinical trial of obeticholic acid for adultNASH will be utilized. Plasma HRE/HRM will be performed and the exposures/metabolic signatures associatedwith NASH histologic progression and response to therapy will be determined using the placebo and obeticholicacid treated patients respectively. NAFLD-ViCTER will transform the clinical understanding of the environmentalcontribution to NAFLD. It will pave the way for precision medicine incorporating exposomics in NAFLD.

project_terms:
Acids;Address;Adult;Agonist;Animal Model;Archives;Biological Markers;Clinical;Clinical Research;Cohort Studies;Controlled Clinical Trials;Cross-Sectional Studies;Data;Disease Progression;Doctor of Philosophy;Double-Blind Method;Effectiveness;Environmental Exposure;Environmental Health;Environmental Risk Factor;Etiology;Fibrosis;Funding Mechanisms;Genes;Genotype;Hepatic;Hepatology;Histologic;Histology;Human;Indiana;Institution;Knowledge;Liver;Liver diseases;Longitudinal Studies;Mass Spectrum Analysis;Measurement;Metabolic;National Institute of Environmental Health Sciences;Natural History;Obesity;Participant;Pathogenesis;Pathway Analysis;Patients;Pilot Projects;Placebos;Plasma;Publishing;Research;Research Personnel;Research Subjects;Resolution;Resources;Sampling;Severities;Severity of illness;Sex Differences;Specimen;Steatohepatitis;Strategic Planning;Study models;Testing;Therapeutic;Treatment outcome;Universities;attenuation;authority;clinical application;clinical care;clinical decision-making;cohort;data de-identification;elastography;environmental chemical;gene environment interaction;insight;mRNA sequencing;metabolome;metabolomics;mortality;multidisciplinary;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;precision medicine;prevent;response;transcriptional reprogramming;transcriptome;vibration;virtual

public_health_relevance:
This project proposes a new high-impact virtual consortium to conduct synergistic multidisciplinary translationalexposome research in nonalcoholic fatty liver disease (NAFLD). It will transform the scientific understanding ofthe environmental contribution to NAFLD thereby paving the way for a new precision medicine approach topatients with this liver disease.


