# projects

application_id: 10090757
project_number: 1RF1NS119165-01
project_title: Translational Approaches to Mitigate Enhanced Alzheimers Disease Risk Following a Mild TBI
administering_ic: NINDS
award_notice_date: 2021-04-01
opportunity_number: PA-19-056
application_type: 1
activity_code: RF1
ic: NS
serial_number: 119165
program_official: AWWAD, HIBAH OMAR
project_start_date: 2021-04-01
project_end_date: 2024-02-29
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
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:
ABSTRACTA traumatic brain injury (TBI) is a well-known risk factor for Alzheimer's disease. There is not a one-to-onerelationship where a TBI will lead to the development of Alzheimer's disease. The lack of a direct connectionsuggests a selective vulnerability. Problematically when a person has a mild TBI it is not possible to know ifthey will recover without an impact on their brain health or if they have now increased their vulnerability todeveloping Alzheimer's disease. What can be done? One approach is a broad administration of therapy shortlyafter the injury. Since this approach requires treating some people who would recover from the TBI withoutintervention the benefit-to-risk ratio must be very high. That is you do not want to cause harm by giving anunneeded drug. Our long-term goal is to identify safe treatments to be used after a mild TBI in an older adultpopulation to lessen the chance of developing Alzheimer's disease. There are currently no FDA approveddrugs to be used after a mild TBI to reduce secondary injury mechanisms. We believe that not treating after amild TBI is a missed opportunity but the treatment needs to be safe. Our preliminary evidence shows that aTBI causes deficits in energy metabolism and increased neuroinflammation both of which are exacerbated bypreexisting proteinopathies such as amyloid-beta. To target these mechanisms we have identified Beta-hydroxybutyrate (BHB; 3-hydroxybutyric acid) as a safe multimodal intervention. BHB is a ketone body whichis continuously produced by the liver at low levels but can rise above 1mM during periods of fasting calorierestriction prolonged exercise or by the ketogenic diet. Clinically BHB is safe to be administered orally BHBrapidly crosses the blood-brain-barrier and in cases of starvation ketones can provide as much as 70% of thebrain's energy. BHB is an alternative biofuel that can bypass blockages in the electron transport systemcaused by amyloid-beta and TBI which decrease mitochondrial bioenergetics. BHB has also been shown tosuppress inflammation via an inflammasome-dependent mechanism and by binding to a recently deorphanizedGPCR called HCA2. We will test the central hypothesis that BHB will be effective at reducing functionaldeficits seen in APP/PS1 KI mice following a mild TBI through both energetic and neuroinflammatorydependent mechanisms in three specific aims (SA). SA1: Dose-dependent effects of BHB on mitochondrialfunction and neuroinflammation after TBI. SA2: Define the immunomodulatory properties of the HCA2receptor via dose-dependent effects of niacin a high-affinity HCA2 agonist. SA3: Define theimmunomodulatory properties BHB through the HCA2 receptor through loss of function experiment. Our workseeks to address the mechanisms associated with the increased fragility of the older brain which keeps it fromrecovering from a mild TBI. We also will define the therapeutic potential of the BHB/HCA2 axis as a post-TBIneuroprotective strategy for use in a population at risk for Alzheimer's disease.

project_terms:
APP-PS1;Acids;Address;Adult;Affinity;Age;Agonist;Agreement;Alzheimer's Disease;Alzheimer's disease risk;Amyloid beta-Protein;Assisted Living Facilities;Binding;Bioenergetics;Blood - brain barrier anatomy;Brain;Bypass;Caloric Restriction;Chronic;Clinical;Closed head injuries;Cognitive;Cognitive deficits;Complex;Data;Dementia;Development;Disease;Dose;Elderly;Electron Transport;Energy Metabolism;Environmental Risk Factor;Epidemiology;Exercise;Experimental Designs;Exposure to;FDA approved;Family member;Fasting;G-Protein-Coupled Receptors;Goals;Head;Implant;Incidence;Independent Living;Individual;Inflammasome;Inflammation;Injury;Interleukin-1 beta;Intervention;Ketone Bodies;Ketones;Knock-in Mouse;Knockout Mice;Life;Liver;Measures;Microglia;Mitochondria;Mus;Neurodegenerative Disorders;Neurologic;Nicotinic Acids;Odds Ratio;Oral;Pathologic;Pathology;Persons;Pharmaceutical Preparations;Population;Populations at Risk;Positron-Emission Tomography;Property;Pump;Radiology Specialty;Receptor Activation;Recovery;Reporting;Risk;Risk Factors;Societies;Starvation;System;TBI treatment;Testing;Therapeutic;Time;Traumatic Brain Injury;Work;beta amyloid pathology;beta-Hydroxybutyrate;brain health;design;efficacious intervention;experience;experimental study;falls;human old age (65+);immunoregulation;ketogenic diet;loss of function;loved ones;medical attention;member;mild traumatic brain injury;mitochondrial dysfunction;modifiable risk;mouse model;multi-component intervention;neurodegenerative dementia;neuroinflammation;pre-clinical;prevent;receptor;subcutaneous;translational approach;young adult;-amyloid burden

public_health_relevance:
A significant way to reduce the overall burden of Alzheimers disease is to identify modifiable risk factors whichcould be avoided or treated that would slow or prevent the onset of Alzheimers disease. Traumatic braininjury is a well-established environmental risk factor for the development of Alzheimers disease. Completion ofthese studies will uncover the largely unexplored therapeutic approach of Beta hydroxybutyrate for individualsexposed to a traumatic brain injury to reduce the risk of developing a neurodegenerative disease.


application_id: 10090470
project_number: 5R01EY027805-04
administering_ic: NEI
award_notice_date: 2021-01-26
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: EY
serial_number: 027805
program_official: LIBERMAN, ELLEN S
project_start_date: 2018-02-01
project_end_date: 2023-01-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 14475772
contact_pi: FAMULSKI, JAKUB K
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-02-01
project_title:
Comprehensive analysis of periocular mesenchyme composition specification and function during anterior segment formation

project_abstract:
PROJECTSUMMARY:Inheritedcongenitalanteriorsegmentdysgenesis(ASD)disordersareamajorcauseofvisionimpairmentandblindness.Theyincludedevelopmentaloculardeficienciesoftheiriscorneaandlensinadditiontosignificantpredisposition~50%toglaucoma.Fromvariousstudiesinrecentyearsithasbecomeclearthatmanycongenitaldisordersandpredispositionsarisefromearlydevelopmentaldefectsbothmajorandsubtle.Examiningthedevelopmentalprocessgivingrisetotheseessentialcomponentsofthevisualsystemisthereforeafruitfulapproachtostudyingthedisease.Theanteriorsegmentderiveslargelyfromtheearlymigratingneuralcrestcellsthattargetspecificallytotheanteriorofthedevelopingretinaandarelooselyclassifiedasperiocularmesenchyme(POM).POMdeficiencyhasbeendemonstratedincertaincasesofASD.IbelieveamajorroadblockineffortstotreatandunderstandASDhasbeenthelimitedexaminationofPOMbiologyandfunctionduringearlyoculardevelopment.ThishamperseffortstocharacterizetheetiologyofdiseaseandscreeninginASDfamiliesinadditiontodelayingattemptsatiPSC-mediatedapproachesfortreatmentofASD.TocircumventtheseproblemsweaimtocomprehensivelycharacterizePOMcellspecificationmigrationtargetingdifferentiationandultimatelycontributiontoanteriorsegmentdysgenesis.ThisisthenextlogicalandnecessarystepinorderforthefieldtocontinuetheevolutionoftherapyandscreeningforglaucomaandASDdisorders.OurimmediategoalistotestthehypothesisthatPOMcellsdelineateintovarioussubpopulationsandspecifytobecometheanteriorsegmentmesenchyme(ASM).TotestourhypothesisweproposetoemploythehighlyversatilezebrafishembryomodelsystemandcomprehensivelyexaminePOMcelldevelopmentwhilecatalogingtheircontributiontotheanteriorsegmentthroughgeneticmolecularandcuttingedgeinvivoimagingapproaches.Ourspecificaimsare:Aim1:CharacterizespecificationanddefinethecompositionoftheASMtheusingacombinationofgeneexpressionanalysispairedwithlight-sheetinvivotimelapseimagingandconfocalmicroscopy.Aim2:TrackthemigratorybehaviorandlineagetracedistinctpopulationsofASMduringanteriorsegmentformationusinglight-sheetinvivotimelapseimagingandconfocalmicroscopypairedwithanovelfatemappingoptogenetictracingmechanism.Aim3:GenerateacomprehensiveASMtranscriptomeforscreeningnoveltargetsinASDpatientsamplesusingacombinationofflowcytometrycoupledtoRNAseqandnextgenerationexomesequencing.

project_terms:
Affect;Animal Model;Anterior;Anterior segment dysgenesis;Behavior;Biological Assay;Biological Models;Biology;Blindness;Candidate Disease Gene;Cataloging;Cells;Cellular biology;Chick;Ciliary Muscle;Classification;Color;Comprehension;Confocal Microscopy;Congenital Disorders;Cornea;Corneal Endothelium;Coupled;Defect;Development;Developmental Process;Disease;Disease model;Embryo;Etiology;Event;Evolution;Eye Development;Family;Flow Cytometry;Future;Gene Combinations;Gene Expression Profiling;Genes;Genetic;Genetic Counseling;Genome engineering;Genomics;Glaucoma;Goals;Health;Human;Image;In Situ Hybridization;Individual;Inherited;Iris;Knowledge;Lesion;Light;Location;Maps;Mediating;Mesenchyme;Microscopy;Molecular;Mus;Neural Crest Cell;Optics;Patients;Pattern;Phenotype;Population;Predisposition;Regulation;Reporter;Research;Retina;Sampling;Sclera;Structure;Testing;Time;Tissues;To specify;Transgenic Organisms;Vision;Visual impairment;Visual system structure;Zebrafish;clinical practice;confocal imaging;exome sequencing;gain of function;imaging approach;in vivo;in vivo imaging;induced pluripotent stem cell;lens;migration;next generation;novel;optogenetics;orbit muscle;screening;stem cell therapy;time use;transcription factor;transcriptome;transcriptome sequencing

public_health_relevance:
PROJECTNARRATIVE/RELEVANCETOHUMANHEALTH:Anteriorsegmentdysgenesis(ASD)disordershavedevelopmentalunderpinningsthatarecrucialtoourcomprehensionofvisiondiseaseandadvancementoftherapy.Clinicalpracticewilldirectlybenefitfromstudiesofanimalmodelslikezebrafishwhichprovidestremendousresearchadvantagesincludingexuterodevelopmentopticaltransparencythroughoutdevelopmentandcapacityforgenomeengineeringanddiseasemodeling.ThegoalofourproposalistogeneratethefirstcomprehensiveclassificationofperiocularmesenchymecellsinordertofacilitateeffortsinscreeningforASDpredispositionandenablefutureinvivostemcelltherapy.


application_id: 10090463
project_number: 5R01EY012354-20
project_title: Isolation of Congenital Stationary Night Blindness Genes
administering_ic: NEI
award_notice_date: 2021-01-22
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: EY
serial_number: 012354
program_official: WRIGHT, CHARLES BAKER
project_start_date: 1999-02-01
project_end_date: 2023-01-31
study_section: Neurotransporters, Receptors, and Calcium Signaling Study Section[NTRC]
contact_pi_person_id: 1885008
contact_pi: GREGG, RONALD G
other_pis: HASAN, NAZARUL ;MCCALL, MAUREEN A
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:
Vision begins when light is converted to an electrical signal in the photoreceptors. Increases in light decreaserelease of the neurotransmitter glutamate from cone and rod photoreceptor terminals and decreases in lightincrease its release. These changes in synaptic glutamate concentration are detected by two classes of bipolarcells that then transmit the signal vertically through the retinal circuit to the ganglion cells. The neurotransmitterchanges also are detected by horizontal cells that provide lateral transmission in the form of feedback andfeedforward inhibition.There are two classes of bipolar cells hyperpolarizing (HBCs) and depolarizing (DBCs). HBCs utilizeionotropic glutamate receptors and hyperpolarize in response to a light flash. DBCs utilize a metabotropicglutamate receptor mGluR6 that signals to TRPM1 depolarizing in response to a light flash. Defects intransmission in DBCs results in complete congenital stationary night blindness (cCSNB). Mutations in GRM6NYX TRPM1 GPR179 and LRIT3 cause cCSNB. The mechanism by which mGluR6 signals TRPM1 is largelyunknown. The long term goal of this project is study the molecular interactions between LRIT3 and known andknown components DBC signal transduction components. The specific aims are: 1) determine the function ofLRIT3 domains on rod and cone DBC mGluR6 signalplex assembly and signaling and 2) Define proteininteractions required for DBC assembly and synaptic function and 3) determine the function of LRFN1 and 2on cone synapse function.At the completion of this project we will have characterized the function of LRIT3 and how it interacts withcurrently unknown presynaptic partners. Further we will have identified new candidate genes for congenitalstationary night blindness.

project_terms:
Binding;Biological Assay;Brain;CRISPR/Cas technology;Candidate Disease Gene;Cells;Complex;Cone;Defect;Disease;Electroretinography;Elements;Feedback;Future;GNB5 gene;Gene Proteins;Genes;Glutamate Receptor;Glutamates;Goals;Immunohistochemistry;Kainic Acid Receptors;Knockout Mice;Label;Lateral;Leucine-Rich Repeat;Light;Mediating;Metabotropic Glutamate Receptors;Methods;Morphology;Mus;Mutation;Nature;Neurons;Neurotransmitters;Night Blindness;Pathway interactions;Photoreceptors;Proteins;Research;Retina;Retinal Cone;Rod;Role;Side;Signal Transduction;Structure;Synapses;Synaptic Transmission;TRPM1 gene;Testing;Therapeutic;Vertebrate Photoreceptors;Vision;cell assembly;ganglion cell;horizontal cell;human disease;in vivo;light intensity;member;mutant;neurotransmitter release;novel;patch clamp;postsynaptic;postsynaptic neurons;presynaptic;receptor;response;retinal rods;synaptic function;transmission process;visual coding

public_health_relevance:
Vision requires a light signal be converted to an electrical signal which is then transmitted to the brain via a neuronal network. The diseases being studied are referred to as congenital stationary night blindness. The studies in this proposal will characterize the nature of the defects and determine the function of newly identified proteins critical for normal vision which will set the stage of therapeutic approaches in the future.


application_id: 10087560
project_number: 5R01NS102196-04
project_title: RIT1-mediated Protection following Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2021-02-13
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 102196
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2018-02-15
project_end_date: 2023-01-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7875195
contact_pi: ANDRES, DOUGLAS ALLEN
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:
Traumatic brain injury (TBI) is a major cause of death and permanent disability in the United States affectingmore than 1.7 million individuals each year. TBI not only results in tissue damage and cell death but canperturb surviving neuronal function leading to alterations in neural connectivity abnormal plasticity andnetwork dysfunction. Due to the inherent diversity in post-TBI dysfunction a critical need exists for therapeuticinterventions that target multiple injury mechanisms. Development of such multi-prong therapeutic approachescould have enormous clinical social and economic benefit. However implementation of this strategy requiresthe identification of endogenous molecular cascades capable of regulating multiple protective/restorativepathways. The discovery that the Rit GTPase (RIT1) is dramatically down-regulated following corticalcontusion injury (CCI) prompted studies to explore the contribution of Rit-directed signaling to functionalrecovery following TBI. Drawing upon a collection of RIT1 transgenic mice exciting preliminary datademonstrate that Rit activation reduces in vivo neurodegeneration and alleviates cognitive dysfunctionfollowing CCI. Additional data suggest that Rit is critical for post-TBI neurogenesis and promotes synapticintegrity by reducing post-contusion synaptic loss. Collectively these data are the first to demonstrate asignificant role for Rit in directing neuroprotection and neuroplasticity following TBI and suggest that Ritfunctions as a linchpin regulator of multiple injury response mechanisms following CCI. The overall hypothesisis that: (1) Rit plays a key role in cellular and functional recovery from brain trauma and (2) that activation ofRit signaling therefore has broad therapeutic potential in the setting of TBI. Three complementary aims guideour studies. Aim 1 will test the hypothesis that contusion-dependent Rit loss disrupts gene expressionprograms that promote neural survival and neurogenesis. In Aim 2 we will evaluate the extent to which Ritsignaling controls neuronal survival after contusive brain injury. The efficacy of Rit-targeted therapies will beevaluated using an inducible knock-in mouse model to permit Rit activation over a clinically relevant period ofhours to days after the onset of brain injury. Aim 3 will test the hypothesis that Rit signaling preserves synapticfunction following traumatic brain injury using transgenic mice electrophysiology and biochemical assays.Overall these studies are expected to identify Rit as a crucial signal integration hub in the setting of brain injury orchestrating diverse endogenous pathways that regulate neuronal survival promote neuronal regenerationand control neuroplasticity mechanisms.

project_terms:
Acute;Affect;Area;Attenuated;Behavioral;Biochemical;Biological Assay;Brain Contusions;Brain Injuries;CREB1 gene;Cause of Death;Cell Death;Cells;Chronic;Clinical;Collection;Contusions;Cortical Contusions;Data;Development;Economics;Electrophysiology (science);Emotional;Experimental Models;Functional disorder;Gene Expression;Genetic Transcription;Guanosine Triphosphate Phosphohydrolases;Hippocampus (Brain);Hour;Impaired cognition;Individual;Injury;Knock-in Mouse;Language;Learning;Leg;Link;Mediating;Memory impairment;Modeling;Molecular;Multiple Trauma;Nerve Degeneration;Nerve Regeneration;Neuronal Dysfunction;Neuronal Injury;Neuronal Plasticity;Neurons;Pathway interactions;Play;Proteins;Recovery;Recovery of Function;Role;Signal Transduction;Speech;Suggestion;Survivors;Synapses;Testing;Therapeutic;Therapeutic Intervention;Thinking;Tissues;Transgenic Mice;Traumatic Brain Injury;United States;adult neurogenesis;arm;bioinformatics tool;brain repair;clinically relevant;dentate gyrus;disability;experience;experimental study;in vivo;injured;injury-related death;insight;loss of function;mouse model;network dysfunction;neurogenesis;neuronal survival;neuroprotection;preservation;programs;relating to nervous system;response to injury;social;synaptic function;targeted treatment;transcriptome sequencing

public_health_relevance:
Traumatic brain injury (TBI) is a leading cause of death and disability in the United States and survivors mayhave persistent loss of function in arms or legs abnormal speech or language loss of thinking ability oremotional problems. The wide range of injuries suggests that the development of multi-prong therapeuticapproaches to TBI could have enormous clinical social and economic benefit. This project will investigate theRIT1 protein as a linchpin capable of counterbalancing diverse injury mechanisms providing a unique avenuefor therapeutic intervention by allowing a combined approach of protecting neurons and promoting brain repairin a single target.


application_id: 10087163
project_number: 1R01ES032396-01
project_title: A university-community partnership to reduce exposure to disinfection byproducts in Appalachia
administering_ic: NIEHS
award_notice_date: 2020-12-29
opportunity_number: RFA-ES-20-002
application_type: 1
activity_code: R01
ic: ES
serial_number: 032396
program_official: O'FALLON, LIAM
project_start_date: 2021-01-01
project_end_date: 2025-10-31
study_section: Special Emphasis Panel[ZES1 ARL-K (R)]
contact_pi_person_id: 14229942
contact_pi: UNRINE, JASON
other_pis: HOOVER, ANNA GOODMAN
congressional_district: 06
department: OTHER BASIC SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acids;Address;Air;Appalachian Region;Birth;Businesses;Cardiovascular system;Characteristics;Chemicals;Chemistry;Chloramines;Chlorates;Chlorine;Coal;Collaborations;Communication;Communities;Congenital Abnormality;Consultations;County;Data;Disinfectants;Disinfection;Economics;Environmental Health;Exposure to;Funding;Goals;Grant;Halogens;Health;Home;Human;Infrastructure;Intervention;Kentucky;Knowledge;Laws;Location;Malignant neoplasm of urinary bladder;Methods;Modeling;National Institute of Environmental Health Sciences;Operating System;Ozone;Participant;Pilot Projects;Population;Process;Public Health;Regulation;Research;Research Personnel;Resources;Risk;Route;Rural Community;Sampling;Scientist;Source;Surface;System;Testing;Training and Infrastructure;Trihalomethanes;Trust;Ultraviolet Rays;United States;United States Environmental Protection Agency;Universities;Variant;Water;West Virginia;base;citizen science;community partnership;drinking water;exposure route;ground water;health communication;health literacy;improved;predictive modeling;public drinking;ranpirnase;rural America;rural dwellers;social;spatial temporal variation;water quality


application_id: 10085644
project_number: 5R01EY028911-03
project_title: Chemical Optimization of c-Cbl Antagonists for Corneal Wound Healing
administering_ic: NEI
award_notice_date: 2021-01-14
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: EY
serial_number: 028911
program_official: MCKIE, GEORGE ANN
project_start_date: 2019-02-01
project_end_date: 2024-01-31
study_section: Special Emphasis Panel[ZRG1-BDCN-J(81)S]
contact_pi_person_id: 1925445
contact_pi: CERESA, BRIAN P.
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary An intact and fully differentiated corneal epithelium is critical for proper vision and to keep foreign objects(bacteria viruses small particles) out of the eye. However damage to the corneal epithelium is one of themost common ocular problems presented in primary care facilities and arises from a variety of factorsincluding trauma disease and a side-effect of drugs. Despite the prevalence discomfort and potential forblindness associated with perturbation of the corneal epithelium there are no FDA-approved agents thatpromote the restoration and homeostasis of this tissue. The long-term goal of our research is to develop newcompounds that promote corneal epithelial wound healing and homeostasis. The overall objective of thisapplication is to chemically optimize a recently identified c-Cbl antagonist to increase its affinity and potencywhile decreasing cytotoxicity. To accomplish this we will test the central hypothesis that compounds thatdisrupt EGFR:c-Cbl interactions will prevent EGFR ubiquitylation divert the activated EGFR from the lysosomeand prolong EGFR signaling. Based on preliminary studies this prolongs EGFR activity and increases therestoration and maintenance of corneal epithelium via cell migration proliferation and differentiation. Therationale for these studies is that knockdown of c-Cbl and inhibits EGFR ubiquitylation prolongs EGFR activityand enhances corneal epithelial wound healing. Following an in silico screen of 25000000 compounds wehave identified several lead compounds that bind c-Cbl and inhibit ligand-mediated EGFR ubiquitylation. Weseek to develop the top compound into a therapeutic agent with the following specific aims. In Aim 1 we willstructurally optimize our lead compound to increase its affinity for c-Cbl and disrupt EGFR:c-Cbl binding.Multiple rounds of chemical modifications to our lead compound will be used to identify new derivatives thatbind recombinant c-Cbl with high affinity and disrupt EGFR:c-Cbl interactions. In Aim 2 we will test the highestaffinity compounds for disruption of c-Cbl-mediated ubiquitylation and trafficking of the EGFR. The topcandidates will be tested for their ability to block ligand-mediated EGFR ubiquitylation and lysosomaldegradation and if they prolong EGFR signaling in corneal epithelial cells. In Aim 3 we will determine whetherinhibitors of EGFR ubiquitylation promote corneal epithelial wound healing. The top compounds will beassayed for corneal epithelial wound healing using in vitro ex vivo and in vivo assays. Our proposed studiesare innovative in our opinion because we will by-pass the limitation of EGFR occupancy and target a novelprotein (c-Cbl) and molecular mechanism (receptor desensitization). These studies are significant becauseaccelerating re-epithelialization and homeostasis of compromised corneas will decrease patient distressminimize infections and reduce the incidence of blindness. Corneal epithelial homeostasis is a major publichealth issue with limited treatments. Our goal is to develop our lead compounds for the topical treatment ofcompromised corneal epithelium to restore tissue homeostasis.

project_terms:
Address;Advanced Development;Affinity;Anatomy;Animal Model;Antineoplastic Agents;Bacteria;Binding;Biochemical;Biological Assay;Biology;Biomedical Engineering;Blindness;Calorimetry;Cell Proliferation;Cell model;Cetuximab;Chemical Injury;Chemical Structure;Chemicals;Complex;Cornea;Corneal Diseases;Corneal Injury;Data;Development;Diabetes Mellitus;Disease;Distress;Drug Side Effects;Drug usage;EGF gene;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Epithelial;Epithelial Cells;Event;Eye;Eye Infections;FDA approved;Generations;Goals;Growth Factor Receptors;Health care facility;Homeostasis;Human;In Vitro;Incidence;Infection;Investigation;Laboratories;Lead;Ligands;Light;Lysosomes;Maintenance;Measures;Mediating;Membrane;Mission;Modeling;Modification;Molecular;Operative Surgical Procedures;Oryctolagus cuniculus;Pain;Patients;Pharmaceutical Preparations;Pharmacology;Prevalence;Primary Health Care;Procedures;Proteins;Public Health;Reagent;Receptor Signaling;Recombinants;Recurrence;Research;Retina;Rodent;Signal Transduction;Structure;Testing;Therapeutic;Therapeutic Agents;Tissue Model;Tissues;Topical application;Trauma;Virus;Vision;Work;base;cancer type;cell growth;cell motility;cell replacement therapy;corneal epithelial wound healing;corneal epithelium;corneal surgery;cytokine;cytotoxicity;desensitization;drug development;experience;heat injury;improved;in silico;in vivo;inhibitor/antagonist;innovation;interest;knock-down;limbal;nanomolar;novel;novel therapeutics;particle;preservation;prevent;receptor;restoration;side effect;stem cell replacement;tissue culture;trafficking;ubiquitin-protein ligase;wound healing

public_health_relevance:
Project NarrativeThe proposed research is relevant to public health because the integrity of the corneal epithelium is frequentlycompromised as the result of trauma surgery side effects of anti-cancer drugs and secondary effects ofdiabetes. This innovative line of investigation seeks to develop a first generation compound that will extend theduration of epidermal growth factor receptor signaling to maintain and promote a healthy corneal epithelium.This project is relevant to the NEIs mission because these findings will advance the development of newstrategies to promote corneal epithelial wound healing and minimize the chances of eye infection andsubsequent blindness.


application_id: 10085528
project_number: 6R44ES028171-03
project_title: Targeted Lead (Pb) Removal for Drinking Water Purification Using INCION
administering_ic: NIEHS
award_notice_date: 2020-02-14
opportunity_number: PA-18-574
application_type: 6
activity_code: R44
ic: ES
serial_number: 028171
program_official: HENRY, HEATHER F
project_start_date: 2017-09-15
project_end_date: 2021-08-31
study_section: Special Emphasis Panel[ZRG1-IMST-B(12)B]
contact_pi_person_id: 14657253
contact_pi: BOEHME, LINDSAY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079388085
primary_uei: JD9MTUKKNG13
duns_number: 079388085
uei: JD9MTUKKNG13
fips: US
organization_id: 10036767
organization_name: POWERTECH WATER, INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40508
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYLead contamination in drinking water is a pervasive health problem across the US. Children areespecially vulnerable to lead poisoning which can have permanent detrimental effects on braindevelopment. Despite corrosion prevention measures taken by public water authorities leadconcentrations in drinking water are routinely elevated nationwide. The EnvironmentalProtection Agency (EPA) established The Lead and Copper Rule in 1991 to limit exposure ofthese elements and set the action level to 15 ppb; however there is no safe level of leadconsumption. The crisis observed in Flint Michigan in 2014 put lead exposure into the publicspotlight increasing consumer awareness.Lead filters currently on the market lack specificity with limited device lifetime dictated by thetotal amount of water volume filtered regardless of lead concentration. PowerTech Water's(PTW) INCION M-Series technology platform is a multifunctional chemical/electrochemicalapproach with  90% specificity for lead removal termed capacitive coagulation; a hybrid ofadsorption (capacitive) and immobilization (coagulation) mechanisms that permanently removeall forms of dissolved lead both complexed and free ions.In this Phase II project PTW's goal is to understand how to develop and validate a 2ndgeneration INCION M-series POU/POE system for dissolved lead removal from drinking waterthat exceeds the performance of current off-the-shelf solutions. The device will be reliable andspecific for lead have a multi-year system lifetime and will not be consumed by abundant waterconstituents. These performance targets will be achieved through the following Specific Aims:1. Factorial design of experiments testing to meet certification. Expected outcome: INCION M- Series performance to meet NSF certification standards NSF/ANSI 53 and 61.2. Investigate electrochemical coagulation mechanisms to tune operating parameters for specific water chemistries. Expected outcomes: Determine the operating parameters that will best exploit capacitive coagulation for lead removal in different water sources and develop an operating matrix.3. Parametric testing of system operations towards the design of a POU/POE device. Expected outcome: A set of design specifications to develop the INCION device into a commercial product.

public_health_relevance:
PROJECT NARRATIVEUnaware to most people lead in drinking water is one the greatest health threats in the UnitedStates and the Environmental Protection Agency (EPA) emphasizes that there is no safe levelof lead exposure. PowerTech Water's goal is to develop the fundamental knowledge andunderstanding of the science and engineering required to produce a point-of-use/point-of-entry(POU/POE) drinking water purification device that is highly specific for lead more reliableefficient and lasts longer than state-of-the-art solutions. If successful this technology will deliversafe drinking water in a low-cost low-complexity and low-maintenance format.


application_id: 10084295
project_number: 5R01DK124112-02
administering_ic: NIDDK
award_notice_date: 2020-12-17
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DK
serial_number: 124112
program_official: SADUSKY, ANNA BURKART
project_start_date: 2020-01-10
project_end_date: 2023-12-31
study_section: Special Emphasis Panel[ZRG1-DKUS-P(02)]
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: 2021-01-01
project_terms:
Acute Renal Failure with Renal Papillary Necrosis;Apoptosis;Autophagocytosis;Biochemistry;Cancer Patient;Carboplatin;Cell Cycle;Cells;Cellular Stress;Ceramidase;Ceramides;Chronic;Chronic Kidney Failure;Cisplatin;Clinic;Data;Deterioration;Development;Diabetes Mellitus;Dialysis procedure;Dose;Dose-Limiting;Elderly;Electrolytes;Ensure;Enzymes;FDA approved;Fibrosis;Foundations;Future;Goals;Grant;Homeostasis;Hour;In Vitro;Inflammation;Injury;Injury to Kidney;Kidney;Knowledge;Laboratories;Lead;Lipids;Liquid substance;Long-Term Effects;Magnesium;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Medical;Metabolic;Metabolism;Methodology;Modeling;Mus;Necrosis;Oncologist;Patients;Phase;Process;Publishing;Recording of previous events;Recurrent disease;Regimen;Renal Replacement Therapy;Renal function;Reproducibility;Research;Risk;Role;Sodium Chloride;Sphingolipids;Supportive care;Testing;Therapeutic;Toxic effect;Treatment Protocols;Up-Regulation;analog;base;cancer type;comorbidity;design;drug development;in vivo;innovation;kidney cell;mortality;new therapeutic target;novel;novel therapeutics;stressor;therapeutically effective;wasting


application_id: 10082463
project_number: 5R01HL149351-02
project_title: Atherogenic Mechanisms of Electronic Nicotine Delivery Systems
administering_ic: NHLBI
award_notice_date: 2020-12-10
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 149351
program_official: CHEN, JUE
project_start_date: 2020-01-01
project_end_date: 2023-12-31
study_section: Special Emphasis Panel[ZRG1-VH-J(02)]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Nicotine is an abundant toxicant in various tobacco products including cigarette smokesmokeless tobacco cigars cigarillos and hookah. The use of tobacco products increase the riskfor atherosclerosis. Although usage of conventional cigarette has steadily declined over the lastthree decades usage of new and emerging tobacco products and electronic nicotine deliverysystems (ENDS) such as electronic cigarettes (e-cig) e-hookah and e-cigars has increasedexponentially. ENDS aerosolize a solution known as an e-liquid (typically a combination ofpropylene glycol PG and vegetable glycerol VG) that contains a small percentage of nicotine.Although several combustion products and toxins such as CO and tobacco-specific nitrosaminesare non-detectable in ENDS carbonyls including short-chain toxic aldehydes (acroleinformaldehyde acetaldehyde etc.) have been detected in e-cig-derived aerosols up to levelsfound in tobacco smoke. Our preliminary data suggest that exposure to e-cig or its componentssuch as acrolein and nicotine (oral exposure) induce macrophage activation (cytokine formationMMP activation and apoptosis) and exacerbate atherosclerosis. Conversely quenching ofendogenous aldehydes by feeding with the endogenous dipeptide - carnosine (-ala-his) oroverexpressing carnosine synthase in macrophages prevents atherosclerosis. Our preliminarystudies also show that chronic exposure to e-cig nicotine and acrolein increase the expressionof micro RNA-21 (miR-21) in the aortae of atherogenic mice; and acrolein and nicotine inducemiR-21 in macrophages in culture presumable as an adaptive response to macrophageactivation. Based on these observations we hypothesize that miR-21 decreases ENDS-inducedatherogenesis by preventing macrophage activation by ENDS-derived aldehydes and nicotine.To test this hypothesis we will 1) Examine the effect of e-cig on atherogenesis. In LDL receptor-null mice exposed to filtered air varying proportions of propylene glycol (PG):vegetable glycerin(VG) PG:VG + nicotine and JUUL-specific e-liquids we will quantify the time- dose- and sex-dependent changes in atherosclerotic lesion formation. We will examine how ENDS and theircomponents affect the plaque composition the nature and the stability; 2) Delineate theatherogenic contribution of ENDS-derived aldehydes. We will examine whether quenching of e-liquid and ENDS-derived aldehydes by oral feeding with carnosine or macrophage-specificoverexpression of carnosine synthase prevents macrophage activation and atherogenesis andhow are these processes regulated by miR-21; 3) Elucidate the atherogenicity of ENDSderivednicotine. We will probe how ENDS activate macrophage 7nAChR and how macrophage-specificdeficiency of 7nAChR affects ENDS-induced macrophage activation and atherogenesis. We willalso examine how miR-21 regulates these processes. Overall the proposed studies will establishnovel animal models of ENDS-induced atherosclerosis and delineate the underling chemicalcellular and molecular mechanisms of toxicity.

project_terms:
Acetaldehyde;Acrolein;Aerosols;Affect;Aldehydes;Animal Model;Animals;Apoptosis;Arterial Fatty Streak;Atherosclerosis;Blood Vessels;Cardiovascular Diseases;Carnosine;Cells;Cessation of life;Characteristics;Chemicals;Chronic;Chronic Disease;Cigar;Collagen;Data;Devices;Dipeptides;Disease;Dose;Electronic Nicotine Delivery Systems;Electronic cigarette;Emerging Tobacco Products;Endothelium;Excision;Exposure to;Fatty acid glycerol esters;Formaldehyde;Glycerol;Human;In Vitro;Inflammation;Inflammatory;JUUL;Knockout Mice;Lesion;Life;Low Density Lipoprotein Receptor;Macrophage Activation;Matrix Metalloproteinases;Measures;Mediating;MicroRNAs;Molecular;Mus;Myeloid Cells;Myocardial Infarction;Nature;Necrosis;Nicotine;Nitrosamines;Oral;Pathway interactions;Play;Process;Propylene Glycols;Proteins;Risk;Role;Signal Transduction;Smoke;Smokeless Tobacco;Smoker;Smoking;Smooth Muscle Myocytes;Stroke;Supplementation;Testing;Thromboplastin;Time;Tobacco;Tobacco smoke;Tobacco use;Toxic effect;Toxin;Trees;Untranslated RNA;Urine;Vegetables;adduct;air filter;alpha-bungarotoxin receptor;atherogenesis;atherosclerosis risk;base;chronic inflammatory disease;cigarette smoke;cigarette smoking;cigarillos;combustible cigarette;combustion product;cytokine;electronic hookah;electronic liquid;feeding;heart disease risk;hookah;insight;macrophage;mortality risk;novel;overexpression;premature;prevent;recruit;response;sex;tobacco products;toxicant;vegetable glycerin

public_health_relevance:
Nicotine is an abundant toxicant in various tobacco products including cigarette smokesmokeless tobacco cigars cigarillos and hookah. While combustible cigarette smoking has beenshown to increase the risk for heart disease little is known about the effect of electronic nicotinedelivery systems (ENDS) on cardiovascular disease. In this project we will examine the effect ofchronic usage of ENDS-derived nicotine on the accumulation of fat and inflammatory cells in theblood vessels which can eventually cause heart attack and stroke.


application_id: 10081459
project_number: 1R43AI155191-01
administering_ic: NIAID
award_notice_date: 2020-06-15
opportunity_number: PA-19-272
application_type: 1
activity_code: R43
ic: AI
serial_number: 155191
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2020-06-15
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZRG1 IDM-A (10)]
contact_pi_person_id: 11545088
contact_pi: MAINS, JAMES WILLIAM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 780816091
primary_uei: F873ZJEX7615
duns_number: 780816091
uei: F873ZJEX7615
fips: US
organization_id: 10027931
organization_name: MOSQUITOMATE, INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40502
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-06-15
project_title:
Integration of Wolbachia-based Incompatible Insect Technique (IIT) and Auto-Dissemination Augmented by Males (ADAM) for mosquito vector control

project_abstract:
AbstractIn the absence of effective approved vaccines or therapeutic measures against dengue Zikaand other mosquito borne pathogens public health efforts must focus on the control of mosquitovectors that are required for transmission. Unfortunately effective control measures are notavailable against invasive mosquito species like Aedes aegypti and Aedes albopictus due inpart to problems resulting from their cryptic behaviour. Specifically Aedes mosquitoes breed inhidden/inaccessible sites that are sheltered from existing control methods e.g. truck and aerialspraying.Autocidal technologies use the insect itself as a self-delivering control tool. As an example theSterile Insect Technique (SIT) has been used successfully against multiple agricultural pestsincluding large scale elimination from the North American continent (e.g. Screwworm;Cochliomyia hominivorax). However despite years of effort SIT has not proven effectiveagainst mosquitoes.Through previous SBIR-funded research MosquitoMate has developed two autocidal methodsagainst Ae. aegypti and Ae. albopictus mosquitoes including: 1) Incompatible Insect Technique(IIT) that uses a naturally occurring bacterium (Wolbachia) to sterilize populations and 2)Auto-Dissemination Augmented by Males (ADAM) that uses males as vehicles to spread apotent insecticide. To date the USA Environmental Protection Agency (EPA) has instructedMosquitoMate to keep the IIT and ADAM approaches separate. In the work proposed hereMosquitoMate will develop data that the EPA can consider for the integration of the twoapproaches.If awarded the resulting research will examine parameters critical to the EPAs efficacy and riskassessments including potential: 1) PPF effects on Wolbachia-induced sterility 2) PPF effectson male mosquito performance (e.g. boosting of male competitiveness) and 3) PPF effects onadult female mosquito fecundity and fitness. The resulting data will be communicated to theEPA including a pre-registration meeting to identify requirements leading to FIFRA Section 3EPA pesticide registration for the combined IIT/ADAM approach.Market potential exists at the local corporate government and area wide control levels for thecontrol of invasive medically important mosquito species. MosquitoMate has an exclusivelicense for the patented Wolbachia technology and additional patents on the ADAM technology.

project_terms:
Abate;Adult;Aedes;Affect;Agriculture;American;Area;Award;Bacteria;Behavior;Breeding;Chikungunya virus;Culicidae;Data;Dengue;Diptera;Dust;Female;Fertility;Funding;Genetic;Government;Ingredients and Chemicals;Insecta;Insecticides;Juvenile Hormones;Laboratories;Legal patent;Licensing;Measures;Medical;Methods;Modification;Mosquito Control;Mosquito-borne infectious disease;Performance;Pesticides;Population;Population Replacements;Process;Public Health;Research;Resistance development;Risk;Risk Assessment;Site;Small Business Innovation Research Grant;Sterility;Techniques;Technology;Testing;Therapeutic;United States Environmental Protection Agency;Vaccines;Virus;Wolbachia;Work;ZIKA;base;chikungunya;combat;cost;egg;fitness;improved;male;meetings;microbial;mosquito-borne pathogen;pathogen;prevent;research and development;risk mitigation;sterile insect technique;tool;transmission process;vector control;vector mosquito

public_health_relevance:
NarrativeVector control remains the only means to combat many mosquito borne diseases includingthose caused by Zika dengue chikungunya viruses and other pathogens. A critical existing gapin vector control is the inability to affect the immature proportion of the mosquito population thatremains hidden/protected within cryptic breeding sites and inaccessible to conventional controltools. The proposed work will test the feasibility of integrating the Incompatible Insect Techniqueand an approach in which male mosquitoes disseminate a potent larvicide. Key advantages ofintegration include improved performance risk mitigation and reduced cost. The data resultingfrom the proposed work can be provided to the EPA in support of FIFRA Section 3 EPApesticide registration.


application_id: 10081219
project_number: 1R43ES032380-01
project_title: Development of Smart Flocculants for the Treatment of PFAS Contaminated Water
administering_ic: NIEHS
award_notice_date: 2020-09-10
opportunity_number: PA-19-272
application_type: 1
activity_code: R43
ic: ES
serial_number: 032380
program_official: HENRY, HEATHER F
project_start_date: 2020-09-10
project_end_date: 2022-08-31
study_section: Special Emphasis Panel[ZRG1 IMST-B (12)]
contact_pi_person_id: 12547580
contact_pi: GUTIERREZ, ANGELA MARIA
other_pis: HILT, JAMES ZACH
congressional_district: 06
department: Unavailable
primary_duns: 078529087
primary_uei: M9JMGN342NR5
duns_number: 078529087
uei: M9JMGN342NR5
fips: US
organization_id: 10032361
organization_name: BLUEGRASS ADVANCED MATERIALS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryPer- and polyfluoroalkyl substances (PFAS) are a family of manmade congeners with dual hydro- and oleo-phobic properties which is why they have been widely used in firefighting foams as well as in a multitude ofother products such as food packaging paints pesticides and microelectronics. Given their extensive use highwater solubility and resistance to conventional wastewater treatment methods PFAS have been detected inpublic water supplies all over the country causing concern for potential toxic human health effects given theirenvironmental persistence. Flocculation is a widely used separation technique in the removal of suspendedsolids from water and wastewater. However traditional flocculants (e.g. inorganic salts and polymeric systems)form aggregate flocs that are usually loosely packed contain a large amount of water due to their hydrophilicityand as such require large settling tanks due to the slow process of separation that is required to collect thesolids. Furthermore they have seldom been used to remove dissolved species like PFAS. To address theseissues BAM proposes an innovative smart polymeric flocculant that consists of a temperature responsivecompound N-isopropylacrylamide (NIPAAm) modified with a cationic co-monomer dimethylaminoethyl acrylate(DMAEA) and a fluorinated co-monomer short chain trifluoroethyl acrylate (TFEA) and long chaindodecafluoroheptyl acrylate (DDFHA). The combination of these three components results in a polymer whichcan rapidly capture the dissolved PFAS molecules and form insoluble solid aggregates at temperatures abovethe lower critical solution temperature (LCST) The core advantages of this system include: (1) slow waterretention in the sediment (2) fast kinetics and (3) lower energy input by shifting the aggregation temperaturescloser to ambient conditions. Specific Aim 1 of the proposed project will involve development and performanceevaluation of the cationic and fluorinated modified smart flocculants. More specifically aim 1 focuses on thematerial development where the cationic and fluorinated NIPAAm copolymer with varying composition andmolecular weight will be synthesized and characterized. Specific Aim 2 will investigate the flocculation efficiencyof the prepared materials in the removal of PFAS such as perfluorooctanoic acid (PFOS) and perfluorooctanesulfonic acid (PFOA) from contaminated water. To study the PFAS removal efficiency various environmentalconditions (e.g. ionic strength pH turbidity) and process variables (e.g. polymer dosage initial PFASconcentration) will be examined and the performance will be evaluated through kinetics sediment compactnessand supernatant composition. Phase I funding of this project will produce a novel smart flocculant system withenhanced solid-liquid separation performance for removing PFAS from contaminated water. When achievedPhase II of this project will be operated to investigate the efficacy of the prepared copolymer flocculants indrinking water and wastewater.

project_terms:
Acrylates;Address;Affinity;Agitation;Alkanesulfonates;American;Attention;Cations;Charge;Country;Development;Dose;Electrostatics;Evaluation;Excision;Exhibits;Family;Flocculation;Food Packaging;Free Radicals;Funding;Hardness;Head;Health;Hour;Human;Hydrogen Bonding;Hydrophobicity;Industrialization;Ionic Strengths;Kinetics;Life Cycle Stages;Liquid substance;Mechanics;Methods;Molecular Weight;N-isopropylacrylamide;Optics;Paint;Performance;Pesticides;Phase;Phase Transition;Poa plant;Polymers;Process;Property;Reaction Time;Recovery;Residual state;Resistance;Salts;Solid;Solubility;Specificity;Sulfonic Acids;System;Techniques;Technology;Temperature;Time;Water;Water Supply;aqueous;base;contaminated water;copolymer;density;dosage;drinking water;hydrophilicity;improved;innovation;monomer;novel;particle;perfluorooctane;perfluorooctanoic acid;polymerization;wasting;water sampling;water solubility

public_health_relevance:
Project NarrativeIn this project a smart flocculant system is proposed to easily remove per- and polyfluoroalkyl substances(PFAS) from drinking water and wastewater effluents minimizing settling times and additional dewatering stepsfound in current flocculant technology. The novelty of the proposed flocculant is that it combines athermoresponsive compound (N-isopropylacrylamide (NIPAAm)) with cationic and fluorinated co-monomersdimethylaminoethyl acrylate (DMAEA) trifluoroethyl acrylate (TFEA) and dodecafluoroheptyl acrylate (DDFHA)respectively. These co-monomers provide high affinity for PFAS molecules through a variety of electrostaticinteractions which greatly accelerates the flocculation kinetics and reduces the water retention in the resultingsediment ultimately producing innovative smart flocculants with enhanced solid-liquid separation performancefor removing PFAS from contaminated water.


application_id: 10080770
project_number: 2R42NS107148-02
project_title: EpiZode: Noninvasive Seizure Screening in Preclinical Models of Epilepsy
administering_ic: NINDS
award_notice_date: 2020-09-10
opportunity_number: PA-19-270
application_type: 2
activity_code: R42
ic: NS
serial_number: 107148
program_official: AUBRECHT, TARYN GRACE
project_start_date: 2018-04-15
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZRG1 ETTN-C (10)]
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;base;circadian;dravet syndrome;drug development;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: 10079396
project_number: 5F31AA027960-02
project_title: Early Maturing Out of Problematic Alcohol Use
administering_ic: NIAAA
award_notice_date: 2020-11-25
opportunity_number: PA-18-671
application_type: 5
activity_code: F31
ic: AA
serial_number: 027960
program_official: CASTLE, I-JEN
project_start_date: 2020-01-05
project_end_date: 2022-01-04
study_section: ZAA1-GG(32)
contact_pi_person_id: 15766856
contact_pi: PETERSON, SARAH JANE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Most research suggests that alcohol use peaks in the college years then declines into the mid-thirties;understanding this maturing out process may clarify who is at risk for ongoing alcohol-related problems(Jochman & Fromme 2010). However there is evidence that some individuals mature out much earlier:downward drinking trends for some individuals begin early in the college years with as many as one third ofcollege students decreasing their drinking (Baer et al. 2001). Work using the developmentally sensitivemethod of trajectory analysis which helps identify different subgroups of a population who experience differentdevelopmental trends has consistently identified a group that decreases drinking beginning during the firstyear of college: an early maturing out group (e.g. Schulenberg et al. 1996; Greenbaum et al. 2005). It iscrucial for risk research and thus for the public health to identify factors that differentiate those who decreasetheir drinking early from those who persist in high levels of alcohol consumption; doing so would clarify risk forcollege-related alcohol problems and alcohol use disorder and aid in developing earlier targeted preventionand intervention efforts. Past research has examined contextual and individual difference factors in relation tovarying trajectories (Chassin et al. 2002; Gates et al. 2016; Jackson & Sher 2005). However those studiesdid not address early maturing out. The proposed research emphasizes two possibilities: 1) perhaps those whomature out early are facing adult-like responsibilities such as paying for their educations/supporting theirfamilies and/or 2) perhaps those who persist have higher levels of personality and learning-based risk factorscompared to those who mature out early. I propose to test both possibilities. Concerning the latter I apply anew model that integrates the personality trait of negative urgency the tendency to act rashly when in a highlynegative mood with psychosocial learning in the form of alcohol expectancies which has proven quiteeffective in understanding drinking risk (Peterson et al. 2018). The research component of this proposalinvolves using a four-wave longitudinal design to (a) identify a group that decreases drinking levels early incollege and a group that persists using trajectory analyses and (b) test whether these groups can bedifferentiated on the basis of contextual or individual difference factors. Studying factors that influence earlymaturing out is novel. A successful test would have clear clinical and public health implications as theproposed project is likely to provide direction for targeted intervention during the college years. The trainingcomponent of this proposal includes training in the following: 1) the execution and management of alongitudinal study including participant recruitment data collection and follow-up; 2) complex statisticalanalyses such as multilevel modeling; 3) the emerging adulthood developmental literature which is likely toprove helpful in understanding early maturing out; 4) further advanced training in research ethics; 5)preparation of research reports for publication; 6) mentoring of junior graduate and undergraduate students.

project_terms:
Adolescent;Adult;Alcohol abuse;Alcohol consumption;Alcoholic beverage heavy drinker;Classification;Clinical;Complex;Consumption;Data Collection;Development;Early identification;Education;Exanthema;Expectancy;Face;Family;Fibrinogen;Heavy Drinking;Home;Impulsivity;Income;Individual;Individual Differences;Intervention;Learning;Life Style;Light;Literature;Longitudinal Studies;Marriage;Measures;Mentors;Methods;Modeling;Occupations;Patient Recruitments;Personality;Personality Traits;Population;Preparation;Prevention;Process;Psychological reinforcement;Public Health;Publications;Readiness;Reporting;Research;Research Design;Research Ethics;Risk;Risk Factors;Sampling;Social Reinforcement;Specialist;Specific qualifier value;Statistical Data Interpretation;Students;Subgroup;Surveys;Testing;Time;Training;Work;aged;alcohol expectancy;alcohol measurement;alcohol related problem;alcohol use disorder;base;career;college;college drinking;community college;drinking;drinking behavior;early drinking;emerging adulthood;experience;falls;follow-up;graduate student;high risk;longitudinal design;morphogens;multilevel analysis;negative mood;novel;programs;psychosocial;trait;trend;underage drinking reduction;undergraduate student;university student

public_health_relevance:
Many individuals decrease their drinking following the college years; however there is evidence that for somethese reductions begin early in the college years. Identifying factors that differentiate those who decrease theirdrinking early from those who persist in heavy alcohol use will clarify the risk process for harmful collegiatedrinking and shed light on risk for adult alcohol use disorders. The proposed project is part of adevelopmentally sensitive program of research designed to examine trends and risk factors for emergingadulthood problem drinking.


application_id: 10078986
project_number: 2R44NS108804-02
project_title: Mimicking synuclein toxicity in plant cells to identify novel neuroprotective leads
administering_ic: NINDS
award_notice_date: 2020-09-20
opportunity_number: PA-19-272
application_type: 2
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)]
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;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: 10077283
project_number: 5K01DK116923-03
project_title: Social Network Analysis and Social Support Intervention for Rural Dwelling Older Adults with T2DM
administering_ic: NIDDK
award_notice_date: 2020-12-16
opportunity_number: PAR-18-418
application_type: 5
activity_code: K01
ic: DK
serial_number: 116923
program_official: SPAIN, LISA M
project_start_date: 2019-01-01
project_end_date: 2023-12-31
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 11808527
contact_pi: SMALLS, BRITTANY L.
other_pis: Not Applicable
congressional_district: 06
department: FAMILY MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
7. PROJECT SUMMARY/ABSTRACT Approximately 29.1 million (9.3%) adults in the US have type 2 diabetes (T2DM).1 T2DM is associatedwith significant complications including premature coronary artery disease kidney disease stroke andblindness.1 Estimates show that prevalence of T2DM is 17% higher in rural dwellers compared to their urbancounterparts.2 For example the prevalence of T2DM for adults in Kentucky's rural Appalachian counties is13.6%3 compared to the overall state prevalence of 10.6% 3. Appropriate self-care behaviors are necessary foroptimal clinical outcomes in T2DM 4-6 and account for 90% of the variance in glycemic control 7. Yet self-careamong T2DM is notoriously poor in general and even worse in rural-dwellers. Without attention to improvingself-care in this population we are facing an epidemic of T2DM complications in rural areas of the US. The impact of living with T2DM in rural communities is compounded in the aging population. Theprevalence of T2DM increases with age and an estimated 25% of older adults (65 years) have T2DM 8. Olderadults living with T2DM have more difficulty than younger people adhering to self-care regimens andsocial/environment factors account for up to 85% of their self-care nonadherence.69-13 Notablesocial/environment factors include competing social demands lack of social support (SS) and stress.14-17 Socialsupport plays a particularly significant role in older adults with T2DM. The extent and type of SS available inrural communities can positively or negatively impact self-care in those diagnosed with T2DM. 18-25 To better understand the effects of the social environment in communities where older rural dwellingadults reside and to lay the foundation for interventions social network analysis (SNA) will be used to determinesocial support network structures. By using SNA social support structures can be developed and relationshipsbetween individuals within a social network can be evaluated. 26 The overall objective of this study is to improveT2DM self-care regimens in older rural dwelling adults by training influential community members to becommunity health workers and provide social support strategies within an older adults' existing social networkthat promotes T2DM self-care.The proposed study seeks to: Aim 1Use social network analysis to identify key players in a rural community to serve as communityhealth workers for those living with T2DM.Aim 2Use mixed methods to evaluate the impact of social support on T2DM self-care and clinicaloutcomes and evaluate social networks in rural dwelling older adults with T2DM.Aim 3Test the feasibility and preliminary effectiveness of a 6-week intervention administered bycommunity health workers with the support of members of older adults' individual social network.

project_terms:
Address;Adherence;Adult;Affect;Age;Aging;Attention;Behavior;Blindness;Blood Pressure;Clinical;Communities;Community Health Aides;Complications of Diabetes Mellitus;Coronary Arteriosclerosis;County;Decision Making;Diabetes Mellitus;Diagnosis;Disease;Education;Effectiveness;Elderly;Epidemic;Exposure to;Foundations;Geriatrics;Glycosylated hemoglobin A;Health Food;Health Personnel;Health behavior;High Prevalence;Individual;Influentials;Intervention;Interview;Kentucky;Kidney Diseases;Knowledge;Life Expectancy;Maps;Medical Records;Methods;Morbidity - disease rate;Neighborhoods;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Pathway Analysis;Play;Population;Positioning Attribute;Poverty;Prevalence;Quality of life;Regimen;Research;Research Personnel;Risk;Role;Rural Appalachia;Rural Community;Self Care;Social Environment;Social Network;Social support;Source;Stress;Stroke;Structure;Surveys;Syndrome;Training;United States National Institutes of Health;aging population;base;blood lipid;cognitive function;diabetes management;diabetes self-management;disease transmission;empowerment;experience;fall risk;feasibility testing;frailty;glycemic control;health care service;health communication;health literacy;improved;individual patient;innovation;member;negative affect;post intervention;premature;programs;recruit;rural area;rural dwellers;rural residence;sarcopenia;social;statistics

public_health_relevance:
8. PROJECT NARRATIVEWith the high prevalence of type 2 diabetes (T2DM) and an aging population with low adherence to self-careregimens I seek to improve T2DM self-care in older rural dwelling adults. Social network analysis will be usedto identify individuals who are influential in their community who can be trained as community health workersas well as identify individuals within an older rural dwelling adult's personal network who can form a dyad withthe older adult and serve as a facilitator for adherence to T2DM self-care regimen via social support. These dyadswill participate in a 6-week T2DM self-care intervention with a booster session at 6 months post-intervention.


application_id: 10076792
project_number: 5R34AT010370-02
administering_ic: NCCIH
award_notice_date: 2021-01-08
opportunity_number: PAR-18-417
application_type: 5
activity_code: R34
ic: AT
serial_number: 010370
program_official: MURRAY, PETER DANIEL
project_start_date: 2020-01-01
project_end_date: 2022-12-31
study_section: ZAT1-PJ(06)
contact_pi_person_id: 14550427
contact_pi: JACOBS, CALE
other_pis: VRANCEANU, ANA-MARIA
congressional_district: 06
department: ORTHOPEDICS
primary_duns: 939017877
primary_uei: 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: 2021-01-01
project_title:
Development of a Mind Body Program to Reduce Knee Pain in Obese Osteoarthritis Patients with Comorbid Depression

project_abstract:
PROJECT SUMMARYDevelopment of a mind body program to reduce cartilage breakdown and knee pain in obese osteoarthritispatients with comorbid depression This is a R34 application that follows the recently released IMMPACT criteria and the InternationalClassification of Functioning Disability and Health (ICF) framework to adapt a multimodal theory groundedmind body program (The Relaxation Response Resilience Program; 3RP) with prior success in patients withmedical illness in pilot and effectiveness studies for the needs of obese patients with knee osteoarthritis (OA)and depression and to specifically target increased physical activity (p3RP-OA). Depression obesity and OAexacerbate one another and share a common pathophysiology involving systemic inflammation and pro-inflammatory cytokines reflecting a complex mind-body interaction. Current treatments for knee OA offerlittle to no benefit over a placebo and do not emphasize mind-body practices or physical activity to target theunderlying pathophysiology. Physical activity alone has shown benefit in the treatment of depression obesityand OA individually but adequate implementation remains challenging. Our guiding hypothesis is that thesynergistic interaction between mindfulness adaptive thinking positive psychology and healthy living skills ofthe 3RP adapted for the needs of OA patients and to target increased physical activity reduces pro-inflammatory cytokine expression while also promoting optimal mechanical loading of the cartilage will slowthe progression of symptomatic knee OA. Toward this goal this R34 proposal aims to 1) adapt the 3RP for theneeds of knee OA patients with depression (PHQ-910) and obesity (BMI30 kg/m2) with a focus of increasingphysical activity; and 2) establish the feasibility credibility and acceptability of the programs and researchprocedures. Using the R34 NCCIH mechanism we propose to use an iterative mixed methods strategy to adaptthe 3RP for the specific needs of obese OA patients with depression including increased activity to maximizetheir feasibility acceptability and credibility. This R34 grant will set the stage for us to conduct a fully poweredRCT through the R61/R33 mechanisms to assess the biopsychosocial mechanisms associated with OAprogression.

project_terms:
Accelerometer;Address;Adherence;Age;Attention;Biochemical;Biological;Biological Markers;Blood;Blood specimen;Body Weight;Body Weight decreased;Body mass index;Cartilage;Catabolism;Classification;Clinic;Clinical;Clinical Trials;Complex;Data;Data Collection;Degenerative polyarthritis;Detection;Development;Eligibility Determination;Focus Groups;Functional disorder;Goals;Grant;Health;Individual;Inflammation;Inflammatory;Instruction;Interleukin-1;Interleukin-1 beta;International;Intervention;Interview;Kentucky;Knee;Knee Osteoarthritis;Link;Logistics;Manuals;Measures;Mechanics;Medical;Mental Depression;Methods;Mind-Body Intervention;Obesity;Pain;Participant;Patient Preferences;Patient Self-Report;Patients;Phase;Physical Function;Physical activity;Pilot Projects;Placebos;Population;Procedures;Program Acceptability;Protocols documentation;Psychology;Relaxation;Reporting;Research;Secure;TLR4 gene;Testing;Thinking;Time;Travel;Universities;Urine;Walking;acceptability and feasibility;arthropathies;articular cartilage;biopsychosocial;body-mind;cartilage degradation;chronic pain patient;comorbid depression;comorbidity;coping;cytokine;depressive symptoms;disability;effectiveness study;high risk;improved;knee pain;mechanical load;medical schools;mind body interaction;mindfulness;multimodality;obese patients;osteoarthritis pain;overexpression;pilot trial;programs;psychologic;recruit;resilience;response;sample collection;satisfaction;screening;skills;statistics;success;symptomatology;systemic inflammatory response;telehealth;theories

public_health_relevance:
Project Narrative The proposed feasibility clinical trial will adapt the Relaxation Response ResiliencyProgram (3RP) for telehealth delivery to meet the needs of obese osteoarthritis patients withdepression. We will finalize study procedures necessary for a fully powered RCT through theR61/R33 mechanisms to assess the biopsychosocial mechanisms associated with osteoarthritisprogression.


application_id: 10076070
project_number: 1R01DA052203-01
project_title: Influence of 5-HT1b Activation on the Abuse Related Effects of Cocaine
administering_ic: NIDA
award_notice_date: 2021-07-28
opportunity_number: PA-19-055
application_type: 1
activity_code: R01
ic: DA
serial_number: 052203
program_official: FOSTER, KATRINA L
project_start_date: 2021-08-01
project_end_date: 2023-07-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTCocaine use disorder continues to be a significant public health concern. Despite strides in our understandingof the neurobiological underpinnings of cocaine addiction in preclinical models a limited amount of researchhas translated those findings into clinical populations. Such translation is crucial to identify neurobiologicalcircuits that contribute to the problems posed by cocaine use disorder and to guide treatment based on thoseclinical neuroscience findings. Cocaine potently inhibits the reuptake of serotonin (5-HT). Increased synaptic 5-HT resulting from this reuptake inhibition activates multiple 5-HT receptor subtypes. Some of these receptorsubtypes have been implicated in the abuse-related effects of cocaine including its primary reinforcing effects(i.e. cocaine taking behavior). 5-HT1b receptors play a particularly important role in cocaine effects likelybecause they are highly expressed in the mesocorticolimbic system. Preclinical data show that zolmitriptan acommercially available selective 5-HT1b agonist migraine medication approved for human use selectivelyattenuates the reinforcing and other abuse-related effects of cocaine. The overarching goal of this project is toadvance these promising preclinical findings into clinical populations thereby demonstrating that the 5-HT1bsystem plays a key role in the effects of cocaine in humans. To this end 20 non-treatment seeking humansubjects meeting diagnostic criteria for cocaine use disorder will sample doses of intravenous cocaine (0 10and 30 mg/70 kg) in experimental sessions after 3 days of maintenance on oral zolmitriptan (0 2.5 5 and 10mg). A placebo-controlled double-blind within-subjects design will be used such that all subjects experienceall dose conditions in random order. The study will require an approximately 1-month admission to our inpatientunit. After sampling a cocaine dose subjects will make nine choices between that dose and an alternativereinforcer (US$6.00) on a concurrent progressive-ratio choice task that was developed and validated in ourlaboratory. A battery of subjective drug-effect measures and tasks that assess distinct domains of impulsivitywill be completed during the same experimental sessions in which cocaine choice is assessed. The researchproposed here will directly translate findings from preclinical research and provide the initial clinical evidencethat 5-HT1b activation achieved through administration of zolmitriptan reduces the reinforcing and otherabuse-related effects of cocaine as well as cocaine-associated impulsivity. This study will also provide basicscience information about the serotonergic mechanisms underlying the pharmacodynamic effects of cocaine inhumans. As such the outcomes will advance our understanding of the clinical neurobiology of cocaineaddiction.

project_terms:
Abstinence;Admission activity;Agonist;American;Area;Attenuated;Autoreceptors;Basic Science;Behavior;Characteristics;Clinical;Cocaine;Cocaine Dependence;Cocaine Users;Cues;Data;Decision Making;Diagnostic;Disease;Disinhibition;Dose;Double-Blind Method;Enrollment;Goals;Human;Impulsivity;Inpatients;Intravenous;Laboratories;Literature;Maintenance;Measures;Mediating;Migraine;Motivation;Nerve Endings;Neurobiology;Neurosciences;Neurosciences Research;Oral;Outcome;Pharmaceutical Preparations;Pharmacodynamics;Placebos;Play;Population;Pre-Clinical Model;Psychological reinforcement;Public Health;Reinforcement Schedule;Research;Research Personnel;Role;Sampling;Schedule;Self Administration;Serotonergic System;Serotonin;Serotonin Receptor 5-HT1B;Short-Term Memory;Sucrose;Synapses;System;Time;Translating;Translations;Underserved Population;base;cocaine overdose;cocaine self-administration;cocaine use;craving;design;discounting;experience;experimental study;human subject;inattention;meetings;neurotransmitter release;non-drug;pre-clinical;pre-clinical research;preclinical study;receptor;reinforcer;reuptake;serotonin receptor;zolmitriptan

public_health_relevance:
PROJECT NARRATIVEThe serotonin 5-HT1b system plays key role in the effects of cocaine as indicated by numerous preclinicalstudies. No clinical neuroscience research has advanced these preclinical findings limiting our ability todetermine whether the 5-HT1b system also contributes to cocaine use in humans. The proposed research willfill that gap by determining how administration of a 5-HT1b agonist zolmitriptan impacts the abuse-relatedeffects of cocaine in humans.


application_id: 10075207
project_number: 5R01AI128862-05
project_title: Biosynthesis and medicinal chemistry of the capuramycin antimycobacterial antibiotics
administering_ic: NIAID
award_notice_date: 2021-01-22
opportunity_number: RFA-AI-16-006
application_type: 5
activity_code: R01
ic: AI
serial_number: 128862
program_official: BOYCE, JIM P
project_start_date: 2017-01-01
project_end_date: 2021-12-31
study_section: Special Emphasis Panel[ZRG1-IDM-W(50)R]
contact_pi_person_id: 9509796
contact_pi: VAN LANEN, STEVEN GARY
other_pis: THORSON, JON SCOTT
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:
Tuberculosis (TB)which is primarily caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb)isan ancient disease that remains one of the deadliest communicable diseases worldwide. A paramount concernheading into the future is the rapid rise in drug-resistant TB. The World Health Organization estimated 480000cases of TB with 190000 deaths in 2014 with resistance to the first-line anti-TB drugs isoniazid and rifampicin.Furthermore totally drug-resistant Mtb has now been documented in multiple countries including the UnitedStates. The capuramycin family of glycosylated nucleoside antibiotics are excellent candidates for anti-TB drugdiscovery and development because they (i) are considered new chemical entities with several unusual structuralfeatures compared to all antibiotics including clinical anti-TB drugs (ii) target a novel and essential enzyme(translocase 1; TL1) in cell wall biosynthesis (ii) have exceptional anti-Mtb activity in vitro and in vivo (iv) arebactericidal and kill Mtb faster than any first-line anti-TB drug in vitro and (v) have no toxicity. Our primaryobjectives in this proposal are to define a biosynthetic mechanism for the assembly of the unusual unsaturatedhexuronic acid component in capuramycins (Aim 1) and establish complementary chemical (vianeoglycorandomization; Aim 2) and biosynthetic (via native and nonnative glycosyltransferases; Aim 3) platformsfor rapidly generating novel hexuronic acid-substituted capuramycins that can be screened for TL1 inhibitionanti-Mtb activity and improved pharmacological properties. Additionally these novel capuramycin analogueswill be screened as potential substrates or inhibitors of the phosphotransferase CapP which covalently modifiescapuramycin as a strategy of self-resistance within the producing strain and is potentially a widespreadresistance mechanism. It is expected that upon completion of the aims a new biosynthetic mechanism for sugarincorporation and modification will be defined. Furthermore the completion of the aims will provide the firstpractical comprehensive strategy to rapidly interrogate/modulate the fundamental features of capuramycin corepharmacophore which will not only be important for the clinical development of capuramycin but can be appliedto other glycosylated nucleoside antibiotics of which dozens are now known with diverse biological activities.

project_terms:
Achievement;Address;Anabolism;Antibiotics;Antimycobacterial Agents;Antitubercular Agents;Applied Research;Biological;Biological Availability;Cell Wall;Cessation of life;Chemicals;China;Clinical;Collaborations;Communicable Diseases;Country;Development;Disease;Drug resistance;Drug resistance in tuberculosis;Engineering;Enzymes;Family;Fostering;Funding Mechanisms;Future;Goals;Health;Hexuronic Acids;Human;In Vitro;Incidence;India;Individual;Lead;Libraries;Modification;Multi-Drug Resistance;Multidrug-Resistant Tuberculosis;Mus;Mycobacterium tuberculosis;Natural Products;Nucleosides;Open Reading Frames;Peptidoglycan;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Phosphotransferases;Population;Preparation;Production;Property;Reaction;Recovery;Reporting;Research;Resistance;Rifampin;Series;Source;Structure;Substrate Specificity;Sugar Substitute;System;Technology;Therapeutic;Toxic effect;Treatment Protocols;Tuberculosis;United States;Uridine;World Health Organization;analog;bactericide;chemical function;clinical development;drug development;drug discovery;extensive drug resistance;fighting;fundamental research;glycosyltransferase;improved;in vitro activity;in vivo;inhibitor/antagonist;innovation;isoniazid;nanomolar;non-Native;novel;pathogenic bacteria;pharmacophore;resistance mechanism;resistant strain;scaffold;sugar;tool;translocase;tuberculosis drugs;tuberculosis treatment;virtual

public_health_relevance:
Tuberculosis is the cause of more than 1.1 million deaths annually and the emergence of multiple andextensively drug-resistant Mycobacterium tuberculosis is becoming a significant threat to global human health.The goals of this proposal are to define a biosynthetic mechanism for the anti-tuberculosis antibiotic capuramycinand use a synergistic combination of innovative synthetic and enzymatic technologies to rapidlyinterrogate/modulate the chemical functionality of this novel class of anti-tuberculosis agents.


application_id: 10073531
project_number: 5P20GM121327-05
project_title: Core C: Imaging Core
administering_ic: NIGMS
award_notice_date: 2020-12-21
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2021-12-31
study_section: ZGM1-RCB-6
subproject_number: 7095
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECTSUMMARYTheproposedUniversityofKentuckyCenterforCancerandMetabolism(CCM)isdesignedtoaddressasignificantgapincancerresearchbyprovidingthemultidisciplinaryinfrastructuretosupportcareerdevelopmentintheareaofmetabolicreprogrammingofthetumormicroenvironment.Routineandhigh-endimagingconstituteacriticalcomponentofthiseffortastheabilitytovisualizeandquantifytargetmoleculesandtheireffectsoncellularstructureandfunctionareheavilydependentontheavailabilityandqualityoftheimagingsystems.TheImagingCoreinthisapplicationwillprovidetechnicalservicesandsupportforCCMprojectresearchlaboratoriesandpilotprojectrecipientsandiswellpositionedtoadvancetheCCMmissionincancerandmetabolismthroughdeliveryofanexpandedrangeofimagingservicestoCOBREinvestigatorsandothers.ThiswillbeaccomplishedbytheachievementofthreeSpecificAims:SpecificAim1.Toprovideproject-specifictrainingandconsultationforCOBREinvestigators.SpecificAim2.Todevelopand/oradaptstate-of-theartimagingtechniquestoenhancetheresearchofearly-stageandpilotprojectCOBREinvestigators.SpecificAim3.Todevelopandimplementnewmethodssuchasproject-specificsamplepreparationtoenhanceCCMimagingservicesandmakesuchservicesavailabletoCOBREandnon-COBREusers.ImagingCoreuserswillhaveaccesstothisno-costfacilitywhereinvestigatorscanevaluatetheirtissueorcellularsamplesusingvarioustypesofinstruments.Thecorewillalsosupportroutineanalysisaswellasintroduceinvestigatorstohigh-endimagingoptionsandcapabilitiesrelevanttotheirstudiestherebyfacilitatingtheresearchsuccessesoftheseusers.Dr.JianhangJiatheDirectoroftheImagingCoreisahighlyproductiveinvestigatorwhohassuccessfullyobtainedsubstantialextramuralresearchsupportthatreliesextensivelyonsophisticatedimagingcapabilities.HehasthusinvestedextensiveeffortinthedevelopmentandimprovementofinstrumentationwithintheMarkeyCancerCenter.HewillconsultwithCCMinvestigatorsonthedesignofexperimentsusingimagingmodalitiesarolethatheassumedinguidingthedevelopmentofthefourCCMresearchprojectsinthisapplication.

project_terms:
Achievement;Address;Aging;Area;Bioinformatics;Biological Sciences;Biomedical Research;Biometry;Cancer Center;Cell physiology;Cellular Structures;Centers of Research Excellence;Clinical;Color;Complex;Computer software;Consult;Consultations;Development;Disease Progression;Distant;Equipment;Evaluation;Extramural Activities;Faculty;Floor;Fluorescence;Focal Adhesions;Goals;Image;Imaging Device;Imaging Techniques;Individual;Infrastructure;Kentucky;Laboratories;Laboratory Research;Lasers;Link;Malignant Neoplasms;Metabolic;Metabolism;Methodology;Methods;Microscope;Mission;Monitor;NCI Center for Cancer Research;Neoplasm Metastasis;Organ;Pathology;Pilot Projects;Positioning Attribute;Preparation;Proteins;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Role;Sampling;Scanning;Scientist;Services;Slide;System;Time;Tissues;Training;Transfection;Universities;advanced analytics;analytical tool;anticancer research;cancer therapy;career development;cost;cost effective;design;digital;experimental study;imaging capabilities;imaging modality;imaging system;in vivo imaging system;instrument;instrumentation;live cell imaging;metabolomics;microscopic imaging;multidisciplinary;novel;skills;success;tumor;tumor initiation;tumor metabolism;tumor microenvironment;tumorigenesis


application_id: 10073529
project_number: 5P20GM121327-05
project_title: Core B: Metabolism Core
administering_ic: NIGMS
award_notice_date: 2020-12-21
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2021-12-31
study_section: ZGM1-RCB-6
subproject_number: 7094
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Metabolomics largely consists of metabolic profiling which is the process of identification andquantification of a large number of metabolites of many different biochemical classes from diversebiological samples including cells culture media tissue and biofluids. However to understand themetabolic underpinning of diseases such as cancer a biochemical mechanism is needed in whichcase it is necessary to introduce appropriate stable isotope tracers which while increasing thenumber of analytes to be quantified also greatly increase the retrieval of biologically relevantinformation. This Stable Isotope Resolved Metabolomics (SIRM) approach is a unique specialty ofthe Metabolism Core. The goals of the Core are to provide services for a wide coverage ofmetabolites with isotopomer and isotopologue analysis. To achieve this we make use of two majoranalytical platforms namely high resolution nuclear magnetic resonance (NMR) and ultra-highresolution Fourier-transform mass spectrometry (UHR-FTMS) with or without chromatography. TheCore personnel will advise on analytical methods and experimental design and additional techniquesmay be developed to address issues of identification and quantification. Because experimentaldesign and sample preparation are integral to the data acquisition and interpretation the Coreprovides expertise in these and informatics relevant to the SIRM approach. These goals will beachieved according to the following: Specific Aim 1. To provide access and expertise across a widerange of NMR and MS technologies to investigators. Specific Aim 2. To provide experimental designsample processing and informatics support to the investigators for data reduction metabolicpathway and biochemical mechanism analyses. Specific Aim 3. To develop and implement newmethods to enhance metabolic capabilities relevant to the COBRE Projects. This Core will supportthe young investigators by providing advanced analytical technologies and expertise in the metabolicrequirements for cancer development.

project_terms:
Address;Algorithms;Biochemical;Biochemistry;Bioinformatics Shared Resource;Biological;Biomass;Biometry;Cancer Biology;Cancer Center;Cell Culture Techniques;Centers of Research Excellence;Chromatography;Classification;Collaborations;Complement;Consult;Culture Media;Data;Data Analyses;Databases;Development;Disease;Experimental Designs;Fourier Transform;Goals;Hour;Human Resources;In Situ;Informatics;Infusion procedures;Isotope Labeling;Isotopes;Kentucky;Label;Liquid Chromatography;Logistic Regressions;Malignant Neoplasms;Mass Fragmentography;Mass Spectrum Analysis;Metabolic;Metabolic Pathway;Metabolism;Methods;Mole the mammal;Nuclear Magnetic Resonance;Pathway Analysis;Pathway interactions;Preparation;Procedures;Process;Protons;Research Personnel;Resolution;Retrieval;Sampling;Schedule;Services;Spectrum Analysis;Standardization;Statistical Data Interpretation;System;Techniques;Technology;Time;Tissue Harvesting;Tissues;Tracer;Universities;Update;advanced analytics;analytical method;animal imaging;base;cell growth;data acquisition;data reduction;experimental study;in vivo;medical specialties;metabolic abnormality assessment;metabolomics;random forest;stable isotope;tumor metabolism;ultra high resolution;wiki


application_id: 10073525
project_number: 5P20GM121327-05
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2020-12-21
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2021-12-31
study_section: ZGM1-RCB-6
subproject_number: 7093
contact_pi_person_id: 11045331
contact_pi: VANDERFORD, NATHAN LANE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY  The University of Kentucky (UK) Center for Cancer and Metabolism (CCM) will be established as a unique multidisciplinary Center of Biomedical Research Excellence (COBRE) designed to develop and deploy a strategically designed sustainable center infrastructure that cultivates cutting-edge research focused on the role of metabolic dysregulation in cancer development and progression. The Administrative Core provides critical scientific and administrative leadership to advance the goals of the CCM: to develop and sustain a thematically focused multidisciplinary center infrastructure dedicated to defining the role of metabolism in the development and treatment of cancer and to use this novel platform to develop promising early-stage investigators with enhanced skills in an exciting new area of cancer research. The goal of the Administrative Core is to enhance the scientific productivity of the center's faculty by delivering efficient administrative services across scientific projects and cores as well as pilot projects through an organizational/leadership framework that supports flexible team-based mentoring and provides for clear accountability. Thus the CCM Administrative Core is the central coordinating hub responsible for integrating highly complementary disciplinary strengths at UK in cancer metabolism and data sciences and leveraging sophisticated metabolomics tools and advanced cancer imaging capabilities. The core has primary responsibility for realizing the CCM's scientific vision operating on principles grounded in transformational leadership and shared administrative oversight. Administrative Core functions will be operationalized through the following three specific aims: 1) to provide coordinated operational management of the center; 2) to facilitate and coordinate research training mentoring and career development activities to develop early-stage investigators in cancer and metabolism and expand research in this area through pilot projects; and 3) to coordinate and conduct overall planning and evaluation. The core will coordinate and implement all administrative activities of the CCM: oversee daily center activities; coordinate program communications fiscal processes meeting organization and advisory committee input; facilitate and expedite interactions among projects and cores; manage the pilot project program; and lead program and project evaluation efforts. The core will oversee a total of four current projects two cores and a biostatistics and bioinformatics support component and ensure highly effective well-planned team-based mentorship including basic and clinical perspectives and external expertise for all early-stage investigators.

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


application_id: 10073518
project_number: 5P20GM121327-05
project_title: University of Kentucky Center for Cancer and Metabolism
administering_ic: NIGMS
award_notice_date: 2020-12-21
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: MCGUIRL, MICHELE
project_start_date: 2017-03-01
project_end_date: 2021-12-31
study_section: ZGM1-RCB-6(CI)
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: ZHOU, BINHUA P
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 Cancer cell survival traits such as suppressed apoptosis rapid cell cycling and proliferation and the abilityto metastasize from a primary location require extensive metabolic reprogramming of the tumormicroenvironment. Intriguing new insights into the novel role of metabolic dysregulation in tumorigenesis andmetastasis increasingly draw attention to currently understudied areas of cancer research: the potential formetabolic modulation to influence therapeutic outcomes and the impact of metabolic events at the clinical levelto impact quality of life for cancer patients. The University of Kentucky (UK) proposes to establish a uniquemultidisciplinary Center of Biomedical Research Excellence (COBRE) on Cancer and Metabolism (CCM) as astrategically designed sustainable framework that cultivates cutting-edge research focused on the role ofmetabolic mediators of cancer development and progression. The proposed multidisciplinary center leverageshighly specialized expertise in redox biology cancer cell signaling systems biochemistry and data sciences aswell as the presence of advanced metabolomics and sophisticated cancer imaging capabilities to create anintegrated cancer-metabolism research framework. Overarching goals are to strengthen UK's cancer researchenterprise by providing a thematically focused multidisciplinary infrastructure dedicated to defining thecontribution of metabolism in the development and treatment of cancer and to use this novel multidisciplinaryplatform to develop promising early-stage investigators with enhanced skills in an exciting new area of cancerresearch. To accomplish these goals we will (1) develop a critical mass of funded investigators with researchprograms directly related to the Center's unifying theme (2) provide strong team-based mentoring combiningbasic and clinical expertise (3) recruit new investigators to the Center through pilot project grant supportleveraged by institutional funds (4) create synergy among research projects via critical links to strong researchcenters at UK including existing COBREs and (5) facilitate the translation of basic findings in cancermetabolism into early therapeutic approaches. Proposed new synergies will be developed through fourresearch projects an Administrative Core important research cores in metabolism and imaging and strongbiostatistics/ bioinformatics support all of which are critical to the proposed studies and will contribute to thedevelopment of institutional resources. The scientific focus of the four research projects is cancer-metabolisminteractions spanning basic and translational perspectives. This concentration of multidisciplinary expertisefocused on a newly recognized cancer paradigm holds promise for significant new understandings ofoncogenesis overall. The CCM's integrative thematic focus and the clinical and translational implications ofinnovative understandings of the cancer-metabolism axis have strong potential to create a cadre of well-trainedscientists who are well equipped to lead future generations of scientists integrating these exciting new avenuesof investigation in metabolic dysregulation into multi-faceted studies on cancer development and therapy.

project_terms:
Address;Apoptosis;Area;Attention;Basic Science;Biochemistry;Bioinformatics;Biology;Biometry;Cancer Center;Cancer Death Rates;Cancer Patient;Cell Cycle;Cell Proliferation;Cell Survival;Centers of Research Excellence;Clinical;Collaborations;Core Facility;Coupled;Data;Data Science;Development;Discipline;Early Diagnosis;Environment;Event;Faculty;Fostering;Foundations;Funding;Future Generations;Goals;Grant;Growth;Image;Incidence;Infrastructure;Interdisciplinary Study;Intervention;Investigation;Kentucky;Lead;Link;Location;Malignant Neoplasms;Mediator of activation protein;Mentors;Metabolic;Metabolic Diseases;Metabolism;Neoplasm Metastasis;Obesity;Outcome;Oxidation-Reduction;Pilot Projects;Proliferating;Quality of life;Research;Research Personnel;Research Project Grants;Research Support;Resources;Role;Scientist;Seeds;Signal Transduction;System;Therapeutic;Training;Translations;United States National Institutes of Health;Universities;anticancer research;base;cancer cell;cancer imaging;cancer initiation;cancer therapy;career;cohesion;defined contribution;design;early detection biomarkers;imaging capabilities;improved;innovation;insight;interdisciplinary approach;metabolomics;mortality;multidisciplinary;novel;novel therapeutics;prevent;programs;recruit;skills;success;sustainability framework;synergism;therapeutic target;therapy outcome;tool;trait;tumor metabolism;tumor microenvironment;tumor progression;tumorigenesis

public_health_relevance:
PROJECT NARRATIVE The Center of Biomedical Research Excellence on Cancer and Metabolism seeks to define underlyingmechanisms that support a body of emerging evidence that links metabolic disorders to the development andprogression of cancer. To this end integrated and synergistic research support across multiple disciplines andfocusing on innovation and translation of ideas from basic research into novel therapy will be provided to juniorfaculty with research programs in this highly significant area. A well-designed and intensive mentoring programand cutting-edge research cores will foster and augment collaborations between project leaders and leadingresearchers from both within and outside UK.


application_id: 10073515
project_number: 5R01EY030060-02
project_title: Role of MRTF signaling in proliferative vitreoretinopathy
administering_ic: NEI
award_notice_date: 2020-12-15
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: EY
serial_number: 030060
program_official: SHEN, GRACE L
project_start_date: 2020-01-01
project_end_date: 2021-06-01
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 9182746
contact_pi: TAMIYA, SHIGEO
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractProliferative vitreoretinopathy (PVR) is a fibrotic complication affecting the retina. In PVR loss of visualacuity and in severe cases blindness is caused by contraction of scar tissue that form on the retinalsurface. PVR is found in ~50% of posterior segment ocular trauma cases and about 5% of cases aftersurgical repair of rhegmatogenous retinal detachment. Reliable treatment for PVR is currently unavailableand therefore prevention is important. The overall goal of this project is to unravel molecular mechanismsinvolved in PVR development to identify targets for potential intervention. The trigger for fibrosis such asPVR is sustained presence of myofibroblasts a cell type specialized ECM deposition and woundcontraction. Recent studies show that stiff ECM activates intracellular signaling essential for differentiationof myofibroblasts. Myofibroblasts in turn feeds back to further enhances ECM stiffness via aberrant ECMdeposition and crosslinking. This positive feedback loop between myofibroblasts and ECM rigidity sustainsmyofibroblast presence and its inhibition successfully prevented lung and liver fibrosis in animal models.However the underlying detailed mechanisms and molecules involved are both tissue and cell typedependent and the role of this positive feedback loop is yet to be examine in PVR. Past studies show thepresence of molecules involved in ECM stiffening in samples from PVR patients. Our preliminary data showtwo key molecules known to be affected by ECM stiffness transient receptor potential vanilloid 4 (TRPV4)channel and myocardin-related transcription factor (MRTF) are required for myofibroblasttransdifferentiation of retinal pigment epithelial (RPE) and Mller glia cells two resident cell types that giverise to myofibroblasts in PVR. Further data also show another molecule regulated by stiffness and known toalter MRTF target expression TAZ interacts with MRTF. We propose studies to determine molecularmechanisms activated by ECM stiffness leading to myofibroblast differentiation and PVR. In Aim1 the effectof ECM stiffening molecules on myofibroblast differentiation and PVR will be examine. Detailed molecularmechanism of regulating MRTF which is key to myofibroblast differentiation by TRPV4 and TAZ will bedetermined in Aim2 and 3 respectively. The project has the potential to uncover key molecular therapeutictargets for the prevention of PVR and possibly other fibrotic diseases.

project_terms:
Actins;Affect;Animal Model;Atomic Force Microscopy;Back;Blindness;Calcium;Cell Nucleus;Cells;Characteristics;Cicatrix;Collagen;Complication;Contracts;Cultured Cells;Data;Deposition;Development;Disease;Enzymes;Epiretinal Membrane;Extracellular Matrix;Eye Injuries;Family;Feedback;Feeds;Fibronectins;Fibrosis;Gene Expression;Goals;In Vitro;Intervention;Literature;Liver Fibrosis;Measures;Molecular;Muller's cell;Myofibroblast;Myosin Light Chain Kinase;Nuclear;Nuclear Translocation;Operative Surgical Procedures;PTK2B gene;Patients;Phosphotransferases;Prevention;Production;Proliferative Vitreoretinopathy;Protein Inhibition;Protein-Lysine 6-Oxidase;Publishing;Pulmonary Fibrosis;Retina;Retinal Detachment;Role;Sampling;Series;Serum Response Factor;Signal Transduction;Small Interfering RNA;Structure of retinal pigment epithelium;Surface;Testing;Time;Tissues;Traction;Transforming Growth Factor beta;Transglutaminases;Vanilloid;Visual Acuity;base;cell type;crosslink;cytokine;fibrillogenesis;in vivo;knock-down;molecular targeted therapies;myocardin;polymerization;porcine model;prevent;receptor;repaired;rho;small hairpin RNA;src-Family Kinases;therapeutic target;transcription factor;transdifferentiation;wound

public_health_relevance:
Project NarrativeProliferative vitreoretinopathy (PVR) is a fibrotic complication that causes retinal folds and/or traction retinaldetachment resulting in loss of visual acuity and in severe cases blindness. We propose to study signalingmechanisms involving both cells and the fibrotic extracellular matrix that creates a positive feedback loopthat results in PVR. The ultimate aim is to identify key molecules that can become therapeutic targets for theprevention of PVR.


application_id: 10070926
project_number: 1R01NS115507-01A1
project_title: RNA Surveillance and Protein Translation in FTD
administering_ic: NINDS
award_notice_date: 2020-08-05
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: NS
serial_number: 115507
suffix: A1
program_official: GUBITZ, AMELIE
project_start_date: 2020-08-15
project_end_date: 2021-06-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Frontotemporal dementia (FTD) is an age-related non-Alzheimer dementia characterized by progressiveneuronal loss in the frontotemporal lobes. A subset of FTD is defined by the pathology of protein inclusionspositive for Fused in Sarcoma (FUS) thus named FUS-FTD. FTD and amyotrophic lateral sclerosis (ALS) sharea wide spectrum of clinical pathological and genetic features. Pathogenic mutations of FUS cause both ALS andFTD and FUS proteinopathy is also detected in sporadic diseases. Thus it is crucial to examine relevant typesof neurons in affected brain regions in different disorders. This project focuses on studying pathogenic FUS inforebrain cortical neurons in FTD. FUS is primarily in the nucleus but the protein with a disease-causing mutationmis-localizes to the cytoplasm and form dynamic membraneless granules which can compromise cellularfunctions and impair neurons. We recently showed that FTD/ALS mutations of FUS suppressed proteintranslation and hyper-activated the nonsense-mediated decay (NMD) of mRNAs. Thus we hypothesize that thedysregulation of protein translation and mRNA surveillance contributes to cortical neuron loss in FUS-FTD. Three specific aims are designed to test the hypothesis using in vitro and animal models as well as FTDpatient tissues. Aim 1 is to determine how mRNA NMD and protein translation are perturbed by pathogenic FUSin FTD mice and patient tissues. We will determine whether NMD factors and translation-related proteins aresequestered in FUS inclusions in forebrain neurons in R521G FUS transgenic mice at different ages. mRNAturnover rates and protein translation efficiency in mouse forebrains will be measured and correlated withneuronal dysfunction and FTD disease progression. Moreover perturbations in NMD factors and proteintranslation will be examined in FTD patient tissues. Aim 2 is to identify specific proteins and mRNAs affected bypathogenic FUS in FTD mice. We will apply proteomic approaches to identify changes in protein translationimpacted by mutant FUS in forebrain neurons. Actively translated mRNAs will be identified and quantified inpolysomes using RNA-Seq. The -omics data will be integrated for pathway analysis to reveal which specificpathways are impaired by mutant FUS. Functional studies of affected pathways will be carry out to determinetheir mechanistic relevance in the FTD etiology. Aim 3 is to elucidate the significance of RNA binding and post-translational modifications in the dysfunction of pathogenic FUS. We will use a cohort of RNA binding-deficientmutations in an optogenetic Cry2olig-FUS-mCherry system to examine the significance of RNA binding in FUSinclusion formation and dysfunction in cortical neurons. We will evaluate the status of FUS acetylation in FTDmice and patient tissues using a new acetylation-specific antibody we generated. We will also test howacetylation-null and -mimicking mutations affect FUS inclusions NMD protein translation and neuronal toxicity.The proposed experiments will thoroughly examine a novel disease mechanism using innovative approaches.Completion of our proposed work will help elucidate molecular mechanisms underlying FUS FTD.

project_terms:
ALS patients;Acetylation;Affect;Age;Amyotrophic Lateral Sclerosis;Animal Model;Antibodies;Autopsy;Brain region;Cell Culture Techniques;Cell Nucleus;Cell model;Cell physiology;Cells;Clinical;Cytoplasm;Cytoplasmic Granules;Data;Disease;Disease Progression;Estrogen receptor positive;Etiology;Frontotemporal Dementia;Functional disorder;Future;Genetic;Impairment;In Vitro;Label;Light;Liquid substance;Lobe;Measures;Mediating;Membrane;Messenger RNA;Methods;Molecular;Mus;Mutation;Names;Nerve Degeneration;Neuronal Dysfunction;Neurons;Nonsense-Mediated Decay;Pathogenesis;Pathogenicity;Pathologic;Pathology;Pathway Analysis;Pathway interactions;Patients;Phase;Play;Polyribosomes;Post-Translational Protein Processing;Process;Prosencephalon;Proteins;Proteomics;Protocols documentation;Publishing;Puromycin;RNA;RNA Binding;Reagent;Ribonucleoproteins;Role;System;Temporal Lobe;Testing;Tissues;Toxic effect;Transgenic Mice;Translating;Translations;Work;age related;base;cohort;design;disease-causing mutation;experimental study;frontal lobe;frontotemporal lobar dementia-amyotrophic lateral sclerosis;innovation;insight;interdisciplinary approach;mRNA Decay;mRNA Surveillance;mouse model;multiple omics;mutant;neuron loss;neurotoxicity;nonalzheimer dementia;novel;optogenetics;polysome profiling;protein aggregation;sarcoma;spatiotemporal;therapeutic development;transcriptome sequencing

public_health_relevance:
Frontotemporal dementia (FTD also known as frontotemporal lobar dementia or FTLD) is an age-relatednon-Alzheimer dementia characterized by progressive degeneration of cortical neurons in the frontal andtemporal lobes which share a wide spectrum of clinical pathological and genetic features with amyotrophiclateral sclerosis (ALS). A subset of FTD is defined by the pathology of protein inclusions containing Fused inSarcoma (FUS) and is caused by FUS mutations (FUS-FTD). This project is to determine the mechanisms howpathogenic FUS interferes with RNA surveillance and turnover suppresses protein translation and disruptscellular pathways in cortical neurons in FTD using cellular and animal models as well as FTD patient tissues.


application_id: 10070910
project_number: 1R01NR019456-01
administering_ic: NINR
award_notice_date: 2020-09-07
opportunity_number: RFA-NR-20-001
application_type: 1
activity_code: R01
ic: NR
serial_number: 019456
program_official: YOON, SUNG SUG
project_start_date: 2020-09-07
project_end_date: 2025-06-30
study_section: Special Emphasis Panel[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: 2020-09-07
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 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;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: 10069746
project_number: 2R13DC016831-04
project_title: International Society for Neurogastronomy Symposium
administering_ic: NIDCD
award_notice_date: 2020-07-28
opportunity_number: PA-18-648
application_type: 2
activity_code: R13
ic: DC
serial_number: 016831
program_official: SULLIVAN, SUSAN L
project_start_date: 2017-09-26
project_end_date: 2023-08-31
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
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:
ABSTRACTThe objective of this conference grant request is to provide support for certain aspects ofthe annual meeting of the International Society of Neurogastronomy (ISN) for the next fiveyears. ISN is a relatively new society whose composition of scientists cliniciansnutritionists agricultural experts food service professionals and chefs naturallypredisposes it to focus on translational issues fundamental to how the chemical sensesimpact human health. The first two specific objectives are to provide a venue andopportunity that brings these groups together and facilitates the synergies that arise whendistinctly different fields interact productively. The third specific objective is to attract andstimulate the young scientists that are the future of the field of neurogastronomy. Thefourth specific objective is to do outreach that serves health and culinary professionals byinforming them about the impact that smell and taste has upon diet nutrition and thegrowing health problems of obesity-related diseases. The fifth specific objective is toensure that this new field embraces a culture of diversity weaving this principle into itsearly development by recruiting persons of diverse backgrounds to the conference.

project_terms:
Agriculture;Area;Chemicals;Clinical;Development;Diet;Diet Habits;Diet and Nutrition;Disabled Persons;Eating;Ensure;Environment;Equation;Equilibrium;Event;Faculty;Food;Food Services;Formulated Food;Fostering;Funding;Future;Goals;Grant;Health;Health Promotion;Human;International;Knowledge;Life;Mission;Neurosciences;Nutritional;Nutritionist;Obesity associated disease;Perception;Persons;Policies;Quality of life;Recruitment Activity;Science;Scientist;Smell Perception;Societies;Stimulus;Structure;Taste Perception;Training;Underrepresented Groups;Veterans;Work;design;drinking;food consumption;improved;interest;meetings;member;multisensory;outreach;preference;recruit;social;sound;symposium;synergism

public_health_relevance:
PROJECT NARRATIVEA major part of the mission of the International Society of Neurogastronomy (ISN) is topromote the study of flavor and its use to enhance the quality of human life channeling ourgrowing knowledge of neurogastronomy and chemosensory science into translationalaction needed to overcome the ways in which flavor preferences are often hijacked tocause unhealthy eating habits. ISN promotes cooperation between scientists and foodprofessionals towards altering the balance of this equation in our culture. ISNs annualmeeting provides an important mechanism for facilitating the interactions betweenchemosensory scientists neuroscientists clinicians nutritional scientists agriculturalscientists and food professionals needed to develop strategies for using flavor properly -strategies that are both practical and scientifically sound.


application_id: 10069712
project_number: 1R13HL154523-01
project_title: Don S. Fredrickson Lipid Research Conference
administering_ic: NHLBI
award_notice_date: 2020-07-20
opportunity_number: PA-18-648
application_type: 1
activity_code: R13
ic: HL
serial_number: 154523
program_official: LIU, LIJUAN
project_start_date: 2020-09-01
project_end_date: 2021-11-30
study_section: Special Emphasis Panel[ZHL1 CSR-C (M2)]
contact_pi_person_id: 8553632
contact_pi: GRAF, GREGORY A
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractThe Don S. Fredrickson Lipid Research Conference (formerly the Southeast Lipid ResearchConference (SELRC)) brings together scientists and trainees investigating the impact of lipid andlipoprotein metabolism on the development and treatment of Cardiometabolic disease. Theconference has been an annual event since 1992 was sponsored by Emory University and held atCallaway Gardens Pine Mountain GA. SELRC participants were generally located within thesoutheastern US but with the retirement of its founding organizer and the changing landscape ofconference support by industry partners the board voted to re-envision the conference and developedan institutional-host model. The first of these partnerships occurred in 2016 at the University ofKentucky. Since 2016 the SELRC has been hosted by Vanderbilt University and the University ofCincinnati. Following a return to UK in 2020 the conference will be hosted by Duke University andthe University of North Carolina in 2021 and again at Vanderbilt in 2022.The move to the institutional-host model resulted in a substantial increase in attendance and a largergeographical footprint that extended beyond the Southeast. With the blessing of the family the boardvoted to rename the SELRC after the late Don S. Fredrickson. Dr. Fredrickson served as the directorof the National Heart Institute (now the NHLBI) from 1966  1974 and later the NIH developed theclinical classification for dyslipidemias (Type I-V) described Tangiers Disease and made seminaldiscoveries in the area of lipoprotein metabolism. Most importantly he trained both basic and clinicalscientists and practitioners who have had a tremendous impact on the field of lipoprotein metabolism.Keynote Lectures at the 2020 Fredrickson conference include Ruth McPherson Ottawa HeartInstitute and Mahmood Hussein NYU on Days 1 and 3 of the conference. The scientific sessionsinclude Hepatic and Peripheral Lipid Metabolism Bioinformatics in Metabolic and CVD ResearchLipids and Inflammation and Genetics and Cardiometabolic Disease. Day 2 of the conference will besponsored by the UK Cardiovascular Research Center and features the Gill Awards for a senior andearly career investigator as well as a provocative noon hour speaker Amy Herman New York Timesbest-selling author of The Art of Perception. The agenda includes additional scientific sessions;multiple Poster Pitch sessions (5-7 90-second presentations by trainees) and two judged postersessions. The combined agenda affords every trainee in attendance the opportunity to present theirresearch on stage network with leaders in the field and broaden their scope and understanding ofresearch in Cardiometabolic disease.

project_terms:
Address;Area;Arts;Award;Bioinformatics;Cardiovascular Diseases;Cardiovascular system;Classification;Clinical;Clinical Investigator;Collaborations;Development;Disease;Dyslipidemias;Ensure;Enzymes;Event;Faculty;Family;Fostering;Gardenal;Genetic;Genetic Diseases;Geography;Gills;Goals;Heart;Hepatic;Hour;Hypertension;Hypertriglyceridemia;Inflammation;Institutes;Institution;Insulin Resistance;Intestines;Kentucky;Lipids;Lipoproteins;Metabolic;Metabolic Diseases;Metabolic syndrome;Metabolism;Midwestern United States;Modeling;Names;National Heart Lung and Blood Institute;New York;North Carolina;Obesity;Oral;Participant;Perception;Peripheral;Plasma;Research;Research Activity;Research Personnel;Research Project Grants;Retirement;Role;Science;Scientist;Seminal;Senior Scientist;Talents;Tangier Disease;Technology;Thinking;Time;Training;United States National Institutes of Health;Universities;Voting;cardiometabolism;cardiovascular risk factor;career;career development;experience;industry partner;lectures;lipid metabolism;meetings;microsomal triglyceride transfer protein;new technology;posters;relative cost;social;social engagement;symposium;translational scientist

public_health_relevance:
Project NarrativeThe Don S. Fredrickson Lipid Research Conference is an annual meeting held since 1992 that bringstogether scientists in the field of lipid and lipoprotein metabolism and their impact on cardiovascularand metabolic disease. Its goal is to provide a venue for senior scientists early career investigatorsand trainees to share cutting-edge science; encourage new lines of thinking experimentation andcollaboration; and the opportunity for host institutions to showcase their research activities in the fieldto have a greater impact in the advancement of our understanding and treatment of cardiometabolicdisease.


application_id: 10069394
project_number: 5R01HL135158-04
project_title: Effect of early life stress on obesity-induced hypertension in mice
administering_ic: NHLBI
award_notice_date: 2020-11-24
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: 2022-11-30
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;Nociception;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 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: 10069307
project_number: 5R01CA222596-04
project_title: Role of Sulfiredoxin in Colorectal Cancer Development
administering_ic: NCI
award_notice_date: 2020-12-08
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 222596
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2018-01-01
project_end_date: 2022-12-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 10043947
contact_pi: WEI, QIOU
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:
Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer deathin both men and women in USA and worldwide. One of the major causes of colorectal cancer mortality is dueto the spreading of cancer cells from primary tumor sites to distant organs a process known as cancer cellinvasion and metastasis. This process is coordinately regulated by various biological molecules and theirassociated signaling pathways. The long-term objective of my research is to understand colon tumorigenesisand metastatic process by identifying critical molecular drivers and to understand their function mechanisms todevelope effective ways for targeted cancer therapy. Sulfiredoxin is a novel redox enzyme that has a criticalrole of promoting tumorigenesis and metastasis of colorectal cancer. In this project our goals are tounderstand molecular mechanisms by which Sulfiredoxin promotes cancer cell invasion and metastasis and totest the efficacy of a novel small molecule inhibitor of Srx in blocking human colorectal cancer invasion andmetastasis using cell culture as well as mouse models.

project_terms:
American Cancer Society;Azoxymethane;Back;Binding;Biological;Biology;C-terminal;Cancer Etiology;Cell Culture Techniques;Cells;Cessation of life;Cetuximab;Clinic;Colorectal Cancer;Data;Deacetylation;Development;Diagnosis;Distant;Drug Kinetics;Enzymes;Epithelial;Fc Receptor;Free Radicals;Future;Goals;Growth;Growth Factor Receptors;Human;Individual;International;Knockout Mice;Malignant Neoplasms;Maximum Tolerated Dose;Mediating;Mesenchymal;Mitogen-Activated Protein Kinases;Modeling;Molecular;Mus;Neoplasm Metastasis;Oncogenic;Organ;Oxidation-Reduction;Oxidative Stress;Oxidoreductase;Pathologist;Patients;Peroxidases;Physicians;Play;Post-Translational Protein Processing;Primary Neoplasm;Process;Receptor Activation;Reporting;Research;Research Personnel;Resistance;Resources;Role;Route;Scientist;Signal Pathway;Signal Transduction;Site;Sodium Dextran Sulfate;Specimen;Subcutaneous Injections;Testing;Therapeutic;Toxic effect;Tyrosine Phosphorylation;Woman;base;cancer cell;cancer diagnosis;colon cancer patients;colon carcinogenesis;colon tumorigenesis;colorectal cancer metastasis;colorectal cancer treatment;dosage;efficacy study;efficacy testing;enzyme activity;fascin;implantation;insight;men;metastatic colorectal;metastatic process;mortality;mouse model;multidisciplinary;novel;novel therapeutics;panitumumab;patient derived xenograft model;peroxiredoxin;receptor;small molecule inhibitor;targeted cancer therapy;tumorigenesis

public_health_relevance:
This project is aimed to understand role of Sulfiredoxin in colon tumorigenesis and molecularmechanism of Sulfiredoxin in promoting colorectal cancer cell invasion and metastasis. Bytesting a novel small molecule inhibitor of Sulfiredoxin in the treatment of colorectal cancer inmouse models we expect to provide proof-of-the-concept data for future translationalapplications.


application_id: 10068786
project_number: 2R01CA133429-13A1
project_title: The Role of PHLPP in Colon Cancer
administering_ic: NCI
award_notice_date: 2020-08-14
opportunity_number: PA-19-056
application_type: 2
activity_code: R01
ic: CA
serial_number: 133429
suffix: A1
program_official: SALNIKOW, KONSTANTIN
project_start_date: 2009-04-01
project_end_date: 2025-04-30
study_section: Molecular Oncogenesis Study Section[MONC]
contact_pi_person_id: 7353657
contact_pi: GAO, TIANYAN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Automobile Driving;Autophagocytosis;Cancer Etiology;Cancer Patient;Cell Death;Cell Proliferation;Cell Survival;Cells;Cellular Stress;Cellular Stress Response;Cessation of life;Collaborations;Colon Carcinoma;Colorectal Cancer;Development;Disease;Down-Regulation;Effectiveness;Ensure;Epithelial Cells;Equilibrium;Estrogen receptor positive;Event;Funding;Grant;HK2 gene;Inflammation;Integrins;Intestines;Knockout Mice;Knowledge;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Metabolic;Metabolism;Mitochondria;Molecular;Oncogenic;Organism;PH Domain;Pathway interactions;Pharmaceutical Preparations;Phosphoric Monoester Hydrolases;Phosphorylation;Physiological;Play;Protein Dephosphorylation;Protein Family;Protein Kinase;Protein phosphatase;Proto-Oncogene Proteins c-akt;Regulation;Resistance;Role;Signal Pathway;Signal Transduction;Stress;Supporting Cell;Testing;Tumor Suppressor Proteins;United States;base;biological adaptation to stress;cancer cell;cancer initiation;cancer survival;cancer type;cell growth regulation;cell motility;chemotherapy;colon tumorigenesis;coping mechanism;endoplasmic reticulum stress;improved;in vivo;insight;leucine-rich repeat protein;mitochondrial autophagy;mortality;mouse model;multicatalytic endopeptidase complex;novel;protein expression;response;sensor;success;tumor initiation;tumor metabolism;tumor progression;tumorigenesis


application_id: 10068121
project_number: 1F31AA028725-01
project_title: Probiotic and intestinal miR194 regulation of bile acid metabolism in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2020-07-28
opportunity_number: PA-19-195
application_type: 1
activity_code: F31
ic: AA
serial_number: 028725
program_official: WANG, JOE
project_start_date: 2020-08-01
project_end_date: 2023-07-31
study_section: Special Emphasis Panel[ZAA1 GG (32)]
contact_pi_person_id: 15957958
contact_pi: JIANG, MENGWEI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Patients with alcoholic liver disease (ALD) often exhibit manifestations of cholestasis a liver pathology definedby accumulation of hepatic bile acids (BAs) which are toxic and an important causative factor in hepatocytedeath and liver injury in ALD. Excess hepatic BA concentration is a result of increased BA de novo synthesisand decreased BA secretion to bile. BA metabolism is regulated by farnesoid X receptor (FXR) signaling inintestine and liver. Previous study suggests that intestinal FXR is likely a major player to regulate hepatic BAsynthesis. Intestinal FXR activation is regulated by gut lumen BA species and concentration. Primary BAchenodeoxycholic acid (CDCA) is an agonist of FXR which is antagonized by taurine--murine cholic acid(TMCA). Previous studies have demonstrated that gut BA is dysregulated in ALD patients and in experimentalALD mice. Modulation of dysregulated BA signaling in the intestine improves experimental ALD. Interestinglyour preliminary data showed that in the NIAAA binge-on-chronic alcohol feeding model intestinal FXR mRNAwas markedly reduced along with decreased intestinal fibroblast growth factor (FGF) 15/19 (mouse/humans)and increased hepatic Cyp7a1 expression elevated BA concentration and liver injury. Targeting intestinal FXRboth in transcription and in activation may be a plausible strategy for inhibiting ALD. FXR transcription isregulated by microRNA194 (miR194) which is highly expressed in the intestine. Our preliminary data showedthat alcohol feeding significantly increased intestinal miR194. Interestingly miR194 is suppressed by taurineupregulated gene 1(TUG1) a long non-coding RNA regulated by taurine concentration. Therefore it is likely thatalcohol-induced miR194 causes a reduction of intestinal FXR in ALD. Supplementation of probiotic Lactobacillusrhamnosus GG (LGG) is protective against experimental ALD through multiple mechanisms. Our preliminarystudy showed that LGG suppressed alcohol-increased miR194 and -decreased FXR in the intestine. Theseprevious and preliminary studies strongly suggest that LGG may exert its function in hepatic BA synthesisthrough modulation of intestinal miR194-FXR signaling. We thus hypothesize that alcohol exposure increasesintestinal miR194 and suppresses FXR and FGF15 leading an increase in hepatic de novo BA synthesis andliver injury; and LGG supplementation inhibits intestinal miR194 and suppresses hepatic BA synthesis and liverinjury in mice. To test our hypothesis we design following specific aims: Aim 1 will determine the role of miR194in the regulation of intestinal FXR signaling and hepatic BA homeostasis in ALD. Aim 2 will determine the role ofintestinal miR194-FXR-FGF15 signaling in the protective effects of LGG on ALD. Aim 3 will identify themechanism(s) of miR194 regulation in ALD. Collectively the training and research proposed here will not onlyfill a significant 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:
Agonist;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Bile Acid Biosynthesis Pathway;Bile Acids;Bile fluid;Caco-2 Cells;Cessation of life;Chenodeoxycholic Acid;Cholestasis;Cholic Acids;Chronic;Clinical Trials;Data;Development;Diet;Disease;Endocrine;Enzymes;Epithelial;Epithelial Cells;Epithelium;Exhibits;FDA approved;FGF19 gene;Fibroblast Growth Factor;Fostering;Genes;Genetic Transcription;Hepatic;Hepatocyte;Homeostasis;Hormones;Human;Intestines;Knockout Mice;Lactobacillus casei rhamnosus;Liver;Liver diseases;Mediating;Messenger RNA;Modeling;Mus;National Institute on Alcohol Abuse and Alcoholism;Organ;Pathology;Patients;Probiotics;Production;Receptor Activation;Receptor Inhibition;Receptor Signaling;Regulation;Research;Research Personnel;Role;Scientist;Signal Transduction;Supplementation;Taurine;Testing;Training;Untranslated RNA;alcohol exposure;bile acid metabolism;design;disorder prevention;feeding;gut microbiota;improved;intestinal epithelium;liver injury;mouse model;non-alcoholic fatty liver disease;probiotic supplementation;protective effect;receptor

public_health_relevance:
Alcoholic liver disease (ALD) is responsible for nearly half of liver disease deaths yet there are no FDA-approved therapies available for the treatment of any stage of its progression. LGG has been used in clinicaltrial for mild alcoholic hepatitis. Elucidating the mechanisms of probiotic action on hepatic bile acid synthesiswill further support an optimization of probiotic usage alone and/or with other strategy targeting bile acidhomeostasis in the ALD prevention/treatment.


application_id: 10067931
project_number: 1F31HL154663-01
project_title: Metabolic regulation of exercise-induced adaptation in striated muscle
administering_ic: NHLBI
award_notice_date: 2020-08-07
opportunity_number: PA-19-195
application_type: 1
activity_code: F31
ic: HL
serial_number: 154663
program_official: HUANG, LI-SHIN
project_start_date: 2020-08-10
project_end_date: 2023-08-09
study_section: Special Emphasis Panel[ZRG1 F10A-K (20)]
contact_pi_person_id: 15945691
contact_pi: FULGHUM, KYLE
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:
AbstractAerobic exercise promotes beneficial adaptations in the heart. Previous studies demonstrate that transientreductions in cardiac glucose catabolism at the level of phosphofructokinase are important for exercise-inducedcardiac growth. Although this finding links changes in metabolism with initiation of growth the mechanisms bywhich glucose metabolism changes during exercise and how metabolism coordinates cardiac growth remainunclear. Metabolic changes could promote exercise-induced muscle growth in two ways. First changes in thelevels of glycolytic intermediates during exercise could regulate carbon availability for building block biosynthesiswhich constitutes a material cause for cardiomyocyte hypertrophy. Second metabolic changes that occur duringexercise could regulate the exercise gene program which is important for exercise-induced tissue remodeling.Nevertheless it has been difficult to disentangle the contribution of these two causes to the adaptations broughtforth by exercise. Addressing these problems requires understanding how metabolism changes both during andafter exercise and then identifying the metabolic components that modulate cardiomyocyte growth. In thisproject I will test the general hypothesis that high levels of competing substrates such as lactate and fatty acidsprompt ancillary biosynthetic pathway activity in the heart and drive gene programs for cardiac growth. Tounderstand how glucose metabolism changes in response to exercise or in the presence of competingsubstrates I have standardized deep network tracing methods to measure glucose-derived carbon fate in vivousing dietary delivery of a 13C6-glucose-containing diet. Specifically the aims are (1) to define changes in cardiacglucose metabolism in response to exercise training and (2) to determine how circulating substrates influencecardiac hypertrophic signaling and gene programs. This research plan will provide training in areas critical to mygrowth as a scientist and prepare me for a career in the exercise sciences. The project will provide freshperspectives about how metabolism regulates cardiac muscle growth and could identify innovative metabolicapproaches to control tissue remodeling or optimize the cardiovascular benefits of exercise. Importantly thesestudies will integrate our current understanding of striated muscle catabolism with new knowledge of howanabolism is regulated within muscle tissue.

project_terms:
Address;Adipose tissue;Aerobic Exercise;Affect;Anabolism;Area;Blood capillaries;Carbohydrates;Carbon;Cardiac;Cardiac Myocytes;Cardiovascular Diseases;Cardiovascular system;Catabolism;Data;Diet;Enzyme Activation;Enzymes;Exercise;FRAP1 gene;Fatty Acids;Genes;Genetic;Glucose;Glucosephosphate Dehydrogenase;Glucosephosphate Isomerase;Glycolysis;Growth;Heart;Hypertrophy;In Vitro;Insulin-Like Growth Factor I;Ketones;Knowledge;Link;Liquid substance;Mass Spectrum Analysis;Measures;Metabolic;Metabolic Pathway;Metabolism;Methods;Molecular;Mus;Muscle;Myocardial;Myocardium;Nucleotides;Pathway interactions;Pharmacology;Phospholipids;Phosphotransferases;Production;Regulation;Research;Role;Science;Scientist;Signal Pathway;Signal Transduction;Standardization;Stimulus;Striated Muscles;Study Subject;Testing;Tissues;Training;aminoacid biosynthesis;carbohydrate metabolism;career;density;effective intervention;energy balance;exercise training;glucose metabolism;heart function;in vivo;innovation;interest;macromolecule;novel;prevent;programs;pyruvate dehydrogenase;respiratory;response

public_health_relevance:
PROJECT NARRATIVEExercise is an effective intervention to treat and prevent cardiovascular diseases; however the mechanismscontrolling exercise-induced adaptations in cardiovascular tissues are poorly understood. In this project we willexamine how exercise regulates carbohydrate metabolism in the heart and how changes in carbohydrateutilization affect tissue responses to exercise.


application_id: 10067729
project_number: 1F31DC019050-01
project_title: Terminal Arbor remodeling of Peripheral Taste Neurons
administering_ic: NIDCD
award_notice_date: 2020-04-20
opportunity_number: PA-19-195
application_type: 1
activity_code: F31
ic: DC
serial_number: 019050
program_official: RIVERA-RENTAS, ALBERTO L
project_start_date: 2020-07-01
project_end_date: 2023-06-30
study_section: Special Emphasis Panel[ZDC1 SRB-R (32)]
contact_pi_person_id: 14783350
contact_pi: WHIDDON, ZACHARY DAVID
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractTaste receptor cells (within taste buds) are constantly replaced through adulthood. This raisesthe question of whether this continuous cell turnover causes remodeling in the taste nerveterminal arbors which innervate taste receptor cells. More specifically how does taste receptorcell entry and cell exit within the taste bud influence arbor structure? To answer thesequestions I propose to develop an in vivo two-photon imaging method to repeatedly sample thesame terminal arbors over time. Aim 1 will examine terminal arbor structure over the averagelifespan of a taste receptor cell (10 days). I hypothesize that terminal arbor structure in theepithelium will remodel in this period while structure beneath the epithelium will remain stable.Aim 2 will examine arbor structure when taste cell turnover is manipulated to elucidate theeffects of cell entry and cell exit. I hypothesize that taste cell exit from the bud will promotebranch retraction and taste cell entry into the bud will promote branch formation/growth. Theseexperiments are the first to investigate changes in taste neuron anatomy over time using a intravital imaging approach and will provide direct evidence of extent of nerve fiber remodeling in thetaste bud. Future studies will use this approach to investigate the specific molecularmechanisms in both neurons and taste cells used to orchestrate plasticity in the taste bud.

project_terms:
Adult;Affect;Afferent Neurons;Anatomy;Cells;Chemicals;Dose;Environment;Epithelial;Epithelium;Erinaceidae;Exposure to;Future;Genetic;Growth;Hour;Image;Individual;Label;Location;Longevity;Maps;Methods;Molecular;Morphology;Mus;Nerve;Nerve Fibers;Nervous system structure;Neurons;Organ;Peripheral;Pharmacology;Process;Receptor Cell;Recovery;Sampling;Sensory;Signal Transduction;Structure;System;Tamoxifen;Taste Buds;Taste Perception;Techniques;Time;Tongue;experimental study;imaging approach;imaging modality;in vivo imaging;in vivo two-photon imaging;intravital imaging;novel;prevent;response;side effect;smoothened signaling pathway;taste system;time use;two-photon

public_health_relevance:
Project NarrativeHere I propose an in vivo imaging method to observe changes in terminal arbor structure ofperipheral taste neurons over time in response to taste receptor cell turnover. Theseexperiments will contribute to our current understanding of structural plasticity in the adultnervous system and how this plasticity is regulated. Of central importance is the application ofthis technique to assess how novel chemotherapeutic side-effects might disrupt the sense oftaste.


application_id: 10067543
project_number: 5R01DE028296-02
project_title: Redox Regulation of Gingival Inflammation
administering_ic: NIDCR
award_notice_date: 2020-11-25
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: 2024-11-30
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/antagonist;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: 10067241
project_number: 2R01DK048498-25
project_title: Mechanistic Impact of PI3K/mTOR Signaling on Intestinal Homeostasis
administering_ic: NIDDK
award_notice_date: 2020-07-30
opportunity_number: PA-19-056
application_type: 2
activity_code: R01
ic: DK
serial_number: 048498
program_official: SERRANO, JOSE
project_start_date: 1996-03-15
project_end_date: 2024-06-30
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
3-hydroxy-3-methylglutaryl-coenzyme A;Biochemical;Cell Differentiation process;Cell Proliferation;Cell model;Cell physiology;Cells;Colorectal Cancer;Data;Development;Differentiation and Growth;Enterocytes;Enteroendocrine Cell;Enzymes;Equilibrium;Event;FRAP1 gene;Glycolysis;Goblet Cells;Grant;Growth;Hexokinase 2;Homeostasis;Human;In Vitro;Inflammation;Inflammatory Bowel Diseases;Intestinal Mucosa;Intestines;Knock-out;Knockout Mice;Lead;Maintenance;Mediating;Metabolic;Metabolism;Molecular;Morbidity - disease rate;Mus;Organoids;Oxidative Phosphorylation;Paneth Cells;Pathology;Pathway interactions;Patients;Play;Process;Protein Family;Proteins;Publishing;Regulation;Role;SIRT1 gene;Seminal;Signal Pathway;Signal Transduction;Sir2-like Deacetylases;Sirtuins;System;Techniques;Testing;Transgenic Model;Tuberous sclerosis protein complex;Villus;base;beta catenin;cell type;clinically relevant;design;differential expression;experimental study;hexokinase;in vivo;innovation;insight;intestinal epithelium;intestinal homeostasis;ketogenesis;ketogentic;knock-down;member;metabolomics;mouse model;novel;novel therapeutic intervention;single cell sequencing;stable isotope;stem cell proliferation;stem cells;stemness


application_id: 10066843
project_number: 1F31DK126400-01
project_title: Role of macrophages in cisplatin-induced kidney injury and progression to chronic kidney disease
administering_ic: NIDDK
award_notice_date: 2020-04-23
opportunity_number: PA-19-195
application_type: 1
activity_code: F31
ic: DK
serial_number: 126400
program_official: MARIC-BILKAN, CHRISTINE
project_start_date: 2020-05-01
project_end_date: 2023-04-30
study_section: Special Emphasis Panel[ZDK1 GRB-G (M1)]
contact_pi_person_id: 16257979
contact_pi: SEARS, SOPHIA MARIE
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryCisplatin is a commonly used chemotherapeutic agent with dose-limiting nephrotoxicity. 30% of patients whoreceive cisplatin develop acute kidney injury (AKI) or a rapid decrease in kidney function. Development of AKIincreases the risk of chronic kidney disease (CKD) and mortality. Even patients that do not develop AKI byclinical standards are still at risk for long term declines in renal function and CKD development. There arecurrently no therapies approved to prevent or treat cisplatin-induced kidney injury (CDDP-KI). In the pastresearch on CDDP-KI utilized a single high dose model of injury. This model is lethal to mice within 3-4 daysand does not allow for study of long-term renal outcomes. We have developed a more clinically relevantrepeated low dose cisplatin (RLDC) model of CDDP-KI. In this model mice receive 4 weekly low doses ofcisplatin and can survive more than 6 months after treatment [1]. This RLDC model has been shown to inducerenal fibrosis and progressive declines in renal function indicative of CKD development [1 2]. Other models ofkidney fibrosis have demonstrated that macrophages can play a pro-fibrogenic role by differentiating intomyofibroblasts the main effector of fibrotic development. Our preliminary studies show that the RLDC modelcauses accumulation of macrophages and myofibroblasts that persists up to 6 months after treatment. This isaccompanied by a sustained increase in transforming growth factor beta (TGF) which is a mediator ofmacrophage to myofibroblast transition. Lastly we have identified a population of F4/80+ SMA+ CD206+ cellsthat appear after the fourth dose of cisplatin indicative of this transition state. This research proposal willexamine the relationship between macrophage response and susceptibility to CDDP-KI using our RLDC modelof cisplatin-induced injury. We hypothesize that the repeated low dose cisplatin model promotes fibrosisand CKD development through stimulating chronic macrophage activity and macrophage tomyofibroblast transition in the kidney. This hypothesis will be tested with the following aims. Aim 1:Characterize immune response and macrophage to myofibroblast transition during repeated low dose cisplatin.In this aim we will use flow cytometry to analyze the immune cell response to cisplatin induced injury in thekidney. We will also isolate renal macrophages following cisplatin treatment and perform RNAseq to evaluatedevelopment of myofibroblast characteristics. Lastly we will utilize bone marrow chimera models to determineif bone marrow derived immune cells are infiltrating the kidney following cisplatin treatment. Aim 2: Determinethe role of macrophages in repeated low dose cisplatin induced fibrosis and chronic kidney disease. In thisaim we will determine how global depletion of macrophages and inhibition of chemokine (C-C motif) receptor 2(CCR2) monocyte trafficking affects renal function and development of fibrosis in our RLDC model. Completionof these aims will identify novel targets to prevent the AKI to CKD transition associated with CDDP-KI.

project_terms:
Acute Renal Failure with Renal Papillary Necrosis;Affect;Aftercare;Apoptosis;Blood Vessels;Bone Marrow;Cancer Patient;Cell Death;Cells;Characteristics;Chimera organism;Chronic;Chronic Kidney Failure;Cisplatin;Clinical;DNA;Data;Development;Dichloromethylene Diphosphonate;Disease Progression;Dose;Dose-Limiting;Effectiveness;Endothelium;Extracellular Matrix;Fibrosis;Flow Cytometry;Functional disorder;Immune;Immune response;Impairment;Infiltration;Inflammation;Injury;Injury to Kidney;Kidney;Knockout Mice;Life;Liposomes;Longitudinal Studies;Mediator of activation protein;Modeling;Mus;Myofibroblast;Outcome;Patients;Pharmaceutical Preparations;Phase II Clinical Trials;Play;Population;Predisposition;Production;Renal function;Reperfusion Injury;Research;Research Proposals;Risk;Role;Signal Transduction;Testing;Therapeutic;Toxic effect;Transforming Growth Factor beta;Tubular formation;Tumor-infiltrating immune cells;Ureteral obstruction;Work;cancer cell;cancer therapy;cell injury;chemokine receptor;chemotherapeutic agent;clinically relevant;crosslink;cytokine;glomerulosclerosis;interstitial;kidney allograft;kidney fibrosis;macrophage;monocyte;mortality;mouse model;nephrotoxicity;novel;prevent;prospective test;recruit;response;side effect;success;trafficking;transcriptome sequencing

public_health_relevance:
Project NarrativeAcute kidney injury (AKI) and chronic kidney disease (CKD) are life threatening side effects commonlyassociated with drug therapeutics. We are using a clinically relevant model of cisplatin-induced kidney injury toexamine the role of macrophages in this pathophysiology. Successful completion of this project will lead toclinical therapies to prevent drug-induced kidney injury.


application_id: 10066601
project_number: 1F30HD103319-01
administering_ic: NICHD
award_notice_date: 2020-07-27
opportunity_number: PA-19-192
application_type: 1
activity_code: F30
ic: HD
serial_number: 103319
program_official: CHINN, JUANITA JEANNE
project_start_date: 2020-08-02
project_end_date: 2024-08-01
study_section: Special Emphasis Panel[ZRG1 F18-Z (20)]
contact_pi_person_id: 16164179
contact_pi: HANSEN, ANNA
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL 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: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-08-02
project_terms:
Address;Adopted;Alaska Native;American;Appalachian Region;Biological;Caring;Cessation of life;Chronic Disease;County;Data;Data Set;Databases;Death Records;Detection;Development;Diabetes Mellitus;Diagnosis;Discipline of obstetrics;Disease;Distress;Emergency Medical Technicians;Epidemiology;Etiology;Evaluation;Evidence based intervention;Extramural Activities;Female of child bearing age;Foundations;Future;Health;Health Personnel;Healthcare;High Prevalence;Home environment;Hospitalization;Hypertension;Intervention;Interview;Investigation;Kentucky;Knowledge;Link;Location;Logistic Regressions;Maternal Health;Maternal-fetal medicine;Medical;Mentors;Mentorship;Methods;Mississippi;Morbidity - disease rate;Mothers;Native Americans;Organ;Outcome;Participant;Patient Care;Patients;Pattern;Physicians;Policies;Population;Populations at Risk;Postnatal Care;Postpartum Period;Postpartum Women;Poverty;Pregnancy;Pregnancy Complications;Pregnancy Outcome;Pregnant Women;Prevalence;Prevention;Provider;Regression Analysis;Research;Research Support;Residencies;Resources;Risk;Risk Factors;Rural;Rural Appalachia;Rural Population;Scientist;Structure;Sum;Training;United States;United States National Center for Health Statistics;United States National Institutes of Health;Universities;Validity of Results;Woman;World Health Organization;burden of illness;data centers;evidence base;experience;health care availability;health equity;implementation science;innovation;insight;maternal outcome;member;mortality;mortality risk;neglect;obstetric care;predictive modeling;prepregnancy;protective factors;research data dissemination;residence;responsible research conduct;rural area;rural health disparities;rural setting;rural underserved;secondary analysis;severe maternal morbidity;social;social determinants;social health determinants;sociodemographic factors


application_id: 10066332
project_number: 5R21CA245560-02
project_title: Overcoming resistance to cancer immunotherapy by targeting MDSC-derived adenosine
administering_ic: NCI
award_notice_date: 2021-06-23
opportunity_number: PAR-18-020
application_type: 5
activity_code: R21
ic: CA
serial_number: 245560
program_official: SOMMERS, CONNIE L
project_start_date: 2019-12-07
project_end_date: 2022-11-30
study_section: ZCA1-SRB-A(O1)S
contact_pi_person_id: 10807180
contact_pi: YADDANAPUDI, KAVITHA
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/ABSTRACT Lung cancer is a prevalent disease and consumes many lives every year. Cancer immunotherapy usingimmune checkpoint inhibitors (ICIs; e.g. anti-PD-1antibody) has revolutionized the treatment of metastatic lungcancer resulting in long-term complete responses for many patients. Nevertheless there remains an urgentneed for new strategies because not all patients respond to ICIs; moreover resistance can occur in those thatdo. Myeloid-derived suppressor cells (MDSCs) in particular monocytic MDSCs (M-MDSCs) are potentimmunosuppressive innate immune cells that actively inhibit CD8+ T cell tumor homing and activation. SinceM-MDSC levels are elevated in multiple human cancers and correlate with decreased patient survival wepostulate that these cells contribute to anti-PD-1 resistance. The purine nucleoside adenosine is produced incopious amounts within the tumor microenvironment (TME) where it serves to suppress the immune systemand promote tumor growth. There is evidence to suggest that overproduction of adenosine can mediateresistance to ICIs. Immune suppressive adenosine is produced via the enzymatic conversion of extracellularAMP by the cell surface enzyme CD73 (ecto-5-nucleotidase; AMP  adenosine). Our preliminary studiesdemonstrate that tumor cell-derived prostaglandin E2 (PGE2) maintains M-MDSC suppressive activity in largepart by directly inducing cell surface CD73 expression leading to increased immune suppressive adenosinewithin the TME. The overall hypothesis of this proposal is that tumor cell-derived PGE2 dictates CD73expression in M-MDSCs leading to substantial increases in adenosine-dependent inhibition of anti-tumor CD8+T cell activation resulting ultimately in anti-PD-1 immunotherapeutic resistance. A major goal of this proposalis to test the anti-tumor efficacy of a novel cancer immunotherapy involving systemic administration ofadenosine deaminase (ADA)an enzyme that irreversibly converts adenosine into inosine a non-immunosuppresive nucleoside. A pegylated version of bovine ADA (PEG-ADA) is already FDA-approved foruse as an enzyme replacement therapy in children with severe combined immunodeficiency (ADA-SCID). Wehypothesize that depletion of adenosine-mediated T cell immune suppression by PEG-ADA sensitizes tumorsto PD-1 inhibitor therapy and improves clinical outcomes for NSCLC patients. To fulfill the stated objectivesthe following aims are proposed: 1) Investigate intra-tumoral M-MDSC functional maintenance in the context ofa PGE2  CD73+ M-MDSC  adenosine dependent pathway; 2) Determine if loss/inhibition of extracellularadenosine-dependent pathway attenuates anti-PD-1 resistance in mouse models of lung cancer; and 3)Validate PGE2  CD73+ M-MDSC  adenosine mediated anti-PD-1 resistance pathway in lung cancerpatients receiving pembrolizumab therapy. Our proposed study will provide important insights towardsdeveloping a safe and novel immunotherapy to attenuate ICI resistance in lung cancer patients.

project_terms:
5'-Nucleotidase;Ablation;Adenosine;Adopted;Advanced Malignant Neoplasm;Attenuated;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Model;Cancer Patient;Cattle;Cell physiology;Cell surface;Cells;Child;Clinical;Consumption;Data;Dinoprostone;Disease;Effectiveness;Enzymes;FDA approved;Frequencies;Generations;Goals;Health;Health Care Costs;Homing;Human;Immune;Immune Cell Suppression;Immune checkpoint inhibitor;Immune system;Immunotherapeutic agent;Immunotherapy;Impairment;Implant;In complete remission;Inosine;KRASG12D;Life;Lung Adenocarcinoma;Lung Neoplasms;Maintenance;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mus;Myeloid Cells;Myeloid-derived suppressor cells;Non-Small-Cell Lung Carcinoma;Nonmetastatic;Nucleosides;Outcome;PD-1 inhibitors;Pathway interactions;Patients;Pharmaceutical Preparations;Polyethylene Glycols;Production;Purine Nucleosides;Resistance;Scheme;Severe Combined Immunodeficiency;Signal Transduction;T cell response;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Transgenic Model;Tumor Immunity;Tumor-Derived;adenosine deaminase;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;cancer cell;cancer immunotherapy;clinically relevant;effector T cell;enzyme replacement therapy;extracellular;improved;inhibitor/antagonist;insight;monocyte;mouse model;neoplastic cell;novel;objective response rate;pembrolizumab;prevent;programmed cell death ligand 1;response;therapeutic target;therapy development;therapy resistant;tumor;tumor growth;tumor microenvironment

public_health_relevance:
Project NarrativeCancer immunotherapy using immune checkpoint inhibitors (ICIs) to target molecules that prevent the immunesystem from attacking cancer cells (e.g. anti-PD-1 antibody) has revolutionized the treatment of metastatic lungcancer resulting in long-term complete responses for many patients. Regardless of these encouraging resultsimmunotherapeutic resistance continues to occur in a significant proportion of patients. A critical determinant ofunresponsiveness in these patients is due to the intra-tumoral accumulation of adenosine which activelysuppresses the effectiveness of immunotherapies. In order to therapeutically deplete the intra-tumoraladenosine we have explored the use of an FDA approved drug [PEGylated]-Adenosine Deaminase (PEG-ADA). We propose to investigate if adenosine depletion with PEG-ADA therapy can induce anti-tumorimmunity and sensitize lung tumors to immunotherapy. Such a therapeutic strategy will reduce health carecosts and loss of life from a disease that is now a major health problem worldwide.


application_id: 10064494
project_number: 2UG1OD024954-03
project_title: The Kentucky ECHO Pediatric IDeA Research Center (KE-PIRC)
administering_ic: OD
award_notice_date: 2020-08-18
opportunity_number: RFA-OD-19-026
application_type: 2
activity_code: UG1
ic: OD
serial_number: 024954
program_official: RAJU, TONSE N
project_start_date: 2016-09-23
project_end_date: 2025-08-31
study_section: Special Emphasis Panel[ZRG1 BBBP-J (51)]
contact_pi_person_id: 14437890
contact_pi: WATSON, SARA E
other_pis: DEVLIN-PHINNEY, LORI ANN
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Academic Medical Centers;Address;Adolescent;Adult;Airway Disease;Alcohol consumption;Appalachian Region;Area;Child;Child Health;Child health care;Childhood;Chronic;Clinical;Clinical Research;Clinical Trials;Clinical Trials Network;Collaborations;Communities;Development;Diabetes Mellitus;Disease;Drug abuse;Education;Educational Status;Environmental Health;Etiology;Faculty;Family;Family Physicians;Feedback;Fetal Development;Funding;Generations;Goals;Health;Health Benefit;Healthcare;Heart Diseases;High Prevalence;Individual;Infant;Institution;Intervention;Kentucky;Leadership;Malignant neoplasm of lung;Mentors;Mentorship;Multi-Institutional Clinical Trial;Neonatal;Neurologist;Obesity;Outcome;Participant;Patients;Pediatric Hospitals;Physicians;Population;Population Heterogeneity;Preventive;Primary Health Care;Process;Provider;Refugees;Research;Research Infrastructure;Research Personnel;Resources;Rural;Rural Population;Scientist;Site;Smoking;Stroke;System;Talents;Teacher Professional Development;Time;Training;Training and Education;Underrepresented Minority;Underserved Population;United States National Institutes of Health;Universities;Vulnerable Populations;Work;Workplace;autism spectrum disorder;biomedical referral center;care outcomes;career;cohort;community partnership;ethnic minority population;fetal;improved;innovation;member;next generation;novel strategies;nutrition;outreach program;patient population;pediatrician;postnatal;programs;racial minority;recruit;rural underserved;senior faculty;skills;success;urban underserved


application_id: 10064363
project_number: 1R01ES032189-01
project_title: Exposome and Precision Medicine in NAFLD
administering_ic: NIEHS
award_notice_date: 2020-08-27
opportunity_number: RFA-ES-18-007
application_type: 1
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: Special Emphasis Panel[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;Genetic Transcription;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;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.


application_id: 10063843
project_number: 5R01CA175105-07
project_title: Targeting Translation Dependence in Colorectal Cancer Progression
administering_ic: NCI
award_notice_date: 2020-11-30
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: CA
serial_number: 175105
program_official: AULT, GRACE S
project_start_date: 2013-04-01
project_end_date: 2024-11-30
study_section: Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1]
contact_pi_person_id: 10534129
contact_pi: SHE, QING-BAI
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:
Binding Proteins;Biological Markers;Biology;Cancer Etiology;Cell Line;Cessation of life;Clinical;Colorectal Cancer;Dependence;Development;Disease;Down-Regulation;EIF4EBP1 gene;Electron Transport Complex III;Environment;Epigenetic Process;FRAP1 gene;Fostering;Foundations;Funding;Genes;Genetic Transcription;Genetic Translation;Goals;Immune Evasion;Immunity;Immunologic Surveillance;Immunologist;Immunotherapy;Internal Ribosome Entry Site;Knowledge;Left;Malignant Neoplasms;Mediating;Messenger RNA;Molecular;Monoclonal Antibodies;Neoplasm Metastasis;Oncogenic;Oncologist;Outcome Study;Pathogenesis;Pathologist;Patients;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Polyribosomes;Positioning Attribute;Process;Property;Protein Biosynthesis;Proteins;Public Health;RNA;RNA Helicase;Reporting;Research;Resistance;Role;Signal Pathway;Signal Transduction;Snails;T-Lymphocyte;Testing;Therapeutic;Transact;Translating;Translation Initiation;Translational Regulation;Translations;Treatment Efficacy;Tumor Immunity;Tumor-Infiltrating Lymphocytes;United States;Woman;Work;anti-PD-1;base;cancer cell;clinically relevant;colon cancer patients;colorectal cancer progression;colorectal cancer treatment;effective therapy;effectiveness evaluation;experience;genetic corepressor;improved;in vivo;inhibitor/antagonist;innovation;insight;kinase inhibitor;mTOR Inhibitor;men;metastatic colorectal;metastatic process;mouse model;novel;novel strategies;novel therapeutics;patient derived xenograft model;polysome profiling;programmed cell death ligand 1;protein complex;recruit;response;silvestrol;targeted treatment;therapeutic target;treatment response;tumor;tumor growth


application_id: 10063547
project_number: 5R01HL141103-03
administering_ic: NHLBI
award_notice_date: 2020-11-30
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: 2022-10-31
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: 2020-11-01
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/antagonist;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: 10063070
project_number: 5R01NS110169-03
project_title: Regulation of swallow and the effects of high cervical spinal cord injury
administering_ic: NINDS
award_notice_date: 2020-12-28
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: NS
serial_number: 110169
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2018-12-15
project_end_date: 2023-11-30
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 10816268
contact_pi: PITTS, TERESA G
other_pis: Not Applicable
congressional_district: 03
department: NEUROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT. Swallow is a basic critical behavior necessary for the movement of liquids and food from themouth through the esophagus to the stomach. When swallow is abnormal (dysphagia) liquid and food mayenter the larynx and trachea (aspiration) causing subsequent pneumonia. While the collective literature reportsa large variance in the incidence of dysphagia a 2017 prospective study shows disordered swallow productionin 76% of cSCI patients. Our long-term goal is to understand the mechanism(s) of dysphagia following cSCIand to develop novel therapies which have a high likelihood of clinical utility. Our central hypothesis is thatspinal circuits are critical for the successful execution of swallow. Specifically the central pattern generator(CPG) in the brainstem controlling this vital airway protective behavior is connected to circuitry in the cervicalspinal cord. Our preliminary data demonstrates that acute C2 and C3 hemisections depress diaphragm activitywhich results in positive intra-thoracic pressure during swallow. These lesions also increased upper airwaymuscle recruitment considerably (~200-800%) with a total loss of sequential muscle recruitment during thepharyngeal phase of swallow. Additionally a high dose of a 5-HT1A agonist increased diaphragm activity duringswallow which was accompanied by restoration of upper airway sequential activation. Guided by strongpreliminary data our central hypothesis will be tested with the following aims: Aim 1: Identify the effects ofcervical spinal cord disruption on the swallow motor pattern; and Aim 2: Determine the therapeutic efficacy of8-OH-DPAT (5-HT1A agonist) on recovery of swallow function after acute spinal hemisection. We will useelectrophysiology techniques to determine the effects of C2 C3 and C4 hemisection on execution of swallow.We will also determine changes in swallow function with a combined protocol of C2 hemisection and medialmyelotomy. The therapeutic effectiveness of 8-OH-DPAT on swallow function will be tested in intact animals aswell as with C2 C3 and C4 hemisections. To ensure the treatment effects are related to 5-HT1A receptoractivation a series of experiments will also be performed with the 5-HT1A antagonist WAY-100635. Thesestudies will be the first to show in an animal model that loss of cervical spinal pathways has a deleteriouseffect on swallow. Additionally we will provide pre-clinical evidence that a 5-HT1A receptor agonist can be usedto treat swallow impairments which will be the first of its kind for dysphagia. This information will educate theclinical community about risk of dysphagia after cSCI and provide options for novel interventions.

project_terms:
Acute;Address;Agonist;Animal Model;Animals;Autoreceptors;Behavior;Brain Stem;Bypass;Cause of Death;Cervical;Cervical spinal cord injury;Cervical spinal cord structure;Clinical;Clinical Treatment;Communities;Coughing;Data;Deglutition;Deglutition Disorders;Depressed mood;Dose;Electrophysiology (science);Ensure;Enteral Feeding;Esophagus;Felis catus;Fiber;Food;Goals;Health;Impairment;Incidence;Individual;Infusion procedures;Injury;Intervention;Larynx;Lesion;Liquid substance;Literature;Longterm Follow-up;Medial;Mental Depression;Motor;Movement;Muscle;Oral;Oral cavity;Oropharyngeal;Patient Selection;Patients;Pattern;Performance;Pharyngeal structure;Phase;Pneumonia;Population;Prevalence;Production;Prospective Studies;Protocols documentation;Quality of life;Receptor Activation;Recovery;Regulation;Reporting;Respiratory Diaphragm;Retrospective Studies;Risk;Series;Serotonin;Serotonin Receptor 5-HT1A;Spinal;Spinal cord injury patients;Stomach;Techniques;Testing;Therapeutic;Trachea;Treatment Efficacy;Tube;Work;airway muscle;artery infusion;central pattern generator;experimental study;improved;insight;novel;novel therapeutics;nutrition;pre-clinical;preservation;pressure;prevent;protective behavior;recruit;rehabilitation strategy;response;restoration;spinal pathway;therapeutic effectiveness;thoracic pressure;treatment effect;vertebral artery

public_health_relevance:
PROJECT NARRATIVEThis study focuses on the importance of spinal circuitry for swallow production the effects of disrupting thiscircuitry and a potential swallow therapeutic. Dysphagia (abnormal swallow) is a critical health problem thatcan cause pneumonia which is a primary cause of death in patients with cervical spinal cord injury.


application_id: 10061521
project_number: 5R01AG061898-03
administering_ic: NIA
award_notice_date: 2020-12-09
opportunity_number: PAR-18-175
application_type: 5
activity_code: R01
ic: AG
serial_number: 061898
program_official: CLARKE, AKANNI YAO
project_start_date: 2019-02-01
project_end_date: 2023-11-30
study_section: Special Emphasis Panel[ZRG1-BBBP-Z(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
budget_start_date: 2020-12-01
project_title:
First-in-human SAD & MAD trials for MW151 a novel Alzheimer's disease drug candidate that attenuates proinflammatory cytokine dysregulation

project_abstract:
ABSTRACTThere are no approved disease-modifying drugs to prevent delay or slow disease progression of Alzheimer'sdisease (AD) and related dementias. The overwhelming majority of AD clinical trials targeted the beta-amyloidpathway with disappointingly ineffective outcomes in >99% of the studies. Therefore there is an urgent need todiversify the portfolio of disease modifying approaches that are distinct from prior art. Our unbiased discoverystrategy for the campaign described here focused on targeting a particular form of dysregulated inflammationinjurious proinflammatory cytokine overproduction in the brain that is a key contributor to synaptic dysfunctionneurodegeneration and cognitive decline in diverse neurodegenerative diseases. We seek funding for therequired phase 1 clinical safety studies of MW01-2-151SRM (=MW151). MW151 is a novel CNS-penetrantorally bioavailable small molecule candidate that selectively suppresses stressor-induced proinflammatorycytokine overproduction. MW151 ameliorates synaptic damage and cognitive impairment at low doses indiverse animal models where proinflammatory cytokine dysregulation is established as a contributor to diseaseprogression. MW151 has no liabilities in investigational new drug (IND)-enabling safety pharmacology andtoxicology tests such as respiratory and cardiovascular safety pharmacology rat and dog 28-day repeatadministration toxicology and genotoxicity. The low risk aspect of MW151 safety is reinforced by an analogdeveloped for the demanding intravenous route of administration and its progression through phase 1a andpromising status in phase 1b. We hypothesize that MW151 will be a successful oral candidate for futuretreatment of individuals with MCI/AD. This application seeks to progress through the required first-in-human(FIH) safety clinical trials. Our specific aims are:Aim 1: Conduct a first-in-human (FIH) phase 1a single ascending dose (SAD) study. This study will determinesafety and tolerability maximum tolerated dose and pharmacokinetics (PK) of MW151 in healthy adultvolunteers. Plasma cytokine levels will be measured to provide baseline data for a future exploratorypharmacodynamic (PD) endpoint in phase 2a clinical trials.Aim 2: Conduct a phase 1b multiple ascending dose (MAD) study of MW151. This study will determine safetyand tolerability maximum tolerated dose and PK of MW151 in healthy adult volunteers. In addition a cohort ofelderly healthy subjects and exploratory PD inflammatory cytokine endpoints in CSF will be included.Aim 3: Prepare clinical protocol and investigators brochure for a future phase 2a clinical trial of MW151 in earlyAD. Based on the outcomes of the proposed phase 1 studies we will design a phase 2a trial and prepare thedocuments required. This will allow immediate progress to future FIP studies for AD.Overall MW151 represents a unique opportunity for development as a first-in-class disease-modifyingtherapeutic.

project_terms:
Address;Adult;Age;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease related dementia;Alzheimer's disease therapeutic;Amyloid beta-Protein;Animal Model;Animals;Anti-Inflammatory Agents;Arts;Attenuated;Award;Bioavailable;Brain;Canis familiaris;Cardiovascular system;Central Nervous System Diseases;Characteristics;Chemicals;Clinical;Clinical Investigator;Clinical Protocols;Clinical Trials;Coenzyme A;Data;Development;Disease;Disease Progression;Dose;Drug Kinetics;Elderly;Exhibits;Formulation;Functional disorder;Funding;Future;Homeostasis;Human;Immunosuppression;Impaired cognition;Individual;Inflammation;Inflammatory;Injury;Intravenous;Investigational Drugs;Maximum Tolerated Dose;Measures;Metabolic;Modeling;Nerve Degeneration;Neurodegenerative Disorders;Neuroglia;Oral;Outcome;Pamphlets;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Pharmacology and Toxicology;Phase;Phase I Clinical Trials;Phase Ib Clinical Trial;Plasma;Population;Predisposition;Public Health;Rattus;Risk;Route;Safety;Synapses;Testing;Therapeutic;Toxicology;analog;base;clinical development;cohort;cytokine;design;dose information;drug candidate;effective therapy;first-in-human;genotoxicity;healthy volunteer;neuroinflammation;novel;novel therapeutic intervention;phase 1 study;physical property;pre-clinical;preclinical development;prevent;respiratory;restoration;safety study;small molecule;stressor;success;volunteer

public_health_relevance:
NARRATIVESuccess in the proposed first-in-human phase 1 clinical trial in healthy adult volunteers will provide safety anddosing information required to progress to the next stage of development for MW151 a promising brain-penetrant small molecule drug candidate that targets dysregulated inflammation in the brain. MW151 has thepotential to be a first-in-class disease modifying therapy for MCI/Alzheimers disease.


application_id: 10058844
project_number: 5R01GM121660-05
project_title: Nucleophilic halogenation reagents
administering_ic: NIGMS
award_notice_date: 2021-06-07
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: GM
serial_number: 121660
program_official: YANG, JIONG
project_start_date: 2016-12-06
project_end_date: 2022-11-30
study_section: Synthetic and Biological Chemistry A Study Section[SBCA]
contact_pi_person_id: 1979376
contact_pi: HAMMOND, GERALD B
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryMost if not all fluorinating reagents (electrophilic or nucleophilic) are actually made fromhydrogen fluoride (HF). However the gaseous and corrosive nature of HF excludes it fromworking laboratories where special equipment and training are not available. The complexes ofHF with organic bases like pyridine-HF complex (Olah's reagent) and triethylamine-HF complexhave been explored extensively as nucleophilic sources of fluorine but use of these organicbases reduce the acidity of the system and may interfere with many metal catalysts. So far thereis no HF-based nucleophilic fluorination reagent that works well in acid or transition metalcatalyzed reactions. Our primary goal is to develop a new generation of HF-based nucleophilicfluorination reagents that is compatible with acids and metal catalysts based on a rationaldesign. The same strategy can also be used for new HX (X = Cl Br I)-based halogenationreagents.Hydrogen bonding rather than an ionic interaction has been identified as the major interactionbetween HF and an organic base in complexes such as pyridine-HF (Olah's reagent). To reducethe volatility of an HF complex (make it a liquid or solid at room temperature) we have to use arelatively good hydrogen bonding acceptor (HBA) to complex with HF. Our hypothesis is: astrong (good) hydrogen bonding acceptor is not necessarily a strong base (Brnsted orLewis base). In this way a compound that serves as good hydrogen bonding acceptor (betterthan pyridine or triethylamine) but is less basic is expected to form a less volatile complex. Anddue to the low basicity of this HBA the resulting HBA-HF complex will be compatible with acidcatalysts or mediators. In this manner we may achieve unprecedented reactivity and selectivityin HF-participating reactions.The first part of our research is the preparation of HBA-HX complexes. We are seeking`anomaly' HBAs that is good hydrogen bond acceptors but weak Brnsted bases. Thequantitative descriptor of hydrogen bond basicity and Brnsted basicity shown in Figure 1(based on Laurence and co-workers' database of hydrogen-bond basicity) is our primaryguideline for the selection of suitable hydrogen bonding acceptors.The nucleophilic fluorination reagents proposed and the methodologies for their use will enablediverse-oriented stereo- and regio-selective synthesis of fluoroamines fluorohydrinsfluoroaminoacids fluorinated aliphatic alkenes cyclic and heterocyclic compounds throughnew synthetic protocols such as tandem HF-addition-metathesis HF trapping in cationiccascade reactions strain-release nucleophilic fluorinations in-situ electrophilic fluorineformation Markovnikov and anti-Markovnikov hydrofluorinations. A similar strategy will be usedto develop designer-HX based (X = Cl Br I) halogenation reagents.One of our reagents (DMPU-HF) is already commercially available and we will commercializeother newly developed reagents to make our methods available to medicinal chemistsworldwide.

project_terms:
Acidity;Acids;Agrochemicals;Alkenes;Amino Acids;Biological;Cations;Chemicals;Complex;Corrosives;Databases;Descriptor;Ethers;Fluorine;Generations;Goals;Guidelines;Heterocyclic Compounds;Hydrogen;Hydrogen Bonding;Hydrogen Fluoride;In Situ;Laboratories;Liquid substance;Mediating;Mediator of activation protein;Metabolic;Metals;Methodology;Methods;Nature;Pattern;Periodicity;Pharmaceutical Chemistry;Pharmaceutical Preparations;Preparation;Property;Protocols documentation;Reaction;Reagent;Research;Resistance;Solid;Source;Special Equipment;System;Temperature;Transition Elements;Work;alkalinity;base;case-by-case basis;catalyst;cyclic compound;design;drug discovery;equipment training;halogenation;organic base;pyridine;stereochemistry;triethylamine;virtual

public_health_relevance:
NarrativeBecause of fluorine's unique propertiessmall size and metabolically resistant C-F bond--theselective substitution of hydrogen by fluorine constitutes a key strategy in drug discovery. Inmost commercial drugs and agrochemicals fluorine is attached to aromatic moieties. Indeedthe chemical space of non-aromatic fluorine in medicinal chemistry is very narrow becausefluorine is not an easy atom to introduce in aliphatic or cyclic systems. Fluoroaliphatic orfluoroheterocycles are currently prepared on a case-by-case basis using boutique-typereactions. Our primary goal is to develop of a new generation of HF-based nucleophilicfluorination reagents that are compatible with acids and metal catalysts based on rational designso as to open the door for reactivities and selectivities hitherto unknown. The nucleophilicfluorination reagents proposed and the methodologies for their use will enable diverse-orientedstereo- and regio-selective synthesis of fluoroamines fluorohydrins fluoroaminoacidsfluorinated aliphatic alkenes cyclic and heterocyclic compounds through new syntheticprotocols such as tandem HF-addition-metathesis HF trapping in cationic cascade reactionsstrain-release nucleophilic fluorinations in-situ electrophilic fluorine formation Markovnikov andanti-Markovnikov hydrofluorinations. A similar strategy will be used to develop designer-HXbased (X = Cl Br I) halogenation reagents.


application_id: 10058531
project_number: 1R01NS114404-01A1
project_title: BMAL1/ARNTL plays a critical non-circadian role in secondary tissue damage after contusive SCI
administering_ic: NINDS
award_notice_date: 2020-08-07
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: NS
serial_number: 114404
suffix: A1
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2020-08-15
project_end_date: 2025-05-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 7612305
contact_pi: HETMAN, MICHAL
other_pis: SARASWAT, SUJATA OHRI;WHITTEMORE, SCOTT R
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
ARNTL gene;Acute;Affect;Agonist;Antioxidants;Apoptosis;Apoptotic;Atherosclerosis;Biological Process;Blood;Blood coagulation;Brain;Cardiovascular Diseases;Cell Count;Cell Proliferation;Cells;Cervical spinal cord injury;Cessation of life;Circadian Dysregulation;Circadian Rhythms;Clinical;Complex;Contusions;Cues;Down-Regulation;Drug Targeting;Endothelial Cells;Endothelium;Enhancers;Extravasation;Feedback;Functional disorder;Gene Expression;Genes;Genetic Transcription;Genetic Translation;Health;Hemoglobin;Hemorrhage;Homeostasis;Human;Impairment;Inflammation;Injury;Intervention;Knock-out;Light;Locomotor Recovery;Longevity;Malignant Neoplasms;Mediating;Mediator of activation protein;Mental Depression;Metabolic syndrome;Microglia;Modeling;Molecular;Mus;Mutant Strains Mice;Natural Immunity;Nerve Degeneration;Oligodendroglia;Organ;Outcome;Pathogenesis;Pathology;Periodicity;Permeability;Pharmacology;Phosphorylation;Play;Protein Kinase;Proteins;Proteolipids;Recovery;Recovery of Function;Regulation;Regulator Genes;Reporting;Research;RiboTag;Role;Secondary to;Signal Transduction;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;TNFRSF10B gene;Technology;Testing;Thoracic spinal cord structure;Time;Tissues;Toxic effect;Transcription Repressor;Vascular Diseases;adaptive immunity;angiogenesis;biological adaptation to stress;cadherin 5;cancer cell;cell type;circadian;cytotoxic;effective therapy;endoplasmic reticulum stress;experimental study;feeding;improved;improved outcome;inhibitor/antagonist;insight;loss of function;macrophage;neuroinflammation;new therapeutic target;novel;selective expression;tissue injury;transcription factor;transcription factor CHOP;transcriptome sequencing;translation factor;white matter;white matter damage


application_id: 10058267
project_number: 5R01DA033862-08
project_title: Effect of structural interventions on substance use and HIV/HCV risk among rural PWUD
administering_ic: NIDA
award_notice_date: 2021-02-05
opportunity_number: PA-15-003
application_type: 5
activity_code: R01
ic: DA
serial_number: 033862
program_official: HAEGERICH, TAMARA
project_start_date: 2012-09-01
project_end_date: 2022-05-31
study_section: Behavioral and Social Consequences of HIV/AIDS Study Section[BSCH]
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER R
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:
DESCRIPTION (provided by applicant): The overarching goal of this renewal application (R01DA033862) is to determine the influence of structural interventions on engagement in risk reduction and health promotion activities among rural Appalachian drug users. Results from the three-year R01 that the investigators seek to continue reveal an ever-changing landscape of prescription drug abuse; an epidemic that is still in its infancy. Unlike many rural and suburban areas there is little evidence for the transition to heroin abuse. In this cohort there has been  marked shift from abuse of OxyContin(r) (extended-release oxycodone) to immediate release oxycodone to more recently buprenorphine and gabapentin-containing products. In addition rates of HCV prevalence and incidence are high especially given the population density of rural Appalachia. Given the syndemic of opioid abuse and infectious disease transmission two structural interventions are particularly relevant to this population of rural people who use drugs(PWUD). Medicaid (MC) expansion (under the Affordable Care Act [ACA]) and syringe access programs (SAP) are two structural interventions that may allow for increased engagement in health promotion among PWUD but are likely heavily influenced by individual network and community-level factors. Utilizing Latkin's Dynamic Social Systems model and leveraging the extant highly successful cohort of rural PWUD the aims include: 1) examining how dynamic factors of these structural interventions influence longitudinal trends in illicit and prescriptiondrug abuse; 2) determining the influence of these structural interventions on HIV/HCV incidence and engagement in risk reduction; and 3) assessing the influence of these structural interventions on uptake of substance abuse treatment. This study is highly significant given that understanding the mechanisms by which these specific structural interventions influence health promotion is key to improving public health in rural Appalachia. Substance abuse and HCV are two of the most important if not the most important health issues facing this region already plagued with marked health disparities. Using innovative measures of network and geospatial risk as well as conjoint analysis and multilevel longitudinal statistical models results will notonly inform development of interventions that optimize uptake and utilization of risk reduction services such as SAP and substance abuse treatment but may inform policies surrounding further implementation of health promotion programs in the rural U.S.

project_terms:
Accounting;Address;Affordable Care Act;Area;Behavior;Biological Models;Buprenorphine;Communicable Diseases;Communities;Complement;County;Data;Data Collection;Development;Disease Outbreaks;Disease Outcome;Drug abuse;Drug user;Effectiveness;Enrollment;Epidemic;Frequencies;Goals;HIV;HIV/HCV;Health;Health Promotion;Hepatitis C Incidence;Hepatitis C Prevalence;Hepatitis C Therapy;Hepatitis C Transmission;Hepatitis C virus;Heroin Abuse;Illicit Drugs;Indiana;Individual;Injecting drug user;Injections;Insurance Coverage;Intervention;Kentucky;Laws;Literature;Longitudinal trends;Measures;Medicaid;Modeling;Natural experiment;Nature;Needle Sharing;Outcome;Oxycodone;Participant;Personal Communication;Pharmacoepidemiology;Policies;Population;Population Density;Prevalence;Public Health;Research;Research Personnel;Resources;Risk;Risk Behaviors;Risk Reduction;Rural;Rural Appalachia;Rural Population;Services;Statistical Models;Sterility;Structure;Substance Use Disorder;Substance abuse problem;Syringes;Time;Treatment outcome;Uninsured;cohort;disease transmission;drug of abuse;follow-up;gabapentin;health disparity;improved;infancy;innovation;opioid abuse;opioid injection;prescription drug abuse;prescription opioid;programs;public health relevance;response;rural area;social;social metrics;substance abuse treatment;substance use;suburb;success;therapy design;therapy development;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Both MC expansion and SAPs have great potential to improve substance abuse and infectious disease outcomes among rural PWUD/PWID; however first we must understand the mechanisms by which these SIs are influencing outcomes. Therefore results may inform ways in which to optimize uptake and utilization of structural interventions as well as to inform policies surrounding further implementation of SIs that will improve public health outcomes in rural Appalachia.


application_id: 10058239
project_number: 5R13AI129382-04
project_title: Autumn Immunology Conference
administering_ic: NIAID
award_notice_date: 2021-10-19
opportunity_number: PA-18-648
application_type: 5
activity_code: R13
ic: AI
serial_number: 129382
program_official: COOPER, SUSAN F
project_start_date: 2016-11-01
project_end_date: 2022-10-31
study_section: ZAI1-AZ-D(S1)
contact_pi_person_id: 1864845
contact_pi: SNOW, ERNEST CHARLES
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This proposal requests funds to support the annual Autumn ImmunologyConference (AIC). The AIC was established in 1972 to promote Immunologyresearch in the upper Midwest region of the United States. The conferenceprovides a forum for the exchange of scientific data and ideas fosterscollaboration between scientists at different institutions and provides careerdevelopment and education opportunities to a diverse group of individuals withan interest in Immunology. The scientific focus of the meeting is intentionally broad; itincludes basic Immunology and related biomedical fields such as cancer biologypathogenesis vaccine development inflammation and autoimmunity. Special emphasisis given to providing pre- and post-doctoral trainees with an opportunity to sharetheir data participate in scientific and career discussions and to meet andexchange ideas with established investigators. The organizers also seek to attractinvolve and promote the careers of women and racial/ethnic minorities that areunderrepresented in science. These objectives are met by inviting a group ofoutstanding Immunology researchers (12-13 each year) from around the world to speakat the meeting. All presenters present both an oral and poster presentation in sessionsthat are designed to provide the greatest opportunity for feedback to the trainees.Finally scholarship programs career development workshops and mentoringluncheons promote the inclusion of minority scientists and seek to recruitundergraduates into the discipline of Immunology.

project_terms:
Address;Allergic Disease;Applied Research;Autoimmunity;Award;Basic Science;Cancer Biology;Collaborations;Communicable Diseases;Data;Discipline;Education;Educational workshop;Equilibrium;Feedback;Fostering;Funding;Gender;Goals;Grant;Immune System Diseases;Immunology;Individual;Inflammation;Institution;Mentors;Midwestern United States;Mission;National Institute of Allergy and Infectious Disease;Oral;Participant;Pathogenesis;Postdoctoral Fellow;Preparation;Public Health;Request for Applications;Request for Proposals;Research;Research Personnel;Scholarship;Science;Scientist;Travel;Underrepresented Minority;United States;United States National Institutes of Health;Vendor;Woman;career;career development;design;interest;meetings;minority scientist;posters;pre-doctoral;prevent;programs;racial and ethnic;recruit;symposium;undergraduate student;vaccine development

public_health_relevance:
Project NarrativeHigh quality scientific conferences are vital to the public health mission of theNIH. This application requests funding for an annual scientific conference calledthe Autumn Immunology Conference. The purpose of this meeting is toexchange and disseminate information and to explore contemporary problems inthe field of Immunology. Thus it is consistent with the fiscal and programmaticpriorities of the National Institutes of Allergy and Infectious Diseases (NIAID)which is to conduct and support basic and applied research to better understandtreat and ultimately prevent infectious immunologic and allergic diseases.


application_id: 10058003
project_number: 1R21NS114982-01A1
project_title: Combined DDE MRI and Electrophysiology Prediction of Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2020-07-30
opportunity_number: PA-18-358
application_type: 1
activity_code: R21
ic: NS
serial_number: 114982
suffix: A1
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2020-08-01
project_end_date: 2022-07-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 6066223
contact_pi: BOAKYE, MAXWELL
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
The International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) neurological examand magnetic resonance imaging (MRI) the prevailing methods to assess severity of injury and predictprognosis suffer from significant limitations and often fail to accurately predict long-term outcome inindividuals and neither provides information on the functional and physiological viability of residual cord tissuealtered by the injury. Using standard MRI physicians may grossly under/overestimate the degree of intrinsiccord injury or functional connectivity of cord tissue. Thus these widely used clinical and radiologicalassessments are often unable to distinguish between incomplete and complete injuries and more sensitivedeterminants of long-term outcomes are critically needed. Diffusion tensor imaging (DTI) is an MRI techniquethat has shown promise in estimating the degree of axonal injury in acutely injured cord in both animal andlimited human studies. However fractional anisotropy (FA) a key DTI parameter that is reduced in acute SCIis confounded by edema and hemorrhage making its interpretation and reliability problematic. A novel diffusionMRI alternative double diffusion encoding (DDE) has shown high sensitivity to axonal injury with minimalcontribution from edema and accurately predicts outcomes in a rat SCI model. However rodent models of SCIare limited and it remains uncertain if DDE performs as reliably in a large animal model more faithfullyreplicating human SCI. Furthermore the relationship between DDE and electrophysiological activity which iscritical to establishing the functional integrity or neural conduction block across the injury site has not beenexplored. Our goal is to enhance the translational applicability of DDE using a validated large animal porcinecontusion model currently being used by our group. Preliminary MRI data from our group using this modelmatches both the quality and challenges of human SCI imaging. To relate DDE-derived axonal injury index(ADC||) with neural function we will conduct both DDE assessments and intraoperative D-wave epiduralelectrophysiology in a porcine contusion SCI model with mild (n=6) and severe (n=6) injury. Successful projectcompletion will lead to direct translation to human SCI patient studies with the long-term goal of improvingpatient outcomes from such a devastating injury.

project_terms:
Acute;Anatomy;Animal Model;Animals;Anisotropy;Axon;Behavioral;Bladder;Classification;Clinical/Radiologic;Conscious;Contusions;Corticospinal Tracts;Craniocerebral Trauma;Data;Diffusion;Diffusion Magnetic Resonance Imaging;Dimensions;Edema;Electrophysiology (science);Family suidae;Functional disorder;Goals;Hemorrhage;Histology;Human;Image;Imaging Techniques;Individual;Inflammation;Injury;International;Length;Lesion;Magnetic Resonance Imaging;Measurement;Measures;Methods;Modeling;Nervous System Physiology;Nervous System Trauma;Neural Conduction;Neurologic;Neurological outcome;Neurophysiology - biologic function;Outcome;Patient-Focused Outcomes;Patients;Physicians;Physiological;Rattus;Recovery;Research;Residual state;Rodent Model;Role;Sedation procedure;Severities;Site;Sphincter;Spinal;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Spinal cord injury patients;Stimulus;Structure;Thoracic Injuries;Tissues;Translating;Urodynamics;anatomic imaging;axon injury;clinical translation;experimental study;functional outcomes;gray matter;imaging approach;imaging system;improved;indexing;individual patient;injured;novel;outcome forecast;outcome prediction;pressure;prognostic;response;severe injury;translation to humans;urologic;white matter

public_health_relevance:
The overall goal of this application is to enhance the ability to predict outcomes in acute traumatic SCI. Theproposed experiments will capitalize on our expertise using a large animal model of SCI to establish therelationship between quantitative diffusion MRI metrics of axonal injury histology electrophysiological functionand long-term neurological outcomes. Successful completion of the project will lead to direct translation tohuman SCI patient studies with the long-term goal of improving acute management and patient outcomes fromsuch a devastating injury.


application_id: 10056416
project_number: 2P50AA024337-06
project_title: Probiotic-derived nano-particles in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2021-06-08
opportunity_number: RFA-AA-20-001
application_type: 2
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: Special Emphasis Panel[ZAA1 DD (50)]
subproject_number: 8880
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Agonist;Alcohol-Induced Disorders;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Aryl Hydrocarbon Receptor;Bacteria;Bacterial Translocation;Bilophila wadsworthia;Biological Markers;Cells;Chronic;Clinical;Development;Digestive System Disorders;Disease;Endocytosis;Environment;Epithelial;Epithelial Cells;Evaluation;Experimental Models;Functional disorder;Future;Ginger;Growth;Homeostasis;Intestines;Lead;Liver diseases;Mediating;Mus;National Institute on Alcohol Abuse and Alcoholism;Natural regeneration;Outcome;Oxidative Stress;Pathogenicity;Pathway interactions;Patients;Play;Prevention;Prevention therapy;Probiotics;Production;Receptor Signaling;Role;Sampling;Signal Transduction;Testing;Therapeutic Effect;Tight Junctions;Tryptophan;Up-Regulation;alcohol abuse therapy;alcohol exposure;aryl hydrocarbon receptor ligand;base;clinical application;disorder prevention;dysbiosis;exosome;gut colonization;gut microbes;gut microbiota;improved;inflammatory disease of the intestine;interleukin-22;intestinal barrier;intestinal epithelium;islet;metabolomics;microbial;mouse model;nanoparticle;nutrition;organ injury;pathogenic bacteria;prebiotics;prevent;probiotic therapy;programs;protective effect;transcytosis


application_id: 10056414
project_number: 2P50AA024337-06
administering_ic: NIAAA
award_notice_date: 2021-06-08
opportunity_number: RFA-AA-20-001
application_type: 2
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: Special Emphasis Panel[ZAA1 DD (50)]
subproject_number: 8878
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-11-01
project_terms:
Address;Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Attenuated;Bacteria;Biological Markers;Butyrates;Clinical;Clinical Data;Clinical Research;Collection;Data;Development;Dietary Intervention;Dietary Supplementation;Disease Marker;Enteral;Exhibits;Fatty Liver;Funding;Hepatic;Histone Deacetylase Inhibitor;Human;Immune;Inflammation;Inflammatory;Injury;Interleukin-17;Intervention;Knowledge;Liver;Liver diseases;Mediating;Mus;Neutrophil Infiltration;Nutritional;Pathogenesis;Pathogenicity;Patient Recruitments;Patients;Play;Preventive treatment;Probiotics;Prodrugs;Production;Resources;Role;Severity of illness;T-Lymphocyte;Testing;Therapeutic;Therapeutic Intervention;Transplantation;United States National Institutes of Health;base;cohort;dietary;dysbiosis;efficacy evaluation;efficacy testing;evidence base;fecal transplantation;gut bacteria;gut dysbiosis;gut-liver axis;human model;human study;immune activation;innovation;insight;liver development;liver injury;microbial;microbial community;mouse model;nutrition;organ injury;preclinical study;prevent;problem drinker;programs;response;systemic inflammatory response;targeted treatment;therapeutic target;treatment strategy;tributyrin


application_id: 10056413
project_number: 2P50AA024337-06
project_title: Role of n3 PUFAs and inflammation-resolving lipid mediator RvD1 in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2021-06-08
opportunity_number: RFA-AA-20-001
application_type: 2
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: Special Emphasis Panel[ZAA1 DD (50)]
subproject_number: 8877
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA A.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Attenuated;Bacteria;Biological Response Modifiers;Chronic;Cytokine Signaling;Data;Development;Diet;Dietary Fats;Dietary Fatty Acid;Dietary Supplementation;Disease Progression;Down-Regulation;Effectiveness;Engineering;Ethanol;Experimental Animal Model;FDA approved;FPR2 gene;Fatty acid glycerol esters;Functional disorder;Health;Heavy Drinking;Hepatic;Hepatocellular Damage;Homeostasis;Host Defense;Human;Immune;Immune response;Impairment;In Vitro;Individual;Inflammation;Inflammatory;Intestinal permeability;Intestines;Kentucky;Linoleic Acids;Liver;Mediating;Mediator of activation protein;Microbe;Modeling;Molecular;Mus;Nuclear;Nutritional;Organoids;Pathogenesis;Patients;Phagocytosis;Phenotype;Plants;Plasma;Play;Production;Prognosis;Research;Resolution;Rodent;Role;Sampling;Severities;Severity of illness;Signal Transduction;Survivors;Technology;Testing;Therapeutic Agents;Tissues;Transcript;Transgenic Organisms;Translating;Whole Blood;attenuation;base;cytokine;exosome;gut-liver axis;improved;in vivo evaluation;inflammatory disease of the intestine;intestinal barrier;lipid mediator;liver inflammation;liver injury;macrophage;monocyte;nanoparticle;novel;novel therapeutic intervention;nutrition;organ injury;peripheral blood;preclinical study;receptor;repaired;systemic inflammatory response;therapeutic effectiveness;tissue repair


application_id: 10056411
project_number: 2P50AA024337-06
project_title: The Role of Nutrition in the Development/Progression of Alcohol-Induced Organ Injury
administering_ic: NIAAA
award_notice_date: 2021-06-08
opportunity_number: RFA-AA-20-001
application_type: 2
activity_code: P50
ic: AA
serial_number: 024337
program_official: MURRAY, GARY
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: Special Emphasis Panel[ZAA1 DD (50)]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Alcohol abuse;Alcoholic Liver Diseases;Alcohols;Brain;Broccoli - dietary;Butyrates;Cause of Death;Chronic;Collaborations;Communities;Country;Development;Dietary Fats;Dietary Intervention;Education;Enhancers;Epigenetic Process;Ethanol;FDA approved;Faculty;Feces;Fetal Alcohol Spectrum Disorder;Fetal Alcohol Syndrome;Fostering;Functional disorder;Funding;Future;Goals;Grant;Health Care Costs;Impairment;Individual;Industry;Injury;Institution;Interdisciplinary Study;Intervention;Intestines;Knowledge;Lactobacillus;Lead;Lipids;Mediating;Mediator of activation protein;Morbidity - disease rate;National Institute on Alcohol Abuse and Alcoholism;Neural Crest Cell;Nutritional;Organ;Pathogenesis;Prevention;Prevention approach;Prevention therapy;Preventive;Probiotics;Proteomics;Research;Research Personnel;Resources;Role;School Dentistry;Signal Transduction;Sulforaphane;Therapeutic Intervention;United States;United States National Institutes of Health;Universities;Volatile Fatty Acids;alcohol abuse therapy;alcohol exposure;alcohol intervention;alcohol research;alcohol use disorder;base;cofactor;cohesion;college;exosome;gut bacteria;gut-liver axis;high school;improved;inflammatory disease of the intestine;intestinal barrier;liver inflammation;metabolome;metabolomics;mortality;mouse model;multidisciplinary;nanoparticle;new therapeutic target;novel;nutrition;organ injury;prevent;teratogenesis;therapeutic effectiveness;therapeutic target


application_id: 10056220
project_number: 5R01ES016893-14
project_title: Particulate Cr(VI) Toxicology in Human Lung Epithelial Cells and Fibroblasts
administering_ic: NIEHS
award_notice_date: 2020-10-29
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: ES
serial_number: 016893
program_official: TYSON, FREDERICK L
project_start_date: 2009-07-06
project_end_date: 2021-10-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 6094413
contact_pi: WISE, JOHN PIERCE
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYLung cancer continues to be the leading cause of cancer death in the U.S. One of the key strategies to combatingit is to better understand its causes. Hexavalent chromium [Cr(VI)] is a human lung carcinogen of major publichealth concern because exposure to it is common in the workplace and in the general environment. Our studyfocuses on investigating the mechanisms of Cr(VI)-induced carcinogenesis which are currently unknown. Inparticular this work focuses on the particulate Cr(VI) compounds because they are the most potent Cr(VI)carcinogens. Recent studies indicate particulate Cr(VI) induces chromosome instability and causes cells toevade DNA double strand break repair which are hallmarks of human lung cancer. Thus this research focuseson how particulate Cr(VI) induces cells to evade DNA double strand break repair leading to chromosomeinstability and carcinogenesis. Our data show prolonged exposure to particulate Cr(VI) specifically impacts theeffector arm of homologous recombination (HR repair) disrupting RAD51 nucleoprotein filament formation lossof which can cause chromosome instability. Therefore the goal of this research is to characterize this impact onHR repair and the underlying changes in order to understand the mechanisms involved. Our hypothesis is:particulate Cr(VI) disrupts the underlying mechanisms of RAD51 nucleoprotein filament formation inactivatingHR repair of Cr(VI)-induced DNA breaks resulting in CIN and neoplastic transformation. We will test thishypothesis through three interrelated specific aims. Aim 1 will determine how Cr(VI) impacts BRCA2 DSS1RAD51B RAD51C RAD51D RPA and XRCC2 to disrupt RAD51 nucleoprotein filament formation in humanlung cells. Aim 2 determines the persistence and cellular heritability of disrupted RAD51 filament formation inhuman lung cells neoplastically transformed by Cr(VI) and the protein levels of BRCA2 DSS1 RAD51BRAD51C RAD51D RPA and XRCC2 in lung tumors from human Cr(VI) workers. Aim 3 determines the impactof Cr(VI) on protein levels of BRCA2 DSS1 RAD51B RAD51C RAD51D RPA and XRCC2 in the lungs andlung tumors of Cr(VI)-exposed animals. Results will lead to the first reports of detailed information of theinteractions of Cr(VI) with the effector arm of HR repair at a cellular and molecular level and the firstcharacterizations of these aspects in neoplastic outcomes including tumors from Cr(VI)-exposed workers.Results will also show which changes are transient and depend on exposure and which changes persist in cellsthat escape cell death and progress to neoplastic outcomes. This research is significant because it provides: 1)An understanding of Cr(VI)s carcinogenic mechanism; 2) Essential information to better assess exposure riskto particulates; and 3) A mechanistic approach for further study of Cr(VI) other metals and lung cancer in general.

project_terms:
Animal Model;Animals;Autopsy;BRCA2 gene;Cancer Etiology;Carcinogens;Cell Death;Cell Nucleus;Cells;Cessation of life;Chemicals;Chromium Compounds;Chromosomal Instability;Cytoplasm;DNA;DNA Double Strand Break;DNA Repair;Data;Disease;Double Strand Break Repair;Dust;Dyes;Environment;Epithelial Cells;Event;Exposure to;Fibroblasts;Filament;Goals;Hazardous Substances;Heritability;Human;Ink;Learning;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Metals;Molecular;Morbidity - disease rate;Neoplastic Cell Transformation;Nuclear;Nucleoproteins;Outcome;Paint;Particulate;Phenotype;Pigments;Proteins;Public Health;RAD51C gene;Rad51 recombinase;Rattus;Reporting;Research;Risk;Structure of parenchyma of lung;Testing;Toxicology;United States;Work;Workplace;XRCC2 gene;arm;carcinogenesis;carcinogenicity;cell growth;chemical carcinogen;chromium hexavalent ion;chromosome loss;fight against;homologous recombination;insight;lung carcinogenesis;neoplastic;neoplastic cell;novel strategies;prevent;protein expression;protein protein interaction;public health relevance;recombinational repair;repaired;response;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE STATEMENTLung cancer is the number one cause of cancer death in the United States. Our study focuses on twohallmarks of lung cancer chromosome instability and evading DNA double strand break repair and advancesour basic understanding of the cellular and molecular mechanisms underlying how Cr(VI) causes theseoutcomes as part of its carcinogenic mechanism. Our findings will help identify new mechanistic insights whichcan spur new potential treatment targets new approaches to reduce and prevent Cr(VI)-induced lung cancerand new insights to better determine safer exposure levels for this major public health concern.


application_id: 10056044
project_number: 1R21NS114771-01A1
administering_ic: NINDS
award_notice_date: 2020-05-12
opportunity_number: PA-18-358
application_type: 1
activity_code: R21
ic: NS
serial_number: 114771
suffix: A1
program_official: AWWAD, HIBAH OMAR
project_start_date: 2020-06-01
project_end_date: 2023-05-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
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_title:
Implementing a novel multimodal technique for monitoring cerebrovascular hemodynamics in mice as a diagnostic and prognostic tool for single and repeated mild TBI

project_abstract:
Project SummaryTraumatic brain injuries (TBIs) are a major societal and public health concern with over 2.8 million TBIsreported each year in the US. Mild TBIs (mTBIs) accounting for over 80% of TBIs can be difficult to diagnose.Because no FDA-approved therapeutic intervention for mTBI exists a period of rest to allow symptomresolution is the primary treatment approach. It is imperative that while symptomatic a person recovering frommTBI avoid sustaining a second mTBI as multiple mTBIs greatly increases the risk for prolonged disability.The period of brain vulnerability after mTBI however extends beyond the resolution of clinical symptomsunderscoring the vital need for accurate assessment of neurophysiological recovery in order to mitigate therisks associated with repeated head injury. Unlike moderate and severe TBI which are typically associatedwith neuron death and vascular disruption mTBI results in more subtle physiological and cellular changessuch as metabolic distress and alterations in cerebral blood flow (CBF). We hypothesize that mTBI inducesacute transient changes in CBF that coupled with metabolic dysregulation form the basis of the window ofvulnerability to repeated mTBI. We predict therefore that a second injury induced during the period of acuteCBF alteration will result in worsened outcome as reflected by greater perturbations in CBF and metabolism.Our group has developed a novel multiple-wavelength speckle contrast diffuse correlation tomography (MW-scDCT) technique that yields non-invasive longitudinal regional mapping of CBF and oxygenation in mice. Wehave validated our technique against established methods and demonstrated its utility in detecting CBFchanges in rodents. In Aim 1 we will first use MW-scDCT to measure cortical and hippocampal CBF andoxygenation after single closed head injury (CHI) to monitor temporal changes and determine the time torecovery. We will then determine whether normalization of CBF is required to prevent synergistic effects of asecond CHI on cerebral hemodynamics. Neurovascular coupling and cerebrovascular reactivity will beassessed at selected time points to inform potential mechanisms underlying CBF changes. Finallyquantitative analysis of cerebrovascular structure and communication will be performed to identify anatomicalplasticity or damage. In Aim 2 a targeted metabolomics approach will be used to identify metabolite profiles incortical tissue and plasma which are unique to mice with single or repeated mTBI. We will further test whetherrestoration of the metabolome coincides with normalization of CBF after mTBI. Such a finding would support adual-pronged approach for assessing concussion recovery through noninvasive CBF monitoring andassessment of plasma metabolite biomarkers. These studies will pair metabolomics with our innovative MW-scDCT technique for monitoring cerebral hemodynamics to provide new insights into the neurophysiologicaldeterminants of the brains vulnerability to repeated mTBI and support the development of diagnostic andprognostic biomarkers for mTBI.

project_terms:
Accounting;Acute;Acute Brain Injuries;Address;Amnesia;Anatomy;Animal Model;Athletic;Bioenergetics;Biological Markers;Blood;Blood Vessels;Blood flow;Brain;Brain Concussion;Cell Death;Cellular Structures;Cerebrovascular Circulation;Cerebrum;Clinical;Clinical Research;Closed head injuries;Cognitive deficits;Communication;Coupled;Craniocerebral Trauma;Detection;Development;Devices;Diagnosis;Diagnostic;Diffuse;Distress;Dizziness;Event;FDA approved;Fingerprint;Functional disorder;Goals;Guidelines;Headache;Health;Hippocampus (Brain);Human;Hyperemia;Image;Imaging Device;Impairment;Individual;Injury;Lead;Light;Maps;Mass Fragmentography;Measurement;Measures;Mediator of activation protein;Metabolic;Metabolism;Methods;Military Personnel;Mitochondria;Modeling;Monitor;Morbidity - disease rate;Mus;Neurologic;Neurologic Dysfunctions;Neurosciences Research;Outcome;Outcome Measure;Pathway interactions;Persons;Photons;Physiological;Plasma;Play;Prognostic Marker;Public Health;Recovery;Reporting;Resolution;Rest;Risk;Rodent;Signal Transduction;Source;Structure;Symptoms;System;Techniques;Testing;Therapeutic Intervention;Time;Tissues;Translating;Traumatic Brain Injury;brain tissue;cerebral hemodynamics;cerebrovascular;clinical application;clinical development;clinically translatable;cranium;diagnostic biomarker;disability;hemodynamics;high resolution imaging;innovation;insight;metabolic profile;metabolome;metabolomics;mild traumatic brain injury;multimodality;neuroimaging;neuron loss;neurophysiology;neurovascular coupling;novel;portability;potential biomarker;pre-clinical research;prevent;prognostic;prognostic tool;prototype;response;restoration;tissue oxygenation;tomography

public_health_relevance:
Project NarrativeMild traumatic brain injuries (TBIs) represent the vast majority of the millions of head injuries that occur eachyear. Sustaining multiple mild TBIs close together greatly increases the chances of long-term disability. Thisproject uses a new blood flow monitoring technique coupled with large scale profiling of brain and bloodmetabolites to provide insights into mechanisms underlying recovery from mild TBI and aid development ofclinically applicable biomarkers.


application_id: 10055850
project_number: 1R21AT010847-01A1
project_title: Mechanisms underlying local and systemic effects of massage
administering_ic: NCCIH
award_notice_date: 2020-07-31
opportunity_number: PA-18-322
application_type: 1
activity_code: R21
ic: AT
serial_number: 010847
suffix: A1
program_official: TUTTLE, ALEXANDER H
project_start_date: 2020-08-01
project_end_date: 2022-07-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
other_pis: BUTTERFIELD, TIMOTHY ALAN
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
SUMMARYThe loss of skeletal muscle mass is a common symptom associated with diseases such as cancer AIDS diabetes congestive heart failure and with aging. Muscle atrophy is associated with poor disease prognosis and decreased quality of life and therefore maintaining muscle size and reducing the loss of muscle during disuse atrophy is of vital significance. Mechanical stimulation of muscle such as during resistance exercise induces protein synthesis needed to increase muscle protein content and muscle size. We showed that mechanical stimulation applied to skeletal muscle in the form of massage is an effective mechanotherapy in rats since it leads to a shift in protein turnover favoring anabolism and enhanced regrowth after disuse-induced atrophy. Whether the same positive effect of massage occurs in humans is currently unknown but would be extremely beneficial for skeletal muscle and overall health in case where resistance exercise is contraindicated or not feasible. In addition to the direct anabolic effects on the massaged rat muscle we showed an equally beneficial response on the homologous muscle in the contralateral non-massaged limb of rats and humans. This novel finding indicated the existence of indirect mechanisms that could have profound systemic effects beyond the massaged muscle. Extracellular vesicles (EVs) are lipid membrane-bound vesicles released from cells with the ability to modulate function of cells from which they are released as well as in cells with which they fuse. As such EVs are likely mediators of the well-documented but poorly-understood effects of massage in humans on the brain and other organs such as relief of pain anxiety or depression or changes in immunity. Therefore the goal of this proposal is to determine anabolic effects of massage in human muscle and to identify whether EVs released with massage are candidates for beneficial effects of this mechanotherapy on muscle as well as other organs. The contribution of neuronal activity will also be investigated. In Aim 1 we will address the following hypothesis: Massage acts as a mechanotherapy by shifting protein biogenesis towards anabolism. Using a novel massage device we will apply mechanical load to muscle undergoing atrophy through unilateral lower limb suspension and mechanisms underlying muscle size regulation determined. Protein synthesis will be the primary outcome. In the exploratory Aim 2 we will test the hypothesis that massage induces cross-over effects through changes in EVs or neuronal activity. We will measure EVs and their miRNA cargo in the serum and markers of EV biogenesis in muscle of human subjects from Aim 1. Muscle activation in the contralateral limb will also be measured. Results from this study will indicate not only how mechanotherapy such as massage can attenuate atrophy and enhance anabolic processes during disuse but also determine whether EVs are a candidate mechanism for the overall health benefits of massage. This application directly addresses the goals set out in the following program announcement from the National Center for Complementary and Integrative Health: PA-18-322 Health: Fundamental Science Research on Mind and Body Approaches (R21).

project_terms:
Acquired Immunodeficiency Syndrome;Address;Aging;Anabolism;Anxiety;Area;Atrophic;Attenuated;Biogenesis;Biopsy;Brain;Cell Count;Cell physiology;Cells;Clinical;Communication;Complementary Health;Congestive Heart Failure;Contralateral;DNA;DNA biosynthesis;Data;Devices;Diabetes Mellitus;Disease;Distant;Disuse Atrophy;Female;Funding Opportunities;Future;Goals;Grant;Health;Health Benefit;Human;Immunity;Integrative Medicine;Intensive Care Units;Intervention;Limb structure;Lipids;Lower Extremity;Maintenance;Malignant Neoplasms;Massage;Measurement;Measures;Mechanical Stimulation;Mechanics;Mediator of activation protein;Membrane Lipids;Mental Depression;MicroRNAs;Mind-Body Intervention;Muscle;Muscle Fibers;Muscle Proteins;Muscular Atrophy;NIH Program Announcements;Neurons;Organ;Orthopedic Surgery procedures;Outcome;Participant;Pathway interactions;Patients;Population;Process;Protein Biosynthesis;Proteins;Quality of life;RNA;Rattus;Regulation;Research;Resistance;Ribosomes;Science;Sedation procedure;Serum;Serum Markers;Site;Skeletal Muscle;Suspensions;Testing;Tissues;Trauma;associated symptom;attenuation;clinically significant;common symptom;extracellular vesicles;human subject;innovation;male;mechanical load;mechanotransduction;muscle form;novel;outcome forecast;pain relief;primary outcome;protein degradation;release factor;resistance exercise;response;satellite cell;secondary outcome;skeletal muscle wasting;standard care;symptom management;vesicular release;young adult

public_health_relevance:
NARRATIVEMaintenance of muscle mass is clinically significant not only because muscles are required for mobilizationand serve as a reservoir for protein but also because loss of muscle is associated with poor health outcomes.We propose that the mechanical activity of massage can produce beneficial effects in humans to maintainmuscle size and protein synthesis during atrophy. Data obtained from this study will form the basis for futuretrials with clinical populations in which muscle atrophy is prevalent and cannot be treated with resistanceexercise such as in patients under sedation in intensive care units or after orthopedic surgery or trauma inwhich non-weight bearing is prescribed.


application_id: 10055139
project_number: 1R01DK123712-01A1
administering_ic: NIDDK
award_notice_date: 2020-06-19
opportunity_number: PAR-19-294
application_type: 1
activity_code: R01
ic: DK
serial_number: 123712
suffix: A1
program_official: NGUYEN, KHOA DINH DANG
project_start_date: 2020-06-20
project_end_date: 2024-03-31
study_section: Special Emphasis Panel[ZRG1 EMNR-F (50)]
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Affect;Affinity;Anti-Inflammatory Agents;Antibodies;Azoxymethane;Binding;Biochemical;Biological;Biological Assay;Biological Response Modifier Therapy;Biophysics;Biopsy;C-terminal;C57BL/6 Mouse;Caco-2 Cells;Cells;Cholera Toxin Protomer B;Cholera Vaccine;Chronic;Clinical Trials;Colectomy;Colitis;Colon;Crohn's disease;Data;Detection;Development;Disease;Disease remission;Dose;Dysplasia;E-Cadherin;Endoplasmic Reticulum;Endoscopy;Enteral;Enzyme-Linked Immunosorbent Assay;Epithelial;Epithelial Cells;Epithelium;Excision;Exposure to;Fibrosis;Formulation;Frequencies;Ganglioside GM1;Gene Expression;Genes;Goals;High Pressure Liquid Chromatography;Histopathology;Human;Immune;Immune System Diseases;Immunohistochemistry;Immunologic Surveillance;Impairment;In Vitro;Individual;Inflammation;Inflammatory Bowel Diseases;Interleukin-10;Intestines;Knock-out;Knockout Mice;Lamina Propria;Lead;Malignant Neoplasms;Mass Spectrum Analysis;Modeling;Modification;Molecular;Monitor;Mononuclear;Mucous Membrane;Mus;Natural regeneration;Nicotiana;Oral;Oral Administration;Organoids;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Phase I Clinical Trials;Piroxicam;Plants;Postoperative Complications;Process;Proteins;Recombinants;Recording of previous events;Recovery;Rectum;Refractory;Relapse;Research;Safety;Scanning;Series;Sodium Dextran Sulfate;Specimen;System;TNF gene;Testing;Therapeutic;Therapeutic Agents;Therapeutic Effect;Tissues;Treatment Efficacy;Ulcerative Colitis;Vaccine Antigen;Validation;Variant;analog;base;cell type;clinical care;colitis associated cancer;comparative efficacy;curative treatments;efficacy study;epithelial injury;first-in-human;healing;holotoxins;immunoregulation;improved;indexing;infection risk;inflammatory disease of the intestine;inflammatory marker;mouse model;mutant;novel;novel therapeutics;overexpression;pre-clinical;prototype;repaired;response;retrograde transport;safety study;screening;tissue culture;tumorigenesis;wound healing


application_id: 10054775
project_number: 1RF1NS118558-01
project_title: Inflammatory contributions of astrocytic RelA in comorbid VCID/AD
administering_ic: NINDS
award_notice_date: 2020-09-08
opportunity_number: PAR-19-070
application_type: 1
activity_code: RF1
ic: NS
serial_number: 118558
program_official: YIN, XILING
project_start_date: 2020-09-15
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1 BDCN-W (91)]
contact_pi_person_id: 10594155
contact_pi: MORGANTI, JOSH
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTMultiple lines of evidence in both humans and animal models suggest that neuroinflammation mediated viareactive gliosis plays a critical role associated with the initiation and progression of vascular contributions tocognitive impairment and dementia (VCID) and Alzheimers disease (AD) potentially suggesting convergentpathophysiological mechanisms. In particular several of these neuroinflammatory hallmarks in comorbidVCID/AD animal models have been linked with the dysfunctional responses of reactive astrocytes. In thehealthy brain it is well known that astrocytes play a critical role in maintaining a variety of homeostaticmechanisms. However as a response to injury or disease astrocytes are able to rapidly respond in ageneralized description referred as astrogliosis with a variety of neuroinflammatory modalities which recentevidence suggests may cause dysfunctional responses of neurons. Contemporary work has demonstrated acritical component to these dystrophic neuroinflammatory response of astrocytes is their utilization of canonicalNFkB (RelA) signaling pathway. However relatively little is known regarding the role of RelA in astrocytesexposed to the co-morbid degenerative milieu in VCID/AD representing a critical knowledge gap for the field.Our overarching hypothesis for this proposal is that astrocytic RelA represents a convergentinflammatory mechanism driving dysfunctional sequelae in the comorbid VCID/AD milieu. This proposalwill examine three specific aims to determine how RelA utilization by astrocytes shapes both intrinsic and non-cell autonomous dysfunctional responses to the comorbid VCID/AD degenerative environment: 1. Determine the capacity of astrocytic-RelA in propagating inflammatory phenotypes of microglia and astrocytes in comorbid VCID/AD. 2. Determine the role of astrocytic-RelA in driving cerebrovascular dysfunction in comorbid VCID/AD. 3. Determine if synaptic and cognitive dysfunction in VCID/AD is linked with RelA expression in astrocytes.

project_terms:
Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease related dementia;Amyloid beta-Protein;Animal Disease Models;Animal Model;Astrocytes;Automobile Driving;Blood Vessels;Brain;Cells;Cerebrovascular Circulation;Cerebrovascular Disorders;Coupling;Data;Degenerative Disorder;Dementia;Deposition;Development;Disease;Disease model;Environment;Excision;Exposure to;FDA approved;Functional disorder;Future;Gliosis;Healthcare;Human;Impaired cognition;Individual;Inflammatory;Inflammatory Response;Ischemia;Knowledge;Label;Lead;Link;Mediating;Medical;Microglia;Modality;Modeling;Multiple Sclerosis;Neuroglia;Neurological outcome;Neuronal Dysfunction;Neurons;Pathologic;Pathology;Pathway interactions;Patients;Phenotype;Play;Population;Publishing;Recording of previous events;Recovery of Function;Research;Risk;Role;Senile Plaques;Shapes;Signal Pathway;Signal Transduction;Spinal cord injury;Synapses;Testing;Tissues;Work;abeta deposition;aged;astrogliosis;base;blood-brain barrier permeabilization;cerebrovascular;comorbidity;conditional knockout;human model;innovation;neuroinflammation;new therapeutic target;novel;response;response to injury;restraint;therapeutic target;vascular cognitive impairment and dementia;vascular contributions;vascular injury;vascular risk factor

public_health_relevance:
PROJECT NARRATIVEGrowing evidence suggests that pure Alzheimers disease is rare among the human population butstrikingly a significant proportion of individuals with Alzheimers present with vascular comorbidities intandem with plaque deposition. Both Alzheimers and VCID are a major unment medical need withno FDA approved therapy. Defining the role of abberant astrocyte inflammatory response in theseconditions and whether RelA is a factor in these responses will enable new lines of development forfuture therapeutic targeting of these pathways to either restrain or enhance critical facets of astrocyteresponse to the comorbid disease milieu.


application_id: 10054203
project_number: 5R00NS097638-05
administering_ic: NINDS
award_notice_date: 2020-11-17
opportunity_number: PA-15-083
application_type: 5
activity_code: R00
ic: NS
serial_number: 097638
program_official: LEENDERS, MIRIAM
project_start_date: 2016-07-15
project_end_date: 2022-11-30
study_section: NST-2 Study Section [NST-2]
contact_pi_person_id: 9428270
contact_pi: CHERRA, SALVATORE JAMES
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
budget_start_date: 2020-12-01
project_title:
Understanding the molecular mechanisms that maintain excitation-inhibition balance in neural circuits

project_abstract:
Many neurological disorders are associated with an imbalance between excitatory and inhibitory (E/I) neuronal signaling. The nervous system normally maintains an E/I balance by regulating the number or strength of synaptic connections between neurons. Neurons in the human brain are outnumbered nearly ten to one by non-neuronal glial cells which provide support for neuronal function. While maintaining the richness of neuronal signaling the reduced cellular complexity of the roundworm Caenorhabditis elegans (C. elegans) makes it an excellent model system to study E/I balance. The overall goal of this proposal is to elucidate how non-neuronal cells and neurons interact to regulate E/I balance. By understanding how glial cells and neurons interact this project will provide novel insights into the treatment and management of neurological disorders such as epilepsy autism spectrum or schizophrenia. C. elegans will be used as a model for thisproject for the following reasons: 1) its nervous system has been fully mapped 2) it's been widely used to study how neuronal networks are formed and maintained 3) the genes and molecular mechanisms that regulate nervous system function are conserved with humans and 4) it is easy to manipulate through genetic techniques. For these reasons C. elegans provides a simple model to study the molecular mechanisms that underlie neurological disorders associated with E/I imbalance. The goals of this study will be accomplished through the following specific aims: Aim 1: Determine how the two immunoglobulin domain transmembrane protein ZIG-10 regulates the phagocytosis pathway to balance excitatory and inhibitory neurotransmission using electron microscopy and electrophysiology. Aim 2: Elucidate the ZIG-10 signaling pathway in maintaining synaptic connections using genetic cell biologic and biochemical approaches. Aim 3: Determine how a novel transporter regulates neuronal activity and E/I balance in vivo. The completion of this proposal will provide a deeper understanding of how neurons and non-neuronal glia cooperate to regulate E/I balance. Additionally this study will uncover the mechanism(s) affecting aberrant neuronal activity associated with neurological disorders. Finally this project will identify potential therapeutic targets for novel treatments of autism spectrum disorders epilepsy schizophrenia and related neurological diseases.The mentored portion of this award will take place at the University of California San Diego under the mentorship of Dr. Yishi Jin. UCSD and the superb neuroscience faculty provide an excellent environment for the proposed research which employs electron microscopy and electrophysiology under the guidance of Dr. Mark Ellisman and Dr. Darwin Berg leaders in their respective fields. Dr. Jin a world-renowned geneticist and neurobiologist will provide both the resources and guidance to accomplish the research proposed during the mentored phase. Through hands-on training and formal meetings with Dr. Ellisman and Dr. Berg I will learn how to use new techniques to dissect the structure-function relationship of the nervous system. This will allow me to understand how neurons and non-neuronal cells interact to regulate E/I balance in the short-term. During the independent phase applying these new techniques with my expertise in molecular and cellular biology andbiochemistry will allow me to decipher how the E/I balance is regulated during normal and disrupted during disease states. Overall the research and career development proposed during this award will enable me to uncover the mechanisms that regulate E/I balance that is disrupted in many neurological disorders including epilepsy schizophrenia and autism spectrum.

project_terms:
Affect;Award;Behavior;Behavioral;Biochemical;Biochemistry and Cellular Biology;Biological;Biological Assay;Biological Models;Brain;CRISPR/Cas technology;Caenorhabditis elegans;California;Cells;Cholinergic Receptors;Cholinesterase Inhibitors;Convulsions;Data;Disease;Electron Microscopy;Electrophysiology (science);Environment;Epidermis;Epilepsy;Equilibrium;Faculty;Frequencies;Future;Genes;Genetic;Genetic Screening;Genetic Techniques;Glutamates;Goals;Human;Immunoglobulin Domain;Immunoglobulins;In Vitro;Integral Membrane Protein;Investigation;Laboratories;Learning;Mammals;Maps;Mediating;Mentors;Mentorship;Modeling;Molecular;Molecular and Cellular Biology;Mutation;Nematoda;Nervous System Physiology;Nervous system structure;Neuroglia;Neurons;Neurosciences;Neurotransmitters;Pathway interactions;Patients;Phagocytosis;Phase;Phenotype;Physiological;Process;Protein Binding Domain;Proteins;RNA interference screen;Regulation;Research;Resistance;Resources;Schizophrenia;Seizures;Signal Pathway;Signal Transduction;Singlet Oxygen;Structure-Activity Relationship;Symptoms;Synapses;System;Techniques;Testing;Training;Universities;Use of New Techniques;autism spectrum disorder;career development;cholinergic;density;gain of function mutation;genomic locus;in vivo;insight;meetings;member;mutant;nervous system disorder;neural circuit;neurotransmission;new therapeutic target;novel;research and development;synaptic function;synaptogenesis;transmission process

public_health_relevance:
Neurological disorders such as autism spectrum epilepsy and schizophrenia are associated with imbalances in neuronal activity within the brain. There are currently no cures or long-term therapies to assuage the symptoms. This project will uncover mechanisms that regulate how neuronal activity is balanced and will provide novel therapeutic targets for future treatments.


application_id: 10053288
project_number: 5R01AI065530-16
project_title: Type III exported effectors of Chlamydia trachomatis
administering_ic: NIAID
award_notice_date: 2020-11-02
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 065530
program_official: VINCENT, LEAH REBECCA
project_start_date: 2005-06-01
project_end_date: 2023-07-31
study_section: Special Emphasis Panel[ZRG1-IDM-R(02)M]
contact_pi_person_id: 7726964
contact_pi: FIELDS, KENNETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Grant title: Type III exported effectors of Chlamydia trachomatisAbstract:The human pathogen Chlamydia trachomatis is a significant concern in the United States dueto its prevalence and the combined health and socioeconomic impact of acute and chronicdisease. Chlamydiae are obligate intracellular pathogens that possess the ability to modulatehost-cell functions while sequestered within a membrane-bound parasitophorous vacuole.Although it is established that a type III secretion system (T3SS) represents one mechanismemployed to modulate critical host cell pathways the overall understanding of this process inChlamydia remains limited. During the past funding cycle we made significant progress inunderstanding the role of T3S effectors designated CT694 and CT695. Importantly we alsoleveraged novel genetic manipulation techniques to investigate the impact of T3S in chlamydialpathogenesis. Perhaps our most important contribution was the development of afluorescence-reported allelic exchange mutagenesis (FRAEM) approach to allow for the firsttime deletion of targeted chlamydial genes. We have used this technique to create nullmutants for ct694 and ct695 and these strains are attenuated in both tissue-culture andanimal-infection models. We propose to elucidate molecular details by which mutantphenotypes are manifested. A balanced combination of genetic biochemical cell-biology andanimal-based studies are proposed that will define developmental defects identify host targetsimportant for effector function(s) and gauge the overall role of effectors and target proteins inpromoting Chlamydia pathogenesis. Completion of this work will extend the efficacy ofgenetically manipulating a challenging pathogen and lead to an enhanced understanding ofChlamydia-mediated disease.

project_terms:
Acute Disease;Address;Alleles;Animal Model;Animals;Attenuated;Biochemical;Biological Assay;Cell physiology;Cells;Cellular biology;Chlamydia;Chlamydia Infections;Chlamydia trachomatis;Chronic Disease;Communities;Data;Defect;Development;Disease;Epithelial Cells;Event;Fluorescence;Funding;Genes;Genetic;Goals;Grant;Health;Human;Individual;Infection;Infection prevention;Integration Host Factors;Lead;Maintenance;Mediating;Membrane;Methods;Microbiology;Modeling;Molecular;Mus;Mutagenesis;Pathogenesis;Pathology;Pathway interactions;Phenotype;Physiological;Prevalence;Process;Proteins;Proteome;Reporting;Role;Science;Sexually Transmitted Agents;Sexually Transmitted Diseases;Techniques;Testing;Time;Type III Secretion System Pathway;United States;Vacuole;Virulence;Work;base;comparative;design;genetic manipulation;human pathogen;member;mutant;novel;novel therapeutic intervention;null mutation;obligate intracellular parasite;pathogen;recruit;socioeconomics;success;suicide vector;tissue culture

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


application_id: 10052862
project_number: 1R37CA234002-01A1
project_title: Targeting 6-Phosphofructo-2-Kinase to increase efficacy of CDK4/6 Inhibitors
administering_ic: NCI
award_notice_date: 2020-07-09
opportunity_number: PA-19-056
application_type: 1
activity_code: R37
ic: CA
serial_number: 234002
suffix: A1
program_official: FORRY, SUZANNE L
project_start_date: 2020-07-09
project_end_date: 2025-06-30
study_section: Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1]
contact_pi_person_id: 8320211
contact_pi: IMBERT-FERNANDEZ, YOANNIS
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
6-Phosphofructo-2-kinase;6-Phosphofructokinase;Attenuated;Automobile Driving;Binding;Bioavailable;Breast Adenocarcinoma;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer cell line;Bypass;CDK4 gene;Cell Cycle;Cell Cycle Progression;Cells;Clinical;Clinical Trials;Cyclin D1;Cyclins;Development;ERBB2 gene;Enzymes;Estradiol;Estrogen Receptors;Estrogen receptor positive;FDA approved;Fructose;Genetic;Genetic Transcription;Glucose;Glycolysis;Growth;In Vitro;Malignant Neoplasms;Mediating;Metabolic;Metastatic breast cancer;Oncogenic;Oral;Pathway interactions;Patients;Pharmacology;Phase;Phase I/II Trial;Phosphorylation;Progression-Free Survivals;Relapse;Resistance;Resistance development;Retinoblastoma Protein;Role;Testing;Time;advanced breast cancer;base;blood glucose regulation;cancer cell;combinatorial;cyclin D3;design;early phase clinical trial;glucose metabolism;hormone receptor-positive;hormone therapy;improved;in vivo;inhibitor/antagonist;malignant breast neoplasm;mouse model;novel;novel strategies;overexpression;prevent;research clinical testing;response;targeted treatment;therapy resistant;treatment response;tumor


application_id: 10052273
project_number: 2R01AA023190-06
project_title: Mechanisms of Probiotics in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2020-08-31
opportunity_number: PA-19-056
application_type: 2
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;Epithelium;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: 10049627
project_number: 1R01CA243529-01A1
administering_ic: NCI
award_notice_date: 2020-05-18
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: CA
serial_number: 243529
suffix: A1
program_official: CHEN, WEIWEI
project_start_date: 2020-06-01
project_end_date: 2025-05-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 8227789
contact_pi: LEGGAS, MARKOS
other_pis: ROHR, JURGEN T;TSODIKOV, OLEG V
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Animal Model;Antineoplastic Agents;Binding;Biochemical;Biological;Biological Assay;Biophysics;Bone Tissue;Cell model;Cells;Child;Clinical;Clinical Treatment;Clinical Trials;Collaborations;Combined Modality Therapy;Complement;Complex;Crystallization;DNA;DNA Binding;DNA Binding Domain;DNA Sequence;Data;Development;Drug Design;Drug Kinetics;EWS-FLI1 fusion protein;Elements;Enhancers;Evaluation;Ewings sarcoma;FLI1 gene;Family;Foundations;Genetic Transcription;Goals;Higher Order Chromatin Structure;Human;In Vitro;Investigational Therapies;Kinetics;Liver;Malignant Bone Neoplasm;Metabolism;Microsatellite Repeats;Modeling;Molecular;Molecular Biology;Molecular Structure;Mus;Natural Products;Oncogenic;Patients;Pharmaceutical Preparations;Pharmacology;Pharmacology Study;Phase I/II Clinical Trial;Plasma;Plicamycin;Preclinical Testing;Property;Proteins;Public Health;Reporter;Reporting;Roentgen Rays;Route;Shunt Device;Side;Site;Specificity;Structure;Testing;Therapeutic;Toxic effect;Translating;Tube;Xenograft procedure;analog;base;cancer cell;cancer diagnosis;cytotoxic;cytotoxicity;design;drug candidate;drug clearance;effective therapy;experience;improved;inhibitor/antagonist;insight;lead candidate;mouse model;neoplastic cell;novel;programs;screening;soft tissue;transcription factor;tumor;tumorigenesis;young adult


application_id: 10047963
project_number: 7R01EB026893-03
project_title: Controllable In Vivo Genome Editing for Immune-Checkpoint Blockade in Solid Tumors
administering_ic: NIBIB
award_notice_date: 2020-04-03
opportunity_number: PA-18-590
application_type: 7
activity_code: R01
ic: EB
serial_number: 026893
program_official: CHEN, JERMONT
project_start_date: 2018-08-21
project_end_date: 2023-05-31
study_section: Special Emphasis Panel[ZRG1-SBIB-Q(58)R]
contact_pi_person_id: 14341515
contact_pi: TONG, SHENG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryThe blockade of immune-checkpoint pathways has emerged as a promising therapeutic strategy for a varietyof cancers. However the diverse tumor responses to immunotherapy seen in preclinical and clinical studiesprompt the development of combination immunotherapies that can be tailored to the complex immune milieuof individual patients. On the other hand the severe adverse effects associated with the combination therapieswith multiple antagonist antibodies address the necessity for alternative safe and effective therapeuticapproaches. In light of this we aim to develop a hybrid nanoparticle-viral vector system for CRISPR/Cas9-based in vivo therapeutic genome editing which will be used for multiplexed disruption of immune suppressivepathways in the tumor microenvironment. CRISPR/Cas9 systems are very efficient in generating DNA double-strand breaks thus disrupting genes through the non-homologous end-joining (NHEJ) pathway. Howeverinducing uncontrolled CRISPR/Cas9 activities in vivo may lead to systemic genotoxicity. We will develop anovel in vivo gene delivery system that integrates a baculoviral vector (BV) with magnetic nanoparticles(MNPs). Our studies have shown that by taking advantage of the interplay between the MNP-mediated BVmargination and endocytosis and the innate immunity against insect viruses this delivery system can providespatial and temporal control of CRISPR/Cas9 activity. We will use the MNP-BV system to deliver optimizedCRISPR/Cas9 for gene disruption of immune suppressive signals PD-L1 and TGF- in the tumor tissue. Wewill evaluate CRISPR/Cas9 induced anti-tumor immune responses using two well-established mouse modelsan immunogenic model (MC38) where monotherapy with PD-1 blockade is sufficient and non-immunogenicmodels pancreatic ductal adenocarcinoma (PDAC) which portrays most non-immunogenic human solidtumors that require combination strategies. In aim 1 studies we will design and optimize CRISPR/Cas9gRNAs for targeting PD-L1 and TGF- package Cas9 and gRNAs into a BV vector and construct the MNP-BV system. In aim 2 studies we will evaluate MNP-BV-induced multiplexed gene disruption in cell cultureand determine the on-target and off-target indel rates. In aim 3 studies we will test the controlled in vivodelivery of CRISPR/Cas9 determine the immunological and therapeutic effects of local gene disruption vs.systemic blockade with antagonist antibody in mouse tumor models. The success of the proposed studies willprovide a multiplexed intratumoral immunoengineering platform and pave the way for the clinical translationof a highly efficient in vivo genome editing strategy for personalized cancer immunotherapy.

project_terms:
Address;Advanced Malignant Neoplasm;Adverse effects;Agonist;Allografting;Antibodies;Antigen-Antibody Complex;Antitumor Response;Biodistribution;CRISPR/Cas technology;Cancer Patient;Cell Culture Techniques;Clinical;Clinical Research;Clustered Regularly Interspaced Short Palindromic Repeats;Colon Adenocarcinoma;Combination immunotherapy;Combined Modality Therapy;Complex;Coupled;DNA Double Strand Break;DNA Sequence;Data;Development;Disease remission;Drug Kinetics;Endocytosis;Engineering;Gene Deletion;Genes;Genetic;Genome;Guide RNA;Human;Hybrids;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunity;Immunologics;Immunooncology;Immunosuppressive Agents;Immunotherapy;In Vitro;Individual;Insect Viruses;Lead;Light;MC38;Magnetic nanoparticles;Magnetism;Malignant Neoplasms;Mediating;Modeling;Modification;Mus;Natural Immunity;Nonhomologous DNA End Joining;Normal tissue morphology;OX40;Organ;PD-1 blockade;PDCD1LG1 gene;Pancreatic Ductal Adenocarcinoma;Pathologic Processes;Pathway interactions;Phenotype;Proteins;Signal Transduction;Solid Neoplasm;Specificity;System;Testing;Therapeutic;Therapeutic Effect;Tissues;Treatment Efficacy;Tumor Immunity;Tumor Tissue;Viral;Viral Vector;anti-cancer;anti-tumor immune response;base;cancer heterogeneity;cancer immunotherapy;cancer type;clinical application;clinical translation;design;engineered nucleases;gene delivery system;genome editing;genotoxicity;human disease;image guided;immune checkpoint;immune checkpoint blockade;immunoengineering;immunogenic;in vivo;individual patient;insertion/deletion mutation;iron oxide nanoparticle;magnetic field;mouse model;multiplexed imaging;novel;nuclease;patient subsets;personalized strategies;preclinical study;response;success;therapeutic genome editing;transduction efficiency;tumor;tumor microenvironment;vector;vector-induced;viral nanoparticle

public_health_relevance:
Project NarrativeThe blockade of immune checkpoints hold great promise for the treatment of advanced cancer. Here we proposeto develop a hybrid nanoparticle-viral vector system for controlled delivery of engineered nuclease CRISPR/cas9which induces multiplexed gene deletions in the immune checkpoint pathways in the tumor tissue. The successof this project will provide a highly integrated efficient and versatile immunotherapy in which the genetic targetscan be readily designed and implemented according to the immunological profile of individual cancer patients.


application_id: 10045688
project_number: 1F99AG068525-01
project_title: Young cardiomyocyte phenotype drives enhanced cardiac recovery in spiny mice
administering_ic: NIA
award_notice_date: 2020-08-31
opportunity_number: RFA-AG-20-009
application_type: 1
activity_code: F99
ic: AG
serial_number: 068525
program_official: KERR, CANDACE L
project_start_date: 2020-09-01
project_end_date: 2022-08-31
study_section: Special Emphasis Panel[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;Biology;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;new therapeutic target;novel;novel therapeutic intervention;preservation;regenerative;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: 10044077
project_number: 1R15MH121445-01A1
administering_ic: NIMH
award_notice_date: 2020-06-11
opportunity_number: PAR-18-714
application_type: 1
activity_code: R15
ic: MH
serial_number: 121445
suffix: A1
program_official: CHAVEZ, MARK RAY
project_start_date: 2020-06-15
project_end_date: 2023-06-14
study_section: Special Emphasis Panel[ZRG1 RPHB-V (90)]
contact_pi_person_id: 10775786
contact_pi: LEVINSON, CHERI ALICIA
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Personalized Networks and Sensor Technology Algorithms of Eating Disorder Symptoms Predicting Eating Disorder Outcomes

project_abstract:
PROJECT SUMMARY/ABSTRACTEating disorders (EDs) are severe mental illnesses with the highest mortality rate of anypsychiatric disorder. The most widely used empirically supported treatment for EDs (cognitivebehavior therapy) is only efficacious for ~50% of individuals. This low response rate is due tothe fact that EDs are heterogeneous conditions with diverse symptom trajectories that are notadequately addressed in current one-size-fits-all psychotherapies. Until we can identify whatmaintains or exacerbates individual symptoms clinicians will continue to have difficultyaccurately predicting prognosis and will have no empirical guidance to develop targetedtreatment plans to promote recovery. Our scientific premise developed from our past work isthat the application of network theory will enable the identification of cognitive-behavioralsymptom networks that maintain and trigger EDs both between and within individuals. Ourstudy goals are to (1) identify individual ED trigger symptoms (cognitions behaviors affectand physiology) and (2) correlate trigger symptoms with real-time physiological data to createan algorithm predicting onset of ED behaviors. These goals will ultimately identify symptomsthat prevent full remission and lead to relapse. We will use a multiple units of analysis approachcombined with novel cutting-edge advances in network science. We will collect intensive real-time data on cognitions behavior affect and physiology using mobile and sensor-technologyfrom 120 individuals with a diagnosis of anorexia nervosa (AN) atypical AN and bulimianervosa across 30 days. At 1-month and 6-month follow ups we will assess ED outcomes (e.g.remission status ED behaviors) to test if trigger symptoms predict ED outcomes. Networkscience and state-of-the-art machine learning techniques will allow us for the first time todiscover whether certain trigger symptoms predict worse outcomes. Specific aims are to (1)develop personalized networks to identify which cognitive behavioral affective andphysiological symptoms maintain EDs and predict ED outcomes and (2) utilize sensor data toidentify physiological patterns both within and across people that correlate with core maintainingsymptoms and that predict ED behaviors. The proposed research uses highly innovativemethods combining intensive longitudinal data collection methods all remote procedures noveladvances in network science and sensor-technology and state-of-the-art machine learningtechniques to answer previously unresolvable questions pinpointing which personalizedsymptoms trigger EDs. The proposed research has clinical impact. If we identify patterns thatcontribute to symptom network variation within individuals these data will provide a model ofpersonalized medicine for the entire field of psychiatry as well as providing novel interventiontargets to prevent and treat EDs.

project_terms:
Acceleration;Accelerometer;Address;Adult;Affect;Affective;Algorithms;Anorexia Nervosa;Anxiety;Behavior;Behavior Disorders;Behavioral;Behavioral Symptoms;Binge Eating;Bulimia;Cellular Phone;Chronic;Clinical;Cognition;Cognitive;Cognitive Therapy;Data;Data Collection;Development;Diagnosis;Disease remission;Eating Disorders;Epilepsy;Evidence based treatment;Fright;Future;Goals;Gold;Health Personnel;Heart Rate;Individual;Individual Differences;Interruption;Intervention;Lead;Machine Learning;Maintenance;Mental disorders;Methods;Modeling;Outcome;Pathway Analysis;Pathway interactions;Patient Self-Report;Patients;Pattern;Persons;Physiological;Physiology;Precision Medicine Initiative;Procedures;Psychiatry;Psychopathology;Psychotherapy;Recovery;Relapse;Research;Science;Seizures;Signal Transduction;Structure;Symptoms;System;Techniques;Technology;Testing;Time;United States National Institutes of Health;Variant;Weight Gain;Work;base;effective therapy;follow-up;food restriction;innovation;mobile computing;mortality;novel;outcome forecast;personalized intervention;personalized medicine;prediction algorithm;prevent;psychologic;public health relevance;purge;recruit;response;sensor;sensor technology;severe mental illness;smartphone Application;standard care;targeted treatment;theories;treatment planning;wearable sensor technology

public_health_relevance:
PROJECT NARRATIVEThis project will identify the maintaining symptoms of eating disorders within individuals. Theproposed research has significant public health relevance as it will lead to personalized noveleffective treatments that promote full remission and decrease the high societal burdenassociated with eating disorders. The proposed research is relevant to NIHs precision medicineinitiative as it will identify within-person maintenance symptoms of eating disorders leading topersonalized treatments delivered via mobile or sensor technology.


application_id: 10039382
project_number: 1R34MH123601-01
project_title: Increasing Treatment Efficiency Using SMART Methods for Personalizing Care
administering_ic: NIMH
award_notice_date: 2020-07-17
opportunity_number: RFA-MH-18-706
application_type: 1
activity_code: R34
ic: MH
serial_number: 123601
program_official: RUDORFER, MATTHEW V
project_start_date: 2020-07-20
project_end_date: 2024-07-19
study_section: Special Emphasis Panel[ZMH1 ERB-K (05)]
contact_pi_person_id: 9522329
contact_pi: SAUER-ZAVALA, SHANNON E
other_pis: LANGER, DAVID A
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Anxiety and depressive disorders are highly prevalent costly and debilitating representing a serious publichealth concern. Although time-limited efficacious interventions have been developed for these commonconditions these treatment protocols often require more sessions than patients in community practice typicallyattend. Thus it is critical to increase the efficiency of our interventions such that the skills that drive therapeuticchange are presented as early as possible. Transdiagnostic interventions designed to directly target coreprocesses implicated in the development of a range of conditions may increase treatment efficiency bysimultaneously leading to improvements across comorbid conditions. However transdiagnostic treatmentscontain multiple treatment elements (modules) and it is possible that some skills may be better suited for targetengagement based on each patient's clinical presentation; prioritization of those modules may lead to earlier andmore robust symptom improvements. Unfortunately we lack empirical evidence to guide treatment planning sothat care is personalized to the patient's unique strengths and weaknesses. Additionally evidence-baseddecision rules regarding when to terminate treatment based on promising early markers of improvement ratherthan complete symptom remission may also improve treatment efficiency making care available to a greaternumber of individuals. It is also possible that engagement of core processes may serve as an early indicationthat a sufficient dose of treatment has been received aiding decisions about when to discontinue care. Theproposed study will determine the feasibility tolerability and acceptability of a study that tests: 1) personalizedtreatment delivery (i.e. module sequencing and treatment discontinuation timing) aimed at increasing theefficiency of care and 2) the research protocol designed to evaluate the effects of this personalized care. Asample of 60 participants with heterogeneous anxiety disorders (and comorbid conditions including depression)will be enrolled in a pilot sequential multiple assignment randomized trial (SMART). Patients will be randomlyassigned to one of three sequencing conditions: transdiagnostic treatment administered in its standard moduleorder module sequences that prioritize capitalizing on relative strengths and module sequences that prioritizecompensating for relative weaknesses. Next after 6 sessions participants will be randomly assigned to eithercontinue or discontinue treatment to evaluate post-treatment change at varying levels of target engagement.This proposal will enable us to 1) test the feasibility acceptability and tolerability of the research protocoltreatment sequencing conditions and early treatment discontinuation 2) determine whether a preliminary signalthat capitalization or compensation module sequencing improves treatment efficiency exists and 3) explorepreliminary associations between core process engagement at treatment discontinuation and later symptomimprovement. The proposed study and the subsequent research it will support will inform evidence-baseddecision rules to make existing treatments more efficient ultimately reducing patient costs and increasing themental health service system's capacity to address the needs of more individuals.

project_terms:
Achievement;Address;Aftercare;Anxiety Disorders;Caring;Clinical;Common Core;Community Practice;Data;Data Collection;Depressive disorder;Development;Disease remission;Dose;Early treatment;Effectiveness;Elements;Enrollment;Financial compensation;Goals;Individual;Intervention;Lead;Mental Depression;Mental Health Services;Methods;National Institute of Mental Health;Outcome;Participant;Patients;Process;Protocols documentation;Public Health;Randomized;Reaction;Research;Research Design;Research Domain Criteria;Sampling;Sequential Multiple Assignment Randomized Trial;Signal Transduction;Symptoms;System;Testing;Therapeutic;Time;Training;Treatment Protocols;Work;anxiety symptoms;base;comorbidity;cost;design;dosage;emotional experience;evidence base;improved;novel;personalized care;personalized medicine;psychologic;recruit;research study;response;service intervention;skills;standard care;symptomatic improvement;therapy design;therapy development;treatment of anxiety disorders;treatment planning

public_health_relevance:
Increasing the efficiency of existing treatments for anxiety and depressive disorders is critical for substantiallyimproving the treatments' impact on public health. This project assesses the feasibility acceptability andtolerability of a research study that (1) compares the efficiency of multiple sequencing approaches to treatmentand (2) tests if core process engagement (avoidant reactions to emotional experiences) can serve as an indicatorof sufficient treatment dose.


application_id: 10038824
project_number: 271201600028C-P00008-9999-3
administering_ic: NIDA
project_start_date: 2016-09-18
project_end_date: 2021-09-17
contact_pi_person_id: 16187878
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 - 09/17/2021.

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: 10038650
project_number: 1K01CA251487-01
project_title: Promoting Cervical Cancer Screening among African American and Sub-Saharan African Immigrant women
administering_ic: NCI
award_notice_date: 2020-09-02
opportunity_number: PAR-18-365
application_type: 1
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;Experimental Designs;Extramural Activities;Frequencies;Fright;Funding;Future;Geographic Locations;Goals;Health;Health Promotion;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;Prevention;Privatization;Quality of Care;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;Vaccination;Visit;Vulnerable Populations;Woman;aged;anticancer research;behavior change;behavior influence;black subgroup;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;men;mortality;peer;prevent;programs;prophylactic;racial and ethnic disparities;recruit;research study;satisfaction;screening;screening participation;skills;social;social cognitive theory;underserved minority;willingness


application_id: 10038513
project_number: 1R21DC018878-01
project_title: Watching cellular dynamics in the taste bud
administering_ic: NIDCD
award_notice_date: 2020-06-08
opportunity_number: PA-19-053
application_type: 1
activity_code: R21
ic: DC
serial_number: 018878
program_official: SULLIVAN, SUSAN L
project_start_date: 2020-06-10
project_end_date: 2022-05-31
study_section: Chemosensory Systems Study Section[CSS]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: A unique feature of the peripheral taste system is that the receptor cells die and are replaced.This requires a constant rewiring of the peripheral system. In order for a new taste receptor cellto form a synapse with an existing neuron it must first come into contact with the correct type ofneuron. Here our goal is to understand the cellular dynamics involved in this process. Wehypothesize that since many receptor cells are replaced within 10 days this cellular influxshould be accompanied by cellular migration of taste bud cells and/or remodeling by the arbor.To test this hypothesis we will combine genetic labeling with intra vital two-photon microscopyto examine plasticity in the taste bud over a 10 day period. Aim 1 will examine the migration ofprecursors into the taste bud as they mature. Aim 2 will measure the growth and retraction ofindividual nerve branches. These studies will be first to examine taste bud plasticity with directobservation of changes over time in a live animal. Future studies will use this approach to helpidentify roles of molecular factors underlying the formation of new connections in the taste bud.

project_terms:
Adult;Anatomy;Animals;Axon;Cell Differentiation process;Cell Maturation;Cell division;Cells;Chemicals;Chronic;Dose;Epithelial;Epithelium;Evaluation;Event;Fiber;Food;Fungiform Papilla;Future;Genetic;Genotype;Goals;Growth;Image;Individual;Label;Length;Location;Longevity;Maps;Measures;Mitotic;Molecular;Monitor;Morphology;Movement;Mus;Nerve;Nerve Fibers;Nervous system structure;Neurons;Pattern;Peripheral;Peripheral Nerves;Pharmaceutical Preparations;Process;Property;Receptor Cell;Resolution;Role;Structure;Structure of geniculate ganglion;Surface;Synapses;System;Tamoxifen;Taste Bud Cell;Taste Buds;Taste Perception;Testing;Time;Tongue;Width;cell motility;chemotherapy;in vivo;in vivo imaging;in vivo two-photon imaging;migration;precursor cell;stem cells;taste system;tongue papilla;two photon microscopy

public_health_relevance:
Project NarrativeHere we propose to develop an in vivo imaging paradigm permitting evaluation of taste receptorcell differentiation/migration and taste neuron plasticity in live animals over time. This paradigmis ideally suited to determine the specific impact of drugs and conditions (includingchemotherapies) that potentially disrupt taste receptor cell turnover and the ability of receptorcells to connect with nerve fibers.


application_id: 10038417
project_number: 1R21AG068370-01
project_title: How does D2-CD33 reduce Alzheimer's disease risk?
administering_ic: NIA
award_notice_date: 2020-09-14
opportunity_number: PA-19-053
application_type: 1
activity_code: R21
ic: AG
serial_number: 068370
program_official: OPANASHUK, LISA A
project_start_date: 2020-09-30
project_end_date: 2024-08-31
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 1859637
contact_pi: ESTUS, STEVEN
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:
Elucidating the mechanism whereby genetics impact the risk of Alzheimers disease (AD) is acritical barrier to progress in translating genetics to pharmacologic strategies. A polymorphismnear CD33 has been identified as an AD risk factor in multiple genome wide association studiesincluding very recent very large studies. CD33 is a member of the sialic acid-bindingimmunoglobulin-type lectin (SIGLEC) family which is linked to regulation of innate immunity.We and others have found that CD33 expression is restricted to microglia in the brain.Moreover the AD-protective allele acts to increase a CD33 isoform lacking exon 2 (D2-CD33) atthe expense of full-length CD33. Since exon 2 encodes the sialic acid ligand binding domain weinterpreted the finding that loss of exon 2 was associated with decreased AD risk as meaningthat a decrease in functional CD33 and its associated immune suppression was AD-protective.However this interpretation needs to be reconsidered given our recent finding that a 4 bp CD33genetic deletion which abrogates CD33 is not associated with AD risk. In summary wecurrently propose a model wherein the D2-CD33 isoform represents a gain of function variant toreduce AD risk because (i) a genetic polymorphism that reduces AD risk increases D2-CD33 atthe expense of full-length CD33 but (ii) a CD33 indel that essentially deletes cell surface CD33does not affect AD risk. To test this model we propose the following Specific Aims. SpecificAim 1: Evaluate whether changes in CD33-related gene expression may compensate for CD33deficiency. Specific Aim 2: Determine D2-CD33 subcellular localization under conditions ofphysiologic D2-CD33 expression. Specific Aim 3: Compare CD33 and D2-CD33 interactomes.Specific Aim 4: Compare impact of CD33 and D2-CD33 on cellular functions critical tomicroglia. Successful completion of these studies will pinpoint D2-CD33 as the primarypharmacologic target in this locus to reduce AD risk.

project_terms:
Alleles;Alzheimer's Disease;Alzheimer's disease risk;Antibodies;Binding;Binding Proteins;Brain;Cell Line;Cell physiology;Cell surface;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Data;Exons;Extracellular Domain;Family;Financial compensation;Gene Expression;Genes;Genetic;Genetic Polymorphism;ITIM;Immunoglobulins;Immunosuppression;Lectin;Length;Ligand Binding Domain;Link;Location;Logic;Mediating;Microglia;Modeling;Molecular Genetics;Natural Immunity;PTPN6 gene;Peptides;Phagocytes;Phagocytosis;Pharmacology;Phosphopeptides;Physiological;Production;Protein Analysis;Protein Isoforms;Proteins;Proteomics;Proxy;RNA Decay;Regulation;Reporting;Risk Factors;Sialic Acids;Signal Transduction;Signaling Protein;Single Nucleotide Polymorphism;Small Interfering RNA;Terminator Codon;Testing;Translating;Variant;Viral;Work;cytokine;gain of function;genetic risk factor;genome wide association study;genomic locus;high risk;immune activation;insertion/deletion mutation;loss of function;member;novel;peroxisome;premature;protective allele

public_health_relevance:
We and others interpreted our prior molecular genetic data as supporting a modelwherein loss of CD33 function protects from Alzheimers disease. However we recentlyfound that genetic deletion of CD33 does not impact AD risk leading to our currenthypothesis that a D2-CD33 isoform mediates AD protection. Here we will compare thefunction of D2-CD33 and CD33 to identify the gain-of-function mechanism whereby D2-CD33 may act to reduce the risk of Alzheimers disease.


application_id: 10033339
project_number: 1R01GM138882-01
administering_ic: NIGMS
award_notice_date: 2020-08-20
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: GM
serial_number: 138882
program_official: BARSKI, OLEG
project_start_date: 2020-09-01
project_end_date: 2024-06-30
study_section: Macromolecular Structure and Function A Study Section[MSFA]
contact_pi_person_id: 8085279
contact_pi: GLAZER, EDITH C
other_pis: HEIDARY, DAVID ;RICHARDS, CHRISTOPHER I
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-09-01
project_terms:
3-Dimensional;Affect;Aromatase;Aromatase Inhibitors;Basic Science;Binding;Biology;CYP17A1 gene;CYP1B1 gene;Cell Line;Cell physiology;Cells;Chemotherapy-Oncologic Procedure;Chimeric Proteins;Cisplatin;Clinical Research;Conflict (Psychology);Cytochrome P450;Cytochrome a;Data;Disease;Dose;Drug resistance;Environment;Environmental Risk Factor;Enzyme Inhibitor Drugs;Enzymes;Estrogen receptor positive;Functional disorder;Generations;Genetic;Genetic Polymorphism;Goals;Half-Life;Heme;Hemeproteins;Homo;Hormones;Hydrophthalmos;Hypoxia;Immune response;In Vitro;Inherited;Iron;Liver;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Medical;Membrane;Metabolic;Metabolic Diseases;Methods;Microscopy;Mitochondria;Modeling;Molecular;Molecular Conformation;Mutagens;Mutation;Mycoses;Nucleotides;Paclitaxel;Patients;Pharmacology;Phase I Clinical Trials;Phenotype;Photobleaching;Physiologic pulse;Play;Point Mutation;Population;Population Distributions;Proteins;Proteolysis;Resistance;Resolution;Role;Scanning;Single Nucleotide Polymorphism;Testing;Thermodynamics;Time;Tissues;Tumor Antigens;Vesicle;Work;cancer cell;cancer initiation;chemotherapy;enzyme activity;epidemiology study;experimental study;fluorescence lifetime imaging;improved;in vivo;inhibitor/antagonist;knock-down;malignant breast neoplasm;mitochondrial membrane;nanoscale;novel;overexpression;protein degradation;protein protein interaction;residence;response;restoration;single molecule;small molecule;small molecule inhibitor;trafficking;tumor;tumor progression


application_id: 10031224
project_number: 1R01DK125801-01
administering_ic: NIDDK
award_notice_date: 2020-07-14
opportunity_number: PA-18-330
application_type: 1
activity_code: R01
ic: DK
serial_number: 125801
program_official: KUCZMARSKI, ROBERT J
project_start_date: 2020-07-15
project_end_date: 2025-06-30
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 10552456
contact_pi: WILLIAMS, LOVORIA B
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: 2020-07-15
project_terms:
Address;Adherence;Adopted;Adult;African American;Aftercare;Age;Behavior;Blood Pressure;Body Weight decreased;Centers for Disease Control and Prevention (U.S.);Church;Clinical;Communities;Community Health Aides;Control Groups;Diet;Early Intervention;Equilibrium;Ethnic group;Expenditure;Future;Gender;Goals;Gold;Individual;Intervention;Intervention Studies;Life Style;Mediating;Mediation;Mediator of activation protein;Mission;Modeling;Morbidity - disease rate;Motivation;National Institute of Diabetes and Digestive and Kidney Diseases;Non-Insulin-Dependent Diabetes Mellitus;Not Hispanic or Latino;Obesity;Outcome;Outcome Measure;Overweight;Participant;Pattern;Phase;Physical activity;Population;Prevalence;Psychosocial Factor;Public Health;Randomized;Research;Research Personnel;Risk Factors;Self Efficacy;Site;Social support;Socioeconomic Status;Standardization;Stress;Structure;Telephone;Time;Training;Translations;Treatment outcome;United States Centers for Medicare and Medicaid Services;Variant;Weight;Work;active control;arm;base;clinically significant;control trial;cost;cost effective;diabetes prevention program;experience;group intervention;improved;intervention cost;intervention effect;intervention program;lifestyle intervention;male;meetings;mortality risk;payment;personalized medicine;personalized strategies;primary outcome;programs;racial and ethnic;response;secondary outcome;sex;sociodemographic variables;standard care;success;treatment arm;treatment group;weight loss intervention


application_id: 10027488
project_number: 75N91019C00054-0-9999-1
project_title: Development of a Machine Learning Model for Prostate Cancer Treatment Planning
administering_ic: NCI
project_start_date: 2019-09-16
project_end_date: 2020-06-15
contact_pi_person_id: 16188204
contact_pi: NICOLALDE, ROBERTO
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 963949107
primary_uei: VKSAV1S1KC77
duns_number: 963949107
uei: VKSAV1S1KC77
fips: US
organization_id: 10027501
organization_name: NICOLALDE R AND D, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40509
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
This projects goal is to develop and test an application that uses Artificial Intelligence (AI) to improve consistency and quality of RT treatment plans for prostate cancer. By understanding expert planner preferences in structure contouring and treatment planning and combining this rationale with data amassed in NRG clinical trials AI models will be trained to produce contours and treatment plans achieving consensus amongst experts and optimal quality of life outcomes based on more clinical evidence than any one experts input.Overall this project will meet a need for improved treatment planning for prostate cancer at reduced economic cost.  This AI system will generate treatment plans that will provide a standard which may be compared against those generated by human planners; in time as teams at individual institutions who employ the product develop greater experience with the system their engagement will foster the achievement of plans at higher quality with lower investment of human capital thereby improving quality of care while reducing costs.

project_terms:
Achievement;Anatomy;Artificial Intelligence;Clinical;Clinical Trials;Computer software;Consensus;Contracts;Data;Development;Dose;Expert Systems;Fostering;Goals;Gold;Human;Individual;Institution;Investments;Knowledge;Learning;Machine Learning;Malignant neoplasm of prostate;Methodology;Modeling;Normal tissue morphology;Outcome;Patient imaging;Patients;Process;Prostate Cancer therapy;Quality of Care;Quality of life;Radiation therapy;Structure;System;Technology;Testing;Time;Training;X-Ray Computed Tomography;base;cost;economic cost;experience;human capital;improved;meetings;preference;prostate cancer model;tool;treatment planning


application_id: 10027404
project_number: 261201800013I-0-759101900129-1
project_title: Virtual Tissue Repository
administering_ic: NCI
project_start_date: 2019-05-28
project_end_date: 2021-05-27
contact_pi_person_id: 16192311
contact_pi: DURBIN, ERIC
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:
Experience and best practices http://biospecimens.cancer.gov/practices/) of the National Cancer Institute (NCI) indicate that the NCI Surveillance Epidemiology and End Results (SEER) Program can support biospecimen research by creating a SEER-linked Virtual Tissue Repository (VTR). A SEER VTR with its population representativeness and large sampling frame would be a unique resource for assembling robust collections of biospecimens even for rare tumors and outcomes.

project_terms:
Collection;Link;Malignant Neoplasms;Molecular;National Cancer Institute;Outcome;Population;Registries;Research;Resources;SEER Program;Sampling;Tissues;case control;experience;rare cancer;repository;virtual


application_id: 10026255
project_number: 2P20GM113226-06
project_title: Project 1 - Yan Li PhD
administering_ic: NIGMS
award_notice_date: 2021-03-25
opportunity_number: PAR-19-312
application_type: 2
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C2)]
subproject_number: 6811
contact_pi_person_id: 9527186
contact_pi: LI, YAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Non-alcoholic steatohepatitis (NASH) a potential precursor of hepatocellular carcinoma (HCC) currently has noFDA-approved treatment. Recent studies of fibroblast growth factor (FGF)19 and FGF21 on metabolism suggestthat endocrine FGFs and their derivatives carry great potential as novel therapeutics to treat metabolic condi-tions including NASH. The Pegylated FGF21 (MS-986036) and FGF19 agonist (NGM282) have been studiedin clinical phase II trials. Our preliminary studies show that the lack of FGF21 accelerates steatohepatities pro-gression and HCC transformation. Overexpression of FGF19/FGF receptor 4 significantly correlated with epithe-lial cell adhesion molecule (EpCAM) as a marker of hepatic cancer stem cells within the fatty liver-steatosis-cirrhosis-HCC sequence in patients. Recent studies indicated that FGF21 down-regulates the Th17-IL-17 axissuppresses NF-B but activates p53 pathways which are the critical anti-cancer mechanism(s). However thereis no evidence demonstrating the specific anticancer effect of FGF21 on the NASH associated HCC. It is alsounknown whether FGF21 could negatively affect the Th17-IL-17 axis and the carcinogenetic signaling to abolishthe carcinogenetic transformation from NASH to HCC. Our central hypothesis is that FGF21 and FGF15/19prevent NASH-HCC through in turn controlling lipolysis clearing excessive FFAs and inhibiting the IL-17A signaling mediated inflammation and carcinogenesis. The hypothesis will be tested in the followingSpecific Aims. Aim 1: Investigate lipid metabolic disorder and IL-17A mediated inflammation during NASH-HCCtransition. Establishing NASH-HCC mice to 1) determine FFA pools (plasma adipose liver and feces) and FAmetabolites by metabolomics; 2) determine metabolic enzymes and components of IL-17A signaling by targetingproteomics. Aim 2: Evaluate the efficacy of FGF21 (LY2405319) and FGF19 (NGM282) against NASH-HCCtransition. Administrating LY2405319/NGM282 in NASH-HCC mice to 1) evaluate NASH score HCC incidencehepatic injury and HCC lesion; 3) determine IL-17A-mediated inflammation/carcinogenesis and tumor-initiatingcells. Aim 3: Explore the preventive mechanism(s) of FGF21/FGF15/19 against NASH-HCC transition. Repro-ducing NASH-HCC in FGF21 knockout (KO) FGF15KO and IL-17A mutation mice to investigate the feedbackloop of FGF21/FGF15/19-IL-17A on molecular target(s) linking to carcinogenetic pathways. The importance ofthis proposal is: 1) to explore pharmacological use of FGF21/FGF15/19 against the NASH-HCC transition; and2) to reveal therapeutic targets and mechanism(s) especially the IL-17 signaling linked carcinogenetic pathwaysduring NASH-HCC transition.

project_terms:
Adipose tissue;Agonist;Attention;Biological Process;Cell Adhesion Molecules;Cells;Centers of Research Excellence;Chimeric Proteins;Cirrhosis;Development;Disease Progression;Doctor of Philosophy;Early treatment;Endocrine;Enzymes;FDA approved;FGF19 gene;FGF21 gene;Fatty Liver;Feces;Feedback;Fibroblast Growth Factor;Goals;Group Structure;Hepatocyte;Hormones;Human;Incidence;Infiltration;Inflammation;Inflammatory;Insulin Resistance;Interleukin-17;Interleukins;Investigation;Knock-out;Knowledge;Lesion;Link;Lipids;Lipolysis;Liver;Malignant neoplasm of liver;Mediating;Metabolic;Metabolic Diseases;Metabolism;Modeling;Molecular Target;Mus;Mutation;Neurons;Nonesterified Fatty Acids;Obesity;Orthologous Gene;Pathway interactions;Patients;Pharmacology;Phase;Phase II Clinical Trials;Plasma;Population;Preventive;Primary carcinoma of the liver cells;Production;Proteomics;Publishing;Research;Risk Factors;Signal Transduction;TLR4 gene;TP53 gene;Testing;Toxicology;Variant;advanced disease;anti-cancer;blood glucose regulation;cancer stem cell;carcinogenesis;clinical application;efficacy evaluation;fatty acid metabolism;fibroblast growth factor receptor 4;high risk;ileum;insight;lipid metabolism;liver injury;markov model;metabolomics;negative affect;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel strategies;novel therapeutic intervention;novel therapeutics;overexpression;polypeptide;prevent;therapeutic target;therapeutically effective;tumor;uptake


application_id: 10026252
project_number: 2P20GM113226-06
project_title: Omics Core
administering_ic: NIGMS
award_notice_date: 2021-03-25
opportunity_number: PAR-19-312
application_type: 2
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C2)]
subproject_number: 6808
contact_pi_person_id: 8487327
contact_pi: ZHANG, XIANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Applications Grants;Attention;Award;Bioinformatics;Biological;Biological Assay;Centers of Research Excellence;Chemicals;Clinical Research;Communities;Complex Mixtures;Continuing Education;Data;Data Analyses;Data Collection;Data Reporting;Development;Disease;Drug Interactions;Ensure;Environment;Equipment;Fatty Liver;Fee-for-Service Plans;Felis catus;Funding;Future;Goals;Health Sciences;Human Resources;Individual;Infrastructure;Institution;Intervention Studies;Leadership;Liver;Liver Dysfunction;Liver diseases;Malignant neoplasm of liver;Mass Spectrum Analysis;Methods;Modality;Modeling;Modification;Molecular Evolution;Peptides;Performance;Phase;Preparation;Procedures;Protein Analysis;Protein Fragment;Proteins;Proteomics;Protocols documentation;RNA;Reagent;Research;Research Activity;Research Personnel;Research Support;Resources;S10 grant;Sampling;Science;Services;Standardization;Statistical Data Interpretation;Techniques;Technology;Toxicology;Training;Training and Education;Translational Research;United States National Institutes of Health;Universities;base;career;career development;clinical infrastructure;data sharing;design;epitranscriptomics;experimental study;innovation;instrument;liver development;liver injury;meetings;member;metabolomics;method development;molecular marker;non-alcoholic;novel;nutrition;operation;problem drinker;programs;sample collection;small molecule;success;theories;tool;toxicant


application_id: 10026251
project_number: 2P20GM113226-06
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2021-03-25
opportunity_number: PAR-19-312
application_type: 2
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C2)]
subproject_number: 6807
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Louisville Hepatobiology and Toxicology COBRE is a multidisciplinary group ofinvestigators focusing on the liver and liver injury gut:liver interactions and liver:environment/toxicant/druginteractions alcoholic and non-alcoholic liver injury infectious liver diseases liver cancer and new livertherapies. The purpose of the administrative core is to provide administrative fiscal and scientific oversight forthis Phase II COBRE. This includes the overall career development and research goals of the Phase IICOBRE (including formative and summative evaluation and specific milestones); the career development plansfor junior faculty (including plans for transitioning to independence); plans for replacing key personnel (e.g.Project PIs Core leaders overall PI pilot project PIs); oversight of the pilot projects; oversight of thebiostatistical support services; and disseminating information to the lay and scientific communities. Liver diseases are some of the most common rapidly increasing and poorly recognized healthproblems afflicting Americans. For example Non-alcoholic fatty liver disease/non-alcoholic steatohepatitisis the most common cause of abnormal liver enzymes in the US affecting about 25% of adults and about 10%of children. Alcoholic Liver Disease is an increasing problem among those who drink. Importantly there is noFDA-approved therapy for either NASH or ALD. Toxicant-Induced Liver Injury is an increasingly recognizedindustrial/environmental problem. Viral Liver Diseases (Hepatitis A B and C) remain major health problemsrelated to drug abuse and homelessness. Hepatocellular carcinoma and Hepatitis C are major causes for liverrelated morbidity and liver transplantation in the US. Drug-Induced Liver Injury is the major reason new drugsdo not come to market and the major cause of fulminant liver failure in the US. Personalized Medicine isincreasingly recognized as an important aspect of drug therapy; and most drugs are metabolized in the liver. Building on the success of the Phase I COBRE Administrative Core the specific aims of this Phase IICOBRE Administrative Core are: 1. continue to provide overall administrative fiscal and scientific oversight 2. enhance and grow the career development enterprise for project PIs 3. enhance and grow the career development/mentor development enterprise for the mentors 4. enhance and grow the research goals of the COBRE 5. continue to provide a process for replacing key personnel 6. continue to provide and enhance a summative and formative evaluation process for the COBRE including specific milestones 7. continue to provide a robust pilot project program to grow the overall research goals of the COBRE 8. disseminate pertinent information to the scientific and lay community

project_terms:
Acute Liver Failure;Adult;Affect;Alcoholic Liver Diseases;Alcohols;American;Area;Bioinformatics;Biometry;Budgets;Cancer Grant Supplements (P30);Centers of Research Excellence;Child;Clinical Trials;Communities;Community Outreach;Conflict (Psychology);Country;Development;Development Plans;Diabetes Mellitus;Drug Interactions;Drug abuse;Ensure;Environment;Environmental Health;Enzymes;Evaluation;FDA approved;Faculty;Funding;Goals;Grant;Health;Hepatitis A;Hepatitis C;Homelessness;Human Resources;Individual;Industrialization;Italy;Kentucky;Letters;Liver;Liver diseases;Malignant neoplasm of liver;Mentors;Morbidity - disease rate;National Institute of Environmental Health Sciences;National Institute on Alcohol Abuse and Alcoholism;Obesity;Overweight;Pharmaceutical Preparations;Pharmacology and Toxicology;Pharmacotherapy;Phase;Physicians;Pilot Projects;Population;Primary carcinoma of the liver cells;Process;Public Health;Research;Research Infrastructure;Research Personnel;Rural;Scientist;Services;Structure;Superfund;Teacher Professional Development;Text;Toxicology;United States National Institutes of Health;Universities;Viral hepatitis;career development;faculty mentor;faculty research;formative assessment;improved;liver injury;liver metabolism;liver transplantation;microbiome;microbiome research;multidisciplinary;non-alcoholic;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel therapeutics;opioid abuse;personalized medicine;problem drinker;programs;ranpirnase;recruit;research and development;senior faculty;success;toxicant;tumor immunology;viral liver disease


application_id: 10026250
project_number: 2P20GM113226-06
project_title: Hepatobiology and Toxicology COBRE
administering_ic: NIGMS
award_notice_date: 2021-03-25
opportunity_number: PAR-19-312
application_type: 2
activity_code: P20
ic: GM
serial_number: 113226
program_official: NANDA, JAGPREET SINGH
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C2)]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute Liver Failure;Address;Adult;Affect;Alcoholic Liver Diseases;American;Area;Basic Science;Biomedical Research;Centers of Research Excellence;Child;Cirrhosis;Collaborations;Communication;Communities;Complex;Core Facility;Data Analyses;Development;Diabetes Mellitus;Discipline;Drug Interactions;Drug abuse;Ensure;Environment;Enzymes;FDA approved;Fostering;Funding;Goals;Grant;Health;Hepatitis A;Hepatitis B;Hepatitis C;Home;Homelessness;Industrialization;Industry;Injury;International;Kentucky;Laboratories;Link;Liver;Liver Failure;Liver diseases;Mentors;Metabolic syndrome;Metabolism;Molecular Target;Morbidity - disease rate;National Institute on Alcohol Abuse and Alcoholism;Obesity;Organ;Overweight;Pharmaceutical Preparations;Pharmacotherapy;Phase;Phase I Clinical Trials;Prevention;Primary carcinoma of the liver cells;Process;Program Sustainability;Publications;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Scientist;Structure;Technology;Therapeutic;Toxic Environmental Substances;Toxicant exposure;Toxicology;Translational Research;United States National Institutes of Health;Universities;University resources;biobank;career development;clinical practice;education research;experience;liver injury;liver transplantation;member;multidisciplinary;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel therapeutics;nutrition;personalized medicine;prevent;programs;recruit;success;toxicant;viral liver disease


application_id: 10025904
project_number: 1R21CA251042-01
project_title: Bio CaRGOS: Capture and release gels for optimized storage of Cancer Biospecimens
administering_ic: NCI
award_notice_date: 2020-07-27
opportunity_number: RFA-CA-19-021
application_type: 1
activity_code: R21
ic: CA
serial_number: 251042
program_official: AGRAWAL, LOKESH
project_start_date: 2020-08-01
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZCA1 TCRB-J (M1)]
contact_pi_person_id: 15717479
contact_pi: GUPTA, GAUTAM
other_pis: KEYNTON, ROBERT S;LINDER, MARK W
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:
Biomarkers play a central role in the detection diagnosis management and monitoring of patientswith cancer. Factors such as analytical sensitivity and reproducibility are critical to the clinicalutility of plasma based biomarkers in the setting of longitudinal surveillance and early detection ofdisease and or recurrence. Currently the state of preservation of biospecimens is accomplishedprimarily using sub freezer techniques and it is cost prohibitive and certainly not practical in mostscenarios. There is clearly a dearth of techniques that can preserve the biospecimens at roomtemperature for long periods of time. Therefore there is a critical unmet clinical need for storinga plethora of biospecimens acquired routinely. Here we propose to demonstrate stability and integrity of Pancreatic Cancer Specificbiomarkers (CA-A19 miRNA21 and ctDNA) in buffers as well as plasma for extended periods oftime at room temperature. There are several hurdles that must be overcome to realize thestabilization of biomarkers in plasma directly due to its inherent complex nature. The proposedtechnology is based upon our innovation in developing CaRGOS: Capture and Release Gels forOptimized storage of Biospecimens. The technical impact of the proposed methodology isachievement of instantaneous one-step aqueous biospecimen preservative method for cancerresearch and clinical samples of interest. The proposed technology is extremely simple userfriendly eliminates several complex processes and more importantly requires no substantialequipment. The key scientific impact includes our fundamental insight into the interactions of thebiomarkers and other proteins/solute with silica precursors. Based on this fundamental principlethe methodology can be easily expanded to other research areas including clinical samplesantigens bio-pharmaceuticals drugs viruses and cell lines. If successful the innovativeproposed research will result in a paradigm shift in storage and preservation of CancerBiospecimens in aqueous formulations that current techniques are unable to achieve.

project_terms:
Achievement;Address;Albumins;Amylases;Antigens;Area;Biological Markers;Biomass;Buffers;Cancer Model;Cell Line;Chemicals;Clinical;Colloids;Complex;Cryopreservation;DNA;Detection;Diagnosis;Disease;Early Diagnosis;Electrolytes;Equipment;Escherichia coli;Experimental Designs;Fibrinogen;Formulation;Freezing;Gel;Globulins;Glucose;Goals;Hemoglobin;Human;Hydrolysis;Immunoassay;Individual;Ionic Strengths;Knowledge;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Methodology;Methods;Modeling;Monitor;Nature;Oxides;Patient Monitoring;Performance;Pharmaceutical Preparations;Pharmacologic Substance;Phosphate Buffer;Physiological;Plasma;Plasma Proteins;Play;Polymerase Chain Reaction;Process;Property;Proteins;RNA;Recovery;Recurrence;Reproducibility;Research;Retrieval;Reverse Transcription;Role;Saline;Sampling;Silanes;Silicon Dioxide;Structure;Techniques;Technology;Temperature;Testing;Time;Uric Acid;Virus;anticancer research;aqueous;base;biomaterial compatibility;cancer biomarkers;clinical diagnostics;cost;digital;high reward;high risk;innovation;insight;interest;macromolecule;microwave electromagnetic radiation;preservation;solute;specific biomarkers;user-friendly

public_health_relevance:
The proposed transformational Capture and Release gels strive to address clinical unmet need for long-term storage of cancer biospecimens at room temperature.


application_id: 10025186
project_number: 5R01NS102920-02
project_title: Transformation of Paraplegic Paralysis to Overground Stepping in Humans
administering_ic: NINDS
award_notice_date: 2020-08-18
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 102920
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2019-09-30
project_end_date: 2024-08-31
study_section: Bioengineering of Neuroscience, Vision and Low Vision Technologies Study Section[BNVT]
contact_pi_person_id: 10737162
contact_pi: GERASIMENKO, YURY
other_pis: EDGERTON, REGGIE
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Agonist;Ankle;Awareness;Body Weight;Buspirone;Chronic;Clinic;Communities;Cutaneous;Development;Devices;Diagnosis;Effectiveness;Electrodes;Family Caregiver;Force of Gravity;Generations;Goals;Health;Health Care Costs;Hip region structure;Human;Individual;Injury;Intervention;Knee;Lead;Lesion;Locomotion;Lower Extremity;Mediating;Motion;Motor;Motor Activity;Movement;Mus;Musculoskeletal Equilibrium;Neurostimulation procedures of spinal cord tissue;Outcome;Painless;Paralysed;Paraplegia;Performance;Pharmacology;Probability;Property;Quality of life;Rattus;Recovery;Recovery of Function;Sensory;Series;Site;Speed;Spinal;Spinal Cord;Spinal Injuries;Spinal cord injury;Spinal cord injury patients;Step training;Technology;Training;Volition;Walkers;Weight-Bearing state;connectome;cost;exoskeleton;exoskeleton device;experience;experimental study;improved;insight;limb movement;motor control;motor function improvement;motor function recovery;neuroregulation;novel;relative effectiveness;robot assistance;robotic device;technology development;tool;treadmill


application_id: 10023829
project_number: 261201800013I-0-759101900130-1
administering_ic: NCI
project_start_date: 2019-09-18
project_end_date: 2021-03-17
contact_pi_person_id: 16187748
contact_pi: DURBIN, ERIC
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_title:
NCI Patterns of Care (POC)/Quality of Care Study: Diagnosis Years 2017(NSCLC) and 2018 (NSCLC and Melanoma)

project_abstract:
SEER Patterns of Care Studies describe characterize and compare practice patterns and treatments provided for cancer in different geographic areas of the United States. SEER Patterns of Care/Quality of Care Studies (POC/QOC) are conducted to satisfy a Congressional directive (under Public Law 100-607 Sec. 413 (a) (2) (C) adopted November 4 1988) to the National Cancer Institute (NCI) to assess the incorporation of state-of-the-art cancer treatments into clinical practice and the extent to which cancer patients receive such treatments and include the results of such assessment in the biennial reports. To select the cancers to satisfy this directive the Division of Cancer Control and Population Sciences has been working closely with the Division of Cancer Treatment. This years Patterns of Care (POC) Study shall investigate state-of-the-art therapies for patients with advanced skin melanoma and advanced non-small cell lung cancer.

project_terms:
Adjuvant Therapy;Adopted;Age;Beds;Body Weight decreased;Cachexia;Cancer Patient;Characteristics;Clinical;Clinical Trials;Communities;Community Practice;Comorbidity;Cutaneous Melanoma;DNA Sequence Alteration;Diagnosis;Diagnostic tests;Distress;Division of Cancer Control and Population Sciences;Educational process of instructing;Ethnic Origin;Fatigue;Financial Hardship;Financial Support;Geographic Locations;Health Professional;Hospitals;Insurance Coverage;Laws;Malignant Neoplasms;Medical Records;Mental Depression;National Cancer Institute;Nausea and Vomiting;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Outcome;Pain;Patient Care;Patients;Pattern;Patterns of Care;Physicians;Quality of Care;Race;Radiation therapy;Reporting;Systemic Therapy;United States;Vomiting;associated symptom;cancer therapy;clinical practice;melanoma;nutrition;psychosocial;sex;targeted treatment


application_id: 10023142
project_number: 5F30AG063422-02
administering_ic: NIA
award_notice_date: 2020-06-23
opportunity_number: PA-19-192
application_type: 5
activity_code: F30
ic: AG
serial_number: 063422
program_official: DIBATTISTA, AMANDA
project_start_date: 2019-09-29
project_end_date: 2021-09-28
study_section: Special Emphasis Panel[ZRG1-F03A-N(20)L]
contact_pi_person_id: 15251375
contact_pi: FARMER, BRANDON CHARLES
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-09-29
project_title:
Astrocyte Lipid Droplets as a Novel Mechanism for Impaired Glucose Metabolism in the E4 and AD Brain

project_abstract:
PROJECT SUMMARY Alzheimers disease (AD) is a societal burden costing the nation 277 billion dollars per year and is thesixth leading cause of death. As the search for disease modifying therapies for AD continues a deeperunderstanding of cellular metabolism in the AD brain is critical to guide research. The apolipoprotein E (APOE)gene is the strongest genetic predictor of late onset AD (LOAD). In humans there are three major isoforms ofapoE: E2 E3 and E4. E3 is the major isoform expressed in humans (~60% of population). E4 confers betweena 2 (heterozygous) to 15-fold (homozygous) increase in risk of LOAD compared to E3. Apolipoprotein E (apoE)is primarily secreted by astrocytes as a primary lipid carrier in the brain and has gained traction as a regulatorof cerebral metabolism. For example E4 carriers exhibit decreased glucose uptake as measured by 18fludeoxy-glucose positron emission tomography (FDG-PET). FDG-PET is similarly lower in AD individuals however E4carriers show low FDG-PET decades before the onset of symptomatic cognitive decline. We recently showedthat E4 expressing astrocytes accumulate significantly more lipid in the form of lipid droplets (LDs) compared toE3 an intriguing finding in light of the initial 1907 report from Alzheimer that implicated glial lipid accumulationas a hallmark of disease. Since LDs have been shown to be involved in metabolic disease  including regulationof glucose uptake  we hypothesize that over accumulation of astrocyte LDs drive the impaired glucose uptakeseen in E4 and AD brains. Therefore this proposal tests a mechanism by which an LD-associated proteinsequesters a critical mediator of glucose transporter trafficking leading to a decrease in astrocyte glucoseuptake. We will test this mechanism (Aim 1A) in vivo in mice homozygous for human E3 and E4 and (Aim 1B-C) in vitro in primary astrocytes that express human E3 and E4. We will also translate our findings (Aim 2) bycharacterizing LD formation in APOE genotyped human post-mortem brain tissue correlating lipid abundancewith clinical data from the UK Alzheimers Disease Center cohort. The key focus of this fellowship is to uncovera cellular mechanism driving impaired glucose uptake in E4 astrocytes as well as equip the trainee with skills inmass spectrometry confocal microscopy immunohistochemistry radioactive tracing translational humanspecimen handling data analysis and more. These skills and excellent mentorship will be instrumental in thetrainees path to become an independent physician-scientist.

project_terms:
Address;Adipose tissue;Alleles;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease risk;Alzheimer's disease therapy;Amyloid;Apolipoprotein E;Astrocytes;Attention;Automobile Driving;Autopsy;Biological Assay;Brain;Cause of Death;Cell membrane;Cells;Cerebrum;Characteristics;Clinical;Clinical Data;Cognitive;Cognitive deficits;Confocal Microscopy;Cytosol;Data;Data Analyses;Development;Dietary Intervention;Disease;Etiology;Exhibits;Fellowship;Genes;Genetic;Genotype;Glucose;Glucose Transporter;High Fat Diet;Human;Immunohistochemistry;Impaired cognition;Impairment;In Vitro;Individual;Label;Late Onset Alzheimer Disease;Lead;Ligation;Light;Link;Lipids;Location;Mass Spectrum Analysis;Measures;Mediating;Mediator of activation protein;Mentorship;Metabolic;Metabolic Diseases;Metabolism;Mus;Neuroglia;Neurons;Pathogenesis;Patients;Physicians;Population;Positron-Emission Tomography;Process;Protein Isoforms;Proteins;Radioactive;Reporting;Research;Resolution;Risk;Role;SLC2A1 gene;SNAP23 gene;Saccule structure;Scientist;Source;Specimen;Specimen Handling;Testing;Tracer;Traction;Translating;apolipoprotein E-4;biobank;blood glucose regulation;brain tissue;cell type;clinically relevant;cohort;cost;fluorodeoxyglucose positron emission tomography;genetic predictors;genetic risk factor;glucose metabolism;glucose uptake;impaired driving performance;in vivo;insight;neuropathology;non-demented;novel;perilipin;skills;therapeutic target;trafficking;uptake

public_health_relevance:
PROJECT NARRATIVE The strongest genetic risk factor for the development of late-onset Alzheimers Disease (AD) isapolipoprotein E4 (E4) and research into how E4 contributes to this risk is critical to find therapeutictargets. Glial lipid droplet (LD) accumulation and glucose hypometabolism are shared characteristicsof the AD and non-AD E4 brain. This project characterizes an E4-associated astrocyte LDaccumulation and its clinical relevance in post-mortem human brain tissue presenting a novelmechanism underlying E4-driven glucose hypometabolism.


application_id: 10022341
project_number: 5U01HL152392-02
project_title: Kentucky Network for Innovation & Commercialization (KYNETIC)
administering_ic: NHLBI
award_notice_date: 2020-08-17
opportunity_number: RFA-OD-19-014
application_type: 5
activity_code: U01
ic: HL
serial_number: 152392
program_official: ROUSCHE, KATHLEEN T
project_start_date: 2019-09-23
project_end_date: 2023-08-31
study_section: ZHL1-CSR-O(S1)
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: BATES, PAULA J.
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:
ABSTRACTKnowledge generated by academic research is a major source of health-related innovations. Transforminginnovative discoveries into commercialized products that improve human health is a difficult process. Howeverall stakeholders (universities funding bodies pharmaceutical and medical device industries federal and stategovernments and the public) have a vested interest in identifying scalable approaches that accelerate thetranslation of academic innovations into biomedical products. The goal of the Kentucky Network for Innovationand Commercialization (KYNETIC) is to build a Research Evaluation and Commercialization Hub (REACH)network of commercialization resources accessible across the entire Commonwealth of Kentucky to acceleratetranslation of academic innovations into biomedical products. To reach this goal the following aims will beconducted: 1) establish KYNETICs organizational and collaborative structure; 2) Find fund and manage productdefinition/development projects; 3) Provide mentoring skills development experiential education and networkingopportunities with industry experts entrepreneurs and investors; and 4) Devise and implement a plan totransition to a self-sustaining entity. KYNETIC will build on lessons learned from developing a regional IDeAtechnology transfer accelerator (at UK) and a current REACH hub (at UL). KYNETIC will be led by the Universityof Kentucky (UK) in partnership with the University of Louisville (UL) and the Commonwealth CommercializationCenter (C3) a private 501(c)3 non-profit commercialization organization. Also KYNETIC will include all ofKentuckys public regional universities and community and technical college system (KCTCS). KYNETICsmission is to nurture innovations and academic innovators by providing funding mentoring education and anetwork of relevant expertise. Required matching funds for KYNETIC have been committed in full by KentuckyCommonwealth Economic Development (CED) and the state R1 universities. KYNETIC will be directed by aleadership team consisting of 2 academic innovators 2 technology transfer professionals (from UK and UL) and2 representatives from partnering entities (C3 and CED). A steering committee including the leadership teamand representatives from each participating institution an External Review Board and the NIH will review andevaluate KYNETIC projects and fund up to 13 projects/yr using an innovative quick kill management strategy.Our services will be available to as many individuals as possible. Diverse role models including innovators andentrepreneurs from underrepresented groups will be sought. The proposed Kentucky-wide REACH program willleverage our collective wealth of resources ecosystems and extensive experience to apply and expand bestpractices for innovator education and mentoring. The overall impact of KYNETIC will be unprecedentedopportunities for collaboration and synergy well-prepared innovators a statewide pro-entrepreneurial cultureand delivery of de-risked technologies to benefit health and overcome the states health disparities.

project_terms:
Address;Area;Back;Biomedical Research;Businesses;Clinic;Collaborations;Complement 3a;Development;Devices;Diagnostic tests;Economic Development;Economics;Ecosystem;Education;Entrepreneurship;Evaluation Research;Federal Government;Fund Raising;Funding;Goals;Grant;Health;Health Benefit;Human;Individual;Industry;Institution;Kentucky;Knowledge;Laboratories;Leadership;Licensing;Medical Device;Mentors;Mission;Modeling;Paper;Pharmacologic Substance;Principal Investigator;Private Sector;Privatization;Process;Publishing;Research;Resources;Risk;Services;Site;Source;State Government;Structure;System;Technology;Technology Transfer;Text;Translational Research;Translations;Underrepresented Groups;United States;United States National Institutes of Health;Universities;Work;biomedical resource;college;commercialization;community college;experience;health disparity;improved;industry partner;innovation;interest;member;novel therapeutics;programs;public-private partnership;role model;skill acquisition;synergism;technical college;tool

public_health_relevance:
NARRATIVEThe goal of the Kentucky Network for Innovation and Commercialization (KYNETIC) is to build a ResearchEvaluation and Commercialization Hub (REACH) network of commercialization resources accessible across theentire Commonwealth of Kentucky to accelerate translation of academic innovations into biomedical products.KYNETIC will nurture innovations and academic innovators by providing funding mentoring education and anetwork of relevant expertise. The overall impact of KYNETIC will be unprecedented opportunities forcollaboration and synergy well-prepared innovators a statewide pro-entrepreneurial culture and delivery of de-risked technologies to benefit health and overcome the states health disparities.


application_id: 10019860
project_number: 7R01AR073906-02
project_title: Epigenetic control of muscle stem cell function by PASK-Wdr5 signaling
administering_ic: NIAMS
award_notice_date: 2020-02-25
opportunity_number: PA-18-590
application_type: 7
activity_code: R01
ic: AR
serial_number: 073906
program_official: BOYCE, AMANDA T
project_start_date: 2020-02-25
project_end_date: 2024-11-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 10909082
contact_pi: KIKANI, CHINTAN K
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acetylation;Acute;Adult;Affect;Age;Aging;Binding;Cell Count;Cell physiology;Cells;Collaborations;Complex;Cues;Data;Disease;Epigenetic Process;Equilibrium;FRAP1 gene;Functional disorder;Genetic Transcription;Goals;Histone H3;Histones;Homeostasis;Human;Injury;Insulin;Legal patent;Lysine;Maintenance;Messenger RNA;Metabolism;Modeling;Modification;Molecular;Mus;Muscle;Muscle Cells;Muscle function;Muscle satellite cell;Muscular Atrophy;Muscular Dystrophies;Myoblasts;Myogenin;Myopathy;Natural regeneration;Nutrient;Pathway interactions;Phosphorylation;Phosphotransferases;Physiological;Play;Population;Process;Proliferating;Property;Protein Kinase;Proteins;Publishing;Reagent;Research;Research Proposals;Role;Signal Pathway;Signal Transduction;Stem cells;Structure;Testing;Therapeutic;Transcription Process;Transferase;Trauma;WD Repeat;Wasting Syndrome;base;functional loss;hormonal signals;human disease;in vivo;inhibitor/antagonist;injured;interest;member;mouse model;muscle aging;myogenesis;normal aging;novel;novel therapeutics;off-patent;overexpression;programs;promoter;recruit;regenerative;response;sarcopenia;self-renewal;stem cell differentiation;stem cell fate specification;transcription factor


application_id: 10018961
project_number: 5DP5OD028155-03
project_title: Histamine in homes: Exposure risks and health effects
administering_ic: OD
award_notice_date: 2020-08-25
opportunity_number: RFA-RM-18-010
application_type: 5
activity_code: DP5
ic: OD
serial_number: 028155
program_official: MILLER, BECKY
project_start_date: 2019-09-16
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1-PSE-H(70)]
contact_pi_person_id: 15186293
contact_pi: DEVRIES, ZACHARY
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: 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_terms:
Address;Adjuvant;Affect;Alcoholic Beverages;Allergens;Allergic Disease;Archives;Arthropods;Asthma;Atopic Dermatitis;Award;Bacteria;Bedbugs;Beds;Behavior;Biological;Biology;Biotechnology;Blood;Bypass;Canis familiaris;Cell Culture Techniques;Characteristics;Chemicals;Chronic;Communities;Defecation;Deposition;Dermal;Development;Disadvantaged;Dust;Educational process of instructing;Eligibility Determination;Entomology;Environmental Health;Environmental Pollution;Environmental Risk Factor;Epidemiology;Exposure to;Extrinsic asthma;Faculty;Fecal analysis procedure;Feces;Fishes;Food;Funding;Health;Health Care Costs;Histamine;Histamine Production;Home environment;House Dust;Human;Hygiene;Hypersensitivity;Hypersensitivity skin testing;Immune response;Indoor environment;Inflammation;Infrastructure;Ingestion;Institution;International;Leadership;Life;Location;Low income;Mass Fragmentography;Mentors;Mentorship;Microbe;Mus;National Institute of Environmental Health Sciences;Outcome;Personal Satisfaction;Phase;Postdoctoral Fellow;Prevalence;Productivity;Pruritus;Public Health;Publications;Quality of life;Reaction;Research;Research Personnel;Research Support;Risk;Risk Factors;Sampling;Science;Scientist;Skin;Source;Spatial Distribution;Testing;Training;United States;United States National Institutes of Health;Universities;Vasodilation;Wages;air sampling;allergic response;asthmatic;career;clinical effect;clinically relevant;cohort;combat;cost;dermal exposure;environmental toxicology;experience;exposed human population;feeding;gut microbiome;inner city;innovation;interdisciplinary approach;multidisciplinary;neuroregulation;post-doctoral training;programs;residence;respiratory;rho;stem;undergraduate student


application_id: 10018812
project_number: 5UH3CA233282-03
project_title: (ACCSIS) Accelerating Colorectal Cancer Screening through Implementation Science in Appalachia
administering_ic: NCI
award_notice_date: 2020-08-21
opportunity_number: RFA-CA-17-038
application_type: 5
activity_code: UH3
ic: CA
serial_number: 233282
program_official: GRIMES, GENEVIEVE M
project_start_date: 2018-09-19
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZRG1-AARR-N(52)R]
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: PASKETT, ELECTRA D.
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Modified Project Summary/Abstract SectionThis multi-site project aims to increase screening and follow-up for colorectal cancer (CRC) in central Appalachia a medically underserved region recognized as one of three distinct hotspots for CRC mortality. Specifically the Appalachian Regional Commission classifies 32 eastern Ohio (OH) counties and the 54 counties in eastern Kentucky (KY) as north central and central Appalachia respectively. CRC incidence and mortality rates in the area are among the highest in the nation and neither state meets the national target of 80% of eligible residents screened for CRC. There have been few randomized intervention trials addressing multiple levels of influence on CRC screening behaviors and outcomes in this region. To address this gap investigators at the University of Kentucky and The Ohio State University will build on a 12-year collaborative history strong relationships with Appalachian communities and health clinics and extensive experience with community-based cancer prevention and control intervention research to develop implement and evaluate a multilevel intervention (MLI)  adapted from evidence-based interventions that include components targeting clinics and providers (in-reach) and the community (outreach)  to increase CRC screening follow-up and referral-to-care among patients age 50-74 in 12 counties in Appalachian KY and OH. The overall goals of this project are to contribute to the evidence-base for a MLI that increases rates of CRC screening follow-up and referral-to-care particularly in rural medically underserved populations and help showcase best practices for how MLIs can be scaled-up to reduce the burden of CRC in the U.S. For the Planning-Exploratory Phase (UG3) in Year 1 our specific aims are to: 1) Pilot test measure and refine a MLI to increase rates of CRC screening follow-up and referral-to-care in Appalachian OH and Appalachian KY; and 2) Provide evidence supporting transition to the Implementation Phase (UH3) [per NCI approval]. For the Implementation Phase (UH4) in Years 2-5 our specific aims are to: 1) Test the revised MLI in a group randomized trial delayed intervention to assess the impact of the MLI on increasing rates of CRC screening follow-up and referral-to-care among Appalachian KY and Appalachian OH populations; and 2) Assess dissemination and sustainability of the intervention. The project will be implemented in collaboration with community and clinical partners in 12 counties 6 in Ohio and 6 in Kentucky. Counties will be randomized to early or delayed intervention after baseline data collection. The main outcome will be CRC screening as defined by US Preventive Services Task Force guidelines and measured by clinic electronic health records and county- level behavioral assessments using random digit dialed telephone surveys similar to CDCs Behavioral Risk Factor Surveillance System. Our work will be accomplished through collaboration with the ACCSIS Coordinating Center other ACCSIS Research Projects ACCSIS Steering Committee and Workgroups NCI and community partners. If effective this MLI will be disseminated to our clinical and community partners throughout Appalachia.

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


application_id: 10018717
project_number: 5R44ES028171-04
project_title: Targeted Lead (Pb) Removal for Drinking Water Purification Using INCION
administering_ic: NIEHS
award_notice_date: 2020-08-10
opportunity_number: PA-18-574
application_type: 5
activity_code: R44
ic: ES
serial_number: 028171
program_official: HENRY, HEATHER F
project_start_date: 2017-09-15
project_end_date: 2022-05-16
study_section: Special Emphasis Panel[ZRG1-IMST-B(12)B]
contact_pi_person_id: 14657253
contact_pi: BOEHME, LINDSAY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079388085
primary_uei: JD9MTUKKNG13
duns_number: 079388085
uei: JD9MTUKKNG13
fips: US
organization_id: 10036767
organization_name: POWERTECH WATER, INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40508
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYLead contamination in drinking water is a pervasive health problem across the US. Children areespecially vulnerable to lead poisoning which can have permanent detrimental effects on braindevelopment. Despite corrosion prevention measures taken by public water authorities leadconcentrations in drinking water are routinely elevated nationwide. The EnvironmentalProtection Agency (EPA) established The Lead and Copper Rule in 1991 to limit exposure ofthese elements and set the action level to 15 ppb; however there is no safe level of leadconsumption. The crisis observed in Flint Michigan in 2014 put lead exposure into the publicspotlight increasing consumer awareness.Lead filters currently on the market lack specificity with limited device lifetime dictated by thetotal amount of water volume filtered regardless of lead concentration. PowerTech Water's(PTW) INCION M-Series technology platform is a multifunctional chemical/electrochemicalapproach with  90% specificity for lead removal termed capacitive coagulation; a hybrid ofadsorption (capacitive) and immobilization (coagulation) mechanisms that permanently removeall forms of dissolved lead both complexed and free ions.In this Phase II project PTW's goal is to understand how to develop and validate a 2ndgeneration INCION M-series POU/POE system for dissolved lead removal from drinking waterthat exceeds the performance of current off-the-shelf solutions. The device will be reliable andspecific for lead have a multi-year system lifetime and will not be consumed by abundant waterconstituents. These performance targets will be achieved through the following Specific Aims:1. Factorial design of experiments testing to meet certification. Expected outcome: INCION M- Series performance to meet NSF certification standards NSF/ANSI 53 and 61.2. Investigate electrochemical coagulation mechanisms to tune operating parameters for specific water chemistries. Expected outcomes: Determine the operating parameters that will best exploit capacitive coagulation for lead removal in different water sources and develop an operating matrix.3. Parametric testing of system operations towards the design of a POU/POE device. Expected outcome: A set of design specifications to develop the INCION device into a commercial product.

project_terms:
Adsorption;American;Awareness;Brain;Certification;Chemicals;Chemistry;Child;Coagulation Process;Communities;Complex;Consumption;Copper;Corrosion;Country;Development;Devices;Disinfectants;Disinfection;Elements;Engineering;Excision;Filtration;Generations;Goals;Guidelines;Hardness;Health;Hybrids;Immobilization;Ions;Knowledge;Lead;Lead Poisoning;Lead levels;Light;Maintenance;Michigan;Monitor;Outcome;Performance;Phase;Prevention Measures;Process;Radar;Sampling;Science;Series;Source;Specificity;System;Technology;Testing;Time;United States Environmental Protection Agency;Water;Water Purification;alkalinity;authority;base;contaminated water;cost;design;drinking water;experimental study;high risk drinking;lead concentration;lead contamination;lead exposure;lead oxide;meetings;operation;oxidation;residence;water environment;water quality

public_health_relevance:
PROJECT NARRATIVEUnaware to most people lead in drinking water is one the greatest health threats in the UnitedStates and the Environmental Protection Agency (EPA) emphasizes that there is no safe levelof lead exposure. PowerTech Water's goal is to develop the fundamental knowledge andunderstanding of the science and engineering required to produce a point-of-use/point-of-entry(POU/POE) drinking water purification device that is highly specific for lead more reliableefficient and lasts longer than state-of-the-art solutions. If successful this technology will deliversafe drinking water in a low-cost low-complexity and low-maintenance format.


application_id: 10017946
project_number: 5R01DE024509-07
project_title: Filifactor alocis interactions with neutrophils
administering_ic: NIDCR
award_notice_date: 2020-08-05
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DE
serial_number: 024509
program_official: MCNEALY, TAMARA L
project_start_date: 2014-07-01
project_end_date: 2024-08-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 8652094
contact_pi: URIARTE, SILVIA M
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_terms:
Address;Adult;Affect;Alveolar Bone Loss;Anaerobic Bacteria;Apoptosis;Apoptotic;Bacteria;Biology;Bone Marrow;Cells;Chemotaxis;Communities;Complex;Cytoplasmic Granules;Data;Development;Disease;Disease Progression;Etiology;Exocytosis;Experimental Models;Focal Infection;Foundations;Fusobacterium nucleatum;Gene Expression;Generations;Gingiva;Goals;Health Status;High-Throughput Nucleotide Sequencing;Human;Immune;Immune response;In Vitro;Indigenous;Infection;Inflammation;Inflammatory;Inflammatory Response;Intention;Knowledge;Laboratories;Leukocytes;Longevity;Mediating;Molecular;Mus;NF-kappa B;Oral;Oral health;Organism;Pathogenesis;Pathogenicity;Pathology;Periodontal Diseases;Periodontal Pocket;Periodontitis;Phagocytes;Phagosomes;Play;Porphyromonas gingivalis;Process;Proteins;Publishing;Reactive Oxygen Species;Regulation;Research;Research Personnel;Rod;Role;Secure;Signal Pathway;Signal Transduction;Site;Stimulus;TLR2 gene;Techniques;Testing;Tissues;United States;Virulence;Work;antimicrobial;bactericide;bone loss;chronic inflammatory disease;combat;cytokine;defined contribution;density;dysbiosis;extracellular;host-microbe interactions;in vivo;in vivo Model;innovation;microbial;microbial community;microbicide;microbiota;neutrophil;novel therapeutic intervention;oral bacteria;oral biofilm;oral pathogen;pathogenic bacteria;periodontopathogen;preservation;prevent;programs;recruit;response;trafficking;transcriptome;transcriptome sequencing


application_id: 10017391
project_number: 7R01AR072061-03
project_title: Myostatin Alters Muscle Composition as The Result of an ACL Injury
administering_ic: NIAMS
award_notice_date: 2019-09-18
opportunity_number: PA-16-160
application_type: 7
activity_code: R01
ic: AR
serial_number: 072061
program_official: CARIFI, EMILY FORAN
project_start_date: 2018-03-26
project_end_date: 2023-02-28
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 11267737
contact_pi: FRY, CHRISTOPHER
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractAnterior cruciate ligament (ACL) reconstruction surgery results in protracted quadriceps weakness that isassociated with poorer outcomes altered biomechanics and heightened risk of subsequent injuries. Littleprogress has been made in improving quadriceps strength and functional outcomes in the past decade.Alterations in the cellular and morphological composition of the knee extensor muscles contribute to weaknessfollowing an ACL reconstruction. ACL reconstruction induces expression of myostatin a negative regulator ofmuscle growth locally within the quadriceps. In addition to mitigating muscle regrowth myostatin alsopromotes connective tissue synthesis through activation of figrogenic cells within muscle. The objective ofthis proposal is to determine the time course of deleterious changes to the injured ligament and limb muscleand identify myostatin as integral in the etiology of protracted muscle weakness in individuals following an ACLtear. Aim 1 will evaluate the timeframe of myostatin induction within the injured ACL and quadriceps. Aim 2will determine the deleterious changes within the muscle using a mouse model of ACL injury and the efficacyof follistatin and a soluble form of the myostatin receptor (activin 2B receptor) to mitigate these maladaptations.Experiments in aim 3 will determine if the competitive inhibition of myostatin is capable of rescuing ACL injury-induced skeletal muscle weakness. Finally aim 4 will define if the acute induction of myostatin signalingfollowing an ACL injury in human subjects predicts reductions in muscle strength connective tissue infiltrationand dysregulation of skeletal muscle progenitor cells. The identification of myostatin as a therapeutic targetwill establish the basis for further research to mitigate myostatin signaling after ACL and other ligamentousinjuries to improve rehabilitative efforts and patient recovery.

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

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


application_id: 10016307
project_number: 5R01ES029496-02
project_title: MGMT down-regulation in the carcinogenicity of hexavalent chromium
administering_ic: NIEHS
award_notice_date: 2020-05-28
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: ES
serial_number: 029496
program_official: LAWLER, CINDY P
project_start_date: 2019-09-12
project_end_date: 2021-05-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 14750127
contact_pi: WANG, ZHISHAN
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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTHexavalent chromium [Cr(VI)] exposure causes multiple toxic effects in humans. The main concern of Cr(VI)toxicity is its carcinogenicity as Cr(VI) is one of the most well-recognized environmental and occupationalcarcinogens causing lung and other cancer in humans. While it is under active study the mechanism of Cr(VI)carcinogenicity remains elusive. Previous studies showed that Cr(VI) exposure causes genotoxic effects whichare thought to play important roles in Cr(VI) carcinogenicity. On the other hand studies also showed that Cr(VI)exposure dysregulates epigenetics such as increased DNA methylation and abnormal histone posttranslationalmodifications. However it remains to be determined how dysregulated epigenetics contributes to Cr(VI)carcinogenicity and if Cr(VI)-caused epigenetic changes play a role in its genotoxic effect. Our preliminary studiesshowed: (i) Chronic Cr(VI) exposure increases the levels of histone H3 repressive methylation marks (H3K9me2and H3K27me3) and their related histone methyltransferases (HMTases) (G9a SUV39H1 and EZH2). (ii) Up-regulation of HMTases play a causal role in Cr(VI)-induced cancer stem cell (CSC)-like property and cell malignanttransformation. (iii) Chronic Cr(VI) exposure down-regulates the expression of O6-methylguanine DNAmethyltransferase (MGMT) a key gene in DNA repair network; and MGMT down-regulation plays a causal rolein Cr(VI)-induced cell transformation. (iv) The level of O6-methylguanine (O6-MeG) a highly mutagenic DNAlesion is significantly increased in Cr(VI)-transformed cells; but stably expressing MGMT greatly reducesCr(VI) exposure-induced O6-MeG. (v) Cr(VI) exposure also significantly decreases the level of MGMT butincreases O6-MeG level in mouse and human lung tissues. (vi) Stably knocking down HMTases G9a orSUV39H1 significantly increases MGMT level but reduces O6-MeG level in Cr(VI)-exposed cells. (vii) Cr(VI)-transformed cells display impaired DNA damage repair capacity but stably expressing MGMT significantlyreduces chronic Cr(VI) exposure-caused DNA damage repair deficiency. And (viii) Treatment with a naturalcompound dihydromethysticin (DHM) is capable of increasing MGMT level and reducing O6-MeG level in Cr(VI)-transformed cells. (viii) We generated a conditional and lung specific MGMT expression transgenic mouse model.Based on these findings from our preliminary studies and that from literature reports our central hypothesis is thatup-regulation of HMTases by chronic Cr(VI) exposure down-regulates the expression of MGMT leading toincreased level of highly mutagenic DNA lesion O6-MeG and promoting Cr(VI) carcinogenesis. Three aims areproposed: Aim 1 will determine the mechanism by which chronic Cr(VI) exposure causes MGMT down-regulation. Aim 2 will determine the role of MGMT in C(VI)-induced lung tumorigenesis using a conditional andlung specific MGMT expression transgenic mouse model. And Aim 3 will determine the protective effect of thenatural compound DHM treatment on Cr(VI)-induced cell transformation and tumorigenesis in mice.

project_terms:
Affect;Alkylating Agents;Animal Model;Cadmium;Carcinogens;Cells;Chromosome abnormality;Chronic;Country;Cultured Cells;DNA Methylation;DNA Modification Methylases;DNA Repair;DNA Repair Disorder;DNA Repair Gene;DNA lesion;Development;Down-Regulation;EZH2 gene;Environmental Health;Epigenetic Process;Exhibits;Exposure to;Frequencies;G9a histone methyltransferase;Genes;Genetic;Genome Stability;Genomic Instability;Goals;Histone H3;Histones;Human;Hypersensitivity;Impairment;Inflammation Process;Lesion;Literature;Liver neoplasms;Lung;MGMT gene;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Metabolism;Metal Carcinogenesis;Metals;Methylation;Modification;Mus;Nickel;Occupational;Phenotype;Play;Post-Translational Protein Processing;Prevention;Promoter Regions;Property;Reporting;Role;Sister Chromatid Exchange;Structure of parenchyma of lung;Testing;Toxic effect;Transgenic Animals;Transgenic Mice;United States;Up-Regulation;base;cancer cell;cancer risk;cancer stem cell;carcinogenesis;carcinogenicity;cell transformation;chromium hexavalent ion;cytotoxicity;genotoxicity;histone methyltransferase;insight;knock-down;lung tumorigenesis;mouse model;novel;overexpression;pollutant;prevent;protective effect;recruit;repaired;stem-like cell;transition mutation;tumorigenesis

public_health_relevance:
PROJECT NARRATIVEHexavalent chromium [Cr(VI)] is one of the most common environmental and occupational pollutants andexposure to Cr(VI) is a major environmental health concern affecting millions of people in the United States aswell many other countries. The goal of this study is to study the mechanism of Cr(VI) exposure causing lungcancer and its mechanism-based prevention using a natural compound.


application_id: 10015192
project_number: 5R01AA026605-03
project_title: Remote alcohol monitoring to facilitate abstinence reinforcement with an underserved population
administering_ic: NIAAA
award_notice_date: 2020-09-01
opportunity_number: PA-18-345
application_type: 5
activity_code: R01
ic: AA
serial_number: 026605
program_official: ROACH, DEIDRA
project_start_date: 2018-09-20
project_end_date: 2023-08-31
study_section: Clinical, Treatment and Health Services Research Study Section[AA-3]
contact_pi_person_id: 10316536
contact_pi: KOFFARNUS, MIKHAIL NIKOLAAS
other_pis: Not Applicable
congressional_district: 06
department: FAMILY MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Lifetime prevalence of DSM-5 alcohol use disorder in the United States is 29% but only 20 to 24% ofpeople with alcohol use disorder ever seek treatment. The most prevalent reasons given for not seekingtreatment relate to an inability or unwillingness (e.g. due to stigmatization) to attend traditional in-persontreatment. For individuals who do receive medical treatment or care for alcohol use disorder their first point ofcontact with the medical community is often for alcohol detoxification. Unfortunately relapse following alcoholdetoxification is common and few people continue utilizing treatment services after being discharged. Thepervasiveness of alcohol use disorder indicates a need for continued development of high-impact treatmentsthat are effective acceptable to the untreated and easily disseminated widely. Contingency management orthe delivery of monetary incentives contingent on verified abstinence is an effective treatment for alcohol usedisorder. However costs and barriers to accurate frequent biochemical verification of alcohol abstinence limitthe widespread use of this technique for alcohol use disorder. In our preliminary data weve successfullydemonstrated the feasibility of remote alcohol monitoring and incentives for the reduction of alcohol use. Weused technologically advanced mobile breathalyzers to verify abstinence remotely cell phones forcommunication and a reloadable debit card to deliver incentives with little delay. Our preliminary study hasshown a high rate of abstinence with this model and participants gave this approach high ratings foreffectiveness and acceptability. Here we will develop this model into two treatment options ready fordissemination: 1) a stand-alone remote treatment directed toward abstinence initiation and maintenance inunderserved individuals and 2) an adjunct to existing treatment services to prevent relapse after hospitaldetoxification. We will also address additional gaps in knowledge in both treatment contexts: 1) what themaximally effective duration and intensity of abstinence incentives is and 2) what the persistence of treatmenteffects are once incentives are discontinued. Through the use of technological advancements combined in anovel way with abstinence incentives the proposed research has the potential to provide a framework forbringing effective evidence-based treatments to a large number of individuals with alcohol use disorder whoare currently underserved by existing treatment options or are unable to maintain abstinence afterdetoxification. Due to the extent of automation and relatively low use of research staff to execute thistreatment model is highly scalable an important feature when addressing the large problem of untreatedalcohol use disorder.

project_terms:
Abstinence;Address;Adult;Alcohol consumption;Alcohols;Area;Automation;Biochemical;Caring;Cellular Phone;Clinical;Clinical Services;Communication;Communities;Control Groups;DSM-V;Data;Development;Drug Metabolic Detoxication;Effectiveness;Evidence based treatment;Goals;Health;Health Personnel;Hospitals;Incentives;Individual;Inpatients;Intervention;Knowledge;Lead;Maintenance;Medical;Modeling;Participant;Persons;Population;Prevalence;Prize;Psychological reinforcement;Randomized;Relapse;Research;Services;Severities;Stigmatization;System;Techniques;Testing;Underserved Population;United States;alcohol abstinence;alcohol monitoring;alcohol services;alcohol use disorder;base;contingency management;cost;disorder later incidence prevention;effective therapy;experimental study;feasibility trial;financial incentive;interest;novel;outpatient programs;prevent;readmission rates;recruit;secondary analysis;treatment as usual;treatment effect;treatment services

public_health_relevance:
PROJECT NARRATIVE Untreated alcohol use disorder among individuals unable or willing to attend existing treatment services aswell as relapse after alcohol detoxification are substantial health concerns. The goals of this project are toevaluate a remote alcohol monitoring and abstinence incentives intervention we have piloted in two contexts:1) the initiation and maintenance of abstinence remotely in underserved adults and 2) the prevention ofrelapse remotely following inpatient clinical detoxification services. Through the use of technologicaladvancements combined in a novel way with abstinence incentives the proposed research has the potential toprovide a framework for bringing effective evidence-based treatments to a large number of individuals withalcohol use disorder.


