# projects

application_id: 9644088
project_number: 5R01NS102196-02
project_title: RIT1-mediated Protection following Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2019-02-05
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_terms:
Acute;Affect;Area;Attenuated;Behavioral;Biochemical;Biological Assay;Brain Contusions;Brain Injuries;CREB1 gene;Cause of Death;Cell Death;Cells;Cessation of life;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;implementation strategy;in vivo;injured;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


application_id: 9644047
project_number: 5R01ES024478-05
project_title: The role of chromatin structural and epigenetic changes in arsenic-induced gene expression
administering_ic: NIEHS
award_notice_date: 2019-02-04
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 024478
program_official: TYSON, FREDERICK L
project_start_date: 2015-04-07
project_end_date: 2021-01-31
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)]
contact_pi_person_id: 10313148
contact_pi: FONDUFE-MITTENDORF, YVONNE NSOKIKA
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:
DESCRIPTION (provided by applicant): Establishing the influence of pollutants on genome function is essential in defining their impact on human health. Arsenic is a ubiquitous environmental toxic metalloid that leads to carcinogenesis. The World Health Organization estimates that over 100 million people worldwide are at risk to drinking arsenic contaminated water. Recent studies indicate that arsenic alters gene expression leading to tumorigenesis. Proper gene regulation is essential for normal growth development and etiology of diseases such as cancer. Eukaryotic DNA stored as chromatin whose basic repeating unit is the nucleosome plays an integral role in gene regulation. Previously we (and others) showed that nucleosome locations within promoters play critical roles in chromatin accessibility thus controlling gene activity. Consequently chromatin accessibility is an essential component in gene regulation yet is not fully understood. Chromatin accessibility appears to be modulated by several key epigenetic factors: histone post-translational modifications (PTMs) DNA methylation nucleosome position/occupancy transcription factors and chromatin architectural proteins (CAPs). Recent studies now indicate that changes in DNA methylation and histone PTMs influence gene expression in response to arsenic: Thus it is critically important to understand how these key epigenetic modulators integrate and interrelate to regulate the chromatin state and gene expression during arsenic exposure. This project will determine the functional changes in gene regulation chromatin composition structure and dynamics genome-wide due to arsenic in normal and iAs- transformed cells. We hypothesize that iAs-induced alterations in nucleosome position and occupancy histone PTMs and CAP occupancy all combine to dynamically restructure chromatin resulting in differential expression of key genes resulting in a failure to ensure proper gene regulation and cancer. We propose in this application the following Specific Aims: (1) determine the effect of iAs on in vivo nucleosome positioning and/occupancy during iAs-induced transformation. (2) Determine the impact of iAs- triggered modulation of CAPs-chromatin structure to impact gene expression. (3) Determine the mechanisms whereby iAs-provoked changes in chromatin composition structure and dynamics control TF occupancy. Our interdisciplinary broad approach will establish unique comprehensive functional and mechanistic data that will provide a detailed understanding of the interplay between arsenic-induced epigenetic changes and chromatin in the mammalian cell. We have developed novel systems that will provide an unprecedented and unique opportunity to discover the functional and mechanistic roles of the epigenome in toxin-induced diseases.

project_terms:
Adhesions;Affect;Architecture;Arsenic;Binding;Biochemical;Bioinformatics;Biophysics;Cell Adhesion;ChIP-seq;Chromatin;Chromatin Structure;Cues;DNA;DNA Binding;DNA Methylation;DNA Sequence;Data;Development;Diagnostic;Disease;Ensure;Epigenetic Process;Etiology;Eukaryotic Cell;Exposure to;Expression Profiling;Failure;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Structure;Generations;Genes;Genetic Transcription;Genome;Goals;Growth and Development function;Health;Heavy Metals;Histones;Human;ITGB4 gene;In Vitro;Integrins;Lead;Location;Malignant Neoplasms;Malignant neoplasm of lung;Mammalian Cell;Mediating;Modification;Molecular Target;NCAM1 gene;Neoplasm Metastasis;Nucleosomes;Organism;Outcome;Pathogenesis;Play;Positioning Attribute;Post-Translational Protein Processing;Prevention;Process;Proteins;Reactive Oxygen Species;Research;Risk;Role;SPT6 Protein;Site;Specific qualifier value;Stimulus;Structure;System;To specify;Toxin;Transcriptional Regulation;World Health Organization;Zinc Fingers;base;carcinogenesis;carcinogenicity;cell transformation;chromatin protein;chromatin remodeling;clinical biomarkers;clinical development;contaminated water;differential expression;drinking;epigenome;epigenomics;epithelial to mesenchymal transition;genome-wide;in vivo;insight;metaplastic cell transformation;novel;novel diagnostics;novel therapeutic intervention;novel therapeutics;pollutant;promoter;public health relevance;response;single-molecule FRET;targeted treatment;tool;transcription factor;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Proper regulation of gene expression is essential to the development and health of all organisms. The DNA in each eukaryotic cell found as chromatin plays an integral part in this gene regulation. Indeed where nucleosomes are located is important in our understanding of gene regulation. Furthermore knowing how chromatin structure responds to particular stimuli to control the on and off state of genes would be helpful in the development of new diagnostic and therapeutic tools.


application_id: 9644038
project_number: 5R01CA207772-03
project_title: Roles of Hsp47 in breast cancer progression
administering_ic: NCI
award_notice_date: 2019-02-13
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 207772
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2017-03-03
project_end_date: 2022-02-28
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Despite recent advance in early diagnosis and adjuvant therapy treatment of triple negative breastcancer (TNBC) remains a significant challenge because of the high incidence of metastasis and relapse aftertreatment. Signaling from extracellular matrix (ECM) an essential component of the tumor microenvironmentis required for TNBC progression and metastasis. However it is not known how cancer cell-deposited ECMproteins and ECM signaling in cancer cells are regulated and promote TNBC metastasis/relapse. We recentlyidentified Hsp47 as a hub of the ECM transcription network. Hsp47 is a molecular chaperon that regulatessecretion and deposition of ECM proteins. Increased Hsp47 expression has been detected in TNBC and isassociated with cancer metastasis. Silencing Hsp47 restrains the aggressive phenotype of TNBC cells in 3Dculture and inhibits tumor growth and lung colonization in the xenograft model indicating that increased Hsp47expression is crucial for the TNBC progression. EMT promotes cancer progression by enhancing cancer celldissemination and endowing cancer cells with stemness properties that favor successful colonization indistant organs and contribute to chemoresistance. Platelet adhesion and activation are required for cancer cellcolonization at the distal sites. We found that silencing Hsp47 in metastatic breast cancer cells significantlyreduced platelet adhesion. These results suggest that Hsp47 promotes TNBC metastasis/relapse by inducingEMT and platelet recruitment. In Aim 1 we will investigate the molecular mechanism by which Hsp47 regulatesEMT and stemness properties. In Aim 2 we will determine the cellular mechanism by which Hsp47 promotescolonization of breast cancer cells at the secondary organs. In Aim 3 we will define the roles of Hsp47 inpromoting cancer metastasis and chemoresistance in TNBC. This investigation will change the currentconcept of ECM microenvironment in cancer metastasis by revealing new roles of cancer cell-derived collagenin inducing cancer cell-platelet interaction and metastasis. Characterization of Hsp47 as a hub ofcollagen/DDR2 signaling will identify a novel pathway to inhibit TNBC progression and chemoresistance.

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

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


application_id: 9642948
project_number: 1R01DA047368-01
project_title: A Translational Determination of the Mechanisms of Maladaptive Choice in Opioid Use Disorder
administering_ic: NIDA
award_notice_date: 2019-04-11
opportunity_number: PA-18-060
application_type: 1
activity_code: R01
ic: DA
serial_number: 047368
program_official: GRANT, STEVEN J
project_start_date: 2019-04-15
project_end_date: 2024-02-29
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: BECKMANN, JOSHUA ;WESLEY, MICHAEL J
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abate;Abstinence;Address;Animals;Area;Back;Behavioral;Behavioral Mechanisms;Biological;Brain Diseases;Brain region;Choice Behavior;Chronic;Clinical;Cognition;Computer Simulation;Cues;Decision Making;Disease;Drug usage;Environment;FDA approved;Fibrinogen;Food;Foundations;Functional Magnetic Resonance Imaging;Future;Half-Life;Human;Impairment;Individual;Intravenous;Knowledge;Learning;Mental disorders;Methods;Modeling;Neurobiology;Neurologic;Neurosciences;Opioid;Opioid agonist;Opioid user;Outcome;Oxycodone;Performance;Pharmaceutical Preparations;Postdoctoral Fellow;Prevention;Prevention strategy;Probability;Procedures;Process;Psychological reinforcement;Rattus;Research;Research Design;Safety;Schedule;Self Administration;Signal Transduction;Task Performances;Techniques;Time;Translating;Translations;Update;Withdrawal;base;experience;experimental study;human subject;innovation;neuroadaptation;neurobehavioral;neuroimaging;neuromechanism;non-drug;novel;opioid exposure;opioid use;opioid use disorder;opioid withdrawal;participant safety;reinforcer;relating to nervous system;remifentanil;theories;therapy development;translational study;treatment strategy


application_id: 9641984
project_number: 1R01DA047391-01
project_title: A Novel Drug Combination as a Pharmacotherapeutic for Methamphetamine-Use Disorder
administering_ic: NIDA
award_notice_date: 2019-07-30
opportunity_number: PA-18-060
application_type: 1
activity_code: R01
ic: DA
serial_number: 047391
program_official: RAMEY, TANYA S
project_start_date: 2019-08-01
project_end_date: 2021-07-31
study_section: Special Emphasis Panel[ZRG1 RPHB-V (02)]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
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:
ABSTRACT/SUMMARY Methamphetamine (MA) use disorder (MUD) is a significant public-health concern. The number of pastmonth MA users increased dramatically (i.e. 60%) between 2010 and 2014 while the number of overdosedeaths involving MA increased 2.7-fold. In 2015 872000 individuals had MUD which accounted for over 8%of treatment admissions in the USA and 225000 individuals initiated MA use. Dramatic increases in MAseizures by law-enforcement agencies suggest the problem may worsen. MUD is characterized byperturbations in central monoamine systems making them logical targets for developing apharmacotherapeutic MUD. The proposed research will demonstrate the initial efficacy of an innovativestrategy for MUD: Triple Monoamine-Uptake Inhibition. Triple monoamine uptake inhibitors are underdevelopment but are not yet available. Triple monoamine-uptake inhibition can however be achieved bycombining medications. Duloxetine (DUL) has high affinity for the serotonin (5HT) and norepinephrine (NE)transporters (ki = 0.8 and 7.5 nM respectively) but lower affinity for the dopamine (DA) transporter (ki = 240nM). Methylphenidate (MTH) has high affinity for the DA transporter (ki = 34 nM) but lower affinity for the 5HTand NE transporters (ki  10000 and 339 nM respectively). Combine DUL and MTH will functionally produce atriple monoamine-uptake inhibitor. A mixed-model study will be conducted in which separate cohorts of non-treatment-seeking MUD participants are randomized to different maintenance doses of DUL (i.e. 0 60 mg/day;DUL is a between-subject factor). Participants (N=14) in each DUL cohort will be maintained concurrently onMTH (i.e. 0 20 40 60 mg/day; MTH is a within-subject factor). MA self-administration will be determined afterparticipants in each DUL cohort are maintained for four days on each of the MTH doses (i.e. MA is a within-subject factor). MA self-administration is the primary outcome measure because the ability to attenuate drugreinforcement is a reliable predictor of an effective pharmacotherapy. We predict DUL-MTH combinations willproduce an additive or supra-additive reduction in MA self-administration relative to the drugs alone.Innovations include: 1) testing a novel pharmacological strategy; 2) testing a combination of marketed drugs asopposed to waiting for novel compounds to be available for testing in humans thereby impacting clinicalresearch and practice more quickly; 3) use of a sophisticated drug self-administration procedure; 4) testingdifferent doses of DUL and MTH alone and in combination to identify the most efficacious dose combinationwhich increases the probability of success when advanced to a clinical trial; 5) providing three-way (i.e. MADUL MTH) safety data that is often required by the FDA for approval of medication combinations forsubstance-use disorders; and 6) providing the impetus for conducting Phase II clinical trials to furtherdemonstrate the efficacy of DUL-MTH combinations. This project will have a significant impact on clinicalresearch and practice by identifying a first-in class pharmacotherapeutic for MUD.

project_terms:
Admission activity;Adverse event;Affinity;Anhedonia;Antidepressive Agents;Attenuated;Behavioral;Blood Pressure;Clinical Pharmacology;Clinical Research;Clinical Trials;Combination Medication;Communities;Data;Development;Diagnosis;Disease;Dopamine;Dose;Funding;Future;Goals;Heart Rate;Human;Impulsivity;Individual;Law Enforcement;Maintenance;Measures;Methamphetamine;Methodology;National Institute of Drug Abuse;Norepinephrine;Outcome;Outcome Measure;Participant;Pharmaceutical Preparations;Pharmacology;Pharmacology Study;Pharmacotherapy;Phase;Phase II Clinical Trials;Physiological;Probability;Procedures;Public Health;Questionnaires;Randomized;Research;Research Design;Ritalin;Safety;Seizures;Self Administration;Serotonin;Study models;Substance Use Disorder;Surveys;System;Temperature;Testing;United States Food and Drug Administration;clinical efficacy;clinical practice;clinical predictors;cohort;dopamine transporter;double-blind placebo controlled trial;drug market;drug reinforcement;duloxetine;inhibitor/antagonist;innovation;methamphetamine use;methamphetamine user;monoamine;noradrenaline transporter;novel;novel drug combination;overdose death;primary outcome;serotonin transporter;success;treatment strategy;uptake

public_health_relevance:
PROJECT NARRATIVEThe research proposed in this application consists of a rigorous human clinical pharmacology study that willdetermine the initial efficacy of a novel drug combination duloxetine and methylphenidate formethamphetamine-use disorder and advance it towards FDA approval. The proposed study is innovative andimportant because it will provide the impetus for NIDA to fund Phase II double blind placebo-controlled trials tofurther demonstrate the efficacy of a duloxetine-methylphenidate combination as a pharmacotherapeutic formethamphetamine-use disorder.


application_id: 9641978
project_number: 1R01DK119619-01
project_title: Exercise-induced skeletal muscle exosomes promote adipocyte lipolysis
administering_ic: NIDDK
award_notice_date: 2018-09-19
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: DK
serial_number: 119619
program_official: HAFT, CAROL R
project_start_date: 2018-09-19
project_end_date: 2023-07-31
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
other_pis: PETERSON, CHARLOTTE A.
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
AR gene;Acute;Address;Adipocytes;Adipose tissue;Adrenergic Agents;Adrenergic Receptor;Aerobic Exercise;Biological Assay;Biological Models;Biopsy;Blood Circulation;Blood specimen;Catecholamines;Colon Carcinoma;Coronary heart disease;Data;Development;Disease;Electric Stimulation;Exercise;Extracellular Matrix;Fatty Acids;Fatty acid glycerol esters;Female;Fibroblasts;Gene Expression;Gene Targeting;Glycerol;Heart failure;High Fat Diet;Human;Isoproterenol;Knowledge;Lipolysis;Mediating;Mediator of activation protein;Metabolism;Modeling;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle satellite cell;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Participant;Pathway interactions;Public Health;Reporter Genes;Reporting;Repression;Role;Serum;Signal Transduction;Skeletal Muscle;Source;Stimulus;Testing;Thinness;Tissues;Untranslated Regions;base;enhancer binding protein;exosome;experimental study;extracellular vesicles;fat burning;gain of function;gene repression;in vitro Model;intercellular communication;male;malignant breast neoplasm;mimetics;muscle hypertrophy;novel;novel therapeutics;obesity development;prevent;resistance exercise;response;subcutaneous;transcription factor;vastus lateralis;young adult


application_id: 9641166
project_number: 1R01EY029719-01
project_title: Glycine subunit specific inhibition and ganglion cell visual responses
administering_ic: NEI
award_notice_date: 2019-02-14
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: EY
serial_number: 029719
program_official: GREENWELL, THOMAS
project_start_date: 2019-03-01
project_end_date: 2024-02-29
study_section: Special Emphasis Panel[ZRG1 MDCN-V (04)]
contact_pi_person_id: 1905800
contact_pi: MCCALL, MAUREEN A
other_pis: GREGG, RONALD G
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Amacrine Cells;Biological Assay;Brain Stem;Cells;Color;Electrophysiology (science);Feedback;Glycine;Glycine Receptors;Goals;Individual;Injections;Interneurons;Kinetics;Knock-out;Knockout Mice;Light;Location;Masks;Mediating;Morphology;Mus;Neuraxis;Neurotransmitters;Object Attachment;Output;Pharmacology;Process;Property;Publishing;Reporter;Rest;Retina;Retinal Ganglion Cells;Role;Shapes;Signal Transduction;Size Perception;Spinal Cord;Stimulus;Stream;Structure;Strychnine;Synapses;System;Time;Vision;Visual;Visual Pathways;Work;biophysical properties;cell type;gamma-Aminobutyric Acid;ganglion cell;knock-down;novel;object motion;parallel processing;postsynaptic;presynaptic;receptor;response;retrograde transport;small hairpin RNA;spatial vision;spatiotemporal;superior colliculus Corpora quadrigemina;vector;visual control


application_id: 9641111
project_number: 1R01NS110169-01
project_title: Regulation of swallow and the effects of high cervical spinal cord injury
administering_ic: NINDS
award_notice_date: 2018-12-14
opportunity_number: PA-18-484
application_type: 1
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_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;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


application_id: 9640959
project_number: 1R01AG061111-01
administering_ic: NIA
award_notice_date: 2019-01-16
opportunity_number: PAR-18-175
application_type: 1
activity_code: R01
ic: AG
serial_number: 061111
program_official: RYAN, LAURIE M
project_start_date: 2019-02-01
project_end_date: 2024-11-30
study_section: Special Emphasis Panel[ZRG1 BBBP-Z (55)]
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: NELSON, PETER T.
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: 2019-02-01
project_terms:
3-Dimensional;ABCC9 gene;Affect;Age;Aging;Agonist;Alzheimer's Disease;Alzheimer's disease related dementia;Alzheimers disease biomarker;Amyloid;Amyloid beta-Protein;Autopsy;Biological Assay;Biological Markers;Brain;CRSP3 gene;Cardiovascular system;Clinical;Clinical Trials;Cognition;Complement;Congestive Heart Failure;Controlled Clinical Trials;Data;Degenerative Disorder;Dementia;Diagnosis;Differential Diagnosis;Diffusion Magnetic Resonance Imaging;Disease;Double-Blind Method;Drug usage;Elderly;Future;Genes;Heart failure;Hippocampus (Brain);Human;Image Analysis;Impaired cognition;Individual;Kentucky;Life;Link;Longitudinal cohort;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Measures;Metabolic;Morbidity - disease rate;Nerve Degeneration;Neurocognitive;Neurofibrillary Tangles;Nicorandil;Outcome Measure;Participant;Pathology;Pathway interactions;Persons;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Phase;Placebos;Population;Prevention trial;Prospective cohort;Proteins;Proteomics;Publishing;Randomized;Research;Risk;Running;Safety;Spin Labels;Structure;Techniques;Testing;Universities;Urea;Work;aging population;base;cognitive testing;cohort;cost;design;disease diagnosis;drug discovery;genetic risk factor;high risk;hippocampal atrophy;hippocampal sclerosis;magnetic resonance imaging biomarker;neurocognitive test;neuroimaging;neuropathology;novel;novel therapeutics;prevent;primary endpoint;primary outcome;receptor;safety testing;sex;tau Proteins;tau-1;treatment duration;trial design;volunteer


application_id: 9640480
project_number: 5R01HL139047-02
project_title: Remote Hind Limb Ischemia Mechanism of Cardioprotection
administering_ic: NHLBI
award_notice_date: 2019-06-17
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 139047
program_official: SCHWARTZ, LISA
project_start_date: 2018-07-01
project_end_date: 2022-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-R(02)S]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Anti-inflammatory;Antioxidants;Apoptotic;Area;Attenuated;Biogenesis;Biological Assay;Bone Marrow Stem Cell;Bone Marrow Transplantation;Cardiac;Coronary heart disease;Cystathionine;DNA;Data;Diabetes Mellitus;Endocrine;Enzymes;Epigenetic Process;Event;Female;Fibrosis;Fluorescence;Functional disorder;Gases;Genes;Goals;Heart;Hematopoietic Stem Cell Mobilization;Hindlimb;Histology;Homocysteine;Hormones;Hydrogen Sulfide;Hyperhomocysteinemia;Hypermethylation;Incidence;Injury;Ischemia;Label;Limb structure;Lyase;Measures;Methylation;Mitochondria;Modification;Mouse Protein;Mus;Muscle;Muscle function;Muscular Atrophy;Myocardial;Myocardial Infarction;Myocardium;Natural regeneration;PPAR gamma;Plasma;Procedures;Production;Proteins;Recovery;Risk;Sampling;Site;Skeletal Muscle;Supplementation;Testing;cardioprotection;conditioning;diabetic;effective therapy;exosome;gene induction;glucose metabolism;improved;ischemic conditioning;male;mitochondrial metabolism;myocardial damage;response


application_id: 9638616
project_number: 7R01HS023783-04
project_title: Hospital Responses to Medicare Readmission Penalties
administering_ic: AHRQ
award_notice_date: 2018-02-05
opportunity_number: PA-13-045
application_type: 7
activity_code: R01
ic: HS
serial_number: 023783
program_official: SANDMEYER, BRENT
project_start_date: 2015-04-01
project_end_date: 2019-03-31
study_section: Health Systems Research[HSR]
contact_pi_person_id: 6985670
contact_pi: WATERS, TERESA M
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Early hospital readmissions (readmission within 30 days) are common costly and potentially preventable. Between 18 and 20 % of Medicare beneficiaries discharged from a hospital in 2003 and 2004 were readmitted within 30 days costing the Medicare program an estimated $17 billion annually. A variety of interventions to reduce readmission have been tested with mixed results. In FY2013 CMS began assessing financial penalties on hospitals with unplanned readmission rates for congestive heart failure (CHF) acute myocardial infarction (AMI) and pneumonia (PN) that exceeded rates expected for their patient population under the Hospital Readmissions Reduction Program (HRRP). Almost half of all U.S. hospitals face penalties under the program. The novelty of financial penalties in hospital reimbursement along with their size and scope make investigation of HRRP's impact a critical priority. Thus we propose the following questions: Q1: Which hospitals are getting penalties and how are their readmission rates changing over time? Using descriptive stratified analyses we will examine penalties and readmission rates over time for various types of hospitals including those with high low and no penalty those serving large low-income and/or minority populations safety net and financially troubled hospitals. Descriptive analyses will provide context for subsequent analyses and timely clear information about whether and how the policy should be changed. Q2: What is the impact of HRRP on Medicare readmission rates targeted by the program? Using hierarchical generalized linear models where patient hospital and market characteristics influence condition- specific readmission rates we will examine readmissions before and after the policy change. Our primary focus will be CHF AMI and PN with a secondary focus on new conditions targeted in FY 2015: chronic obstructive pulmonary disease coronary artery bypass graft surgery and percutaneous coronary interventions. Q3: Do we observe any spillover effects of HRRP on other readmission rates? If hospitals find it unethical impractical or unprofitable to treat Medicare CHF/AMI/PN patients differently from other patients we may see spillover effects. We will look for these among readmissions for similar conditions to those covered by HRRP and among non-Medicare readmissions for the same conditions. For comparison we will also look at readmissions for dementia and back pain two clinically unrelated conditions not covered by HRRP.  Using 2010-2014 Health Care Utilization Project (HCUP) State Inpatient Databases from 9 states publicly reported penalties American Hospital Association Annual Survey of Hospitals data Medicare hospital data Area Resource File and Census data we will address study questions. We use HCUP data since they are released earlier than Medicare claims and include non-Medicare patients. Our combined descriptive and multivariate approach facilitates timely policy-oriented publications (Q1) and rigorous assessment of HRRP's effect on targeted and non-targeted readmissions for Medicare and non-Medicare populations (Q2 and Q3).

public_health_relevance:
PUBLIC HEALTH RELEVANCE: We propose to examine the impact of Medicare's Hospital Readmission Reduction Program (HRRP) by focusing on which hospitals are getting penalties and how their readmission rates are changing over time. Using hierarchical generalized linear models we will also examine the impact of HRRP on Medicare readmission rates targeted by the program and look for evidence of spillover effects on other readmission rates (e.g. similar conditions non-Medicare readmissions). The novelty of financial penalties in hospital reimbursement along with their size and scope make investigation of HRRP's impact a critical policy priority.


application_id: 9638444
project_number: 5R01HD064993-10
project_title: Aging and Dementia in Down Syndrome: Connectivity Inflammation and Cerebrovascular Contributions
administering_ic: NICHD
award_notice_date: 2019-04-29
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HD
serial_number: 064993
program_official: PARISI, MELISSA
project_start_date: 2009-09-30
project_end_date: 2021-01-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 9662252
contact_pi: SCHMITT, FREDERICK
other_pis: HEAD, ELIZABETH
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Down syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over 300000 individuals with this genetic disorder in the United States. Virtually all DS individuals have sufficient neuropathology for a diagnosis of AD in their 40th year. However dementia may not develop until up to a decade later and some people remain cognitively intact. In this competitive renewal we propose to continue following (and expand) our cohort of aging adults with DS as well as recruit younger individuals to establish the role of white matter (WM) integrity losses cerebrovascular dysfunction (CVF) and neuroinflammation on cognitive decline. Aim 1 will continue to cognitively characterize a cohort of adults with DS and follow individuals for a period of 5 years as well as recruit a younger cohort that is pre-AD pathology. Magnetic resonance imaging (MRI) using diffuse tensor imaging will be used to track losses in WM integrity. Aim 2 will use MRI methods to detect cerebrovascular dysfunction by susceptibility weighted imaging fluid attenuated inversion recovery and arterial spin labeling. Aim 3 will use magnetic resonance spectroscopy and blood biomarkers to detect neuroinflammation as a function of age AD neuropathology and declines in cognition. Aim 4 will measure proteins and RNA to reflect protein and RNA changes to determine the neurobiological mechanisms underlying losses in WM integrity CVF and shifts in neuroinflammation in the brains of autopsy cases with DS. We will be able to identify targets for intervention studies (Aim 4) that could be implemented to promote healthy brain aging and would result in cognitive (Aim 1) WM structural integrity (Aim 1) and CVF improvements (Aim 2) and reduced neuroinflammation (Aim 3) in future clinical trials. Identifying the earliest signsof dementia and indicators of individual variation in cognitive decline provides opportunities to implement DS appropriate preventative approaches to slow or halt the development of AD neuropathology and significantly improve the quality of life of DS individuals who are vulnerable to neurodegeneration.

project_terms:
Adult;Age;Age-Years;Aging;Alzheimer's Disease;Amyloid beta-Protein;Antigen-Antibody Complex;Attenuated;Autopsy;Behavior;Biological Markers;Blood;Brain;Case Series;Cerebrovascular Disorders;Chromosomes Human Pair 21;Classification;Clinical;Clinical Trials;Cognition;Cognitive;Cognitive aging;Data;Dementia;Dependence;Development;Diagnosis;Diffuse;Down Syndrome;Encephalitis;Event;Future;Genes;Genetic Diseases;Goals;Human;Image;Impaired cognition;Individual;Inflammation;Inflammatory;Intellectual functioning disability;Intervention Studies;Link;Liquid substance;Longitudinal cohort;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Measures;Mediating;Molecular;Molecular Target;Nerve Degeneration;Neurobiology;Neurofibrillary Tangles;Outcome;Parietal Lobe;Pathology;Pathway interactions;Pattern;Phenotype;Plasma;Play;Predisposition;Proteins;Quality of life;RNA;Recovery;Reporting;Research;Research Design;Role;Senile Plaques;Signal Transduction;Spin Labels;Structure;Syndrome;Testing;United States;United States National Institutes of Health;abeta accumulation;abeta deposition;age related;aging brain;brain tissue;cerebrovascular;cerebrovascular pathology;cognitive function;cohort;functional decline;imaging modality;improved;individual variation;middle age;neurobiological mechanism;neuroinflammation;neuropathology;novel;prevent;public health relevance;recruit;virtual;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  The proposed study will identify early changes in brain inflammation cerebrovascular dysfunction and white matter integrity losses that signal changes in cognition behavior and functioning reflecting Alzheimer disease (AD) in adults with Down syndrome (DS). Identifying the earliest signs of dementia and indicators of individual variation incognitive decline provides opportunities to implement DS appropriate preventative approaches to slow or halt the development of AD neuropathology and significantly improve the quality of life of DS individuals who are vulnerable to neurodegeneration. .


application_id: 9637339
project_number: 5R01CA205400-04
project_title: Distinct Redox Mechanism in Normal and Cancer Cells as a Novel Therapeutic Target
administering_ic: NCI
award_notice_date: 2019-02-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 205400
program_official: PRASANNA, PAT G
project_start_date: 2016-04-01
project_end_date: 2021-03-31
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: ST CLAIR, WILLIAM H
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:
DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of male cancer deaths in the U.S. but it is the most frequently diagnosed cancer in men. Although current therapeutic radiation strategies are successful in treating the initial cancer there are fw effective therapeutic options for patients with aggressive prostate cancer. Addition of cytotoxic or hormone therapy offers some benefit but each is associated with unwanted side effects to normal tissues. The goal of this research project is to develop an anticancer regimen that improves the efficacy of radiation therapy by sensitizing tumor tissue to radiation while simultaneously protecting normal tissue against the side effects of radiation therapy. It addresses the critical gap in scientific knowledge of how the intrinsic differences in the redox conditions of normal and tumor cells trigger differential adaptive responses to prooxidants and demonstrates the outcome of the proposed approach in a preclinical setting with the expectation that changes in clinical practice could result. We propose that the differences in redox homeostasis in normal and cancer cells create a therapeutic window for pushing cancer cells towards oxidative stress overload and death while stimulating adaptive responses in normal cells to enhance survival. Our preliminary data show that dimethylaminoparthenolide (DMAPT) a lactone water soluble prodrug of parthenolide selectively sensitizes prostate cancer cells to ionizing radiation (IR) but protects normal prostate epithelial cells against IR-induced injury. W screened a library of 760 FDA-approved compounds for drugs that can radiosensitize tumor cells but radioprotect normal cells and identified betamethasone (BET) a steroid as a lead compound with these properties. Interestingly both DMAPT and BET exhibit opposing effects in normal vs cancer cells on RelB a member of the NF-B alternative pathway. These results are very important as they allow us to focus on testing a concept and pathway rather than on a specific agent.  This proposed study involves proof-of-concept studies in experimental animal models coupled with in-depth mechanistic molecular and cellular studies using DMAPT and BET. Aim 1 will test the concept that aberrant redox conditions of cancer cells enables a redox-based approach that enhances radiation therapy efficacy by sensitizing cancer cells to radiation treatment while protecting normal cells from the side effects of radiation therapy of prostate cancer. Aim 2 will test the hypothesis that RelB mediates the effect of DMAPT and BET in protecting normal cells but sensitizing prostate cancer cells to IR.  The results of this study wil facilitate the translation of novel radiation sensitizers for clinical use and will fill in critica gaps in scientific knowledge of how the differences in redox conditions of normal and tumor cells trigger differential responses to pro-oxidants. Translation of this paradigm-shifting concept will have a major impact on the efficacy and morbidity of radiation therapy.

project_terms:
Acute;Address;Affinity Chromatography;Amino Acids;Apoptosis;Autophagocytosis;Autopsy;Betamethasone;Biochemical;Biological Markers;Cancer Survivor;Cell Culture Techniques;Cell Line;Cells;Cessation of life;Clinical;Clinical Treatment;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Coupled;Couples;Cultured Cells;Cytotoxic Chemotherapy;Data;Development;Disulfides;Dose;Electron Spin Resonance Spectroscopy;Epithelial Cells;Exhibits;Experimental Animal Model;FDA approved;Family;Gene-Modified;Genetic Transcription;Goals;Histology;Homeostasis;In Vitro;Inflammatory;Injury;Ionizing radiation;Knowledge;Lactones;Lead;Libraries;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mediator of activation protein;Messenger RNA;Methods;Modeling;Molecular;Molecular Biology;Morbidity - disease rate;Mus;Necrosis;Neoplasm Metastasis;Normal Cell;Normal tissue morphology;Outcome;Oxidation-Reduction;Oxidative Stress;PC3 cell line;Pathway interactions;Patients;Pharmaceutical Preparations;Phase I Clinical Trials;Primary Neoplasm;Prodrugs;Property;Prostate;Prostate Cancer therapy;Prostate carcinoma;Proteins;Proteomics;Quality of life;Radiation;Radiation Tolerance;Radiation exposure;Radiation therapy;Radiation-Sensitizing Agents;Radiodermatitis;Reactive Oxygen Species;Recurrence;Regimen;Research Project Grants;Role;Sesquiterpenes;Small Interfering RNA;Stable Isotope Labeling;Steroids;Sulfhydryl Compounds;Testing;Therapeutic;Tissues;Translations;Treatment Efficacy;Tumor Tissue;United States;Water;Work;anti-cancer;base;cancer cell;cancer diagnosis;clinical practice;cytotoxic;expectation;gene product;hormone refractory prostate cancer;hormone therapy;improved;in vivo;in vivo evaluation;in vivo imaging;luminescence;male;member;men;morphometry;neoplastic cell;new therapeutic target;novel;novel therapeutics;overexpression;parthenolide;personalized therapeutic;pre-clinical;prostate cancer cell;public health relevance;radiation resistance;radiation response;radiation-induced injury;radiosensitizing;response;side effect;treatment response;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  This application will test a paradigm-shift concept for the development of novel therapeutic strategies that aim to increase radiation therapy efficacy while protecting normal tissue injury against the side effects of radiation therapy. We will test this concept by employing a lactone: dimethylaminoparthenolide which is in early stage clinical trials; and a steroid betametazone which is FDA approved for inflammatory related conditions. Results from these studies will lead to very concrete information potentially offering a specific course of action to improve radiation therapy efficacy and quality of life for cancer survivors.


application_id: 9636368
project_number: 5F31DE027585-02
project_title: Exploitation of the host immune response by Aggregatibacter actinomycetemcomitans mediated by QseBC
administering_ic: NIDCR
award_notice_date: 2019-01-02
opportunity_number: PA-16-308
application_type: 5
activity_code: F31
ic: DE
serial_number: 027585
program_official: FRIEDEN, LESLIE A
project_start_date: 2018-01-01
project_end_date: 2022-12-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 14913835
contact_pi: OZUNA, HAZEL
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Anaerobic Bacteria;Animal Model;Antibodies;Asses;Binding;Catecholamines;Complex;Cytoplasmic Granules;Development;Endocrinology;Enterobactin;Environment;Enzyme-Linked Immunosorbent Assay;Exposure to;Foundations;Future;Gene Expression;Genes;Growth;Homeostasis;Hormones;Human;Immune response;Infection;Infiltration;Inflammatory;Iron;Kinetics;Knowledge;Ligands;Location;Measures;Mediating;Membrane;Metabolism;Microbial Biofilms;Nutrient;Operon;Organism;Outcome;Periodontal Diseases;Periodontitis;Phagocytes;Play;Process;Proteins;Regulation;Research Design;Respiration;Role;Siderophores;Signal Transduction;Stress;Surface Plasmon Resonance;System;Testing;Therapeutic;Transferrin;Virulence;Virulence Factors;Work;design;enteric pathogen;environmental change;exposed human population;macrophage;microbial;mutant;neutrophil;periplasm;receptor;response;sensor;therapeutic target;uptake


application_id: 9635751
project_number: 5R01CA213990-03
project_title: Transcriptional Regulation of Immunosuppressive Macrophages by c-Maf in Cancer
administering_ic: NCI
award_notice_date: 2019-02-01
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 213990
program_official: XI, DAN
project_start_date: 2017-02-06
project_end_date: 2022-01-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Immunosuppressive macrophages have been linked to cancer-related inflammation and therapeuticresistance in cancer including chemotherapy and immunotherapy thus representing attractive therapeutictargets. Macrophages can be polarized into extreme M1 or M2 phenotype depending on the environmentalcues. Although macrophage phenotype within the tumor microenvironment is more complicated it is clearthat immunosuppressive tumor-associated macrophages (TAM) phenotypically more resemble M2-likemacrophages. In the preliminary studies we discovered that transcription factor c-Maf is highly expressed inmouse and human polarized M2 macrophages and immunosuppressive TAM. In addition natural productyeast-derived particulate -glucan treatment significantly downregulates c-Maf expression leading toenhanced T cell responses in mice. We also demonstrated that M1 and M2 macrophages have distinctmetabolic profiles and c-Maf regulates many genes related to glycolysis. Based on these preliminary studieswe hypothesize that transcription factor c-Maf is an essential controller and a metabolic checkpointfor immunosuppressive TAM functional activity. Three Aims are proposed. Aim 1 determines thecellular and molecular mechanisms by which c-Maf is regulated in immunosuppressive TAM. We willinvestigate whether tumor secreted factors regulate c-Maf expression in TAM. We will also determine howthe Raf-1 kinase pathway regulates c-Maf and c-Maf-related gene expression. Finally we will test whetherloss of function of c-Maf in TAM significantly delays tumor progression and metastasis. Aim 2 determineswhich TAM metabolic pathway(s) is regulated by c-Maf using systems metabolomics approach. We will firstdetermine TAM metabolic pathways using Stable Isotope Resolved Metabolomics (SIRM) approach.Furthermore we will determine which metabolic pathways are regulated by c-Maf. Finally we will determinethe causative role of metabolic reprogramming in -glucan-mediated TAM functional conversion. Aim 3determines whether the dectin-1 agonist -glucan modulates TAM function of human non-small cell lungcancer (NSCLC) via the c-Maf pathway. We will determine whether -glucan treatment downregulates c-Maf expression and alters c-Maf-regulated genes in human NSCLC TAM. We will also determine whetherhuman TAM functions are reversed upon -glucan treatment. Finally we will examine whether -glucantreatment in patients with NSCLC downregulates c-Maf expression and alters monocyte suppressivefunction. The overall goal of this proposal is to understand the transcriptional regulation ofimmunosuppressive TAM by c-Maf and establish the transcription factor c-Maf as a novel target for humancancer immunotherapy.

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

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


application_id: 9634206
project_number: 3R01ES016893-11S1
administering_ic: NIEHS
award_notice_date: 2018-05-17
opportunity_number: PA-17-055
application_type: 3
activity_code: R01
ic: ES
serial_number: 016893
suffix: S1
program_official: TYSON, FREDERICK L
project_start_date: 2009-07-06
project_end_date: 2019-01-31
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
budget_start_date: 2018-05-18
project_title:
PARTICULATE CR(VI) TOXICOLOGY IN HUMAN LUNG EPITHELIAL CELLS AND FIBROBLASTS (Admin Supplement/PA-17-055)

project_abstract:
Project Summary Abstract - R01ES016893Hexavalent chromium (Cr(VI)) also known as chromate is a major public health concern.Chromates particularly the insoluble compounds are well-established human lung carcinogens.Our study focuses on investigating the mechanisms of Cr(VI)-induced carcinogenesis which arecurrently unknown. Recent studies indicate that particulate Cr(VI) induces chromosomeinstability which is a hallmark of human lung tumors. However how Cr(VI) induces chromosomeinstability is poorly understood. Our preliminary data show that chronic exposure to particulateCr(VI) induces a DNA repair deficient phenotype that underlies the chromosome instability andthus the goal of this research is to characterize this repair deficiency and its impactand understand the mechanisms that cause it to occur. We will test the hypothesis thatparticulate Cr(VI) induces epigenetic changes inactivating homologous recombination repair ofCr(VI)-induced DNA double strand breaks resulting in increased chromosome instability andcarcinogenesis. We will test this hypothesis through four interrelated specific aims. Aim 1 willcharacterize the homologous recombination repair defect and show that particulate Cr(VI) causescells to inactivate Rad51-mediated response and switch to lower fidelity non-homologous endjoining (NHEJ) repair using immunoblotting immunofluorescence and repair assays. Aim 2 willshow that the cells with particulate Cr(VI)-inactivated Rad51 response acquire chromosomeinstability and undergo neoplastic transformation using cytogenetic techniques and assays forcontact- uninhibited and anchorage independent growth. Aim 3 will identify an epigenetic change(increased acetylation) that causes the loss of Rad51 response by affecting E2F1 ATM Rad51Cand Rad51 with assays for acetylation status gene expression and protein interactions andlocalization. Finally Aim 4 will characterize the mechanism for particulate Cr(VI)-inducedacetylation changes studying Cr(VI) binding to acetyl groups using assays for acetylation andhistone deacetylase activity. Each aim will focus on human lung cells and confirm key findings inhuman Cr(VI) tumors. Results will lead to the first reports of detailed information of theinteractions of Cr(VI with DNA double strand break machinery acetylation status and the firstcharacterizations of these aspects in tumors from Cr(VI)-exposed workers. This researchis significant because it will provide: 1) An understanding of particulate Cr(VI)'s carcinogenicmechanism; 2) Essential information to better assess the risk of exposure to particulates; and 3)A mechanistic approach for further study of Cr(VI) other metals and lung cancer in general.

project_terms:
Acetylation;Affect;Anchorage-Independent Growth;Binding;Biological Assay;Cancer Etiology;Carcinogen exposure;Carcinogens;Cells;Chromates;Chromium Compounds;Chromosomal Instability;Chronic;Cytogenetic Analysis;Cytoplasm;DNA Double Strand Break;DNA Repair;Data;Defect;Double Strand Break Repair;E2F1 gene;Environmental and Occupational Exposure;Epigenetic Process;Epithelial Cells;Event;Exposure to;Fibroblasts;Frequencies;G-Banding;Gene Expression;Genomic Instability;Goals;Histone Deacetylase;Histone Deacetylation;Human;Immunoblotting;Immunofluorescence Immunologic;In Vitro;Ions;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Mediating;Metals;Modeling;Molecular;Mutation;Neoplastic Cell Transformation;Nonhomologous DNA End Joining;Nuclear;Particulate;Peptide Mapping;Phenotype;Proteins;Public Health;Publishing;Reporting;Research;Risk;Salts;Solubility;Spectral Karyotyping;Techniques;Testing;Toxicology;Zinc;carcinogenesis;carcinogenicity;chromium hexavalent ion;homologous recombination;interest;prevent;public health relevance;recombinational repair;repaired;response;tandem mass spectrometry;tumor;zinc chromate

public_health_relevance:
Public Health Relevance StatementHexavalent chromium (Cr(VI)) is a human lung carcinogen with widespread occupational and environmentalexposure. How Cr(VI) causes human cancer is unknown. Our study advances our basic understanding of thecellular and molecular mechanisms underlying how Cr(VI) causes cancer and informs us about how cellsprotect against Cr(VI)-induced genomic instability.


application_id: 9632566
project_number: 5R01NR016262-03
project_title: Corazn de la Familia (Heart of the Family)
administering_ic: NINR
award_notice_date: 2019-02-01
opportunity_number: PA-14-142
application_type: 5
activity_code: R01
ic: NR
serial_number: 016262
program_official: YOON, SUNG SUG
project_start_date: 2017-03-02
project_end_date: 2022-01-31
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 9701191
contact_pi: MUDD, GIA
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTHispanics have significantly higher rates of type 2 diabetes (T2D) and cardiovascular disease (CVD) riskburden compared to non-Hispanic whites. Dramatic increases in rates of type 2 diabetes and cardiovasculardisease in U.S. Hispanics are anticipated as the population ages and acculturation lends to engagement inunhealthy behaviors. Culturally appropriate lifestyle modification strategies are needed for effective riskreduction. Most lifestyle modification strategies have focused on individuals and sustained engagement inhealthy behaviors is seldom achieved. Respectful of the Hispanic cultural value of familismo prioritizing of thewell-being of the family over that of the individual we propose to conduct a family dyad-focused interventionthat addresses family members as active participants in a lifestyle intervention for Hispanics with high risk forT2D or CVD. Corazn de la Familia (Heart of the Family) is a promotores- (community health workers)facilitated intervention that integrates evidence-based education and health behavior skills development withsocial support strategies through the involvement of family members. We will conduct a randomized controlledtrial using a 2-group design and compare the short-term and long-term impact of the family dyad-focusedactive intervention to an individual-focused control condition on biological and behavioral T2D and CVD riskfactors. Furthermore we will determine how each active intervention dyad members engagement in healthylifestyle behaviors and level of support for their partners engagement in healthy lifestyle behaviors affects theirown and their partners outcomes. Guided by community-based participatory research principles ourcommunity-academic partnership was formed in response to needs recognized by Hispanic residents ofKentucky for socioculturally tailored health promotion programs to reduce T2D and CVD risk. Hispaniccommunity partners have been integrally involved in all phases of sociocultural tailoring and pilot testing theCorazn de la Familia intervention. The result of the work of our community-academic partnership is a familydyad-focused intervention that provides a unique approach to sustain engagement in healthy lifestylebehaviors to reduce T2D and CVD risk among at-risk Hispanics. Further this community-based interventionhas significant potential for broad implementation to successfully address T2D and CVD health disparitiesacross U.S. Hispanic communities.

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

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


application_id: 9632023
project_number: 1R25CA221765-01A1
project_title: Appalachian Career Training in Oncology (ACTION) Program
administering_ic: NCI
award_notice_date: 2018-09-18
opportunity_number: PAR-17-059
application_type: 1
activity_code: R25
ic: CA
serial_number: 221765
suffix: A1
program_official: GHOSH, SANGEETA AHUJA
project_start_date: 2018-09-18
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZCA1 RPRB-Z (O2)]
contact_pi_person_id: 11045331
contact_pi: VANDERFORD, NATHAN LANE
other_pis: EVERS, BERNARD MARK;FRAZIER, DONALD T
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Academic achievement;Achievement;Address;Appalachian Region;Area;Award;Cancer Burden;Cancer Center;Cancer Research Project;Clinical;Communities;Country;County;Data;Degree Completion;Degree program;Doctor's Degree;Early Intervention;Economically Deprived Population;Education;Education and Outreach;Educational Intervention;Educational workshop;Faculty;Family;Fostering;Funding;Goals;Health;Health Personnel;Healthcare;Home environment;Incidence;Income;Intervention;Kentucky;Knowledge;Link;Literature;Localized Malignant Neoplasm;Malignant Neoplasms;Mentors;Mentorship;Participant;Population;Poverty;Preparation;Primary Schools;Readiness;Research;Research Project Grants;Research Training;Rest;Rural;Rural Population;Schools;Science;Secondary Schools;Socioeconomic Status;Students;Training;Training and Education;Underrepresented Students;Underserved Population;Underserved Students;United States;Universities;Youth;anticancer research;cancer care;cancer education;cancer health disparity;cancer site;career;career development;career preparation;clinical care;economic indicator;education research;experience;faculty mentor;health literacy;high risk;high school;higher education;literacy;matriculation;medically underserved;mortality;oncology program;outreach;peer;peer learning;peer networks;programs;science education;skills;socioeconomic disparity;socioeconomics;student training;undergraduate student


application_id: 9631450
project_number: 5R01DC014658-05
project_title: Repair of mechano-electrical transduction in mammalian auditory hair cells
administering_ic: NIDCD
award_notice_date: 2019-01-11
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DC
serial_number: 014658
program_official: FREEMAN, NANCY
project_start_date: 2015-02-15
project_end_date: 2021-07-31
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 8360158
contact_pi: FROLENKOV, GREGORY I
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:
DESCRIPTION (provided by applicant): It is presumed that the mechanosensory machinery in the stereocilia bundles of the inner ear hair cells is very vulnerable to intense mechanical stimulation. Yet we still do not know what exactly is damaged within the transduction machinery and whether these damages can be repaired. However it may represent a significant component in noise-induced hearing loss. The ability of the hair cell to repair these damages may determine whether the noise-induced temporary shift of hearing thresholds would recover or progress into permanent hearing loss. Interestingly damage to the actin core of stereocilia has been known as a hallmark of permanent noise-induced hearing loss for more than two decades. However little is known on how this damage develops or repairs. We have recently initiated a systematic study of the effects of mechanical overstimulation on the mechano-electrical transduction and the ultrastructure of stereocilia bundle in young postnatal cochlear hair cells. An anticipated effect of overstimulation is the loss of tip links that are known to regenerate. Using a novel immunogold scanning electron microscopy technique we have discovered that the tip link regeneration may involve a two-step molecular remodeling that includes formation of the temporary links with protocadherin-15 at both ends of the link and then replacing them with the more mature links containing protocadherin-15 and cadherin-23. Specific Aim 1 of the proposed project will explore regeneration of the tip links in mechanically damaged cochlear inner hair cells and determine whether molecular remodeling occurs in regenerating tip links. Our preliminary data also show that mechanical overstimulation does not abolish all tip links in the cochlear hair cells; many of them withstand overstimulation. However the remaining mechanotransducer current loses slow adaptation and has no evidence of the tension within the transduction machinery that is normally present at rest. Specific Aim 2 will explore the mechanisms of re-tensioning of the transduction apparatus in mechanically damaged cochlear inner hair cells. Investigating Ca2+ entry into individual stereocilia we found that the cochlear inner hair cells regulate resting tension within the transduction apparatus via anovel extremely slow Ca2+-dependent process. This regulation is likely to be affected in mechanically damaged hair cells. Specific Aim 3 will determine the mechanisms of this slow regulation and its potential disruption by intense deflections of the hair bundle. Finally we foun that overstimulation causes small nanometer-scale gaps in the actin core of stereocilia similar to the ones that we previously observed in degenerating stereocilia lacking gamma-actin. Specific Aim 4 will explore whether the hair cells can repair these gaps and whether gap formation or repair depends on gamma-actin. We believe that our study is a long-awaited step in exploring the potential mechanisms of the noise-induced hearing loss.

project_terms:
Actins;Affect;Auditory;CDH23 gene;Cells;Cochlea;Data;Exposure to;Freeze Substitution;Freezing;Genes;Hair;Hair Cells;Human;Immunogold Technics;Impairment;Individual;Inner Hair Cells;Knock-in Mouse;Labyrinth;Link;Mechanical Stimulation;Mechanics;Modeling;Molecular;Mus;Mutation;Myosin ATPase;Natural regeneration;Noise;Noise-Induced Hearing Loss;PCDH15 gene;Point Mutation;Predisposition;Probability;Process;Public Health;Recovery;Regulation;Research;Rest;Role;Sampling;Scanning Electron Microscopy;Techniques;Time;Transmission Electron Microscopy;deafness;experimental study;extracellular;gamma Actin;hearing impairment;hearing threshold;mouse model;nanoscale;novel;overexpression;permanent hearing loss;postnatal;progressive hearing loss;public health relevance;repaired;response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This research is relevant to the public health because it investigates the basic mechanisms of noise-induced hearing loss a leading cause of hearing impairment in the US and worldwide. The proposal is unique because it explores largely uninvestigated effects of mechanical damage to the mechano-sensory apparatus of the inner ear hair cells.


application_id: 9627977
project_number: 5R01ES025515-05
project_title: Oxidative stress Cr(VI) carcinogenesis and prevention
administering_ic: NIEHS
award_notice_date: 2019-01-08
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 025515
program_official: REINLIB, LESLIE J
project_start_date: 2015-05-01
project_end_date: 2019-08-22
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: ZHANG, ZHUO
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:
DESCRIPTION (provided by applicant): Cr(VI) is well known environmental carcinogen. Its mechanism of action or prevention remains to be investigated. Our preliminary studies have shown that exposure of human bronchial epithelial (BEAS-2B) cells to Cr(VI) generates reactive oxygen species (ROS) which are responsible for Cr(VI)-induced cell transformation. After transformation these cells exhibit constitutive expressions of Nrf2 and its target antioxidant proteins resulting in decreased ROS generation. The constitutive expression of Nrf2 activates Bcl-2 through binding of Nrf2 to antioxidant responsive element (ARE) of Bcl-2 gene promoter leading to increased survival and tumorigenicity of these transformed cells. These preliminary studies indicate that in non-transformed cells activation of Nrf2 may decrease ROS generation thus inhibit Cr(VI)-induced cell transformation. In contrast in Cr(VI)-transformed cells inactivation of constitutive expression of Nrf2 may decrease Bcl-2 and increase ROS leading to inhibitions of survival and tumorigenicity of transformed cells. We have screened various natural compounds attempting to select those with two properties: (a) to activate Nrf2 and decrease ROS in non- transformed cells to prevent Cr(VI)-induced cell transformation and (b) to inhibit constitutive expression of Nrf2 and enhance ROS and apoptosis in Cr(VI)-transformed cells to prevent tumorigenesis. We have found that luteolin a natural compound has such dual properties. The central hypothesis is that luteolin protects Cr(VI)- induced carcinogenesis both by inducing transient activation of Nrf2 in non-transformed cells resulting in inhibition of Cr(VI-induced cell transformation and by inactivating constitutive expression of Nrf2 in Cr(VI)- transformed cells resulting in inhibitions of survival and tumorigenesi of Cr(VI)-transformed cell and angiogenesis. Aim 1 will study prevention of luteolin against Cr(VI)-induced cell transformation. We will study luteolin-induced activations of Nrf2 and its target antioxidant genes and decreases of Cr(VI)-generated ROS. The integration of these molecular events is likely to be responsible for protection of luteolin against Cr(VI)- induced cells transformation. Aim 2 will demonstrate that in Cr(VI)-transformed cells luteolin is able to inhibit constitutive expressions of Nrf2 increase ROS level and decrease survival and tumorigenicity of Cr(VI)- transformed cells. The protection of luteolin against Cr(VI)-induced angiogenesis in animal exposed to Cr(VI) via drinking water will also be investigated. Aim 3 will investigate protection o luteolin against Cr(VI)-induced carcinogenicity in CD1 mice using a recently established animal model of "whole-life" chronic metal exposure. The animals will be exposed to Cr(VI) in the presence and absence of luteolin via drinking water in the whole life time from breeding to adulthood. The roles of Nrf2 and its key target will be studied. Tumors will be assessed in the offspring up to 2 years of adulthood. The proposed study will not only gain novel mechanistic insight in Cr(VI) carcinogenesis but also have potential translational impact of using chemopreventive compounds targeting Nrf2 signaling pathway to combat Cr(VI)-induced carcinogenicity.

project_terms:
2 year old;Adult;Animal Model;Animals;Antioxidants;Apoptosis;Apoptotic;BCL2 gene;Binding;Breeding;Cell Death;Cells;Chemopreventive Agent;Chronic;Data;Development;Diet;Elements;Environmental Carcinogens;Enzymes;Epithelial;Event;Exhibits;Exposure to;Female;Gene Expression;Generations;Genes;Lactation;Life;Literature;Lung;Luteolin;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Metal exposure;Molecular;Mus;Nutritional;Occupational;Oncogenic;Oxidative Stress;Pathway interactions;Pregnancy;Premalignant;Prevention;Prevention strategy;Property;Proteins;Reactive Oxygen Species;Resistance;Role;Signal Pathway;Signal Transduction;Source;Stress;Superoxide Dismutase;Time;Tumor Tissue;Tumorigenicity;Up-Regulation;angiogenesis;cancer cell;carcinogenesis;carcinogenicity;cell transformation;chromium hexavalent ion;combat;drinking water;epidemiology study;exposed human population;in vivo;insight;male;malignant state;novel;offspring;pregnant;prevent;promoter;public health relevance;translational impact;tumor;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    NARRATIVE The study will show that luteolin protects Cr(VI) carcinogenesis by activation of inducible Nrf2 in pre-malignant stage to prevent cell transformation and by inactivation of constitutive expression of Nrf2 in later stage to prevent tumorigenesis. The expected results will demonstrate the roles of oxidative stress and Nrf2 in the mechanism of Cr(VI) carcinogenesis and the strategy for prevention.


application_id: 9627516
project_number: 1UG3CA233282-01
project_title: (ACCSIS) Accelerating Colorectal Cancer Screening through Implementation Science in Appalachia
administering_ic: NCI
award_notice_date: 2018-09-19
opportunity_number: RFA-CA-17-038
application_type: 1
activity_code: UG3
ic: CA
serial_number: 233282
program_official: GRIMES, GENEVIEVE M
project_start_date: 2018-09-19
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1 AARR-N (52)]
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:
Accelerating Colorectal Cancer Screening through Implementation Science in AppalachiaThis multi-site project aims to increase screening and follow-up for colorectal cancer (CRC) in central Appalachiaa medically underserved region recognized as one of three distinct hotspots for CRC mortality. Specifically theAppalachian Regional Commission classifies 32 eastern Ohio (OH) counties and the 54 counties in easternKentucky (KY) as north central and central Appalachia respectively. CRC incidence and mortality rates in thearea are among the highest in the nation and neither state meets the national target of 80% of eligible residentsscreened for CRC. There have been few randomized intervention trials addressing multiple levels of influenceon CRC screening behaviors and outcomes in this region. To address this gap investigators at the University ofKentucky and The Ohio State University will build on a 12-year collaborative history strong relationships withAppalachian communities and health clinics and extensive experience with community-based cancer preventionand control intervention research to develop implement and evaluate a multilevel intervention (MLI)  adaptedfrom evidence-based interventions that include components targeting clinics and providers (in-reach) and thecommunity (outreach)  to increase CRC screening follow-up and referral-to-care among patients age 50-74 in12 counties in Appalachian KY and OH. The overall goals of this project are to contribute to the evidence-basefor a MLI that increases rates of CRC screening follow-up and referral-to-care particularly in rural medicallyunderserved populations and help showcase best practices for how MLIs can be scaled-up to reduce the burdenof CRC in the U.S. For the Planning-Exploratory Phase (UG3) in Year 1 our specific aims are to: 1) Pilot testmeasure and refine a MLI to increase rates of CRC screening follow-up and referral-to-care in Appalachian OHand Appalachian KY; and 2) Provide evidence supporting transition to the Implementation Phase (UH3) [per NCIapproval]. For the Implementation Phase (UH4) in Years 2-5 our specific aims are to: 1) Test the revised MLIin a group randomized trial delayed intervention to assess the impact of the MLI on increasing rates of CRCscreening 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 withcommunity and clinical partners in 12 counties 6 in Ohio and 6 in Kentucky. Counties will be randomized toearly or delayed intervention after baseline data collection. The main outcome will be CRC screening as definedby 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 RiskFactor Surveillance System. Our work will be accomplished through collaboration with the ACCSIS CoordinatingCenter other ACCSIS Research Projects ACCSIS Steering Committee and Workgroups NCI and communitypartners. 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 Centers;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;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 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 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;therapy design;uptake

public_health_relevance:
This project will implement and evaluate community and clinical interventions designed to reduce the burden ofcolorectal cancer in Appalachian regions of Ohio and Kentucky. The first year of the project will develop andrefine the interventions to be implemented and tested in the next 4 years. Results will showcase best practicesfor how multilevel interventions can be scaled-up to reduce the burden of colorectal cancer in the U.S.


application_id: 9626914
project_number: 5F30EY026792-03
administering_ic: NEI
award_notice_date: 2019-02-21
opportunity_number: PA-14-150
application_type: 5
activity_code: F30
ic: EY
serial_number: 026792
program_official: AGARWAL, NEERAJ
project_start_date: 2017-03-01
project_end_date: 2021-02-28
study_section: Special Emphasis Panel[ZRG1-F02B-D(20)L]
contact_pi_person_id: 14147214
contact_pi: CAMPBELL, PETER W
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
budget_start_date: 2019-03-01
project_title:
Formation and Maturation of Projections Between Thalamic Reticular Nucleus and Dorsal Lateral Geniculate Nucleus

project_abstract:
Project SummaryOne of the preeminent models used to study the development of thalamic circuitry is the mouse visualthalamus. Most studies on this system have focused on the retinogeniculate pathway that connects retinalaxons with relay neurons of the dorsal lateral geniculate nucleus (dLGN). These relay neurons transmit visualinformation to the visual cortex via their axonal projection to primary visual cortex but this projection also sendsaxon collaterals to the thalamic reticular nucleus (TRN). The TRN is a GABAergic nucleus that projects to thedorsal thalamus including dLGN and is the main inhibitory projection to these brain regions. Thus there is afeedback loop between dLGN and TRN which is known to mediate visual attention select thalamocorticalrhythms and is involved in multiple diseases processes. However when this loop is formed and how itdevelops is currently not known. Furthermore it is unknown whether the development of these projections areregulated like other nonretinal projections to dLGN by retinal signaling. These questions will be addressed inthree specific aims: Aim 1 will determine when TRN terminals arrive in dLGN when synapses onto relayneurons become functional and how both terminal expanse and synaptic responses mature; Aim 2 willinvestigate similar parameters for the innervation of TRN by dLGN determining when terminals arrive whensynapses are made and how synaptic responses change over early development; Aim 3 will compare thedevelopmental time course of these projections TRN and dLGN in the presence and absence of retinal input tocentral visual structures in order to determine if retinal terminals coordinate the developmental timing ofinnervation. These experiments will utilize transgenic mice that specifically label either the projections fromTRN or those from dLGN. Specifically the GAD65 mouse will be used to visualize TRN innervation of dLGNwith EGFP while the somatostatin-cre mouse will be crossed to a channelrhodopsin-2 mouse in order tophotoactivate TRN terminals in electrophysiological recordings (aim 1). The corticotropin releasing hormonecre-recombinase mouse will be used to both stimulate and visualize dLGN inputs to TRN with crosses to eitherthe channelrhodopsin-2 mouse or an Ai9 reporter line that will label this projection with TdTomato (aim 2).Finally these experiments will be repeated after crossing all these mice into a math 5 null background togenetically remove retinal inputs (aim 3). Together these experiments will determine how an importantcomponent of the visual system develops and they will test the hypothesis that retinal terminals in dLGNcoordinate the innervation of non-retinal projections to dLGN as well as the axonal projections of dLGN relayneurons. These studies will not only advance the current understanding of the visual system but will haveimplications for circuit development in the thalamus as a whole.

project_terms:
Acute;Address;Adopted;Anatomy;Attention;Axon;Biological Models;Brain;Brain region;CRH gene;Cell Nucleus;Cells;Corticotropin-Releasing Hormone;Data;Development;Disease;Dorsal;Electrophysiology (science);Enterobacteria phage P1 Cre recombinase;Epilepsy;Feedback;Imagery;Knock-in Mouse;Knock-out;Knowledge;Label;Lateral Dorsal Nucleus;Lateral Geniculate Body;Light;Mathematics;Mediating;Modeling;Mus;Mutant Strains Mice;Neurons;Optic Nerve;Output;Pathway interactions;Presynaptic Terminals;Process;Reporter;Retina;Retinal;Retinal Ganglion Cells;Signal Transduction;Slice;Somatostatin;Source;Structure;Synapses;System;Testing;Thalamic Nuclei;Thalamic structure;Time;Transgenic Mice;Visual;Visual Cortex;Visual attention;Visual system structure;area striata;autism spectrum disorder;experimental study;loss of function;mouse Cre recombinase;nerve supply;optogenetics;postnatal development;postsynaptic;response;retinal axon;retinogeniculate;synaptogenesis;transcription factor;transmission process;visual information

public_health_relevance:
Project NarrativeInhibitory circuits of the thalamus are involved in multiple disease states includingepilepsy and autism but they also direct our attention in normal situations. Sinceunderstanding the development of a circuit is critical for determining its function wepropose to determine when these connections are formed and how they mature duringearly development. This study will determine when an important inhibitory feedback loopdevelops in the visual thalamus - a structure that has been used to discover much ofwhat we currently understand about thalamic circuitry.


application_id: 9626906
project_number: 5R01ES024771-05
project_title: Community-Engaged Research and Action to Reduce Respiratory Disease in Appalachia
administering_ic: NIEHS
award_notice_date: 2019-01-16
opportunity_number: PA-12-153
application_type: 5
activity_code: R01
ic: ES
serial_number: 024771
program_official: O'FALLON, LIAM
project_start_date: 2015-04-15
project_end_date: 2021-01-31
study_section: Health Disparities and Equity Promotion Study Section[HDEP]
contact_pi_person_id: 1939811
contact_pi: BROWNING, STEVEN R
other_pis: SCHOENBERG, NANCY E.
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Rural Appalachian residents experience the nation's highest rates of serious respiratory illnesses with Appalachian Kentuckians twice as likely to be diagnosed with adult asthma and chronic obstructive pulmonary disease as their national counterparts. In response to community concern and to address the critical need to reduce respiratory health disparities in Appalachia we draw on our decade-long community-academic partnership to undertake three aims and activities: (1) to investigate the extent nature and source of respiratory health inequities we will implement a community-engaged assessment of environmental and individual-level exposures; (2) to enhance community knowledge about respiratory illness and refine a culturally appropriate environmental public health action strategy(EPHAS) we will disseminate results from the epidemiologic assessment and gather input to refine the EPHAS; and (3) to test the efficacy of the EPHAS we will implement and evaluate a three arm RCT involving self-management and home modification. Outcomes include appropriate health care use; improvement in quality of life pulmonary function respiratory illness knowledge and self-efficacy; extent of community participation; and programmatic satisfaction. The proposed application is responsive to "Research to Action: Assessing and Addressing Community Exposures to Environmental Contaminants" (PA-12-153) encouraging "community-engagement projects designed to investigate the potential health risks of environmental exposures of concern to a community and to implement an environmental public health action plan based on research findings." The proposed community-academic effort represents the first of its kind to undertake a comprehensive environmental behavioral and social determinants assessment leading to a community-endorsed environmental public health action strategy to rectify Appalachian respiratory health inequities.

project_terms:
Address;Adult;Adult asthma;Affect;Age;Air Pollutants;Appalachian Region;Area;Asthma;Back;Behavioral;Chronic Obstructive Airway Disease;Coal Mining;Collaborations;Communities;Community Participation;Data;Development;Diagnosis;Diet;Environmental Exposure;Environmental Pollution;Environmental Risk Factor;Epidemiology;Evaluation;Exposure to;Gender;Goals;Health;Health education;Healthcare;Home environment;Individual;Intervention;Kentucky;Knowledge;Lung diseases;Measurement;Measures;Modification;Nature;Neighborhoods;Occupations;Outcome;Outcome Assessment;Physical activity;Population;Process;Public Health;Quality of life;Randomized;Reporting;Research;Research Design;Research Personnel;Risk;Risk Factors;Role;Rural Appalachia;Self Efficacy;Self Management;Smoking;Source;Symptoms;Testing;Voice;arm;base;community partnership;design;efficacy testing;environmental justice;epidemiology study;experience;health disparity;improved;innovation;low socioeconomic status;meetings;member;public health relevance;pulmonary function;residence;respiratory;respiratory health;response;rural dwellers;satisfaction;social

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Residents of Rural Appalachia have the nation's highest rates of respiratory disease (asthma chronic obstructive pulmonary disease etc.). This project is the first to (1) study the many factors-environmental social and behavioral- that may account for this health inequity and (2) test an innovative approach to improve respiratory health. We draw on our long standing partnerships with several community groups-- a community research organization a community coalition/advisory board local media and health education and faith organizations- to do an epidemiologic assessment share the results and then implement and evaluate an environmental public health strategy.


application_id: 9626568
project_number: 1R35GM130349-01
project_title: Functional Analysis of Programmed Genome Rearrangement
administering_ic: NIGMS
award_notice_date: 2019-01-28
opportunity_number: PAR-17-094
application_type: 1
activity_code: R35
ic: GM
serial_number: 130349
program_official: VATAKIS, DIMITRIOS NIKOLAOS
project_start_date: 2019-02-01
project_end_date: 2024-01-31
study_section: Special Emphasis Panel[ZRG1 CB-J (55)]
contact_pi_person_id: 9381521
contact_pi: SMITH, JERAMIAH JAMES
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Anaphase;Biology;Cell Lineage;Chromatin;Chromosome Structures;DNA;DNA Methylation;DNA Sequence;Development;Epigenetic Process;Funding;Genes;Genome;Genome Stability;Germ;Germ Cells;Health;Heritability;Higher Order Chromatin Structure;Human;Human Biology;Human Genome;Individual;Instruction;Lampreys;Life;Light;Maintenance;Malignant Neoplasms;Mediating;Modification;Molecular;Pathway interactions;Petromyzon marinus;Philosophy;Physiology;Regulator Genes;Regulatory Element;Reproducibility;Research;Somatic Cell;Stem cells;Structure;Vertebrates;Work;comparative;functional outcomes;gene function;histone methylation;migration;next generation;novel;novel strategies;pluripotency;tumorigenesis;vertebrate genome


application_id: 9626386
project_number: 5K08DK102542-04
project_title: Nephritogenic autoantibodies in systemic lupus
administering_ic: NIDDK
award_notice_date: 2019-01-23
opportunity_number: PA-14-046
application_type: 5
activity_code: K08
ic: DK
serial_number: 102542
program_official: RANKIN, TRACY L
project_start_date: 2016-02-25
project_end_date: 2021-02-24
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 11177796
contact_pi: CASTER, DAWN
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:
DESCRIPTION (provided by applicant): Up to 60% of SLE patients develop clinical evidence of kidney injury termed lupus nephritis (LN). LN is thought to be caused by glomerular immune complex deposition activating an inflammatory cascade that injures glomerular cells leading to proteinuria and loss of filtration capacity. LN is classified based on renal histopathology into si classes of which proliferative LN (ISN/RPS class III or IV) is most likely to cause renal failure.Most studies examining the causes of proliferative LN have focused on the nephritogenic potential of anti-nuclear antibodies diverting attention from a potential role for tissue/cell-specific autoantibodies. There is increasing evidence that autoantibodies to tissue specific target antigens contribute to the pathogenesis of many glomerular diseases including LN. Our preliminary data show that sera from patients with proliferative LN contain autoantibodies to human glomerular proteins including annexin A2 and moesin. These findings support our central hypothesis that autoantibodies targeting glomerular proteins including annexin A2 and moesin result in immune complex deposition that causes proliferative LN. This mentored career development proposal will focus on further characterization of autoantibodies to annexin A2 and moesin in proliferative LN validation of those autoantibodies as biomarkers for disease examination of the functional changes in podocytes and mesangial cells exposed to those autoantibodies and evaluation of the nephritogenic potential of those antibodies in animal models. As evidenced by the advances in understanding primary membranous nephropathy after the identification of target antigens this will lead to improved understanding of the pathogenic mechanisms of disease and provide new diagnostic and prognostic biomarkers. This mentored career development award also will provide protected time for the applicant to develop the skills required to become an independent physician-scientist investigating clinical and basic aspects of lupus nephritis through an individualized career development plan which has been developed by the mentorship team.

project_terms:
Actins;Address;Affect;American;Animal Model;Annexins;Antibodies;Antigen Targeting;Antigen-Antibody Complex;Antinuclear Antibodies;Attention;Autoantibodies;Autoimmune Diseases;Award;Biological Markers;Cell physiology;Cells;Clinical;Cytoskeleton;Data;Deposition;Development;Development Plans;Diagnosis;Dialysis procedure;Discipline;Disease;End stage renal failure;Evaluation;Exposure to;Filtration;Functional disorder;Goals;Histopathology;Human;Immunoglobulin G;Impairment;Inflammatory;Inflammatory Response;Injections;Injury;K-Series Research Career Programs;Kidney;Kidney Failure;Knowledge;Lead;Life;Lupus;Lupus Nephritis;Membranous Glomerulonephritis;Mentors;Mentorship;Nucleosomes;Pathogenesis;Pathogenicity;Patients;Physicians;Prognostic Marker;Proteins;Proteinuria;Publications;Renal glomerular disease;Research;Role;Scientist;Serum;Systemic Lupus Erythematosus;Testing;Therapeutic immunosuppression;Time;Tissues;Training;Treatment Protocols;Validation;base;career;career development;diagnostic biomarker;disease diagnosis;ds-DNA;experience;experimental study;improved;improved outcome;injured;lupus prone mice;mesangial cell;moesin;mouse model;novel diagnostics;podocyte;programs;public health relevance;skills;treatment response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The objective of this mentored Career Development proposal is to characterize cell/tissue specific nephritogenic autoantibodies that cause proliferative LN (class III/IV). This research is expected to establish the pathophysiologic basis for proliferativeLN as well as identify biomarkers for the diagnosis of this disease providing the technologic and intellectual framework necessary for the applicant to develop an independent research program in this discipline.


application_id: 9625827
project_number: 5R01NS092680-03
project_title: ER Ca2+ store mediated white matter injury
administering_ic: NINDS
award_notice_date: 2019-01-22
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 092680
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2017-05-01
project_end_date: 2022-01-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 11601659
contact_pi: STIRLING, DAVID PAUL
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract: Protecting white matter following SCI is a major goal to improve neurological recovery followingspinal cord injury (SCI). Whether the axoplasmic reticulum (AR) the major endomembrane system and Ca2+store within axons contributes to secondary bystander central myelinated fiber degeneration following SCIremains unknown. Furthermore the role of the AR's major release channels ryanodine receptors (RyR) andinositol 145-trisphophate receptors (IP3R) in white matter injury remain poorly understood; however ourpreliminary data support an important role for RyR in mediating secondary degeneration of axons following aclinically-relevant contusion SCI in vivo. Our overall objective is to protect central myelinated fibers followingSCI by targeting AR Ca2+ release channels. We will test the following hypothesis within this proposal. RyRand IP3R mediate intra-axonal Ca2+ store release of Ca2+ within spinal axons and cause secondary axonaldegeneration following contusion SCI. Therefore inhibiting Ca2+ store mediated Ca2+ release by targeting RyRor upstream signaling pathways that converge on RyR and IP3R will protect white matter following SCI. Ourspecific aims are to: 1. Determine the role of RyR and IP3R in secondary axonal degeneration followingcontusion SCI in real-time. 2. Determine the role of upstream signaling pathways in AR Ca2+ release inreal-time. 3. Evaluate clinically relevant approaches to inhibit AR-mediated intra-axonal CICR toimprove neurological recovery following contusion SCI. To accomplish this goal we will utilize two-photonmicroscopy combined with an ultrafast resonant scanner (capable of collecting images at up 420 frames persecond) to assess axonal swelling spheroid formation axonal retraction degeneration (Advillin-Cre: tdTomatotransgenic mice) axonal Ca2+ wave generation and Ca2+ accumulation in axons (Advillin-Cre: tdTomato:CaMP6f and Thy1GCaMP6f transgenic mice) myelin integrity (fluorescent lipophilic dyes) and changes in AR(e.g. ER tracker dyes and 3D electron microscopy) as these dynamic events are unfolding in real-time in vivofollowing a contusion SCI. The technology and approach proposed may help advance the field as live imagingof axons over time allows unequivocal determination of the fate of injured axons and whether they can berescued in real-time with treatment. Furthermore it allows direct visualization of myelin and the fate of this vitalelement simultaneously with axons as these events are unfolding in the injured spinal cord. This proposal isinnovative and uses advanced imaging techniques to explore overlooked areas of SCI research. The approachtaken may also unveil potential novel therapeutic targets and clinically relevant treatments (e.g. FDA approvedcarvedilol) to promote neurological recovery after SCI. The underlying mechanisms of white matter injury mayalso be relevant to multiple sclerosis and other neurological diseases.

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

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


application_id: 9625808
project_number: 5R01NS089324-05
project_title: Functional consequences of silencing propriospinal pathways after SCI in the adult rat
administering_ic: NINDS
award_notice_date: 2019-01-15
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 089324
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2015-02-01
project_end_date: 2021-01-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
other_pis: 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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Despite the more than 100 years since the recognition of intrinsic spinal locomotor circuits many of the physiological details of those circuits and their contributions to functional recovery following spinal cord injury (SCI) remain t be determined. Recent development of powerful molecular tools enables functional dissection of neural circuitry by selectively and temporarily silencing neurotransmission. We will focus on two classes of spinal cord interneurons that have been described anatomically but remain a mystery functionally. These are the long-ascending propriospinal neurons (LAPNs) and the long descending propriospinal neurons (LDPNs) that together comprise a population we have termed "inter-enlargement" because they provide direct and indirect connections between the cervical and lumbar enlargements. The LAPNs and LDPNs are assumed to play critical roles in forelimb-hindlimb coordination in quadrupeds and to coordinate arm-swing and upper body-lower body movements in people. We hypothesize that LAPNs and LDPNs provide detailed temporal information about the step cycle and limb movement to the corresponding enlargement and thus play critical roles in forelimb-hindlimb coordination in the normal adult rat and in functional recovery following a contusive SCI. This proposal will directly test these hypotheses. Strong preliminary data unequivocally support the rationale of this proposal. Specifically: Aim 1 will determine the role of LAPNs/LDPNs in locomotion as we will independently silence these pathways bilaterally ipsilaterally and commissurally. Sophisticated gait and kinematic analyses as well as terminal histological analyses will be used to quantify functional deficits. Aim 2 will determine the role of LAPNs/LDPNs in recovered function after SCI. These pathways will be silenced after functional recovery has plateaued following two different injury severities. Aim 3 will determine the role of LAPNs/LDPNs in the process of functional recovery after SCI. LAPN/LDPN networks will be silenced 3-10 and 28-35 days post-SCI time periods of initial weight bearing and stabilization of locomotor function respectively. Collectively the proposed experiments will hopefully delineate how these pathways may be therapeutically targeted for functional recovery after SCI.

project_terms:
Address;Adult;Anatomy;Animals;Behavior;Behavioral;Bilateral;Cells;Cervical;Contusions;Data;Development;Dissection;Doxycycline;Elements;Excision;Forelimb;Gait;Grant;Hindlimb;Histologic;Histology;Injury;Interneurons;Ipsilateral;Locomotion;Locomotor Recovery;Lumbar Regions;Molecular;Motor Activity;Movement;Neural Pathways;Neurons;Neurotransmitters;Outcome;Pathway interactions;Phenotype;Physiological;Play;Population;Presynaptic Terminals;Process;Rattus;Recovery;Recovery of Function;Role;Severities;Spinal;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Subfamily lentivirinae;Synaptic Transmission;System;Testing;Tetracycline Control;Therapeutic;Time;Virus;Walking;Weight-Bearing state;Work;anterograde transport;arm;central pattern generator;drinking water;experimental study;insight;kinematics;limb movement;neural circuit;neurotransmission;neurotropic;novel;public health relevance;retrograde transport;therapeutic target;tool;vector;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This grant examines the role of the long ascending and descending propriospinal neurons (LAPNs LDPNs) in the inter-enlargement control of forelimb hindlimb coordination. Using a novel two virus vector system we can transiently silence these neural pathways and examine the effects on both normal walking behavior and their contribution to functional recovery after spinal cord injury (SCI). Successful completion of the experiments outlined in this proposal would provide important insight in the potential for harnessing these pathways to enhance functional recovery after SCI.


application_id: 9625666
project_number: 5R01NS088555-06
project_title: B cells alter adaptive autoimmunity to protect from ischemic injury after stroke
administering_ic: NINDS
award_notice_date: 2019-03-08
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 088555
program_official: BOSETTI, FRANCESCA
project_start_date: 2018-12-20
project_end_date: 2021-07-14
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9562586
contact_pi: STOWE, ANN MARIE
other_pis: Not Applicable
congressional_district: 06
department: 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:
DESCRIPTION (provided by applicant): More than 800000 people in the U.S. will suffer from stroke each year yet there remains only one FDA- approved acute intervention. Clinical trials to minimize post-stroke inflammation failed highlighting the need to better understand inflammatory and neuroprotective mechanisms within the central nervous system (CNS). Repetitive hypoxic preconditioning (RHP) naturally protects from stroke for months beyond treatment minimizing infarct volumes blood-brain barrier (BBB) disruption and monocyte T cell and neutrophil diapedesis into the ischemic brain. In contrast RHP specifically induces an immunosuppressed B cell phenotype that is enhanced in the injured CNS of preconditioned mice following stroke. The adoptive transfer of RHP-treated B cells (B(RHP)cells) 6h after transient stroke in male mice reduced infarct volumes and improved functional recovery compared to PBS- or wild type (WT) B cell-treated controls. B(RHP)cell therapy also suppressed a post-stroke autoimmune response to CNS-derived neuronal and myelin antigen (Ag) a novel finding for adaptive autoimmunity that has only been studied in preclinical models of stroke in the context of secondary infection. The goal of this New Investigator grant is to determine if B(RHP)cells as part of a transferrable adaptive immunity to mild hypoxia mediate endogenous protection through the production of interleukin 10 (IL10) a cytokine that promotes neuronal repair as well as interferon (IFN)- a cytokine that converts effector (i.e. pro-inflammatory Th1) T cells to regulatory T cells (Tregs) that suppress other neuropathological immune cells. Specific Aim 1 will test the hypothesis that B cells confer acute neuroprotection through the production of IL10 and direct neuronal interaction. We will confirm using state-of-the-art 3-D serial two-photon tomography for whole brain imaging MRI and behavioral assays that IL10- enhanced B(RHP)cells colocalize to a higher number of surviving neurons in the ischemic hemisphere to improve long-term functional recovery. We will also confirm the role of B(RHP)cell-derived IL10 on neuronal viability and axon outgrowth in vitro following oxygen-glucose deprivation (OGD) with B(RHP)cells harvested from IL10-null and WT mice. Specific Aim 2 will test the hypothesis that B(RHP)cells from WT but not IFN--null mice will induce a novel Treg population to suppress pro-inflammatory autoreactive responses from Th1 cells. The transfer of Tregs exposed in vitro to B(RHP)cells will also promote long-term neurovascular and functional recovery (Aim 1A methods) in addition to suppressing CNS-derived autoreactivity. Finally Glatiramer Acetate or Copaxone(r) is an FDA-approved drug that upregulates B cell-derived IL10 and Treg conversion in patients with multiple sclerosis. Specific Aim 3 will test the hypothesis that WT B cells treated with Copaxone will upregulate IL10 and IFN- to phenocopy B(RHP)cell-mediated protection. We will test the efficacy of Copaxone-treated B cells on neuronal viability in vitro following OGD (Aim 1B methods). Copaxone- or control Betaseron-treated B cells will be adoptively transferred post-stroke to determine efficacy on long-term recovery (Aim 1A methods).

project_terms:
3-Dimensional;Acute;Adoptive Transfer;Antigens;Attenuated;Autoimmune Responses;Autoimmunity;Axon;B cell therapy;B-Lymphocytes;Behavioral;Behavioral Assay;Blood - brain barrier anatomy;Blood Preservation;Brain;Brain Injuries;Brain imaging;Cause of Death;Cell Communication;Cells;Clinical Treatment;Clinical Trials;Coculture Techniques;Data;FDA approved;GTP-Binding Protein alpha Subunits Gs;Glucose;Goals;Grant;Harvest;Hypoxia;Immune;Immune response;In Vitro;Infarction;Inflammation;Inflammatory;Inflammatory Response;Injury;Interferon Type II;Interferons;Interleukin-10;Intervention;Ischemia;Knockout Mice;Leukocytes;Longitudinal Studies;Magnetic Resonance Imaging;Measures;Mediating;Mediator of activation protein;Methodology;Methods;Modeling;Morbidity - disease rate;Motor;Mus;Myelin;Neuraxis;Neuronal Injury;Neuronal Plasticity;Neurons;Oxygen;Pathology;Patients;Pharmaceutical Preparations;Phenocopy;Phenotype;Population;Pre-Clinical Model;Production;Recombinant interferon beta-1b;Recovery;Recovery of Function;Regulatory T-Lymphocyte;Research;Research Personnel;Role;Stroke;T-Lymphocyte;Testing;Th1 Cells;Therapeutic;Three-Dimensional Imaging;Time;Treatment Efficacy;Wild Type Mouse;Work;adaptive immune response;adaptive immunity;autoreactive T cell;autoreactivity;base;cohort;copolymer 1;cytokine;deprivation;efficacy testing;excitotoxicity;immunoregulation;immunosuppressed;improved;in vitro testing;injured;interleukin-10 receptor;macrophage;male;migration;monocyte;mortality;motor deficit;multiple sclerosis patient;neglect;neurogenesis;neuroprotection;neurovascular;neurovascular injury;neutrophil;novel;post stroke;preclinical study;preconditioning;prevent;public health relevance;recruit;repaired;response;secondary infection;stroke model;stroke recovery;tomography;two-photon

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Stroke the fourth leading cause of death has few successful clinical treatments to reduce injury due to an incomplete understanding of injury and recovery mechanisms. This proposed research challenges the current dogma that all post-stroke inflammation is detrimental to recovery by identifying a new immune cell (B cell) population that is a part of the brain's natural protection from stroke (ischemic) injury. These studies will be th first to determine how the transfer of B cells as a post-stroke neurotherapeutic reduces injury and improves recovery and how this therapy alters a previously unstudied post-stroke autoimmune response that contributes to neuronal protection.


application_id: 9622033
project_number: 1R43HL144277-01
administering_ic: NHLBI
award_notice_date: 2018-08-28
opportunity_number: PA-17-302
application_type: 1
activity_code: R43
ic: HL
serial_number: 144277
program_official: LEE, ALBERT
project_start_date: 2018-09-01
project_end_date: 2020-02-29
study_section: Special Emphasis Panel[ZRG1 SBIB-Y (12)]
contact_pi_person_id: 11058700
contact_pi: TOPAZ, STEPHEN R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 832402486
primary_uei: RK1ZDCXE3LJ7
duns_number: 832402486
uei: RK1ZDCXE3LJ7
fips: US
organization_id: 10024870
organization_name: W-Z BIOTECH, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-09-01
project_title:
Development of a Percutaneous Pulmonary Artery Drainage Device to Unload LV During VA ECMO Support for Severe Cardiogenic Shock

project_abstract:
Cardiogenic shock (CS) is a serious clinical condition of reduced cardiac output (CO) with end organhypoperfusion. In severe CS end organ hypoperfusion leads to multi-organ failure and elevated left ventricle(LV) preload increases LV wall stress exacerbating myocardial injury. Venoarterial extracorporeal membraneoxygenation (VA ECMO) has been increasingly used to support severe CS patients due to its high efficiencycost effectiveness wide availability and minimally invasive capability. VA ECMO pumps almost total CO tonormalize end organ perfusion. However VA ECMO is unable to unload the LV in severe CS patients withmore than 50% of these patients developing LV distension which further damages the myocardium andprevents myocardial recovery. In VA ECMO some blood still goes to the left heart but the compromised LVfails to pump this blood out resulting in LV blood accumulation (LV distension). Currently there is no minimallyinvasive device specifically designed for LV unloading during VA ECMO. Our ultimate goal is to develop apercutaneous device to unload the LV during VA ECMO facilitating myocardial recovery. The enablingtechnology is a percutaneous pulmonary artery (PA) drainage device that keeps the PA/tricuspid valvespersistently open allowing blood flow from the PA toward the right atrium for ECMO drainage. This results in alower PA pressure (PAP) which decreases blood flow toward the left heart and enables retrograde blood flowfrom the left atrium to PA to efficiently unload the LV. Our percutaneous PA drainage device: 1) is minimallyinvasive to eliminate complicated surgery 2) decreases PAP to decompress the heart 3) prevents drainage-induced low central venous pressure to enhance VA ECMO drainage and 4) monitors PAP to confirm/evaluateLV unloading. In our LV distension sheep model with massive myocardial infarction (MI)-induced severe CSand VA ECMO support our first percutaneous PA drainage device prototype was properly deployed andefficiently unloaded the LV (n=2) demonstrating the LV unloading feasibility of our device. Our objective inthis Phase I SBIR is to develop/fabricate a new percutaneous PA drainage device prototype for in vitro testingand in vivo testing in our LV distension sheep model. Specific Aim 1: To design fabricate and bench-test apercutaneous PA drainage device prototype. The prototype will be a 7 Fr triple lumen catheter-basedmemory alloy wire cage. This cage will be close to the catheter for easy installation/removal and will openinside the PA/tricuspid valves to create valve regurgitation. Back flow efficiency and valve opening reliabilitywill be tested in a simulation mock loop. Specific Aim 2: To test a percutaneous PA drainage deviceprototype in a LV distension sheep model. Our established LV distension sheep model with massive MI-induced severe CS and VA ECMO support will be used to test our percutaneous PA drainage device prototypefor ease of deployment LV unloading efficiency and 6 hour reliability (n=5). W-Z Biotech will design fabricateand perform in vitro testing while the University of Kentucky will conduct the in vivo animal studies.

project_terms:
Acute myocardial infarction;Address;Alloys;Animals;Aorta;Arrhythmia;Back;Biotechnology;Blood;Blood Circulation;Blood flow;Cannulas;Carbon Dioxide;Cardiac;Cardiac Output;Cardiogenic Shock;Catheters;Central venous pressure;Cessation of life;Clinical;Complex;Development;Devices;Drainage procedure;Drug toxicity;Engineering;Equipment;Excision;Extracorporeal Membrane Oxygenation;Failure;Goals;Heart;Heart Atrium;Heart Transplantation;Heart Valve Diseases;Hour;Human Resources;In Vitro;Injury;Kentucky;Label;Laboratory Animal Production and Facilities;Lead;Left;Left atrial structure;Left ventricular structure;Low Cardiac Output;Lung;Mechanics;Memory;Modeling;Monitor;Myocardial;Myocardial Infarction;Myocarditis;Myocardium;Operative Surgical Procedures;Organ;Outcome;Patients;Perfusion;Phase;Polyurethanes;Publications;Pulmonary artery structure;Pulmonary valve structure;Pump;Recovery;Research Support;Right atrial structure;Risk;Scientist;Sheep;Small Business Innovation Research Grant;Stress;Surgeon;Techniques;Technology;Testing;Tricuspid Valve Insufficiency;Tricuspid valve structure;Universities;Venous;Ventricular;artificial lung;base;blood pump;cost effectiveness;design;experience;hypoperfusion;in vitro testing;in vivo;in vivo evaluation;minimally invasive;mortality;multidisciplinary;performance tests;pressure;prevent;prototype;research and development;simulation;ventricular assist device

public_health_relevance:
We are proposing to develop a percutaneous pulmonary artery drainage device to address the critical problemof left ventricular distension in VA ECMO-supported severe cardiogenic shock patients. The enablingtechnology is a 7 Fr triple lumen catheter-based memory alloy wire cage that keeps the pulmonary andtricuspid valves persistently open to efficiently unload the left ventricle. Our percutaneous pulmonary arterydrainage device will facilitate myocardial recovery in severe cardiogenic shock patients significantly impactingtheir outcomes.


application_id: 9621878
project_number: 1R41AI141060-01
project_title: Evaluating Synthetic Biology Produced Triterpene Oils in Adjuvant Formulations
administering_ic: NIAID
award_notice_date: 2018-09-06
opportunity_number: PA-17-303
application_type: 1
activity_code: R41
ic: AI
serial_number: 141060
program_official: MINNICOZZI, MICHAEL
project_start_date: 2018-09-06
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1 IMM-R (12)]
contact_pi_person_id: 8279550
contact_pi: CHAPPELL, JOE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 080540683
primary_uei: P3KJFJJR58R4
duns_number: 080540683
uei: P3KJFJJR58R4
fips: US
organization_id: 10045877
organization_name: ENEPRET, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405032006
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTVaccine adjuvants help stimulate the body to generate an immune response when co-injected with an antigen(the compound for which immunity is desired). Although the human body is capable of producing antibodies tomost injected antigens adjuvants can help boost the bodys ability to mount a successful and acquired immuneresponse to the presented target. Adjuvants have been shown to enhance immunity against targets that usuallyexhibit poor immune responsessuch as highly-purified and recombinantly-produced antigens. This isparticularly important for individuals which may have a less robust immune system such as children or the elderly.One of the well-studied adjuvants that is approved for use in humans nearly worldwide is the oil-in-water emulsionMF59. The oil used in this formulation is the hydrocarbon triterpene squalene. Squalene is a natural oil producedin all eukaryotic organisms as it is the precursor to sterols (e.g. cholesterol). MF59 is a component of Fluad anFDA-approved seasonal influenza vaccine for people 65 years old. The traditional source of squalene has beenfrom shark liver oil which is no longer viable nor sustainable. In light of these limitations and the desire todevelop more efficacious adjuvants fermentable yeast and transgenic plants have been engineered to producehigh amounts of squalene and several related novel triterpenes. These include botryococcene plus mono- anddi-methylated forms of squalene and botryococcene. The experiments proposed here are designed toaccomplish two specific aims: (1) using a mouse model demonstrate that our Synthetic Biology generatedsqualene performs equivalent to shark derived squalene in adjuvant vaccine formulations; and (2) evaluate our5 novel triterpenes in adjuvant formulations for their abilities to induce elevated or altered immune responsescompared to squalene. Our studies will quantitatively compare the immunogenicity of a trivalent influenzavaccine plus and minus the different triterpene adjuvant formulations by measuring antibody (IgG1 IgG2a andIgE) and hemagglutination inhibition (HI) titers. The possibility that our antigen-triterpene adjuvant formulationsmight induce undesirable effects will be assessed by measuring inflammatory cytokine levels in sera samples ofthe inoculated animals. Once the feasibility of using these compounds in an adjuvant system is demonstrated inthis Phase I study the foundation for several follow-on Phase II studies will be established: one demonstratingthe biological equivalency of our Synthetic Biology produced squalene would endorse efforts to use processengineering methodologies to scale-up our squalene manufacturing capabilities for marketplacecommercialization; and two if any of our novel triterpenes proves efficacious in stimulating antibody titers wewould need to pursue additional pre-clinical evaluations of their safety and potential for inciting undesirableinflammatory responses.

project_terms:
Address;Adjuvant;Adjuvant Study;Aluminum;Animals;Antibodies;Antibody Response;Antibody titer measurement;Antigens;Attenuated;Biological;Biological Assay;Child;Cholesterol;Data;Dermis;Development;Elderly;Emulsions;Engineering;Enzyme-Linked Immunosorbent Assay;Evaluation;Exhibits;FDA approved;Female;Food;Formulation;Foundations;Future;Genetic;Green Algae;Growth;Harvest;Hemagglutination;Hemagglutinin;Hour;Human;Human body;Hydrocarbons;IgE;IgG1;Immune response;Immune system;Immunity;Immunization;Immunize;Immunoglobulin G;Immunoglobulins;Inbred BALB C Mice;Individual;Inflammation;Inflammatory;Inflammatory Response;Influenza virus vaccine;Injections;Laboratories;Light;Liver;MF59;Measures;Methodology;Monitor;Mono-S;Mus;National Institute of Allergy and Infectious Disease;Nature;Oils;Organism;Pharmacologic Substance;Phase;Plant Sources;Play;Positioning Attribute;Preclinical Testing;Process;Production;Recombinants;Research Priority;Role;Safety;Sampling;Serum;Shark;Source;Squalene;Sterols;System;Technology;Testing;Transgenic Plants;Triterpenes;United States;Vaccine Adjuvant;Vaccines;Visual;Water;Whales;Yeasts;adaptive immune response;analog;base;commercial application;commercialization;cost;cytokine;design;expectation;experimental study;global health;human old age (65+);immunogenicity;improved;irritation;male;medical specialties;mouse model;novel;novel vaccines;pathogen;phase 1 study;phase 2 study;preclinical evaluation;preclinical safety;prospective;response;scale up;seasonal influenza;sound;synthetic biology;trivalent influenza vaccine;vaccine development;vaccine efficacy

public_health_relevance:
PROJECT NARRATIVEVaccine adjuvants play a special role in the development of adaptive immunological responses because theystimulate more robust titers of antibodies without inciting undue inflammation. Although triterpene basedadjuvants are recognized for their efficacy in stimulating desirable immune response limiting sources ofsqualene and squalene analogs have impeded use and development of these oil-in-water adjuvants. We willprovide equivalency testing of new Synthetic Biology generated triterpenes paving the way for scale-up processengineering towards commercialization and providing the justification for advanced pre-clinical safetyevaluations.


application_id: 9621581
project_number: 1UT2GM130174-01
project_title: Southeast Xlerator Network
administering_ic: NIGMS
award_notice_date: 2018-09-01
opportunity_number: RFA-GM-18-001
application_type: 1
activity_code: UT2
ic: GM
serial_number: 130174
program_official: ARORA, KRISHAN
project_start_date: 2018-09-01
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1 IMST-K (14)]
contact_pi_person_id: 15333536
contact_pi: WILLMOT, JACQUELINE
other_pis: GIERSCH, RICHARD F;KRENTSEL, EUGENE ;MCCLURE, IAN D;SAUNDERS, ROBERT
congressional_district: 03
department: Unavailable
primary_duns: 080949252
primary_uei: JYN1A3M4LD29
duns_number: 080949252
uei: JYN1A3M4LD29
fips: US
organization_id: 10048196
organization_name: XLERATEHEALTH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402023346
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acceleration;Address;Adopted;Advocate;Astronomy;Award;Basic Science;Biological Sciences;Biomedical Technology;Businesses;Capital;Development;Economic Development;Ecosystem;Education;Electronics;Entrepreneurship;Evaluation;Faculty;Fostering;Funding;Goals;Grant;Health Sciences;Healthcare;Incubators;Industry;Institution;Intellectual Property;Kentucky;Knowledge;Leadership;Learning;Legal patent;Licensing;Medical Device;Medical Technology;Mentors;Outcome;Pathway interactions;Pharmacologic Substance;Phase;Privatization;Process;Puerto Rico;Research;Resources;Services;Small Business Innovation Research Grant;Small Business Technology Transfer Research;Structure;Survival Rate;Talents;Techniques;Technology;Technology Transfer;Trainers Training;Training;Training Programs;Training and Education;United States National Institutes of Health;Universities;Vision;West Virginia;commercialization;design;exhaustion;experience;improved;innovation;inter-institutional;operation;product development;programs;public-private partnership;success;technology development;tool


application_id: 9621389
project_number: 5R01GM070559-13
project_title: Epigenetic and post-translational modifier regulation of juvenile hormone action
administering_ic: NIGMS
award_notice_date: 2019-01-11
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: GM
serial_number: 070559
program_official: AINSZTEIN, ALEXANDRA M
project_start_date: 2005-02-01
project_end_date: 2021-06-02
study_section: Vector Biology Study Section[VB]
contact_pi_person_id: 7355989
contact_pi: PALLI, SUBBA R
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_abstract:
DESCRIPTION (provided by applicant): There has been a continuous demand for the development of insect control methods that are target-specific. Juvenile hormone (JH) and ecdysteroids are the major hormones that regulate development and reproduction in insects. Since these hormones are not present in vertebrates they represent attractive targets for the development of insect control methods. Hindering this effort is the lack of understanding on the molecular basis of JH action. Tremendous progress has been made in understanding JH action at the molecular level during the past few years. A bHLH transcription factor methoprene tolerant (Met) has been identified as a JH receptor. A steroid receptor co-activator homologue (SRC/Taiman/FISC) and Cycle have been identified as important co-factors involved in JH action. Kruppel homologue (Kr-h1) and bHLH transcription factor Hairy and E93 have been identified as important transcription factors that mediate JH action. Preliminary experiments showed that Cyclic AMP response-element binding protein (CBP) is required for acetylation of histone H3 as well as for JH induction of JH-response genes in Tribolium castaneum tissues TcA and Aag-2 cells. In addition histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) also induces expression of JH-response genes in TcA and Aag-2 cells. Chromatin modifiers Brahma Snr1 and CHD1 but not DNA methyl transferase are required for regulation of metamorphosis and reproduction in T. castaneum. JH exerts diverse functions in different tissues and under various physiological conditions. We hypothesize that epigenetic and post- translational modification of proteins involved in JH action play critical roles in multi-dimensionl gene regulation strategies employed by JH. Therefore the main objective of this proposal is to capitalize on these latest developments to identify epigenetic modifiers and determine their mechanisms of action in modulation of JH response using T. castaneum TcA and Aag-2 cells. The two Specific Aims of the proposal are 1. To identify key players involved in epigenetic and post-translational modifier regulation of JH action and 2. To determine the mechanisms involved in epigenetic and post-translational modifier regulation of JH action. In the first Specific Aim w will employ RNAi cell culture and reporter assays to identify and characterize key proteins including histone acetyl transferases (HAT) HDACs and chromatic modifiers involved in modulation of JH action. Temporal spatial and hormonal regulation of identified genes as well as their function in JH action will be determined. In the second Specific Aim we will employ mass spectrometry RNAi two-hybrid pull- down Chip and reporter assays to identify acetylated lysines in Met domains of HATs HDACs and Brahma Snr1 and CHD1 required for JH action localize HATs HDACs and Brahma Snr1 and CHD1 on Kr-h1 Hairy and E93 promoters and identify interacting partners of HATs HDACs Brahma Snr1 and CHD1. The expected outcome of this study an understanding of the molecular basis of JH action and identification of critical proteins involved in JH action will help in development of methods for control of insect vectors. The proposed studies will also advance our knowledge on epigenetic and post-translational modification of histones and other nuclear proteins especially on the functions and mechanisms of action of the modifiers.

project_terms:
Acetylation;Adult;Agonist;Biological;Biological Assay;Biological Metamorphosis;Biological Models;CHD1 gene;Cell Culture Techniques;Cells;Chromatin Remodeling Factor;Culicidae;Cyclic AMP-Responsive DNA-Binding Protein;Development;Disease;Disease Vectors;Ecdysone;Ecdysteroids;Ensure;Epigenetic Process;Event;Food;Gene Expression Regulation;Genes;Helix-Turn-Helix Motifs;Histone Acetylation;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone H3;Histones;Homologous Gene;Hormone Receptor;Hormones;Human;Insect Control;Insect Vectors;Insecta;Insecticides;Juvenile Hormones;Knowledge;Laboratories;Livestock;Lysine;Mass Spectrum Analysis;Mediating;Medicine;Methods;Methoprene;Molecular;Molting;Nuclear Proteins;Outcome Study;Physiological;Play;Post-Translational Protein Processing;Post-Translational Regulation;Proteins;RNA Interference;Regulation;Reporter;Reproduction;Research;Role;Steroid Receptors;Testing;Tissues;Transferase;Tribolium;Trichostatin A;Vertebrates;base;brahma;epigenetic regulation;experimental study;genome sequencing;histone modification;hormone regulation;human disease;method development;novel;promoter;public health relevance;receptor;response;success;transcription factor;vector control;whole genome;yeast two hybrid system

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Mosquitoes transmit deadly diseases. The research proposed in this application will provide information of potential importance for development of insecticide for vector control. The proposed studies will reveal functions and mechanisms of action of epigenetic marks which will help in understanding epigenetics of human diseases.


application_id: 9620217
project_number: 1R56DC016585-01
project_title: Diagnosis of Noise-Induced Hidden Hearing Loss
administering_ic: NIDCD
award_notice_date: 2018-03-02
opportunity_number: RFA-DC-17-002
application_type: 1
activity_code: R56
ic: DC
serial_number: 016585
program_official: KING, KELLY ANNE
project_start_date: 2018-03-02
project_end_date: 2019-02-28
study_section: ZDC1-SRB-Y(60)
contact_pi_person_id: 8536073
contact_pi: ZHAO, HONG-BO
other_pis: EARL, BRIAN RICHARD;SHINN, JENNIFER B
congressional_district: 06
department: OTOLARYNGOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Diagnosis of Noise-Induced Hidden Hearing LossSummary Recent research has demonstrated that although a short-term exposure to moderate levels ofnoise does not cause apparent hair cell loss it can induce irreversible auditory nerve degeneration inparticular loss of low spontaneous rate (LSR) auditory neurons and their synapses with inner haircells. This may eventually result in difficulty hearing speech in noisy environments. Unfortunatelysuch hearing loss and synaptopathy are not readily detectable by current clinical auditory testsleading to hidden hearing loss (HLL). The goal of this project is to develop a simple clinically-feasible method to diagnose such cochlear synaptopathy and associated HHL in humans. Auditory nerves can be divided into three groups based on their spontaneous discharge rates.Medium and high spontaneous rate (M/HSR) fibers have low-threshold but their discharges arequickly saturated as sound intensity increases whereas LSR fibers have high threshold and theirdischarge rates can still increase at high-intensity levels. However most routine audiologicalmeasures are based on gross threshold detection. Thus these tests mainly reflect M/HSR fiberfunction and thereby miss LSR fiber impairment leading to HHL. In this study we hypothesize that ifwe use a moderate level of noise to mask or saturate M/HSR fibers only the LSR fibers are activated.Thus LSR fiber function and impairment can be detected. That is the measured threshold of auditorybrainstem response (ABR) or auditory nerve compound action potential (CAP) responses under suchconditional noise masking (CNM) will mainly reflect LSR fiber activity and function. Moreover if theLSR fibers are damaged or degenerated the measured CNM ABR thresholds or CAP thresholds willbe substantially increased in comparison with those in the normal group without noise-exposure.Since human auditory nerve histopathology analysis is not possible in life we will first test whetherthis simple but novel CNM method can detect noise-induced HHL and synaptopathy in mice (SpecificAim 1) in which auditory nerve and synapse degeneration can be directly assessed withmorphological examinations. Thus the direct link between the diagnosis and the underlying cochlearsynaptopathy can be established and verified. Then we will apply this CNM method to humans to testwhether it can detect noise-induced HHL (Specific Aim 2). Combined with behavioral audiologicaltests we will further assess perceptual function to investigate if the cochlear synaptopathy inducespoor speech-in-noise ability in the central auditory system. Undoubtedly completion of these studieswill provide a novel clinically-feasible auditory test to diagnose noise-induced HHL. This techniquemay also provide an early diagnosis of age-induced hearing loss since it may share common andsimilar neuropathy and synaptopathy with noise-induced HHL in particular in its early stage.

project_terms:
Acoustic Nerve;Action Potentials;Adult;Age;Animal Experimentation;Animals;Audiometry;Auditory;Auditory Brainstem Responses;Auditory Threshold;Auditory system;Behavioral;Clinic;Clinical;Control Groups;Data;Detection;Development;Diagnosis;Diagnostic;Early Diagnosis;Electrophysiology (science);Environment;Evaluation;Exposure to;Fiber;Goals;Hair Cells;Health;Hearing;Histopathology;Human;Impairment;Inner Hair Cells;Life;Link;Masks;Measurable;Measurement;Measures;Methods;Morphology;Mus;National Institute on Deafness and Other Communication Disorders;Nerve Degeneration;Nerve Endings;Nerve Fibers;Neuraxis;Neurons;Neuropathy;Noise;Noise-Induced Hearing Loss;Occupational;Physiological;Population;Presbycusis;Protocols documentation;Public Health;Recovery;Research;Risk Factors;Speech;Surveys;Synapses;Techniques;Testing;Therapeutic Intervention;United States;United States National Institutes of Health;Well in self;Work;auditory processing;base;behavior test;clinical investigation;hearing impairment;mouse model;multidisciplinary;neuropathology;novel;nutrition;prevent;public health relevance;response;social;sound;spiral ganglion;standard measure;translational study

public_health_relevance:
Public Health Relevance Statement: In this proposal we will develop a simple clinically-feasible method to detect noise-inducedhidden hearing loss and cochlear synaptopathy in humans. This will enhance our understandingof noise-induced hearing loss and even age-related hearing loss since both may share thesame synaptopathy. Besides this study will directly provide a simple practicable method todetect noise-induced hidden hearing loss and even early diagnosis of age-related hearing lossin the clinic this study will also provide invaluable clues for developing and applying protectiveand therapeutic interventions for noise-induced or even age-related hearing loss.


application_id: 9619389
project_number: 5P20GM121327-03
project_title: Project 3: Role of RORa in Breast Cancer Metastasis
administering_ic: NIGMS
award_notice_date: 2019-01-10
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
study_section: ZGM1-RCB-6
subproject_number: 7098
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-01-01
budget_end_date: 2019-12-31
project_abstract:
PROJECT SUMMARY Tumors have been described as wounds that do not heal. Similarities between tumors and wounds include traits such as loss of polarized tissue structure and chronic inflammation. We showed that disruption of tissue polarity induced activation of the NF-B pathway and macrophage infiltration. However little is known of how disruption of epithelial cell polarity induces the NF-kB pathway and macrophage infiltration. We have identified the RAR-related orphan nuclear receptor  (ROR) as a potent tumor suppressor by analyzing global gene expression profiles in polarized and non-polarized mammary epithelial cells. Our recent findings show that ROR inhibits NF-B activation and macrophage infiltration in the syngeneic mouse mammary tumor model. These results suggest that ROR is a potent suppressor of macrophage infiltration in mammary epithelial cells. We found that knockdown of ROR significantly induced ROS production in mammary epithelial cells. Reactive oxygen species (ROS) is a driver of cancer progression and a critical regulator of the NF-B pathway. Based on these novel findings the central hypothesis of our proposal is that downregulation of ROR in non-polarized breast cancer cells induces ROS-dependent NF-B activation thereby enhancing macrophage infiltration and differentiation in cancer tissue. We will integrate high-throughput metabolic analysis and global gene expression profiling to delineate mechanisms by which ROR inhibits ROS production. The long-term goal of this proposal is to define the impact of the ROR/NF-B axis in mediating mammary epithelial cell-macrophage crosstalk and regulating breast cancer progression. We have proposed following specific aims to test the hypothesis: The first aim is to elucidate the molecular mechanisms by which ROR inhibits the NF-B pathway in polarized acinus; the second aim is to determine how reduced ROR expression in non-polarized breast cancer cells induces macrophage infiltration and differentiation; and the third aim is to define the impact of ROR in suppressing breast cancer formation and metastasis. This proposed study involves in-depth mechanistic molecular biochemical and cellular studies using state-of-the art metabolomics imaging techniques and model systems. The results will establish a novel link between disruption of tissue polarity and macrophage infiltration/differentiation a critical gap in scientific knowledge in this important research area. Expected study outcomes will also provide new insights in function and regulation of the NF-B pathway during breast cancer development and progression that will facilitate the development of mechanistic based target for cancer therapy.

project_terms:
3-Dimensional;Acinus organ component;Antibodies;Area;Arginine;Biochemical;Biological Assay;Biological Models;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Treatment;Breast Epithelial Cells;Breast cancer metastasis;Cancer Center;Cell Polarity;Centers of Research Excellence;Chronic;Coculture Techniques;Coupled;Development;Disease;Down-Regulation;Epithelial Cells;Event;Expression Profiling;Gene Expression Profiling;Goals;Human;Imaging Techniques;Infiltration;Inflammation;Kentucky;Knockout Mice;Knowledge;Link;Malignant Neoplasms;Mammary gland;Mass Spectrum Analysis;Mediating;Metabolic;Methylation;Molecular;Mus;NF-kappa B;Neoplasm Metastasis;Nuclear Orphan Receptor;Outcome Study;Oxidative Phosphorylation;Pathway interactions;Production;Protein-Arginine N-Methyltransferase;Reactive Oxygen Species;Regulation;Research;Role;Structure;TP53 gene;Testing;Tissue Microarray;Tissues;Transgenic Mice;Transplantation;Tumor Suppressor Proteins;Universities;base;breast cancer progression;cancer prevention;cancer subtypes;cytokine;experimental study;extracellular;in vivo;insight;knock-down;macrophage;malignant breast neoplasm;metabolomics;novel;stable isotope;targeted cancer therapy;trait;transcriptome;tumor;tumor metabolism;tumor progression


application_id: 9619388
project_number: 5P20GM121327-03
project_title: Project 2: Functional Role of the Serine Biosynthesis Pathway in Basal-like Breast Cancer
administering_ic: NIGMS
award_notice_date: 2019-01-10
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
study_section: ZGM1-RCB-6
subproject_number: 7097
contact_pi_person_id: 11716117
contact_pi: WU, YADI
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-01-01
budget_end_date: 2019-12-31
project_abstract:
PROJECT SUMMARY Basal-like breast cancer (BLBC) is one of the most aggressive forms of human cancer because it lacks effective targeted therapies and presents with development of recurrence distant metastasis shorter survival and usually occurs in young women. BLBC has the activated epithelial-mesenchymal transition (EMT) program which provides cancer cells with the phenotypic and cellular plasticity required for invasion cancer stem cell (CSC)-like features and drug resistance. In the last several years we have systematically studied the role of Snail and Twist two key EMT-inducers in BLBC. We discovered that Snail functions to repress genes that prevent EMT (such as E-cadherin) whereas Twist by interacting with BRD4 serves as a transcription activator to induce genes that enhance EMT (such as Wnt5A). We also discovered that EMT is coupled with a metabolic reprogramming which provides a metabolic growth advantage for BLBC cells. Our metabolic analyses clearly indicate that BLBC cells also have increased activity for the pathway driving de novo serine synthesis which is a significant branch derived from glycolysis. The serine biosynthetic pathway is intimately coupled to one-carbon metabolism which intertwines with the folate and methionine cycles to integrate nutritional inputs from glucose amino acids and vitamins for the biosynthesis of nucleotides lipids and proteins as well as the methylation of chromatin. Our laboratory has discovered that phosphoserine aminotransferase 1 (PSAT1) expression a key enzyme in serine biosynthesis is markedly increased in cell lines and clinical BLBC samples. In addition we found that expression of Twist correlated with the level of PSAT1 in BLBC and that Twist significantly induced PSAT1 expression. Knockdown of PSAT1 expression not only reduced glucose uptake and lactate production but also inhibited cell proliferation migration and invasion in BLBC. We hypothesize that Twist is the key molecule controlling the expression of PSAT1 which is responsible for the elevated activity of the serine biosynthetic pathway seen in BLBC. Guided by strong preliminary data we will test this hypothesis by pursuing three specific aims: (1) to elucidate the regulatory mechanism of PSAT1 by Twist in BLBC; (2) to delineate the function of the serine/PSAT1 pathway in BLBC; and (3) to determine the function of the serine/PSAT1 pathway in vivo. Our proposal is innovative and significant because it incorporates a merged investigation of two essential cancer markers in BLBC metabolic reprogramming and EMT and because it leads to the development of an effective precision cancer therapy approach in treating BLBC by combining metabolic drugs with epigenetic inhibitors.

project_terms:
Amino Acids;Anabolism;Antioxidants;Automobile Driving;Brain;Breast Cancer Cell;Breast Cancer cell line;Bromodomain;Cancer Cell Growth;Cancer Center;Carbon;Cell Line;Cell Proliferation;Centers of Research Excellence;Chromatin;Clinical;Coupled;Data;Development;Disease;Distant Metastasis;Drug resistance;E-Cadherin;Enzymes;Epigenetic Process;Epithelial;Folic Acid;Folic Acid Antagonists;Fructose;Genes;Glucose;Glycolysis;Goals;Grant;Growth;Human;Intrinsic factor;Investigation;Kentucky;Laboratories;Lipids;Lung;Maintenance;Malignant Neoplasms;Mediating;Mesenchymal;Metabolic;Metabolic Pathway;Metabolism;Methionine;Methylation;Molecular;Mus;Neoplasm Metastasis;Nucleic Acids;Nucleotide Biosynthesis;Nutritional;Pathway interactions;Patients;Pemetrexed;Pharmaceutical Preparations;Phenotype;Phosphoserine aminotransferase;Production;Proteins;Recurrence;Repression;Role;Sampling;Serine;Signal Transduction;Snails;Specificity;Specimen;Testing;Transcription Coactivator;Universities;Warburg Effect;Xenograft Model;aerobic glycolysis;base;cancer biomarkers;cancer cell;cancer stem cell;cancer therapy;druggable target;glucose uptake;in vivo;inhibitor/antagonist;innovation;knock-down;malignant breast neoplasm;migration;neoplastic cell;novel therapeutic intervention;outcome forecast;overexpression;prevent;programs;stem-like cell;targeted treatment;tumor;tumor metabolism;tumor microenvironment;vitamin biosynthesis;young woman


application_id: 9619386
project_number: 5P20GM121327-03
project_title: Project 1: The Role of Vitamin D in Protecting Against Cachexia in Cancer Patients
administering_ic: NIGMS
award_notice_date: 2019-01-10
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
study_section: ZGM1-RCB-6
subproject_number: 7096
contact_pi_person_id: 10544123
contact_pi: THOMAS, DAVID TRAVIS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-01-01
budget_end_date: 2019-12-31
project_abstract:
PROJECTSUMMARY Vitamin D repletion is linked to improved muscle mitochondrial function lipid deposition and preservation; however while vitamin D insufficiency is common in cancer the mechanistic effects of vitamin D on muscle metabolic health in cancer patients have not been studied. This is important to address because cancer cachexiaischaracterizedbymarkedmusclewastinganabolicresistanceectopicfatinfiltrationmitochondrial dysfunctionandcontributestodecreasedsurvival.Withnovelstrategiestoaddressthisknowledgegapwewill use a combination of advanced metabolic analytical approaches with complementary model systems in cell culture and human subjects to understand the biochemical and physiological mechanisms underlying cancer cachexia in relation to the role of Vitamin D in conjunction with resistance exercise (RE). By combining analysesofmusclesizeandlocaltissuehemodynamicsinvivometabolomicsanalysesofmuscletissueand isolated mitochondria and changes in anabolic cell signaling lipid metabolism and oxidative capacity of primary muscle cells in vitro we will identify mechanisms underlying muscle response to vitamin D repletion. Our previous findings together with data that exercise improves muscle vitamin D storage and retrieval suggest that vitamin D repletion synergizes with RE to improve muscle metabolic function and protein synthesis. Our overall objective is to examine mitochondrial function and anabolic resistance as potential targets of action of vitamin D on muscle metabolism size and strength in preventing the progression of cachexia. The aims of this study are to: 1) non-invasively quantify lipid redistribution local muscle tissue metabolismandmusclemassandstrengthofcancerpatientsbeforeandafter12weeksofvitaminDrepletion withexerciseandproteinsupplementation(VitD)comparedtoexerciseandproteinsupplementationonly(Ctl); 2) determine differences in muscle mitochondrial function in live tissue biopsied from human gastrocnemius from VitD compared to Ctl; and 3) identify mechanisms whereby vitamin D and exercise regulate muscle anabolicsignalingandmitochondrialactivityinprimaryhumanmyotubecultures.Ourcentralhypothesisisthat vitamin D promotes muscle lipid availability for -oxidation in response to exercise thereby preventing lipotoxicityinthemuscleandpotentiallyimprovinganabolicsensitivityinmuscleduringcancercachexia.The impact of this project the first nutrition and exercise study designed as an inexpensive intervention is to understand the effect of vitamin D on the metabolic and anabolic dynamics which underpin dysfunction in cachecticmuscle.IfvitaminDpromoteslipidpartitioningmusclemetabolicfunctionand/oranabolicsensitivity theseadaptationswillultimatelyimprovecancertherapybycombatingcancercachexia.Furtherdiffuseoptical spectroscopy techniques have the potential to identify the minimum effective intervention dose for optimizing metabolichealthleadingtomorepracticalandindividualizedlifestyleprescriptionstoreducehealthcarecosts.

project_terms:
Address;Amino Acids;Biochemical;Biological Models;Biopsy;Cachexia;Calcitriol;Cancer Center;Cancer Patient;Caprylates;Cell Culture Techniques;Consumption;Coupled;Data;Defect;Deposition;Dietary Intervention;Dietary Proteins;Diffuse;Dose;Elderly;Energy Metabolism;Enrollment;Exercise;Fatty acid glycerol esters;Fiber;Functional disorder;Gastrocnemius Muscle;Glucose;Glutamine;Health;Health Care Costs;Human;Hybrids;In Vitro;Infiltration;Intervention;Kentucky;Knowledge;Lead;Life Style;Link;Lipids;Magnetic Resonance Imaging;Maintenance;Malignant Neoplasms;Measures;Mentorship;Metabolic;Metabolism;Mitochondria;Modeling;Muscle;Muscle Cells;Muscle Fibers;Muscle Mitochondria;Muscular Atrophy;Optics;Outcome;Oxygen;Patients;Periodicity;Physical activity;Physiological;Population;Protein Biosynthesis;Proteins;Research Design;Resistance;Retrieval;Role;Signal Transduction;Spectrum Analysis;Stem cells;Stretching;Supplementation;System;Techniques;Testing;Tissues;Translating;Universities;Vitamin D;cancer cachexia;cancer therapy;combat;effective intervention;functional improvement;hemodynamics;human subject;improved;in vivo;lipid metabolism;metabolomics;mitochondrial dysfunction;mitochondrial metabolism;muscle form;muscle metabolism;muscle strength;novel strategies;nutrition;oxidation;preservation;prevent;resistance exercise;response;spectroscopic imaging;stable isotope;standard of care;tumor metabolism


application_id: 9619385
project_number: 5P20GM121327-03
project_title: Core C: Imaging Core
administering_ic: NIGMS
award_notice_date: 2019-01-10
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
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
budget_start_date: 2019-01-01
budget_end_date: 2019-12-31
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;Image Analysis;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;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: 9619384
project_number: 5P20GM121327-03
project_title: Core B: Metabolism Core
administering_ic: NIGMS
award_notice_date: 2019-01-10
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
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
budget_start_date: 2019-01-01
budget_end_date: 2019-12-31
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;analytical method;animal imaging;base;cell growth;data acquisition;data reduction;experimental study;in vivo;medical specialties;metabolic abnormality assessment;metabolic profile;metabolomics;random forest;stable isotope;tumor metabolism;ultra high resolution;wiki


application_id: 9619383
project_number: 5P20GM121327-03
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2019-01-10
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
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
budget_start_date: 2019-01-01
budget_end_date: 2019-12-31
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;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: 9619078
project_number: 5R01CA222596-02
project_title: Role of Sulfiredoxin in Colorectal Cancer Development
administering_ic: NCI
award_notice_date: 2018-12-21
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_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;Xenograft Model;Xenograft procedure;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;peroxiredoxin;receptor;small molecule inhibitor;targeted cancer therapy;tumorigenesis


application_id: 9618285
project_number: 1R43NS108804-01
project_title: Mimicking synuclein toxicity in plant cells to identify novel neuroprotective leads
administering_ic: NINDS
award_notice_date: 2018-08-31
opportunity_number: PA-17-302
application_type: 1
activity_code: R43
ic: NS
serial_number: 108804
program_official: TRZCINSKI, NATALIE KATHERINE
project_start_date: 2018-09-01
project_end_date: 2020-02-29
study_section: Special Emphasis Panel[ZRG1 ETTN-P (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:
AbstractAlpha-synuclein (ASYN) is believed to play an important role in the pathology of several neurodegenerativeconditions including some forms of Parkinson's disease Dementia with Lewy Bodies and Multiple SystemsAtrophy. The most recent hypothesis is that the ASYN proteins (particularly genetic variants such as A53T thatare prone to misfolding) are cleaved by the lysosomal enzyme asparagine endopeptidase (AEP) to generatepeptides that promote ASYN aggregation and initiate programmed cell death (PCD) in vulnerable neurons[Zhang et al 2017]. Inhibition of AEP and of ASYN aggregation are therefore prime molecular targets forpharmacotherapy of these synucleinopathies [see Brundin et al 2017] and maybe other neurodegenerativediseases. Chemical synthesis has yielded few leads and this proposal will use a novel plant biotech platformto generate active compounds. In this approach plant root cells are transformed by expression of humanneuronal proteins to make them susceptible to a specific mechanism of neuronal toxicity. Mutants of thesetransgenic plant cells are then selected for survival when exposed to this neurotoxic mechanism. Thismutagenesis and survival selection evolves plant secondary metabolism toward biosynthesis of metabolitesthat inhibit the neurotoxic mechanism. Proof of concept used expression of the human dopamine transporter(hDAT) in plant cells. This makes the plant cells highly susceptible to cytotoxicity induced by the dopaminergicneurotoxin MPP+ which is accumulated by the hDAT. When transgenic (hDAT) mutants are selected forsurvival in MPP+ the resulting sub-population includes many individuals that overproduce known or novelmetabolites that inhibit the hDAT and/or the cytotoxic mechanisms of MPP+ [Brown et al 2017]. As regardsthe AEP/ASYN mechanism of neurotoxicity plant cells naturally contain a homolog to lysosomal AEP whichlike the human neuronal AEP is linked to PCD [Hatsugai et al 2015]. Metabolites that regulate this processalmost certainly exist in plants and so mutant plant cells that survive AEP activation should include many thatoverproduce natural inhibitors of plant (p)AEP. Because plant and human (h)AEP are homologs thesemetabolites are potential neuroprotective leads. However plant cells do not naturally contain homologs ofhuman (h)ASYN so to mimic the proposed mechanism of synucleinopathies we will create transgenic plantcells that express the hASYN variant A53T. Because pAEP has similar substrate specificity to hAEP andbecause the peptides produced by hASYN-A53T cleavage are highly cytotoxic these transgenic (hASYN-A53T) plant cells should show increased susceptibility to PCD when pAEP is activated (to be established inPhase I). Consequently transgenic (hASYN-A53T) mutants that survive AEP activation should include manyindividual clones in which inhibitors of pAEP or of peptide-induced hASYN aggregation are over-produced. Inaddition to natural metabolites mutation and selection should evolve plant secondary metabolism towardnovel metabolites with greater inhibitory activity. This will be established in Phase II using conventional in vitroscreens identifying active metabolites by assay-guided fractionation. The objective is to develop these activeplant metabolites as therapeutic agents or leads for synthetic modification by the applicants in partnershipwith a major pharmaceutical company. The application of the proprietary biotechnology to these importanttargets will also strengthen its commercial importance as a plant drug discovery platform.

project_terms:
1-Methyl-4-phenylpyridinium;Abscisic Acid;Agrobacterium;Anabolism;Apoptosis;Asparagine;Biological Assay;Biotechnology;Cell Culture Techniques;Cells;Chemicals;Cleaved cell;Complementary DNA;Disease Progression;Endopeptidases;Enzymes;Exposure to;Fractionation;Homologous Gene;Human;Immunoblotting;In Vitro;Inclusion Bodies;Individual;Lead;Letters;Lewy Body Dementia;Link;Lobelia;Mediating;Metabolism;Methods;Modeling;Modification;Multiple System Atrophy;Mutagenesis;Mutation;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Neurotoxins;Parkinson Disease;Parkinson's Dementia;Pathologic;Pathology;Peptides;Pharmacologic Substance;Pharmacotherapy;Phase;Plant Growth Regulators;Plant Roots;Plants;Play;Population;Predisposition;Procedures;Process;Production;Proteins;RNA;Role;Substrate Specificity;Testing;Therapeutic;Therapeutic Agents;Toxic effect;Transgenic Organisms;Transgenic Plants;Universities;Variant;aged;alpha synuclein;asparaginylendopeptidase;cell transformation;chemical synthesis;cytotoxic;cytotoxicity;dopamine transporter;dopaminergic neuron;drug discovery;gain of function;gain of function mutation;genetic variant;inhibitor/antagonist;molecular drug target;mutant;neurotoxic;neurotoxicity;novel;novel therapeutics;phase 2 study;screening;synuclein;synucleinopathy

public_health_relevance:
Project narrativeSeveral human neurodegenerative diseases including familial Parkinsons disease share a mechanism in whichthe enzymatic modification and subsequent aggregation of a nerve cell protein called alpha-synuclein kills nervecells. Plant root cells contain a similar enzyme but they do not contain alpha-synuclein. By creating plant cellsexpressing human alpha-synuclein the applicants will be able to seek novel plant metabolites that inhibit thisneurotoxic process and that will lead to novel drugs to treat these devastating neurodegenerative diseases.


application_id: 9618270
project_number: 5R01HL124015-04
project_title: Latexin function in the maintenance and regeneration of the hematopoietic system
administering_ic: NHLBI
award_notice_date: 2018-12-31
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 124015
program_official: BAI, C BRIAN
project_start_date: 2016-01-01
project_end_date: 2020-12-31
study_section: Molecular and Cellular Hematology Study Section[MCH]
contact_pi_person_id: 9839693
contact_pi: LIANG, YING
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY The long-term goal of this study is to develop new strategies to mitigate and protect radiation-inducedhematopoietic injury by delineating the molecular mechanisms responsible for enhancing hematopoietic stemcells (HSC) self-renewal and survival. Radiation therapy commonly results in not only acute hematopoieticsuppression but also long-term bone marrow (BM) injury. To date no effective treatment has been developedto prevent or treat these pathological consequences. Enhancing HSC survival and maintaining their genomicintegrity upon radiation are crucial for preservation of HSC self-renewal function and for protection againstradiation-induced BM injury. However the molecular mechanisms for regulating HSC survival and self-renewalare not well defined. HSC number and function demonstrate natural variations and underlying genetic diversityis an important yet largely unknown mechanism involved in the regulation of HSC function. Latexin (Lxn) waspreviously identified as the first stem cell regulatory gene whose natural variation negatively contributes to theHSC population size in different mouse strains. In preliminary studies constitutive gene ablation approacheswere developed to define the role of Lxn in HSCs and hematopoiesis in normal and radiation stress conditions.Results showed that Lxn inactivation protects HSCs and hematopoietic progenitor cells (HPCs) from radiation-induced cell death thus mitigating acute hematopoietic suppression and conferring a survival advantage.Moreover Lxn knockout mice do not develop hematological malignancies following single or fractionateddosages of radiation. Mechanistically Lxn inactivation in vivo increases HSC self-renewal and survival. At themolecular level our published and preliminary work showed that ribosomal protein subunit 3 (Rps3) is a novelLxn-binding protein and Lxn overexpression inhibits Rps3 activity thus enhancing radiation sensitivity andtoxicity. In addition the number of human HSCs/HPCs negatively correlates with Lxn expression levelindicating the potential role of Lxn in regulating human hematopoiesis. These findings lead to the hypothesisthat Lxn maintains homeostatic HSC and hematopoiesis and inhibition of Lxn function protects againstradiation-induced hematopoietic injury via Rps3-dependent prosurvival pathways. Specific aims are to: 1)determine the cellular mechanisms by which Lxn inactivation enhances HSC survival and self-renewal andconfers radioprotection 2) identify the molecular mechanisms by which Lxn inactivation enhances Lxn-Rps3-NF-kB prosurvival pathway and 3) determine the role of Lxn in mitigating human hematopoietic cell toxicityfrom radiation injury. This research will advance understanding of a critical but understudied mechanisminvolved in the natural regulator of HSC function and self-renewal. By using mouse and human model systemsand state-of-the-art molecular and genomic techniques findings from the proposed study may facilitate to thedevelopment of novel mechanism-based therapeutic strategy to protect against radiation-induced BM injurywhich could be beneficial for the patients receiving cancer therapy and BM transplantation.

project_terms:
Ablation;Acute;Apoptosis;Attenuated;Binding;Binding Proteins;Biological Models;Blood;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;CD34 gene;Cancer Patient;Cell Count;Cell Death;Cell Survival;Cell model;Cell physiology;Cells;Complex;DNA Damage;Development;Exposure to;Genes;Genetic;Genetic Transcription;Genetic Variation;Genomics;Goals;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Transplantation;Hematopoietic System;Hematopoietic stem cells;Human;In Vitro;Injury;Knockout Mice;Late Effects;Lead;Liquid substance;Maintenance;Mediating;Modeling;Molecular;Mouse Strains;Myelosuppression;NF-kappa B;Natural regeneration;Nuclear Translocation;PC3.1 antigen;Pathologic;Pathway interactions;Patients;Pharmacology;Population Sizes;Process;Protein Subunits;Publishing;Quality of life;Radiation;Radiation Dosage;Radiation Injuries;Radiation Protection;Radiation Tolerance;Radiation Toxicity;Radiation therapy;Reactive Oxygen Species;Regulation;Regulator Genes;Reporting;Research;Ribosomal Proteins;Role;Second Primary Cancers;Signal Transduction;Solid;Stem cells;Stress;Techniques;Therapeutic;Variant;Work;Xenograft procedure;base;cancer therapy;cell injury;cell transformation;chemotherapy;effective therapy;functional decline;genome integrity;hematopoietic stem cell self-renewal;human model;in vivo;knock-down;mortality;mouse model;novel;overexpression;p65;preconditioning;preservation;prevent;promoter;radiation mitigation;radiation response;radiation-induced injury;recruit;replication stress;response;self-renewal;senescence;small hairpin RNA;stem cell population;tumor

public_health_relevance:
PROJECT NARRATIVEMitigation and protection of bone marrow cells particularly hematopoietic (blood forming) stem cells fromradiotherapy-induced acute and permanent injury is critical for the quality of life of cancer patients receivingradiotherapy and bone marrow transplantation. This study will investigate the radiomitigation andradioprotection of inhibition of a novel HSC regulatory gene latexin and will have great therapeutic value forpatients receiving radiation chemotherapy and bone marrow transplantation.


application_id: 9617153
project_number: 5F31AA026175-02
project_title: Intentional personality change: Towards preventing problem drinking
administering_ic: NIAAA
award_notice_date: 2018-08-20
opportunity_number: PA-16-309
application_type: 5
activity_code: F31
ic: AA
serial_number: 026175
program_official: RUFFIN, BEVERLY
project_start_date: 2017-09-17
project_end_date: 2019-09-16
study_section: ZAA1-GG(32)
contact_pi_person_id: 14181742
contact_pi: RILEY, ELIZABETH
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:
I have begun a program of research on the precipitants of change in personality traits that confer high risk foryoung adult problem drinking. This work has focused on the trait of negative urgency the tendency to actrashly when distressed; negative urgency has been shown in meta-analytic research to relate more stronglythan other impulsigenic traits to problem drinking (Berg et al. 2015; Stautz & Cooper 2013) and inprospective work to predict the onset of and increases in drinking behavior (Riley et al. 2016). Usinglongitudinal designs my colleagues and I have demonstrated that (1) very early onset drinking predictedsubsequent increases in negative urgency which in turn predicted yet further drinking suggesting a positivefeedback loop of prospective increases in both negative urgency and drinking (Riley et al. 2016); and (2)increases in negative urgency following early drinking behavior mediated the predictive impact of elementaryschool drinking on multiple negative high school outcomes including increased drinking smoking and bingeeating (Riley & Smith in press). Recently a co-sponsor of this proposed traineeship published evidence that atraining program produced reductions in negative urgency in a small sample of women suffering from PTSD(Weiss et al. 2015). The scientific premise of this proposal is to test whether this training program produces (a)reductions in drinking behavior (b) reductions in negative urgency among heavy drinking young adults and (c)evidence that reduced negative urgency mediates the impact of the training on drinking behavior. I propose totest these hypotheses using a within-subjects laboratory design within a sample of heavy drinking youngadults. A successful test will have direct implications for the prevention of heavy drinking behavior. Becausenegative urgency has been shown to increase risk transdiagnostically findings may have implications forcomorbid disorders and reducing other risky impulsive behaviors as well. A key component of the training planof this proposal is for me to receive training in conducting laboratory experimental studies because my workthus far has primarily involved longitudinal studies. Thus the training plan includes: (1) training in the designand execution of laboratory experimental studies; (2) training in how to conduct the negative urgencyreduction training which focuses on emotion modulation; (3) training in multilevel modeling: my plannedprogram of research will involve studies of observations nested within people nested within groups; (4) furtheradvanced training in research ethics including a second graduate course on ethical research with clinicalpopulations and attendance at the University's clinical ethics grand rounds and research ethics lecture series;(5) preparation of research reports for publication including learning how to respond effectively to revise andresubmit decisions; (6) presenting original research at leading international scientific meetings; and (7) trainingin the mentoring of junior graduate students and undergraduate research assistants including those assistingwith the proposed research.

project_terms:
Alcohol abuse;Alcohol consumption;Behavior;Binge Eating;Clinical;Clinical Ethics;Comorbidity;Disease;Distress;Drug Use Disorder;Drug usage;Eating Disorders;Emotions;Environment;Ethics;Exanthema;Feedback;Functional disorder;Future;Heavy Drinking;Impulsive Behavior;Impulsivity;International;Laboratories;Laboratory Study;Learning;Literature;Longitudinal Studies;Measures;Mediating;Mediation;Mentors;Minority;Modeling;Negative Reinforcements;Observational Study;Outcome;Participant;Personality;Personality Traits;Persons;Population;Post-Traumatic Stress Disorders;Preparation;Prevention;Process;Public Health;Publications;Publishing;Reporting;Research;Research Assistant;Research Ethics;Research Personnel;Rewards;Risk;Risk Factors;Risk Reduction;Sampling;Series;Smoking;Students;Testing;Time;Traineeship;Training;Training Programs;Trauma;Universities;Woman;Work;Youth;base;design;distraction;drinking;drinking behavior;drinking onset;early adolescence;early drinking;early onset;elementary school;experimental study;fifth grade;graduate student;heavy drinking young adult;high risk;high school;lectures;longitudinal design;meetings;multilevel analysis;negative affect;non-suicidal self injury;prevent;programs;prospective;reinforced behavior;response;sexual assault;success;therapy design;trait;trauma exposure;undergraduate research;young adult

public_health_relevance:
Negative urgency is a personality trait that reflects the tendency to act impulsively when distressed and thatpredicts alcohol consumption in young adults. If researchers can reduce negative urgency they might well beable to reduce risk for problem drinking and thus advance the public health. The proposed project constitutesthe first test of the possibility that an emotion modulation training program could reduce drinking behavior byreducing negative urgency


application_id: 9616847
project_number: 5R01CA214638-02
project_title: A redox-mediated mechanism of UVB-induced metabolic switch in skin carcinogenesis
administering_ic: NCI
award_notice_date: 2018-11-21
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 214638
program_official: JOHNSON, RONALD L
project_start_date: 2017-12-18
project_end_date: 2022-11-30
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affinity;Anions;Antioxidants;Autophagocytosis;Basal cell carcinoma;Bioenergetics;Chemistry;Chemoprevention;Co-Immunoprecipitations;Consumption;Coupled;Data;Development;Diagnosis;Energy Metabolism;Epithelial Cells;Event;Exposure to;Genetic Enhancer Element;Genetic Transcription;Glucose;Glycolysis;Goals;Histologic;Human;Intervention;Kinetics;Knowledge;Luciferases;Malignant Epithelial Cell;Malignant Neoplasms;Manganese;Mediating;Mediator of activation protein;Metabolic;Metabolism;Mitochondria;Modeling;Molecular;Molecular Biology;Molecular Chaperones;Molecular Genetics;Nitrates;Normal tissue morphology;Ontology;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Peroxonitrite;Prevention;Production;Proteins;Proteomics;Reporter Genes;Research;Risk;Role;Skin;Skin Cancer;Skin Carcinogenesis;Skin Carcinoma;Squamous cell carcinoma;Superoxide Dismutase;Superoxides;Testing;Tissues;Transgenic Mice;UV induced;UVB carcinogenesis;UVB induced;Ultraviolet B Radiation;Ultraviolet Rays;United States;Validation;Warburg Effect;base;cancer prevention;carcinogenesis;design;genetic approach;insight;knock-down;lifetime risk;member;metabolomics;mimetics;nitration;novel;prevent;promoter;prototype;response;skin cancer prevention;stable isotope;transcriptome;tumor;ultraviolet


application_id: 9616480
project_number: 1R01AI140758-01
project_title: Mechanisms of actin cytoskeleton modulation by Pneumoviruses
administering_ic: NIAID
award_notice_date: 2018-06-11
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: AI
serial_number: 140758
program_official: KIM, SONNIE
project_start_date: 2018-06-11
project_end_date: 2023-05-31
study_section: Special Emphasis Panel[ZRG1 IDM-W (02)]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
other_pis: LEUNG, DAISY W
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Actins;Address;Affect;Affinity Chromatography;Bacteria;Binding;Biochemical;Biochemistry;Biological;Biological Assay;Biological Models;Biophysics;Bronchiolitis;Calorimetry;Cell physiology;Cells;Cellular Morphology;Cellular biology;Childhood;Co-Immunoprecipitations;Complex;Coupled;Cytoskeletal Proteins;Cytoskeleton;Data;Deuterium;Disease;Dyes;Elderly;Elements;Epithelial;Family;Fluorescent in Situ Hybridization;Human;Human Metapneumovirus;Hybrids;Hydrogen;Immunocompromised Host;In Vitro;Individual;Infection;Life Cycle Stages;Ligation;Lower Respiratory Tract Infection;Mass Spectrum Analysis;Mediating;Microscopy;Modification;Molecular;Molecular Sieve Chromatography;Mutation Analysis;NMR Spectroscopy;Nature;Nucleocapsid;Pathogenesis;Phosphoproteins;Physiological;Play;Pneumovirus;Pneumovirus Infections;Population;Process;Proteins;RNA;RNA Viruses;Respiratory Syncytial Virus Infections;Respiratory Tract Infections;Respiratory syncytial virus;Role;Structure;System;Testing;Time;Titrations;Viral;Viral Proteins;Virus;Virus Diseases;Virus Replication;X-Ray Crystallography;cell motility;cellular targeting;effective therapy;insight;intercellular communication;light scattering;member;mutant;new therapeutic target;novel;pathogen;polymerization;respiratory;structural biology;therapeutic development;therapeutic target;viral RNA;virology


application_id: 9615567
project_number: 2RF1AG027297-11A1
project_title: Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2018-07-30
opportunity_number: PA-16-160
application_type: 2
activity_code: RF1
ic: AG
serial_number: 027297
suffix: A1
program_official: OPANASHUK, LISA A
project_start_date: 2006-09-01
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZRG1 BDCN-Q (90)]
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
AbstractMounting evidence suggests that comorbid vascular contributions to cognitive impairment and dementia(VCID) may complicate the treatment of Alzheimers disease (AD)-related dementia. Our overarchinghypothesis is that AD and VCID pathological sequelae converge at the level of activated astrocytes providinga common druggable target for a wide range of dementias (i.e. AD alone VCID alone and mixed dementia).Central to this hypothesis is the Ca2+ -dependent phosphatase calcineurin (CN) which appears at high levelsin activated astrocytes and positively regulates multiple components of the activated astrocyte phenotypethrough direct interactions with NFAT transcription factors. We and others have shown that hyperactivation ofCN/NFAT occurs in astrocytes during early stages of cognitive decline in humans and mice with AD-likepathology and is linked to glutamate-dependent hyperexcitability. However little is known about astrocyticCN/NFAT in VCID presenting a critical knowledge gap in our understanding of mixed dementia. New preliminary data obtained from human cerebrovascular pathology cases and from an establisheddiet-based VCID mouse model suggest that hyperactive CN/NFAT signaling also arises with cerebrovascularpathology. Based on these observations we predict that combined AD and VCID pathology will exacerbateaberrant CN/NFAT signaling leading to a neurotoxic astrocyte phenotype characterized by the loss ofEAAT2/Glt-1 glutamate transporters and impaired glutamate uptake. We further predict that normalization ofthe CN/NFAT/Glt-1 axis using cell-type specific AAV vectors and novel pharmacologic agents will alleviateneuronal and cerebrovascular abnormalities in AD VCID and mixed AD/VCID models. Our overarchinghypothesis and corollary predictions will be tested using human biospecimens and relevant mouse modelsincluding the hyperhomocysteinemia (HHcy) model of VCID and the 5xFAD model of A pathology. Aim 1 willtest the hypothesis that mixed AD and VCID pathologies in both humans and mice converge to exacerbateCN/NFAT hyperactivity in astrocytes leading to a neurotoxic astrocyte molecular phenotype. Aim 2 will test thehypothesis that the astrocytic CN/NFAT/Glt-1 axis drives cerebrovascular dysfunction in AD VCID and mixedVCID/AD models. And Aim 3 will test the hypothesis that the astrocytic CN/NFAT/Glt-1 axis driveshyperexcitability synapse dysfunction and cognitive loss in AD VCID and mixed VCID/AD models. Theseaims will be pursued using novel reagents and cutting-edge multidisciplinary approaches. This work isessential for assessing the role of astrocytic CN/NFATs in VCID and mixed pathology and may help stimulatethe development of astrocyte-targeted approaches for treating a broad range of dementia cases.

project_terms:
Acute;Aging;Algorithms;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Animal Model;Astrocytes;Autopsy;Biological Assay;Blood Vessels;Brain;Calcineurin;Calcineurin inhibitor;Cells;Cerebrovascular Circulation;Cerebrovascular Disorders;Cerebrovascular system;Cerebrum;Cognition;Comorbidity;Corrosion Casting;Data;Data Set;Dementia;Deposition;Development;Diet;Electrophysiology (science);Endothelial Cells;Exhibits;Functional disorder;Funding;Gap Junctions;Gene Delivery;Gene Expression Profile;Glutamate Transporter;Glutamates;Hippocampus (Brain);Homeostasis;Human;Hyperactive behavior;Hyperhomocysteinemia;Immunohistochemistry;Impaired cognition;Impairment;Individual;Infarction;Inflammatory;Injury;Investigation;Knowledge;Lead;Link;Magnetic Resonance Imaging;Mediating;Metabolism;Modeling;Molecular Profiling;Mus;Neurons;Outcome;Pathologic;Pathology;Patients;Peptides;Perfusion;Pharmacology;Phenotype;Phosphoric Monoester Hydrolases;Prevalence;Process;Protein phosphatase;Proteolysis;Publishing;Reagent;Role;Signal Transduction;Slice;Specimen;Synapses;Tacrolimus;Techniques;Testing;Transgenic Animals;Vascular Cognitive Impairment;Vascular Diseases;Work;adeno-associated viral vector;base;behavior test;brain metabolism;cell type;cerebrovascular;cerebrovascular pathology;combat;data modeling;density;design;druggable target;effective therapy;fluorescein isothiocyanate dextran;functional decline;inhibitor/antagonist;interdisciplinary approach;laser capture microdissection;mixed dementia;molecular phenotype;mouse model;multidisciplinary;multiphoton imaging;nano-string;neurotoxic;neurovascular coupling;novel;nuclear factors of activated T-cells;synaptic function;transcription factor;treatment strategy;uptake;vascular cognitive impairment and dementia

public_health_relevance:
Project NarrativeProject will investigate the role of astrocyte activation in vascular cognitive impairment usingpostmortem human brain specimens transgenic animal models and multidisciplinary techniques.This work could lead to nonconventional cell-directed strategies for combating dementia.


application_id: 9615160
project_number: 1R01ES029846-01
project_title: Urban Greenness and Cardiovascular Health
administering_ic: NIEHS
award_notice_date: 2018-06-29
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: ES
serial_number: 029846
program_official: SCHUG, THADDEUS
project_start_date: 2018-07-01
project_end_date: 2023-03-31
study_section: Cancer, Heart, and Sleep Epidemiology B Study Section[CHSB]
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Admission activity;Adopted;Affect;Air;Air Pollutants;Air Pollution;Area;Biochemical;Biological Markers;Blood;Carbon Black;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Characteristics;Chronic Disease;Cities;Communities;Data;Developed Countries;Developing Countries;Development;Ecosystem;Environment;Evaluation;Exposure to;Formulation;Grasslands;Green space;Hair;Health;Health Policy;Heart;Hospitals;Human;Individual;Intervention;Intervention Trial;Kentucky;Lead;Life Expectancy;Link;Location;Maintenance;Measurement;Measures;Mediating;Modeling;Neighborhoods;Noise;Outcome;Ozone;Particulate;Perception;Physiological;Plants;Poaceae;Pollution;Population;Prevalence;Prevention strategy;Psychosocial Stress;Public Health;Questionnaires;Reporting;Research;Risk;Risk Factors;Sampling;Severities;Stress;Sunlight;Surface;Surveys;Testing;Trees;Ultrafine;Unspecified or Sulfate Ion Sulfates;Urine;Vascular Plant;Wood material;Work;air filtration;built environment;cardiovascular disorder prevention;cardiovascular disorder risk;cardiovascular health;cohesion;cohort;demographics;design;fine particles;foot;insight;land use;mortality;pollutant;premature;prevent;psychologic;recruit;residence;social;trial design;urinary;volatile organic compound


application_id: 9615097
project_number: 7R01HL123540-05
project_title: CXCR4 signaling in lung epithelial repair
administering_ic: NHLBI
award_notice_date: 2018-02-23
opportunity_number: PA-16-285
application_type: 7
activity_code: R01
ic: HL
serial_number: 123540
program_official: ZHOU, GUOFEI
project_start_date: 2014-07-18
project_end_date: 2020-03-31
study_section: Lung Injury, Repair, and Remodeling Study Section[LIRR]
contact_pi_person_id: 1860187
contact_pi: WATERS, CHRISTOPHER M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Community-acquired pneumonia (CAP) is the most common cause of acute respiratory distress syndrome (ARDS) a severe form of acute lung injury that is one of the most frequent causes of admission into the intensive care unit. Few therapeutic options are available and mortality is high. Supportive therapy with supplemental oxygen and mechanical ventilation are essential but additional injury can be caused by the ventilator termed ventilator-induced lung injury (VILI). Epithelial repair is critical for diseaseresolution and survival but we have limited knowledge of the underlying mechanisms of repair and how mechanical stretch impacts these mechanisms. The long term objective of this project is to increase our understanding of the mechanisms of epithelial repair and how overdistention of pulmonary epithelial cells contributes to VILI and maladaptive repair mechanisms. We previously identified an autocrine role for the chemokine CXCL12 in alveolar epithelial repair involving its receptor CXCR4. We now have preliminary data showing that patients with CAP-induced ARDS that had high levels of CXCL12 in their bronchoalveolar lavage fluid had shorter duration of mechanical ventilation and lower mortality. Based upon additional preliminary data we propose that CXCR4 interacts with a complex of signaling molecules including focal adhesion kinase (FAK) and apoptosis signal-regulating kinase-1 (ASK1) that regulates epithelial repair. The central hypothesis of this application is that CXCL12 promotes epithelial repair but mechanical stretch causes disruption of CXCR4-FAK-ASK1 signaling that inhibits cell spreading migration and repair. We will first examine whether CXCL12 is a biomarker for ARDS patients undergoing adaptive repair by measuring CXCL12 in banked samples of bronchoalveolar lavage fluid and plasma. In addition we will use autopsy samples from ARDS patients to evaluate expression of CXCR4 and phosphorylated (activated) ASK1. In the second aim we will investigate the interactions between CXCR4 FAK and ASK1 during recovery from lung injury caused by LPS as a model of pneumonia. We will use mice with conditional deletion of CXCR4 in lung epithelial as well as ASK1 knockout mice. We will also examine the biochemical interactions of these signaling molecules in cultured alveolar epithelial cells in a scratch wound model. In the third aim we will investigate how high stretch mechanical ventilation or cyclic stretch of cultured cells disrupts these signaling pathways during repair in  combined model of pneumonia (LPS) and mechanical ventilation. These studies will elucidate new signaling pathways involved in alveolar epithelial repair and how mechanical stretch disrupts the repair processes.

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Pneumonia is the most common cause of acute lung injury a devastating illness that results in significant loss of life and substantial economic impact due toextended stays in the intensive care unit. The proposed studies will investigate the mechanisms of epithelial repair following lung injury and during mechanical ventilation and will identify potential targets for therapeutic intervention.


application_id: 9615090
project_number: 1R01AR071789-01A1
project_title: Reversing Skeletal Muscle Myopathy by Hydrogen Sulfide
administering_ic: NIAMS
award_notice_date: 2018-09-21
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: AR
serial_number: 071789
suffix: A1
program_official: BOYCE, AMANDA T
project_start_date: 2018-09-21
project_end_date: 2024-01-31
study_section: Special Emphasis Panel[ZRG1 MOSS-C (02)]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Angiography;Atrophic;Attenuated;Biological Assay;Birth;Body Weight;CRISPR/Cas technology;Caliber;Cell Differentiation process;Cell Line;Cell Proliferation;Child;Chronic;Collagen;Cystathionine beta-Synthase;Cysteine Desulfhydrase;Data;Deposition;Deterioration;Endothelial Cells;Enzymes;Exhibits;FOXO1A gene;Fatigue;GDF8 gene;Generations;Genes;Genetic Transcription;Goals;Homocysteine;Homocystinuria;Hydrogen Sulfide;Hyperhomocysteinemia;Hypoxia;Image;Immunohistochemistry;Impairment;In Vitro;Ischemia;Isolated limb perfusion;Lasers;Lead;Ligation;Measures;Mediating;Metabolic;Modality;Mus;Muscle;Muscle Fibers;Muscular Atrophy;Mutation;Myopathy;Natural regeneration;Phosphorylation;Plasma;Predisposition;Proto-Oncogene Proteins c-akt;Roentgen Rays;Role;Signal Transduction;Signaling Molecule;Skeletal Muscle;Starvation;Teenagers;Testing;Therapeutic;Tissues;Transcript;Transduction Gene;Transgenic Organisms;Vascular Endothelial Growth Factors;attenuation;density;design;femoral artery;frailty;hypoxia inducible factor 1;in vivo;knock-down;muscle regeneration;novel;prevent;response;satellite cell;skeletal muscle wasting;small molecule;tissue oxygenation;vasculogenesis


application_id: 9614585
project_number: 1R01DK116591-01A1
project_title: miRNA Mechanism of Acute Kidney Injury in Aging
administering_ic: NIDDK
award_notice_date: 2018-07-30
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: DK
serial_number: 116591
suffix: A1
program_official: MARIC-BILKAN, CHRISTINE
project_start_date: 2018-07-31
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZRG1 VH-C (02)]
contact_pi_person_id: 9501257
contact_pi: SEN, UTPAL
other_pis: TYAGI, SURESH C.
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
3-Mercaptopyruvate sulfurtransferase;Acute Renal Failure with Renal Papillary Necrosis;Aging;Angiography;Animals;Anti-Inflammatory Agents;Antioxidants;Atherosclerosis;Barium;Bilateral;Blood flow;Cardiac Surgery procedures;Clinical;Collagen;Complex;Creatinine;Cystathionine;Cystathionine beta-Synthase;Cysteine;Deposition;Diagnostic;Disease;Disease Progression;Down-Regulation;Enzymes;Equilibrium;Extracellular Matrix;Failure;Female;Fibrosis;Flow Cytometry;Fluorescein-5-isothiocyanate;Functional disorder;Future;Gelatin Zymography;Gelatinase B;Generations;Glomerular Filtration Rate;Goals;Health;Histology;Hydrogen Sulfide;Hypertension;Impairment;Infection;Inflammation;Inflammation Mediators;Inflammatory;Injury;Ischemia;Kidney;Kidney Diseases;Kidney Transplantation;Knowledge;Lasers;Lead;Lyase;Matrix Metalloproteinases;Measures;Mediating;Meprin;Mesenchymal;Messenger RNA;Metabolic;Methods;MicroRNAs;Mus;Older Population;Organ Transplantation;Outcome;Peritoneal;Phase;Physiological;Plasma;Play;Population;Prevention strategy;Process;Production;Protective Agents;Proteins;Quality of life;Renal Artery Stenosis;Renal Blood Flow;Renal function;Reperfusion Injury;Reperfusion Therapy;Reporting;Reverse Transcriptase Polymerase Chain Reaction;Roentgen Rays;Sepsis;Severities;Shock;Testing;Therapeutic;Transaminases;Transcript;Translations;Ultrasonography;Untranslated RNA;Up-Regulation;Vascular Diseases;Western Blotting;base;density;design;differential expression;experimental study;improved;inhibitor/antagonist;injured;kidney vascular structure;macrophage;male;older patient;prevent;renal ischemia;repaired;treatment strategy


application_id: 9614461
project_number: 3R41HD090792-01A1S1
project_title: TheraBracelet: The first and only wearable to instantly improve stroke hand function
administering_ic: NICHD
award_notice_date: 2018-02-27
opportunity_number: PA-18-314
application_type: 3
activity_code: R41
ic: HD
serial_number: 090792
suffix: A1S1
program_official: CRUZ, THERESA
project_start_date: 2018-04-01
project_end_date: 2018-06-01
contact_pi_person_id: 9744137
contact_pi: SEO, NA JIN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 045576080
duns_number: 045576080
fips: US
organization_id: 10041408
organization_name: THERABRACELET, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402041715
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-04-01
budget_end_date: 2018-06-01
project_abstract:
Project Summary: Post-stroke hand impairment is highly prevalent and severely restricts functional ability andindependence. In fact every 40 seconds a new stroke occurs and stroke is recognized as the leading cause oflong-term disability. Yet there is no assistive device to help hand function at home every day during activitiesof daily living. Existing devices such as hand-opening orthoses are expensive (e.g. Myomo and Bioness arepriced at $7500+) uncomfortable bulky and meant for use during short therapy sessions as opposed toduring daily living. Thus their impact is limited. Consequently the development of efficacious and affordableassistive device is of paramount importance. This proposal addresses this critical gap by providing aninnovative patent-pending technology. The TheraBracelet is a wristband applying imperceptible white-noisevibration to skin. TheraBracelet is efficacious as it has been shown to immediately improve chronic strokesurvivors touch sensation and hand dexterity in preliminary studies. TheraBracelet is affordable by using onlya low-cost vibrator. TheraBracelet is also translational because a vibrator strategically placed at the wrist doesnot interfere with dexterous finger motions and it is low-risk by involving only imperceptible vibration on skin.These practicalities assure easy adoption in home environment for large impact on sensorimotor impairment.The essential next step toward commercialization thus the objective of this Phase I proposal is to determinethe feasibility and safety of using this assistive device all day every day for a month during daily activity and todetermine if TheraBracelets instant effects are sustained during prolonged use. This objective will beaccomplished in a double-blinded randomized controlled crossover design study. Feasibility (compliance ofusing the device everyday) and safety (no worsening of sensation strength dexterity pain spasticity skinirritation) will be assessed for the treatment condition compared to the control condition (wearing the devicewithout vibration) through weekly evaluations. The feasibility and safety level comparable to those of wearing awatch and of a comparable FDA-approved device will support commercial viability of TheraBracelet withnecessary regulatory approvals. In addition TheraBracelets instant benefits in improving hand function will beassessed weekly. Persistence of TheraBracelets instant benefits across all weekly evaluations will supportdurability (i.e. desensitization to vibration does not occur during extended daily use over a one-month period).The knowledge of feasibility safety and durability will pave the way toward commercialization of this noveltechnology. This project is expected to lead to an assistive wristband that increases hand function duringactivities of daily living thus increasing independence and quality of life and reducing caregiver burden for alarge number of stroke survivors with hand impairment.

project_terms:
Activities of Daily Living;Address;Adoption;Adverse event;American;Budgets;Calibration;Caregiver Burden;Communities;Crossover Design;Data;Development;Device or Instrument Development;Devices;Double-Blind Method;Economics;Employment;Engineering;Esthesia;Evaluation;FDA approved;Facilities and Administrative Costs;Feedback;Fingers;Forearm;Frequencies;Future;Hand;Hand Strength;Hand functions;Home environment;Hour;Hygiene;Impairment;Intellectual Property;Investigation;Knowledge;Laboratories;Lead;Legal patent;Lower Extremity;Medical;Medical Device;Medicare;Minor;Monitor;Motion;Muscle;Noise;Orthotic Devices;Pain;Participant;Patient Self-Report;Phase;Price;Quality of life;Randomized;Research;Research Design;Risk;Safety;Self Care;Self-Help Devices;Severities;Skin;Stroke;Technology;Testing;Therapeutic;Time;Touch sensation;Upper Extremity;Visit;Vocation;Wrist;base;chronic stroke;commercialization;cost;desensitization;dexterity;disability;hand dysfunction;hand rehabilitation;improved;innovation;new technology;phase 1 study;post stroke;rehabilitation service;research clinical testing;safety and feasibility;skin irritation;spasticity;stroke survivor;vibration;wearable device

public_health_relevance:
Project Narrative: There are approximately 6.6 million Americans who have had a stroke with a totalprojected cost of $2.2 trillion from 2005 to 2050 and $13 billion annually in indirect costs associated with lossof earnings. Following a stroke more than two-thirds end up with a disability in the upper limb that lowers theability to perform many daily activities including self-care and vocations thus diminishing the quality of life.This project aims to test a new technology that may improve hand function impaired from a stroke therebyimproving independence and quality of life.


application_id: 9613236
project_number: 5R01DE017921-09
project_title: Role of JAKs in innate responses to P. gingivalis
administering_ic: NIDCR
award_notice_date: 2018-12-12
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DE
serial_number: 017921
program_official: CHANDER, PREETHI
project_start_date: 2006-12-01
project_end_date: 2021-12-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Inflammatory responses to pathogenic bacteria are essential for protection of the host and control of bacterial infection. However inflammatory responses that are sustained in duration and intensity can be damaging to susceptible tissues. To limit the ferocity of inflammation and curtail possible tissue damage a number of pathways exist that dampen the innate immune response. Our studies have focused on a tyrosine kinase of the Janus kinase (JAK) family JAK3. We have found that that challenge with the periodontal pathogen P. gingivalis increases both the activation state and the amount of JAK3 in human monocytes and murine bone marrow derived macrophages. Moreover JAK3 inhibition enhances the production of pro-inflammatory cytokines upon P. gingivalis stimulation and concurrently diminishes levels of the anti-inflammatory cytokine IL-10. Thus we have identified a novel role for JAK3 as a negative regulator of inflammation and propose that stimulation of this endogenous anti-inflammatory pathway in the host will help limit or prevent P. gingivalis- induced tissue destruction. The specific hypothesis to be tested in this application is that P. gingivalis-modified JAK3 activation in innate immune cells directs negative regulation of inflammation and ultimately controls alveolar bone loss through dedicated downstream signaling pathways. We will challenge this hypothesis with three specific Aims: 1) To characterize JAK3 signaling pathways that control anti-inflammatory responses induced by P. gingivalis; 2) To functionally dissect P. gingivalis modification of JAK3 expression and activationin innate immune cells; 3) To determine the effect of JAK3 inhibition in vivo on inflammatory responses and the disease process induced by P. gingivalis using a mouse chamber model and bone loss model. Successful completion of these studies will define for the first time the host anti-inflammatory responses to P. gingivalis that flow through JAK3. In addition this work will characterize an important but relatively understudied aspect of the overall host-P. gingivalis interaction and increase our understanding both of the role of JAK3 in innate immune cells and of anti-inflammatory mechanisms in general. This work could be translated into the identification of novel targets for therapeutic intervention designed to enhance anti-inflammatory signaling and prevent or limit tissue destruction. Such an approach has relevance both for periodontal disease and for chronic inflammatory conditions in general.

project_terms:
Adopted;Affect;Agonist;Alveolar Bone Loss;Anti-inflammatory;Autocrine Communication;Bacteria;Bacterial Infections;Bone Marrow;Cells;Chronic;Data;Disease;Equilibrium;Event;Family;Genetic Transcription;Gingiva;Goals;Health;Homeostasis;Human;Immune;Immune response;Impairment;Inflammation;Inflammatory;Inflammatory Response;Innate Immune Response;Interleukin-10;Interleukin-4;JAK3 gene;Janus kinase;Knock-in;Knockout Mice;Mass Spectrum Analysis;Mediating;Microbe;Modeling;Modification;Mus;Natural Immunity;Neutrophil Infiltration;Organism;Pathway interactions;Pattern;Periodontal Diseases;Periodontitis;Periodontium;Phosphorylation;Porphyromonas gingivalis;Process;Production;Protein Tyrosine Kinase;Proto-Oncogene Proteins c-akt;Regulation;Role;Signal Pathway;Signal Transduction;Signaling Protein;Site-Directed Mutagenesis;Testing;Time;Tissues;Translating;Work;bone loss;cytokine;design;immunoreaction;in vivo;knock-down;macrophage;member;microbial;microbial community;monocyte;new therapeutic target;novel;oral infection;pathogen;pathogenic bacteria;periodontopathogen;prevent;public health relevance;response;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: To protect against bacterial infection our bodies mount an inflammatory response; however this response must be regulated to prevent excessive inflammation and associated tissue damage. We have identified a host signaling protein called JAK3 that can dampen inflammatory responses to a gum disease causing organism. In this study we will characterize the role of JAK3 with the ultimate goal of designing means to stimulate this molecule and curtail inflammatory destruction in gum disease.


application_id: 9612925
project_number: 1R01CA228236-01A1
administering_ic: NCI
award_notice_date: 2018-05-25
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: CA
serial_number: 228236
suffix: A1
program_official: VENKATACHALAM, SUNDARESAN
project_start_date: 2018-06-01
project_end_date: 2018-09-18
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
other_pis: DIPAOLA, ROBERT S.
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Targeting p62 as a more optimal approach to inhibit autophagy using verteporfin as a repurposed therapeutic in prostate cancer

project_abstract:
Given the importance of autophagy as a cell survival and resistance pathway understanding and unlocking akey autophagic target could lead to an innovative approach to abrogate drug resistance. The goal of this projectis to develop p62 as a more optimal approach to inhibit autophagy and provide a rapid path to enter clinical trialsfor therapeutic drug development using the prototype agent verteporfin a drug that inhibits p62 and is approvedby FDA to treat macular degeneration. Although autophagy is considered a target for resistance to initialandrogen axis-targeting therapies in prostate cancer existing approaches to target autophagy(hydroxychloroquine (HCQ) for example) with collateral induction of p62 may be a reason for suboptimal results.Using a genetically engineered mouse model we showed that autophagy-related-7 (Atg7)-deficiency delayedPten-deficient prostate tumor progression in both castrate-nave and castrate-resistant cancers demonstratingthe potential of autophagy as a therapeutic target although with associated induction of p62. To further optimizethis approach we targeted p62 using the prototype agent verteporfin as it is known to inhibit p62 by formation ofcrosslinked p62 leading to inhibition of autophagy. Our preliminary studies show that verteporfin inhibitedprostate cancer cell growth decreased p62 and generated crosslinked p62 oligomer resulting in inhibition ofconstitutive activation of Nrf2 and its target proteins leading to reduced apoptosis resistance. In normal prostateepithelial cells elevation of p62 is sufficient to cause constitutive Nrf2 activation apoptosis resistance andtumorigenesis. Verteporfin inhibited tumorigenesis of both p62-exprssing prostate epithelial cells and prostatecancer cells. The central hypothesis is that inhibition of p62 is a more effective approach to target autophagy;that verteporfin can be developed as a therapeutic against prostate cancer by inhibiting p62 autophagy andNrf2 signaling a drug resistance pathway; and that the combination of verteporfin with other therapies such asdocetaxel HCQ or ADT reduces prostate cancer growth and progression in a synergistic or additive manner.Aim 1 will determine if verteporfin decreases constitutive activation of Nrf2 and downstream pathways throughinhibition of p62 leading to decreased apoptosis resistance and tumorigenesis. Aim 2 will further determine ifverteporfin and/or p62-deficiency (a) results in delayed Pten-deficient prostate cancer growth and enhancedAtg7-deficiency-caused delay in Pten-deficient prostate cancer growth in both castrate-nave andcastrate-resistant cancers; (b) inhibits autophagy; (c) decreases constitutive Nrf2 activation and its downstreampathways; and (d) reduces the androgen receptor pathway. Aim 3 will investigate the effect of verteporfin incombination with docetaxel or HCQ to better design clinical trials with greater likelihood of impacting synergy withknown standard approaches including combination therapies with docetaxel or hormonal agents. Successfulcompletion of these studies will result in the development of new therapeutic approaches against prostate cancerthrough inhibition of p62.

project_terms:
Androgen Receptor;Androgens;Antimalarials;Antineoplastic Agents;Apoptosis;Autophagocytosis;Autophagosome;BCL2 gene;Cancer Cell Growth;Cancer Patient;Cell Survival;Clinical;Clinical Trials;Clinical Trials Design;Combined Modality Therapy;Data;Development;Down-Regulation;Drug resistance;Drug resistance pathway;Drug usage;Elderly man;Epithelial Cells;Exhibits;FDA approved;Future;GTF2H1 gene;Genes;Genetically Engineered Mouse;Goals;Growth;Hormonal;Hydroxychloroquine;In Vitro;Investigation;Lead;Lysosomes;Macular degeneration;Malignant Neoplasms;Malignant neoplasm of prostate;Modeling;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Phosphorylation;Prostate;Prostate Cancer therapy;Prostatic Neoplasms;Proteins;Publishing;Radiation therapy;Resistance;Role;Signal Transduction;Stress;TNF gene;Therapeutic;Therapeutic Agents;Therapeutic Clinical Trial;Tumor Tissue;Verteporfin;androgen deprivation therapy;anticancer activity;chemotherapy;clinical care;crosslink;cytotoxic;design;docetaxel;drug development;improved;in vivo;inhibition of autophagy;inhibitor/antagonist;innovation;new therapeutic target;novel therapeutic intervention;novel therapeutics;pre-clinical;preclinical study;prostate cancer cell;prototype;resistance mechanism;response;superoxide dismutase 1;synergism;targeted agent;targeted treatment;therapeutic target;tumor;tumor growth;tumor progression;tumor xenograft;tumorigenesis;tumorigenic

public_health_relevance:
PROJECT NARRATIVE The goal of this project is to target the p62 protein as a more optimal approach to inhibit autophagy using theprototype agent verteporfin a drug approved by FDA to treat macular degeneration for the treatment of prostatecancer. Through investigation of the decrease of drug resistance caused by verteporfin via reducing p62/Nrf2signaling a drug resistance pathway this project will develop a new therapeutic paradigm of verteporfin alone orin combination with other drugs such as docetaxel and hydroxycholoquine or androgen depletion therapywhich may exhibit a synergistic or additive effect.


application_id: 9611919
project_number: 1F32DA045483-01A1
project_title: Big Data to Treatment: Repurposing pharmacotherapies for psychostimulant use disorder
administering_ic: NIDA
award_notice_date: 2018-07-16
opportunity_number: PA-16-307
application_type: 1
activity_code: F32
ic: DA
serial_number: 045483
suffix: A1
program_official: DUFFY, SARAH Q
project_start_date: 2018-08-01
project_end_date: 2019-07-07
study_section: Special Emphasis Panel[ZRG1 F16-E (20)]
contact_pi_person_id: 11626364
contact_pi: HANKOSKY, EMILY RUTH
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACTMisuse of psychostimulants such as cocaine and amphetamines poses a serious public healthproblem with an estimated 1.3 million users meeting diagnostic criterion for a psychostimulant usedisorder (StUD). Currently there are no pharmacotherapies approved to treat StUDs and existingpsychosocial interventions have limited success. Moreover less than 20% of individuals with a StUDreceive treatment resulting in a substantial population with untreated or under-treated StUDs. Thegoal of this proposal is to address this unmet clinical need through observational and exploratoryanalyses to identify pharmacotherapies that could be repurposed to treat StUDs. Application of bigdata analytics to health claims data is emerging as a tool to inform biomedical research policy andclinical practice including guiding the development of hypotheses for drug discovery and clinicaltrials. Big data analytics will be used to conduct hypothesis-driven and data-driven analyses of theTruven Health MarketScan database to evaluate the potential of prescribed medications to berepurposed for StUDs. In Aim 1 a retrospective cohort study will be used to test the hypothesis thatamong individuals with StUD exposure to antidepressants increases the likelihood of StUDremission. Aim 2 will leverage the power of big data to discover complex relationships betweenprescribed medications and StUD remission. Specifically an association rule mining algorithm will beused to generate knowledge of therapeutics that may be beneficial for the treatment of StUDs.Achievement of the proposed aims will improve the understanding of StUDs provide insights for thedesign of future randomized clinical trials and identify novel biological targets for drug discoveryresearch thereby advancing translational research efforts to identify pharmacotherapies to treatStUDs.

project_terms:
Achievement;Address;Adolescent;Advanced Development;Algorithms;American;Amphetamines;Antidepressive Agents;Basic Science;Big Data;Big Data to Knowledge;Biodiversity;Biological;Biomedical Research;Biometry;Bupropion;Characteristics;Clinical;Clinical Research;Clinical Trials;Cocaine;Complex;Data;Data Analytics;Databases;Detection;Development;Diagnostic;Disease;Disease remission;Drug Targeting;Epidemiology;Etiology;Exposure to;Female;Female Adolescents;Future;Goals;Health;Healthcare;Heterogeneity;Impaired cognition;Individual;Intervention;Knowledge;Lead;Logistic Regressions;Mining;Mission;Neurotransmitters;Norepinephrine;Outcome;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Policies;Population;Public Health;Randomized Clinical Trials;Research;Research Design;Retrospective cohort study;Sampling;Science;Selective Serotonin Reuptake Inhibitor;Serotonin;Stress;Subgroup;System;Testing;Therapeutic;Time;Training;Translational Research;Ulcer;United States;United States National Institutes of Health;United States Substance Abuse and Mental Health Services Administration;Withdrawal Symptom;base;biomedical informatics;clinical practice;cost effective;data mining;design;disability;drug discovery;epidemiology study;experience;gut microbiome;health record;improved;inhibitor/antagonist;insight;male;meetings;multidisciplinary;nonmedical use;novel;novel therapeutics;population health;preventable death;programs;psychosocial;psychostimulant;reuptake;severe psychiatric disorder;smoking cessation;success;tool;treatment effect;trend

public_health_relevance:
PROJECT NARRATIVENonmedical use of psychostimulants such as cocaine and amphetamines poses a serious public healthproblem but there are currently no pharmacotherapies approved to treat psychostimulant use disorders(StUDs). This revised F32 proposal seeks to apply big data analytics to population health records to evaluatethe potential of approved medications to be repurposed for StUDs. Successful completion of this research willidentify potential medications to treat StUD thereby providing insights for the design of future randomizedclinical trials to evaluate these medications and identifying novel biological targets associated with therepurposed medication that may lead to backtranslation for future StUD drug discovery research.


application_id: 9611775
project_number: 1F31NS105443-01A1
administering_ic: NINDS
award_notice_date: 2018-06-15
opportunity_number: PA-16-309
application_type: 1
activity_code: F31
ic: NS
serial_number: 105443
suffix: A1
program_official: JAKEMAN, LYN B
project_start_date: 2018-07-01
project_end_date: 2021-06-30
study_section: Special Emphasis Panel[ZRG1 F01A-F (20)]
contact_pi_person_id: 14385763
contact_pi: KOPPER, TIMOTHY JOSEPH
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_title:
Contributions of Myelin Derived Arachidonic Acid to Macrophage Polarization and Secondary Damage after Spinal Cord Injury

project_abstract:
Project summary/Abstract Spinal cord injury (SCI) produces a chronic inflammatory state primarily mediated by resident microgliaand infiltrating monocytes (here collectively referred to as macrophages). These chronically activated SCImacrophages adopt a pro-inflammatory pathological state that continues to cause additional damage after theinitial injury and inhibits recovery. Myelin debris generated after SCI can directly stimulate macrophages toadopt these maladaptive functions; however the mechanisms by which this stimulation occur are poorlyunderstood. Myelin contains an inflammatory lipid molecule arachidonic acid stored in an inactive form withinmyelin's extensive membranes. After injury macrophages clear and accumulate myelin debris long after injury.Here we propose that the inflammatory environment within the SCI lesion induces the expression of theenzyme cytosolic phospholipase A2 (cPLA2) within macrophages. cPLA2 releases arachidonic acid fromcellular membranes. Free active arachidonic acid invokes direct pro-inflammatory functions or throughsynthesis forms various eicosanoids with pro-inflammatory properties. This is the basis for the centralhypothesis that increased cPLA2 activity in SCI macrophages releases arachidonic acid from myelindebris thereby driving chronic SCI inflammation and tissue damage. . Using in-vitro and in-vivo approaches Aim 1 of this proposal will identify cPLA2 as the regulator ofmyelin-mediated inflammation in macrophages. We will thereby demonstrate the importance of myelin-derivedarachidonic acid in these critical inflammatory responses. Aim 2 will utilize cPLA2-/- bone marrow chimeric miceto interrogate the importance and influence of macrophage cPLA2 in the pathogenesis of SCI. Chronic pro-inflammatory macrophage activation is a key mediator of secondary damage and impaired recovery after SCIyet the mechanisms behind this process are poorly understood. Here I propose a novel mechanism by whichmyelin debris and subsequent processing by macrophage cPLA2 continuously produces free arachidonic acidthereby driving the chronic inflammation observed after SCI.

project_terms:
Address;Adopted;Affect;Anatomy;Animals;Arachidonic Acids;Automobile Driving;Behavioral;Biological Assay;Bone Marrow;Cellular Membrane;Chest;Chimera organism;Chronic;Cytosolic Phospholipase A2;Data;Eicosanoids;Environment;Enzymes;Fatty Acids;Genes;Health Care Costs;Immunohistochemistry;Impairment;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Injury;Knock-out;Lesion;Lipids;Macrophage Activation;Mass Fragmentography;Measures;Mediating;Mediator of activation protein;Membrane;Microglia;Molecular;Mus;Myelin;Nerve Degeneration;Paralysed;Pathogenesis;Pathologic;Pathology;Patients;Peripheral;Phagocytes;Phagocytosis;Phenotype;Phospholipase;Phospholipids;Process;Property;Proteins;Publishing;Reactive Oxygen Species;Recovery;Reporting;Role;Spinal Cord Contusions;Spinal cord injury;Stimulus;Tissues;base;cytokine;in vivo;inflammatory milieu;inhibitor/antagonist;macrophage;membrane model;monocyte;novel;repaired

public_health_relevance:
Project NarrativeAfter spinal cord injury (SCI) there is incomplete recovery often resulting in chronic paralysis and expensivehealth care costs for patients. One major contributor to this inability to recover is a chronic inflammatoryresponse that inhibits the normal repair process. While the negative effects of this inflammatory response havebeen well studied the molecular mechanisms that drive this inflammation long after the initial injury remainunclear; to address this this proposal will examine the mechanisms by which the cellular debris generatedafter injury can be continuously broken down into a potent inflammatory stimulus.


application_id: 9609660
project_number: 1R01NS108529-01
project_title: The integrated stress response and oligodendrocyte survival after spinal cord injury
administering_ic: NINDS
award_notice_date: 2018-06-04
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: NS
serial_number: 108529
program_official: JAKEMAN, LYN B
project_start_date: 2018-06-15
project_end_date: 2023-03-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: HETMAN, MICHAL
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_terms:
Acute;Address;Affinity Chromatography;Amino Acids;Anabolism;Attenuated;Biological Assay;Brain Injuries;Cell Death;Cessation of life;Chronic;Data;Disease;Double-Stranded RNA;Enzymes;Experimental Designs;Functional disorder;Gene Expression;Gene Targeting;Genes;Glucose;Grant;Homeostasis;Hypoxia;Hypoxia Inducible Factor;Impairment;In Vitro;Inflammation;Intracranial Hemorrhages;Iron;Mediating;Mediator of activation protein;Metabolism;Mitochondria;Mus;Nutrient;Oligodendroglia;Outcome;Oxidative Stress;PERK kinase;Pathogenesis;Pathway interactions;Peptide Initiation Factors;Pharmacological Treatment;Pharmacology;Phosphotransferases;Play;Procollagen-Proline Dioxygenase;Proteasome Inhibition;Protein Synthesis Inhibition;Recovery;Recovery of Function;Response to stimulus physiology;Ribosomes;Role;Signal Pathway;Signal Transduction;Spinal Cord Contusions;Spinal cord injury;Spinal cord injury patients;Starvation;Stress;Stroke;Testing;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Time;Tissue Sample;Tissues;Transcriptional Activation;Translating;Translational Regulation;Translations;Traumatic CNS injury;Up-Regulation;Work;base;biological adaptation to stress;central nervous system injury;cytotoxic;deprivation;functional decline;functional outcomes;genetic approach;improved;in vivo;inhibitor/antagonist;loss of function;new therapeutic target;novel;novel therapeutics;response;stressor;targeted treatment;transcription factor;transcription factor CHOP;transcriptome sequencing;white matter;white matter damage


application_id: 9609495
project_number: 5R01HL135158-02
project_title: Effect of early life stress on obesity-induced hypertension in mice
administering_ic: NHLBI
award_notice_date: 2018-12-13
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_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;Comorbidity;Diet;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;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


application_id: 9609421
project_number: 5R01AT008617-04
project_title: Plant exosomes non-coding RNA-mediated anti-inflammatory mechanisms
administering_ic: NCCIH
award_notice_date: 2018-11-09
opportunity_number: PAR-13-375
application_type: 5
activity_code: R01
ic: AT
serial_number: 008617
program_official: WANG, YISONG
project_start_date: 2015-12-01
project_end_date: 2020-11-30
study_section: Special Emphasis Panel[ZRG1-EMNR-V(55)R]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this proposal is to define the role of edible plant exosomal non-coding small RNA (nc-sRNA) in the prevention of gut inflammation using the dextran sulfate sodium (DSS) induced colitis and three other gut inflammatory related mouse models. Although evidence is supportive of the beneficial effects for most edible plants taken as part of the diet the evidence that specific plant-based supplements are beneficial is controversial and the underlying mechanisms are not clear. The challenge is to isolate and characterize the biological activities of the essential functional unit contained in specific naturl products to determine if and how it's cellular and molecular effects on the host can be used in a beneficial manner. Our recently published data (1-5) indicates that exosome-like nanoparticles (ELNs) present in a number of edible plants including grapefruit and ginger have anti-inflammatory properties. Mice fed grapefruit ELNs (FELNs) are protected against DSS induced mouse colitis. Up take of FELNs by intestinal macrophages inhibits the release of IL-1 and IL-6 and the induction of HO-1 and IL-10 expression. Our preliminary data further indicate that FELNs carry high levels of specific nc-sRNA that inhibit the induction of proinflammatory cytokines by targeting intestinal macrophages. The nc-sRNA is associated with inactivation of macrophage miR155. A specific FELN nc-sRNA complexed with naringin binds to miR155 and subsequently prevents miR155 binding to 3-UTRs of certain anti-inflammatory genes thus inhibiting the induction of proinflammatory cytokines. We have also demonstrated that ginger ELN nc-sRNAs promotes the production of IL-10 in lamina propria macrophages under steady-state as well as inflammatory conditions. Therefore we hypothesize that plant ELNs carrying the nc-sRNA bioactive complex are taken up by intestinal macrophages and subsequently bind to inflammatory microRNAs resulting in inhibition of induction of chronic inflammation cytokines thereby preventing chronic intestinal inflammation. Our hypothesis will be tested in vitro and in vivo to determine: (1) whether FELN taken up by intestinal macrophages leads to induction of tolerant dendritic cells (DCs) through nc-sRNA-155 mediated anti-inflammatory effects since DCs are critical for gut immune tolerance and homeostasis through cross-talk with intestinal macrophages; (2) the factors that regulate sorting of anti-inflammatory nc-sRNA-155 into macrophage exosomes; and (3) which ginger ELNs nc-sRNA(s) are required for induction of anti- inflammatory IL-10 expressed in macrophages. Demonstration of the ELNs complex targeting to gut inflammatory cells would be a significant step forward in the understanding of how the plant kingdom interacts with the mammalian species to regulate anti-inflammatory responses through ELNs. The data generated should provide a foundation for selecting specific ELNs from different types of plants for personalized complementary medicine for patients and determine whether oral administration of a customized exosome isolated from different plants will have a synergistic/additive effect on prevention or treatment of disease.

project_terms:
Anti-inflammatory;Antigens;Antiinflammatory Effect;Bacteria;Binding;Biological;Cells;Chronic;Colitis;Communication;Complementary Medicine;Complex;Crohn's disease;Custom;Data;Dendritic Cells;Diet;Disease;Edible Plants;Encapsulated;Escherichia;Escherichia coli;Exposure to;Food;Foundations;Genes;Ginger;Goals;Grapefruit;Gut Mucosa;Health;Homeostasis;Immune;Immune Tolerance;Immune response;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Inflammatory disease of the intestine;Ingestion;Interleukin-1;Interleukin-1 beta;Interleukin-10;Interleukin-6;Intestines;Investigation;Lamina Propria;Lipids;Literature;Macrophage Activation;Mediating;MicroRNAs;Modeling;Molecular;Mononuclear;Mus;Myeloid Cell Activation;Natural Products;Oral Administration;Pathway interactions;Patients;Phagocytes;Plant Extracts;Plants;Play;Prevention;Production;Property;Proteins;Publishing;RNA;RNA Binding;Role;Sampling;Signal Transduction;Small RNA;Sodium Dextran Sulfate;Sorting - Cell Movement;Study models;TNF gene;Testing;Untranslated RNA;Untranslated Regions;base;bioactive natural products;cytokine;exosome;experimental study;fruits and vegetables;gut bacteria;in vitro testing;in vivo;interspecies communication;lymph nodes;macrophage;mouse model;nanoparticle;prevent;public health relevance;transcription factor;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Although evidence is supportive of the beneficial effects for most edible plants taken as part of the diet molecule mechanisms underlying beneficial of edible plants and extracts for sustaining health is not clear. The studies that we have accomplished to date suggest that edible plant exosome-like nanoparticles encapsulated with non-coding small RNAs that binds to miRNAs prevent mouse colitis- standard mouse models for studying Crohn's disease. The focus of this application is to further characterize these mechanisms and then to determine whether targeting of these mechanisms is through communication with different subsets of miRNAs expressed in the intestinal macrophages and this will also allow for further investigations as to how interspecies communication takes place via plant derived exosomes.


application_id: 9609412
project_number: 5R01AI119022-05
project_title: Structure and mechanism of the ESX secretion system from pathogenic mycobacteria
administering_ic: NIAID
award_notice_date: 2018-12-14
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 119022
program_official: MENDEZ, SUSANA
project_start_date: 2015-07-25
project_end_date: 2021-03-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 11365624
contact_pi: KOROTKOV, KONSTANTIN V
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Tuberculosis (TB) is a devastating infectious disease caused by Mycobacterium tuberculosis that results in more than 8 million new cases and 1.4 million deaths every year. The efficacy of currently available anti-TB drugs has been compromised by the emergence of multidrug-resistant and extensively drug-resistant strains therefore there is an urgent need to develop novel therapeutic strategies against TB. In M. tuberculosis three paralogous protein secretion systems - ESX-1 ESX-3 and ESX-5 - secrete PE-PPE dimers during defined stages of the infection process. PE and PPE proteins represent two large families of highly polymorphic proteins that are especially abundant in pathogenic mycobacteria. PE/PPE proteins are either cell wall associated or secreted into the extracellular milieu. These protein families are targets for vaccine development and diagnostic reagents. Multiple PE/PPE proteins play a role in in virulence immune evasion and persistence in host. An outstanding question in the field is what the mechanisms of PE/PPE secretion and assembly in the cell wall of mycobacteria. This proposal is designed to help answer this important biological question by using a range of genetic biochemical and structural approaches including X-ray crystallography and mass-spectrometry. This study is significant because the protein secretion systems of M. tuberculosis the ESX system in particular are attractive targets for drug development. The results of our study will significantly advance our understanding of mycobacterial pathogenesis and will provide structural knowledge that will guide the development of novel therapeutic targets and the design of a better vaccine against TB.

project_terms:
Affect;Amino Acids;Antigens;Architecture;Binding;Biochemical;Biological;Biological Process;C-terminal;Carrier Proteins;Cell Wall;Cell surface;Cessation of life;Communicable Diseases;Complex;Data;Development;Diagnostic;Diagnostic Reagent;Drug Targeting;ELF3 gene;Environment;Enzymes;Essential Amino Acids;Family;Future;Genetic;Genus Mycobacterium;Goals;Growth;Homologous Gene;Immune Evasion;Individual;Infection;Investigation;Knowledge;Macromolecular Complexes;Mass Spectrum Analysis;Membrane;Methods;Modeling;Molecular;Molecular Chaperones;Multi-Drug Resistance;Mutation;Mycobacterium tuberculosis;Pathogenesis;Pathogenicity;Pathway interactions;Peptide Hydrolases;Pilum;Play;Process;Protein Family;Protein Secretion;Proteins;Role;Specificity;Structure;Surface;System;Testing;Therapeutic;Tuberculosis;Vaccines;Virulence;Work;X-Ray Crystallography;design;dimer;drug development;drug discovery;experimental study;extensive drug resistance;extracellular;human pathogen;improved;inhibitor/antagonist;insight;mycobacterial;new therapeutic target;novel therapeutics;protein aggregation;protein protein interaction;protein transport;public health relevance;resistant strain;tool;tuberculosis diagnostics;tuberculosis drugs;vaccine candidate;vaccine development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed studies are expected to uncover the architecture and mechanism of the ESX secretion system a pathway essential for virulence and involved in the transport of multiple proteins to the cell surface or extracellular milieu in humanpathogen M. tuberculosis. The generated data will provide a framework for developing novel therapeutics and improved vaccines against tuberculosis.


application_id: 9608743
project_number: 5R21ES028911-02
project_title: Mechanisms of carcinogenic effects of nickel nanoparticles
administering_ic: NIEHS
award_notice_date: 2018-11-30
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: ES
serial_number: 028911
program_official: RAVICHANDRAN, LINGAMANAIDU V
project_start_date: 2017-12-15
project_end_date: 2021-11-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 8567542
contact_pi: ZHANG, QUNWEI
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The development of nanotechnology has allowed the identification of unique properties in nanomaterials thathave in turn led to the development of commercial applications in many fields such as chemical catalysissemiconductors water purification cosmetics microelectrodes biosensors the food industry biomedicineetc. In 2009 developers generated more than $1 billion from the sale of nanomaterials and the market fornanotechnology is expected to grow to 75.8 billion by 2020 with several hundreds of thousands of jobs. Thusthe levels of human exposure to anthropogenic nanoparticles will substantially increase. As an importanttransition metal nickel nanoparticles (Nano-Ni) have wide ranging applications in the fields of batterieselectrical conductors permanent magnets magnetic fluids magnetic recording media solar energyabsorption fuel cell electrodes and catalysts. In addition due to structural and inherent chemical and physicalproperties nickel alloy nanomaterials have received special interest in biomedical applications. In thisproposal we selected Nano-Ni as a model metal nanoparticle because of its wide industrial interest andbiological and medical applications. Based on our preliminary data our working hypothesis is that Nano-Nican cause oxidative stress and DNA damage in lung epithelial cells and long-term exposure to Nano-Ni results in DNA repair deficiency by down-regulating Rad52 increased genomic instability and celltransformation through up-regulation of miR-210 and nuclear accumulation of the hypoxia induciblefactor 1 (HIF-1). The following two Specific Aims will be pursued. Specific Aim 1. Examine the role ofHIF-1 pathway in Nano-Ni-induced genotoxic effects in vitro and in vivo. We will first examine whetherexposure to Nano-Ni will induce DNA damage in normal human lung epithelial cells BEAS-2B and in mice bymeasuring the phosphorylation level of ataxia telangiectasia mutated (ATM) at Ser1981 and p53 at Ser15 andexpression level of Rad52 and phosphorylated histone H2AX (-H2AX). We will then investigate the role ofHIF-1 in Nano-Ni-induced DNA damage by using: (1) HIF-1 - specific siRNA; and (2) HIF-1 knock-outcells. Specific Aim 2. Examine whether exposure to Nano-Ni causes down-regulation of Rad52 throughup-regulation of miR-210 induced by HIF-1 activation during Nano-Ni-induced cell transformation. Wewill first determine whether long-term exposure to low doses of Nano-Ni will induce normal BEAS-2B cells totransform. We will then measure the levels of Rad52 miR-210 and HIF-1 in cells with long-term exposure toNano-Ni and in Nano-Ni-transformed cells. Finally we will explore the role of Rad52 in Nano-Ni-induced celltransformation through overexpression or knockout of Rad52.

project_terms:
8-hydroxy-2'-deoxyguanosine;Address;Alloys;Area;Biological;Biosensor;Caliber;Catalysis;Cell Proliferation;Cells;Characteristics;Chemicals;Cosmetics;DNA Damage;DNA Repair Disorder;Data;Deposition;Development;Dimensions;Dose;Down-Regulation;Electrodes;Epigenetic Process;Epithelial;Epithelial Cells;Equipment;Exposure to;Food Industry;Formulation;Free Radicals;Gases;Gelatinase A;Gelatinase B;Genetic;Genomic Instability;H2AFX gene;Hazard Identification;Human;Hypoxia Inducible Factor;In Vitro;Industrialization;Inflammatory Response;Knock-out;Knowledge;Length;Leukocytes;Light;Liquid substance;Lung;Magnetism;Measures;Medical;Metals;Microelectrodes;Modeling;Mus;Nanotechnology;Nickel;Nuclear;Occupations;Oxidative Stress;Oxygen;Particulate;Paste substance;Pathway interactions;Phosphorylation;Procedures;Process;Property;RAD52 gene;Rattus;Risk Assessment;Role;Sales;Semiconductors;Small Interfering RNA;Solar Energy;Structure;Surface;Surface Properties;TNF gene;TP53 gene;Testing;Toxic effect;Toxicology;Transition Elements;Up-Regulation;Vacuum;Water Purification;Work;absorption;anthropogenesis;ataxia telangiectasia mutated protein;base;carcinogenesis;carcinogenicity;catalyst;cell transformation;chemical property;cold temperature;commercial application;cytokine;exposed human population;genotoxicity;in vivo;interest;melting;nano;nanomaterials;nanometer;nanoparticle;nanosized;novel;overexpression;particle;peripheral blood;physical property;titanium dioxide;tool;vapor

public_health_relevance:
This project aims to clarify whether and how exposure to nickel nanoparticles causes genotoxic andcarcinogenic effects. We expect that our results will provide scientific knowledge and tools for evaluating othernanomaterials. Successful completion of this project will lead to a better understanding of the mechanisms bywhich metal nanoparticles induce genotoxic and carcinogenic effects.


application_id: 9608090
project_number: 3R01AG054130-03S1
administering_ic: NIA
award_notice_date: 2018-05-29
opportunity_number: PA-16-287
application_type: 3
activity_code: R01
ic: AG
serial_number: 054130
suffix: S1
program_official: MCLINDEN, KRISTINA
project_start_date: 2018-06-01
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZRG1(55)-R]
contact_pi_person_id: 10700978
contact_pi: MOGA, DANIELA CLAUDIA
other_pis: JICHA, GREGORY A
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_title:
INtervention for Cognitive Reserve Enhancement in delaying the onset of Alzheimers Symptomatic Expression: The INCREASE study

project_abstract:
Alzheimer's disease (AD) represents one of the most important public health issues our society is facing today.An estimated 5 million people age 65 and older in the United States (US) are currently living with AD and thisnumber may nearly triple by 2050. To address this impeding population burden the National Alzheimer's ProjectAct (NAPA) 2015 report emphasized the need for identifying preventive strategies that can delay symptomaticdisease onset. While much emphasis has been placed on developing and testing effective disease-modifyingstrategies targeting this asymptomatic preclinical phase of AD (pAD) little emphasis has been placed oncurrently available strategies that target cognitive reserve resulting in (1) delaying symptom onset (2) shorteningthe overall course of symptomatic disease and (3) substantially reducing the financial and societal impact of AD.We hypothesize that targeted reductions in inappropriate medication use (Beers Criteria 2015) will bolstercognitive reserve in subjects at risk for AD delaying the onset of clinical symptoms and reducing the prevalenceand duration of symptomatic disease. The impact of this strategy if successful includes a dramatic reduction inoverall health care expenditures for the millions affected by AD by delaying the symptomatic phase of diseasein accord with NAPA aims. Our specific aims are:Specific Aim 1. Conduct a 12-month randomized placebo-controlled trial to evaluate the impact of our patient-centered pharmacist-physician team MTM intervention in reducing unnecessary and inappropriate medicationuse in community-dwelling elderly non-demented subjects. Primary outcome measures will include pre- to post-intervention measures of: (1) use of inappropriate medications as measured by the Medication AppropriatenessIndex (MAI); 2) Cognitive Reserve Change Score (CRCS) defined as the difference in the scopolamine-challenged vs unchallenged measures on the neurocognitive score.Specific Aim 2 Evaluate the impact of preclinical amyloid burden on cognitive reserve deficits and decline(measured as CRCS) to evaluate efficacy of delaying symptomatic disease progression in pAD.While not eliminating AD or shortening duration of biological disease the delay in symptom onset andprogression to functional decline resulting from reduction in inappropriate medication use could lessen ADprevalence and significantly reduce healthcare expenditures related to not only AD but potentially all forms ofdementia involving a prodromal asymptomatic period. Study results would enable the larger implementation ofsimilar medication management strategies in clinical practice to address the need for multifaceted preventivestrategies to maintain cognitive health in the aging population.

project_terms:
AD pathology;Address;Adverse drug effect;Aerobic Exercise;Affect;Alzheimer's Disease;Alzheimer's disease risk;American;Amyloid;Amyloid beta-Protein;Anti-Cholinergics;Beer;Biological;Brain;Clinical;Cognitive;Communities;Comorbidity;Complex;Data;Dementia;Diet;Disease;Disease Progression;Drug usage;Elderly;Enrollment;Health;Health Care Costs;Health Expenditures;Impaired cognition;Intervention;Intervention Trial;Measures;Medical;Medication Management;Neurocognitive;Neurofibrillary Tangles;Onset of illness;Outcome Measure;Pathologic;Pathology;Patients;Pharmaceutical Preparations;Pharmacists;Pharmacology;Pharmacy facility;Phase;Physicians;Population;Positron-Emission Tomography;Prevalence;Prevention strategy;Public Health;Reporting;Research;Scopolamine;Senile Plaques;Societies;Standardization;Symptoms;Testing;Time;United States;aging population;base;clinical practice;cognitive reserve;disability;exhaust;functional decline;human old age (65+);indexing;insight;non-demented;older patient;patient oriented;placebo group;post intervention;pre-clinical;primary outcome;psychosocial;public health relevance;randomized placebo controlled trial;randomized trial;stressor;therapy design;uptake

public_health_relevance:
Public Health Relevance StatementThe study will examine the impact on cognitive reserve of a pharmacist-physician patient-centered medicationtherapy management intervention to address inappropriate medication use as identified by the Beers 2015 list.By bolstering cognitive reserve our project will directly address the National Alzheimer's Project Act 2015priorities serving to delay onset of symptoms in preclinical dementia. The results of this study will providevaluable insights on how to expand this intervention to reduce the prevalence and associated healthcare costsof symptomatic Alzheimer's disease.


application_id: 9608073
project_number: 5R01NS091146-05
project_title: Anti-Oxidant Promoting Cytokine LIF Enhances Neural Cell Survival During Ischemia
administering_ic: NINDS
award_notice_date: 2018-12-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 091146
program_official: BOSETTI, FRANCESCA
project_start_date: 2016-05-01
project_end_date: 2021-01-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 1879898
contact_pi: PENNYPACKER, KEITH R
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Leukemia inhibitory factor (LIF) is an anti-inflammatory cytokine that activates the expression of endogenous antioxidants in neural cells. Our laboratory has been examining the efficacy of LIF in the rodent stroke model of middle cerebral artery occlusion (MCAO) which reflects the most commonly occluded vessel in humans. We have found that LIF administered at 6 h after MCAO improves anatomical and functional outcomes in rats. Of interest this treatment reflects a 33% extension of the therapeutic window when extrapolated to the current clinical stroke window for therapy. LIF increased the expression of antioxidant proteins via Akt in cultured neurons and oligodendrocytes. Aim 1: Is the efficacy of LIF dependent on SOD? We have found total superoxide dismutase (SOD) levels are significantly elevated and protein levels of one isoform SOD3 are increased several-fold at 3 days following MCAO. In this Aim we will determine if specific SOD subtype(s) are responsible for the LIF-induced effects and determine cell-specific expression of these SOD isoforms. MCAO studies will first use knockout mice to examine the SOD subtypes and these results will then be confirmed in rats. Aim 2: Does this LIF dosing regimen translate into long-term behavioral recovery? This Aim will determine whether this treatment regimen has lasting effects. These data will be used to devise a treatment regimen to extend the short-term efficacy to long-term histological and functional recovery at 90 days post-MCAO in rats. Aim 3: Which signals are transduced following LIF activation? The efficacy of LIF is dependent on the protein kinase Akt. From analysis of antioxidant promoters the transcription factor MZF-1 is the putative transcription factor that activates their gene expression via Akt. We will use immunohistochemistry and gel shift assays to quantify their expression and promoter binding respectively in the infarct regions of rats treated with LIF after MCAO. siRNA techniques with neuronal cultures will be employed to knock down expression of this factor to validate previous findings. Aim 4: Will LIF administration be effective in elderly rats after MCAO?In this Aim we will treat elderly male and female rats in short-term studies. These studies will b used to determine if there are any age- or sex- dependent differences in LIF efficacy after MCAO. Both histological and functional recovery will be examined. This proposal is aimed to further elucidate the mechanism(s) of LIF treatment and optimize the treatment regimen for long-term efficacy. While treatment with exogenous antioxidants has failed we believe that the systemic activation of endogenous antioxidants is a better approach and could have substantial implications for treating clinical stroke.

project_terms:
Address;Age;Anatomy;Anti-inflammatory;Antioxidants;Behavioral;Binding;Cell Survival;Cells;Clinic;Clinical;Data;Dose;Elderly;Electrophoretic Mobility Shift Assay;Exploratory/Developmental Grant for Diagnostic Cancer Imaging;FDA approved;Female;Gene Expression;Histologic;Human;Immunohistochemistry;Infarction;Intravenous;Ischemia;Knockout Mice;LIF gene;Laboratories;Measures;Middle Cerebral Artery Occlusion;Motor Skills;Neurologic;Neurons;Occlusion injury;Oligodendroglia;Performance;Protein Isoforms;Protein Kinase;Proteins;Public Health;Rattus;Records;Recovery;Recovery of Function;Regimen;Rodent;Safety;Sex Differences;Signal Transduction;Small Interfering RNA;Stroke;Superoxide Dismutase;Techniques;Therapeutic;Translating;Treatment Protocols;activating transcription factor;base;combat;cytokine;enhancing factor;experimental study;functional outcomes;gray matter;improved;individualized medicine;interest;knock-down;male;pre-clinical;promoter;public health relevance;response;sex;stroke model;transcription factor;treatment optimization;treatment strategy;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Stroke is a major public health problem in the USA with only one FDA-approved treatment that has a limited treatment window. We have found that leukemia inhibitory factor (LIF) protects neural cells from stroke. The proposed experiments will identify how LIF increases the cells own antioxidants to protect it from stroke induced damage.


application_id: 9607594
project_number: 5R01ES028984-02
project_title: Role of Autophagy in Cd(II) Carcinogenesis
administering_ic: NIEHS
award_notice_date: 2018-11-28
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 028984
program_official: REINLIB, LESLIE J
project_start_date: 2017-12-15
project_end_date: 2019-08-22
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
other_pis: SHI, XIANGLIN
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Although the mechanism of Cd(II)-induced carcinogenesis remains to be investigated recent studieshave indicated that autophagy plays a significant role. Our preliminary studies have shown that exposure ofhuman lung bronchial epithelial BEAS-2B cells to Cd(II) generates reactive oxygen species (ROS) whichare responsible for Cd(II)-induced malignant cell transformation. We have also shown that Cd(II) is able toinduce autophagy in normal BEAS-2B cells. The activation of autophagy by Cd(II) is likely to be a cell self-defense mechanism against Cd(II)-induced oxidative damage. Our preliminary studies have also shown thatCd(II)-transformed BEAS-2B cells exhibit autophagy deficiency (autophagy incompetence) resulting inaccumulation of autophagosomes and increased level of p62 protein. The increased p62 causes aconstitutive activation of Nrf2 which in turn upregulates its target antioxidant proteins superoxide dismutase1 (SOD1) and superoxide dismutase 2 (SOD2) and anti-apoptotic proteins Bcl-2 and Bcl-xL most likely dueto increased binding of Nrf2 to antioxidant response element (ARE) sites of these target proteins. Theupregulations of these antioxidants (decrease ROS) and anti-apoptotic proteins result in development ofapoptosis resistance of Cd(II)-transformed cells. The constitutively elevated p62 and Nrf2 are responsible forsurvival advantage of Cd(II)-transformed cells. Natural compound sulforaphane increased autophagy innormal cells exposed to Cd(II) and restored autophagy competence in Cd(II)-transformed cells. The centralhypothesis of this application is that autophagy is a cell defense mechanism in Cd(II)-induced malignant celltransformation and that autophagy deficiency is responsible for tumorigenesis of Cd(II)-transformed cells.Aim 1 will investigate the protective role of autophagy against Cd(II)-induced malignant cell transformation.The hypothesis of this aim is that autophagy protects against Cd(II)-induced malignant cell transformation bydecreasing ROS through facilitating mitochondrial turnover in normal cells and that sulforaphane enhancesautophagy and decreases the cell transformation. Aim 2 will demonstrate that autophagy deficiency in Cd(II)-transformed cells increases cell survival through constitutive activation of p62/Nrf2 signaling. The hypothesisof this aim is that Cd(II)-transformed cells are autophagy deficient resulting in accumulation ofautophagosomes constitutive activations of p62/Nrf2 elevated levels of antioxidants Bcl-2 and Bcl-xLdecreased levels of ROS and acquisition of apoptosis resistance. Aim 3 will investigate roles of autophagydeficiency elevation of p62 constitutive activation of Nrf2 and apoptosis resistance in tumorigenesis ofCd(II)-transformed cells and protection by sulforaphane in vivo. The hypothesis of this aim is that autophagydeficiency in Cd(II)-transformed cells promotes tumorigenesis through elevation of p62 constitutiveactivation of Nrf2 and acquisition of apoptosis resistance and that sulforaphane restores autophagycompetence and inhibits tumorigenesis.

project_terms:
Antioxidants;Apoptosis;Apoptotic;Arsenic;Autophagocytosis;Autophagosome;BCL2 gene;Binding;Cadmium;Cancer Etiology;Carcinogenesis Inhibition;Carcinogens;Cell Survival;Cells;Competence;Cytoprotection;Defense Mechanisms;Development;Epidemiology;Epithelial;Epithelial Cells;Exhibits;Exposure to;Feedback;GTF2H1 gene;Generations;Goals;Human;International Agency for Research on Cancer;Lung;Lysosomes;Malignant neoplasm of lung;Mitochondria;Modeling;Normal Cell;Organ;Play;Prevention;Property;Proteins;Reactive Oxygen Species;Resistance;Response Elements;Role;SOD2 gene;Signal Transduction;Site;Sulforaphane;Superoxides;Up-Regulation;antioxidant enzyme;cancer cell;carcinogenesis;carcinogenicity;cell transformation;exposed human population;in vivo;inhibition of autophagy;oxidation;oxidative damage;restoration;superoxide dismutase 1;tumor xenograft;tumorigenesis

public_health_relevance:
NARRATIVE This application investigates the role of autophagy in Cd(II)-induced carcinogenesis. If goals areaccomplished this study will demonstrate that autophagy protects against Cd(II)-induced malignant celltransformation by decreasing ROS through facilitating mitochondrial turnover in normal cells thatautophagy deficiency in Cd(II)-transformed cells increases cell survival through constitutive activation ofp62/Nrf2 signaling that autophagy deficiency in Cd(II)-transformed cells promotes tumorigenesis throughconstitutive activations of p62 and Nrf2 and acquisition of apoptosis resistance and that sulforaphanerestores autophagy competency and inhibits tumorigenesis.


application_id: 9607119
project_number: 5R01NS104289-02
project_title: Validation of a Point of Care Diagnostic Test for Sports Related Concussion
administering_ic: NINDS
award_notice_date: 2018-11-21
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 104289
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2017-12-01
project_end_date: 2020-11-30
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
other_pis: SMOOT, KYLE
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:
AbstractMild traumatic brain injury (mTBI) resulting from sports related concussion (SRC) is a substantial public healthconcern with ~ 1.6  3.8 million injuries per year in the United States. Although extremes of head injury arerecognizable mTBI associated with SRC is more difficult to diagnose and is complicated by subtle physicalcognitive and emotional symptoms that may manifest up to 48 h following a concussive blow. In preliminarystudies using a rat model of mTBI and in a small clinical trial of patients with mTBI due to motor vehicleaccidents or unintentional falls we identified a novel post translationally modified marker of neuronal injuryubiquitinated visinin like protein 1 (ubVILIP-1) that is released into blood rapidly after injury. To facilitate rapidmeasurement of circulating ubVILIP-1 we developed a lateral flow device (LFD) that provides detection of thebiomarker in less than 20 min. The aim of the current proposal is determine if ubVILIP-1 levels can be used toidentify athletes with SRC by establishing baseline levels of the marker and then quantifying changes thatoccur following SRC and to correlate ubVILIP-1 levels with clinical metrics including SCAT3 measures.

project_terms:
Accident and Emergency department;Age;Assessment tool;Athletic Injuries;Awareness;Bedside Testings;Biological Assay;Biological Markers;Blood;Blood specimen;Brain Concussion;Chronic;Clinical;Clinical Data;Clinical Trials;Conscious;Craniocerebral Trauma;Data;Detection;Devices;Diagnosis;Diagnostic;Diagnostic tests;Drops;Early identification;Effectiveness;Enzyme-Linked Immunosorbent Assay;Equilibrium;Evaluation;Exertion;Fingers;Future;Glial Fibrillary Acidic Protein;Human;Injury;Kentucky;Lateral;Legal patent;Manufactured football;Measurement;Measures;Modeling;Monitor;Neurobehavioral Manifestations;Neuronal Injury;Neurons;Operative Surgical Procedures;Patients;Physicians;Play;Post-Translational Protein Processing;Proteins;Public Health;Rattus;Recording of previous events;Recovery;Research;Sampling;Seasons;Serum;Soccer;Specificity;Sports;Standardization;Symptoms;System;Tablets;Testing;Time;Training;Ubiquitination;United States;Universities;Validation;Weight;Woman;associated symptom;base;blood-based biomarker;conditioning;controlled cortical impact;emotional symptom;falls;male;men;mild traumatic brain injury;novel;novel marker;off-patent;physical symptom;point-of-care diagnostics;recruit;research clinical testing;risk minimization;sensor;tau Proteins;vehicular accident;visinin

public_health_relevance:
NarrativeMild traumatic brain injury (mTBI) resulting from sports related concussion (SRC) is a substantial publichealth concern with ~ 1.6  3.8 million injuries per year in the United States. Despite considerableresearch there remains a critical need for a point of care test that can rapidly measure a maker of injuryin blood on the playing field during a clinically useful time frame. Preliminary and future studiesdescribed in this proposal aim to test the usefulness of a lateral flow device (LFD) that quantifies aspecific post-translational modification of visinin like protein 1 (VILIP-1) a neuron specific Ca2+-sensorprotein released into blood following mTBI as an objective marker of SRC.


application_id: 9606425
project_number: 5R01AI051517-15
project_title: Paramyxovirus F protein mediated membrane fusion
administering_ic: NIAID
award_notice_date: 2018-11-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 051517
program_official: PARK, EUN-CHUNG
project_start_date: 2002-05-15
project_end_date: 2020-12-31
study_section: Virology - B Study Section[VIRB]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
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:
DESCRIPTION (provided by applicant): Compelling work in the last decade has shown that transmembrane domains (TMDs) once thought to function solely as hydrophobic anchors are central players driving cellular protein oligomerization cell signaling and regulation of channelfunction. However the role of TMDs in viral glycoprotein stability and function remains poorly understood. During the previous funding period our studies of the Hendra virus (HeV) fusion (F) protein identified key roles for TMDs in regulation of F protein stability cellular trafficking ad fusion function. Our novel studies utilizing sedimentation equilibrium (SE) analysis established that F protein TMDs efficiently trimerize separate from the rest of the protein. Altered TM-TM association was found for multiple functionally important mutations implicating TM-TM interactions in regulation of F protein folding and function. The long-term goal of our research isto understand the molecular details and regulation of membrane fusion promoted by the paramyxovirus F proteins. The overall hypothesis of this proposal is that interactions of the TMD with itself and the lipid environment are critical for fusion protein stability and function makin these interactions potential targets for antiviral therapeutics. To test this important hypothesiswe will pursue three specific aims. First we will define key elements driving F protein TM-TM interactions including defining the role of a L/I heptad in TM-TM association and Hendra F protein stability. Second we will determine how the TMD affects fusion triggering and promotion of membrane fusion with a focus on the role of C-terminal -branched residues and a determination of the conformational changes that can occur when TM-TM interactions cannot be released. Third we will dissect the role of the lipid environment in prefusion F stability in the context of cellular and viral membranes. These important experiments will provide critical new insight into the role of TMDs in regulation of F protein stability and fusion promotion.

project_terms:
Address;Affect;Antiviral Agents;Automobile Driving;C-terminal;Ca(2+)-Transporting ATPase;Cells;Characteristics;Chimeric Proteins;Cholesterol;Cytoplasmic Tail;Data;Development;Dissociation;Elements;Environment;Family;Funding;Glycoproteins;Goals;Hendra Virus;Human Metapneumovirus;Hydrophobicity;Individual;Infection;Kinetics;Lipids;Measles;Mediating;Membrane;Membrane Fusion;Membrane Fusion Activity;Membrane Lipids;Molecular;Molecular Conformation;Mutation;Neuropilins;Paramyxovirus;Paramyxovirus Fusion Protein;Peptides;Process;Proteins;Regulation;Research;Respiratory syncytial virus;Rest;Role;Sarcoplasmic Reticulum;Signal Transduction;Sphingolipids;Structure;System;Testing;Therapeutic;Time;Transmembrane Domain;Vaccines;Viral;Viral Fusion Proteins;Viral Proteins;Virus;Virus-like particle;Work;Zoonoses;disulfide bond;experimental study;human pathogen;insight;mutant;novel;particle;prevent;protein folding;protein function;public health relevance;sedimentation equilibrium;trafficking;virus envelope

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Viral fusion proteins promote fusion between the viral membrane and a membrane of the target cell a critical first step in the infection of enveloped viruses. Studies to determine factors regulating the stability and function of these proteins are important to the development of novel antiviral approaches targeting these viral proteins. This proposal addresses the role of the paramyxovirus fusion protein transmembrane domain is control of fusion protein stability and membrane fusion activity potentially identifying a novel target for antivirals.


application_id: 9605787
project_number: 5R01ES028102-02
project_title: The role of autophagy in cadmium induced prostate carcinogenesis
administering_ic: NIEHS
award_notice_date: 2018-11-29
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 028102
program_official: REINLIB, LESLIE J
project_start_date: 2017-12-01
project_end_date: 2022-11-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 7649061
contact_pi: DAMODARAN, CHENDIL
other_pis: FREEDMAN, JONATHAN H
congressional_district: 03
department: UROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryIt has been clearly demonstrated that exposure to the environmental toxicant cadmium is associatedwith a variety of human diseases including prostate cancer. Prostate cancer is the second leading causeof cancer death in United States. Although an association has been established the mechanism bywhich this metal induces cellular transformation has yet to be defined. One underexplored process thatmay be affected by cadmium is oncogenic autophagy a process that promotes cancer cell survival. Ourpreliminary data clearly shows that chronic exposure to cadmium leads to cellular transformation andthat this transformation occurs via autophagy through changes in Placenta Specific 8 (Plac8) expression.Additionally Plac8 is observed in human prostate cancer but not in benign prostatic hyperplasia tissues.Based on our preliminary results we hypothesize that cadmium-induced cellular transformation ismediated by the induction of autophagy and that Plac8 is an essential regulator of this process.We will test this hypothesis using a combination of approaches in normal prostate epithelial (RWPE-1)transforming cells and cadmium-transformed prostate epithelial (CTPE) cells mice and human prostatecancer. The goals of this project are to explore an innovative model for the regulation of autophagy bycadmium; where short term metal exposure induces the apoptosis while chronic low dose exposurewhich more accurately represents human etiology of cadmium toxicity; autophagy acts oncogenicleading to transformation. The interaction between cadmium autophagy/apoptosis and Plac8expression will be defined using three approaches: Specific Aim 1: Establish the mechanistic relationshipbetween cadmium exposure and the induction of autophagy in prostate epithelial cells. Specific Aim 2:Determine the mechanism by-which cadmium induces Plac8 expression to regulate pro-survivalsignaling autophagy. Specific Aim -3: Determine the oncogenic role of Plac8 in vivo. The successfulcompletion of these goals represents the first studies on the role of autophagy/Plac8 in cadmium-induced prostate cancer. It will also inform on the applicability of using Plac8 as a prostate cancerbiomarker and of targeting this protein to inhibit metal-induced prostate cancer.

project_terms:
Acute;Affect;Apoptosis;Autophagocytosis;Benign Prostatic Hypertrophy;Cadmium;Cancer Etiology;Cell Death;Cell Line;Cell Survival;Cells;Cessation of life;Chronic;Data;Dose;Epithelial;Epithelial Cells;Etiology;Exposure to;Genes;Gleason Grade for Prostate Cancer;Goals;Human;Human Pathology;Hypoxia;Malignant neoplasm of prostate;Mediating;Metal exposure;Metals;Modeling;Molecular;Mus;Nude Mice;Oncogenic;Organelles;Oxidative Stress;Patients;Pharmacology;Placenta;Population;Prevention;Process;Prostate;Prostatic Neoplasms;Proteins;Regulation;Research;Resistance;Role;Screening for Prostate Cancer;Serum;Signal Transduction;Site-Directed Mutagenesis;Specimen;Starvation;Stress;System;Testing;Time;Tissues;Toxic Environmental Substances;Toxic effect;Translational Research;Tumor Tissue;United States;Urine;Xenograft Model;base;cancer biomarkers;cancer cell;carcinogenesis;cell transformation;early detection biomarkers;environmental chemical;genetic activator;genetic inhibitor;human disease;in vivo;innovation;lysosomal proteins;malignant phenotype;metaplastic cell transformation;mouse model;novel;overexpression;prostate carcinogenesis;transcription factor;tumor growth;tumor xenograft;virtual

public_health_relevance:
Project NarrativeThis research outlined in this proposal aims to delineate the mechanism by which cadmium affectsautophagy ultimately leading to transformation. The study is examining for the first time several novelprocesses autophagy and the gene Plac8 not typically associated with environmental chemical inducedprostate cancer. The successful completion of these goals will inform on the applicability new prostatecancer biomarkers and targets to treat metal-induced prostate cancer.


application_id: 9605088
project_number: 5R21AI135225-02
project_title: Zinc acquistion in Yersinia pestis
administering_ic: NIAID
award_notice_date: 2018-10-25
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: AI
serial_number: 135225
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2017-11-24
project_end_date: 2021-10-31
study_section: Special Emphasis Panel[ZRG1-IDM-B(81)]
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract Yersinia pestis is the causative agent of plague and has caused widespread loss of human life during threepandemics. Y. pestis is also firmly established in animal reservoirs on nearly every inhabited continent with thelargest reservoir in the southwestern United States. Each year multiple outbreaks occur resulting in 1000-5000 human cases reported worldwide (likely an underestimate). Currently there is not a FDA approvedvaccine for plague and the bacterium has a high potential for bioterrorism misuse. Consequently Y. pestis isconsidered a Tier 1 Select Agent. In order to grow Y. pestis must acquire essential biometals such as Fe Mnand Zn. However the host restricts access to these metals through nutritional immunity. Therefore Y. pestislike other pathogens has evolved high affinity metal acquisition systems that are essential for virulence. Werecently discovered that the yersiniabactin (Ybt) synthetase system not only contributes to Fe acquisition butalso to Zn acquisition in Y. pestis. Furthermore we have shown that the inner membrane permease YbtX(which is not required for Fe-Ybt acquisition) is required for Ybt synthetase-dependent Zn acquisition. Thesediscoveries have opened a new area in Ybt and Zn acquisition research. Specifically we hypothesize that Y.pestis produces a Ybt synthetase-dependent zincophore that is distinct from the Ybt siderophore. FurthermoreY. pestis uses a dedicated uptake system to reacquire this zincophore once bound to Zn. Along with ZnuABCthis new system is essential for Zn acquisition during infection. In Specific Aim 1 we will use a biochemicalapproach to purify and define the chemical structure and Zn affinity of the secreted Ybt synthetase-dependentzincophore. In Specific Aim 2 we will determine the contribution of the Ybt synthetase-dependent zincophoreto virulence using a hemochromatosis mouse model. Importantly the hemochromatosis mouse is defective inFe nutritional immunity. Thus this model will allow us to separate contributions of Ybt synthetase-dependentFe acquisition from Ybt synthetase-dependent Zn acquisition to Y. pestis virulence. Finally as Y. pestis alsoinfects fleas for transmission we will determine the contribution of Zn acquisition to colonization and survival inthe flea vector. Completion of these aims will provide a comprehensive understanding of the role of Znacquisition in Y. pestis virulence. Furthermore as Ybt is a conserved virulence factor this work will also berelevant to other bacterial pathogens that use the Ybt system.

project_terms:
Affinity;Animals;Area;Asians;Attenuated;Bacteria;Binding;Biochemical;Biology;Bioterrorism;Bubonic Plague;Case Study;Chemical Structure;Data;Disease Outbreaks;Enzymes;FDA approved;Fleas;Future;Gene Silencing;Goals;Growth;Hemochromatosis;Human;Infection;Insecta;Invaded;Iron;Life;Ligase;Manganese;Membrane;Membrane Transport Proteins;Metals;Modeling;Modification;Molecular;Mus;Nutritional Immunity;Organism;Pathogenesis;Plague;Plague Vaccine;Pneumonic Plague;Predisposition;Rattus;Research;Role;Septicemic plague;Siderophores;Southwestern United States;Structure;System;Testing;Trace Elements;Transition Elements;Up-Regulation;Virulence;Virulence Factors;Work;Yersinia pestis;Zinc;antimicrobial;defined contribution;flea-borne;mouse model;mutant;new therapeutic target;novel;pandemic disease;pathogen;pathogenic bacteria;permease;small molecule;transmission process;uptake;vector;yersiniabactin

public_health_relevance:
PROJECT NARRATIVEBacterial pathogens need to obtain essential biometals such as iron and zinc during infection and recently wehave identified a novel zinc acquisition system in Yersinia pestis the causative agent of human plague. Thisproject will characterize this system and define its role during mammalian and insect infection. As metalacquisition systems are essential for virulence they are viable targets for new therapeutics.


application_id: 9604117
project_number: 1R21CA231904-01
project_title: An Ontology-driven Faceted Query Engine for the Kentucky Cancer Registry
administering_ic: NCI
award_notice_date: 2018-06-06
opportunity_number: PAR-15-334
application_type: 1
activity_code: R21
ic: CA
serial_number: 231904
program_official: RIVERA, DONNA
project_start_date: 2018-06-06
project_end_date: 2019-02-03
study_section: Special Emphasis Panel[ZCA1 SRB-X (M2)]
contact_pi_person_id: 7938505
contact_pi: ZHANG, GUO-QIANG
other_pis: CUI, LICONG
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:
ABSTRACTA key barrier in cancer research is the traditional data access workflow that requires a hypothesis prior toaccessing patient data rather than a workflow that begins with data exploration while protecting privacy.Existing query engines allow researchers to explore clinical data build queries and execute queries withoutthe need for the user to understand how the data is stored. However the interfaces of such query engineshave not achieved usability approaching the levels of those for consumer websites due in critical part to thelack of faceted capabilities. Faceted systems for querying clinical data is currently unavailable due to thecomplexity of data and the mismatch between the ontologies used for organizing and annotating clinical data(such as NCI Thesaurus) and the desired facet structures and properties.We propose to overcome these challenges by developing OncoSphere a query engine using the NCIThesaurus as a nested facet system (NFS) to provide web-based exploration of the Kentucky Cancer Registrydata using 3 Specific Aims. In Aim 1 we will develop an approach to transform and implement NCI Thesaurusinto an NFS to enable OncoSpheres interface features. In Aim 2 we will develop methods to perform qualityauditing on the hierarchical structure of the NCI Thesaurus to enhance its quality in supporting faceted queryfor OncoSphere. In Aim 3 we will perform evaluation on OncoSpheres query expressiveness queryperformance and conduct preliminary usability assessment. OncoSphere will break new ground in web-basedtools and capitalize on available data resources to accelerate cancer research. We expect OncoSphere and itsfuture versions to become an invaluable resource for the cancer research community. The long-term goal ofthis study is to create data exploration systems for NCIs Surveillance Epidemiology and End Results (SEER)program and other related cancer data resources through data science innovations to transform userexperience with a new generation of data interaction modalities.

project_terms:
Address;Adopted;Area;Biomedical Research;Characteristics;Clinical Data;Clinical Research;Clinical Trials;Communities;Computer software;Data;Data Science;Databases;Detection;Development;Ensure;Evaluation;Future;Generations;Goals;Kentucky;Knowledge;Lead;Malignant Neoplasms;Metadata;Methods;Modality;NCI Thesaurus;Online Systems;Ontology;Patients;Performance;Privacy;Property;Research Personnel;Resources;Role;SEER Program;Site;Software Tools;Structure;System;Terminology;Time;Translations;Trees;Work;anticancer research;data access;data integration;data management;data registry;data resource;design;experience;human data;improved;innovation;insight;lexical;neoplasm registry;neoplasm resource;novel;query optimization;sound;success;tool;usability;web app;web site;web-based tool

public_health_relevance:
PROJECT NARRATIVEThe main goal of this project is to develop!OncoSphere a novel ontology-driven faceted query system toenhance web-based exploration of Kentucky Cancer Registry data. Success of this study will address afundamental barrier in making query interfaces easier to use ultimately as easy as shopping on Amazon tosupport a broad range of cancer data exploration modalities. Ultimately this study can lead to the creation of anew generation of tools for querying data in the NCIs Surveillance Epidemiology and End Results program aswell as other related cancer resources.


application_id: 9601637
project_number: 5R01AG049806-04
project_title: The effects of exercise on satellite cell dynamics during aging
administering_ic: NIA
award_notice_date: 2018-11-13
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AG
serial_number: 049806
program_official: WILLIAMS, JOHN
project_start_date: 2016-01-01
project_end_date: 2020-11-30
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: MCCARTHY, JOHN JOSEPH
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:
AbstractA key determinant of geriatric frailty is sarcopenia the age-associated loss of skeletal muscle mass andstrength. Although the etiology of sarcopenia remains to be determined studies in humans and rodents havereported a strong correlation between the loss and/or dysfunction of satellite cells and sarcopenia. Despite thecorrelation between declining satellite cell-dependent regenerative capacity and age no studies to date havedirectly tested this relationship to determine if the loss of satellite cells causes sarcopenia. To test this idea wedepleted (>85%) satellite cells in five month old mice to a level dramatically lower than that observed withnormal aging. A detailed analysis of multiple muscles through 24 months of age revealed that despitesignificantly reduced regenerative capacity the life-long depletion of satellite cells did not accelerate norexacerbate sarcopenia; however the depletion of satellite cells at a young age was associated with asignificant increase in fibrosis in old mice. These highly provocative findings together with our data on thefiber-type specific role of satellite cells in response to exercise reveal our limited understanding of how agingaffects the function of satellite cells in skeletal muscle maintenance the development of fibrosis and inresponse to a growth stimulus; addressing these fundamental gaps in our knowledge clearly requires newtools. Towards this end we will utilize a novel mouse strain (Pax7-H2B-GFP) that will allow us to track satellitecell dynamics for the first time in adult skeletal muscle aging. To better understand how aging and exerciseaffects satellite cell dynamics and the regulation of fibrosis the following aims will be pursued: 1) determinehow age and life-long exercise affects satellite cell dynamics in the maintenance of skeletal muscle 2)determine how age and life-long exercise affects satellite cell regulation of fibrosis and 3) determine how ageaffects satellite cell dynamics in response to a growth stimulus. The approaches described herein usepowerful new genetic tools to determine how aging and life-long exercise alters the function of satellite cells inskeletal muscle homeostasis regulation of fibrosis and adaptability. The development of the Pax7-H2B-GFPmouse represents a long sought-after method for tracking satellite cells especially following fusion into themyofiber. This novel mouse strain will allow us to address formally intractable questions regarding how satellitecell dynamics are affected by age and life-long exercise. Such fundamental knowledge is necessary to criticallyevaluate the therapeutic value of satellite cells for the treatment of muscle mass loss and function associatedwith aging.

project_terms:
Ablation;Address;Adult;Affect;Age;Age-Months;Aging;Biological Assay;CD34 gene;Cell Nucleus;Cell physiology;Cells;Coculture Techniques;Collagen;Data;Development;Disease;Elderly;Environment;Etiology;Exercise;Expression Profiling;Fiber;Fibroblasts;Fibrosis;Functional disorder;Gastrocnemius Muscle;Genes;Genetic;Goals;Growth;Homeostasis;Human;Hypertrophy;Immunohistochemistry;Individual;Integrins;Intervention;Knock-out;Knowledge;Label;Life;Longevity;MAPK14 gene;Maintenance;Measures;Mediating;Methods;MicroRNAs;Modeling;Mouse Strains;Mus;Muscle;Muscle Fibers;Nucleosomes;Outcome;Phase;Phenotype;Physical activity;Production;Proteins;Publishing;Quality of life;Regulation;Reporter;Reporting;Research;Rodent;Role;Running;Skeletal Muscle;Skeletal Muscle Satellite Cells;Stem cells;Stimulus;Testing;Therapeutic;Time;Untranslated Regions;base;exosome;experimental study;extracellular;falls;frailty;improved;loss of function;muscle aging;muscle form;muscle hypertrophy;muscle strength;normal aging;novel;progenitor;regenerative;response;sarcopenia;satellite cell;sedentary;senescence;skeletal muscle growth;skeletal muscle wasting;tool

public_health_relevance:
RelevanceA hallmark of aging in humans is the progressive loss of skeletal muscle mass and strength which is known tohave a negative impact on an individual's quality of life by robbing them of their daily independence as well asincreasing the occurrence of falls and other diseases. The primary goal of the proposed research is tounderstand how stem cell dynamics change with age how stems cells influence the muscle environment andthe impact of exercise on satellite cell function during aging. This knowledge is required to evaluate thetherapeutic potential of these cells to treat the loss of skeletal muscle mass and fucntion duirng aging.


application_id: 9600651
project_number: 5R01CA133429-12
project_title: The Role of PHLPP in Colon Cancer
administering_ic: NCI
award_notice_date: 2018-11-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 133429
program_official: YASSIN, RIHAB R
project_start_date: 2009-04-01
project_end_date: 2020-07-31
study_section: Tumor Cell Biology Study Section[TCB]
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Approximately 142000 new cases and 51000 deaths are predicted for the year 2013. A better understanding of the molecular events leading to cancer progression and chemoresistance is needed in order to improve the overall survival of CRC patients. Our lab has been intensively focused on elucidating the role of a novel family of protein phosphatases PHLPP (PH domain Leucine-rich-repeats Protein Phosphatase) in inhibiting CRC initiation and progression. We have made substantial progress in understanding the functional importance of PHLPP as a tumor suppressor as well as the molecular mechanism underlying PHLPP regulation. In this proposed study we will determine the effect of PHLPP-loss on modulating lipid metabolism in CRC. Although recent advances in cancer metabolism research have begun to elucidate how metabolic changes support cancer cell growth and survival the regulation and functional importance of altered lipid metabolism in CRC remain elusive. This proposal centers on a novel hypothesis that PHLPP-loss plays a pivotal role in driving CRC progression by promoting lipogenesis. In exciting recent findings we demonstrate that downregulation of PHLPP expression results in an increase in the expression of activated SREBP1 a key activator of lipid biosynthesis. Consistently MEF cells isolated from PHLPP knockout mice have enhanced lipogenesis during differentiation into adipocytes. In addition we have found that silencing PHLPP expression leads to increased glucose uptake lactate production Krebs cycle activity and triacylglycerides accumulation in CRC cells suggesting a role of PHLPP in regulating cellular metabolism. The central hypothesis driving this proposed study is that PHLPP plays an essential role in inhibiting lipogenesis by negatively regulating the PI3K/Akt/mTOR pathway and loss of PHLPP expression promotes CRC progression as the result of metabolic reprogramming. The following specific aims are proposed: 1) to delineate the molecular mechanism by which PHLPP regulates lipogenesis in CRC cells. We will perform the Stable Isotope-Resolved Metabolomics (SIRM) analysis to determine how PHLPP-loss affects lipid metabolism in CRC cells; 2) to determine the functional importance of PHLPP-mediated regulation of lipogenesis. We will test if PHLPP-loss renders CRC cells more resistant to metabolic stress and chemotherapy drugs as the result of alterations in lipogenesis; and 3) to define the role of PHLPP in suppressing lipogenesis in vivo. The effect of PHLPP-loss on modulating lipid metabolism will be determined using both genetically modified mouse models and patient-derived xenograft models. Results from our studies will fill an important knowledge gap on how altered lipogenesis affects the prognosis and treatment efficacy in CRC patients. Ultimately by providing insight into the mechanisms by which PHLPP-mediated lipogenesis our findings will help to develop new treatment strategies in CRC patients.

project_terms:
Adenocarcinoma;Adipocytes;Affect;Automobile Driving;Cancer Cell Growth;Cancer Center;Cancer Etiology;Cell Proliferation;Cell Survival;Cells;Cessation of life;Citric Acid Cycle;Collection;Colon Carcinoma;Colorectal Cancer;Development;Down-Regulation;Ensure;Event;FRAP1 gene;Genetic;Human;Hypoxia;In Vitro;Intestines;Knockout Mice;Knowledge;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolic stress;Metabolism;Molecular;NOD/SCID mouse;Oncogenes;PH Domain;Pathway interactions;Patients;Pharmaceutical Preparations;Play;Production;Protein Family;Protein phosphatase;Proteins;Ras/Raf;Regulation;Research;Resistance;Role;Signal Transduction;Testing;Tissues;Translations;Treatment Efficacy;Tumor Suppressor Proteins;United States;Xenograft Model;cancer cell;cancer initiation;cancer therapy;chemotherapy;colon cancer patients;colon tumorigenesis;colorectal cancer progression;design;experimental study;glucose uptake;improved;in vivo;insight;leucine-rich repeat protein;lipid biosynthesis;lipid metabolism;mTOR Inhibitor;macromolecule;metabolomics;mouse model;novel;outcome forecast;public health relevance;stable isotope;success;therapy resistant;treatment strategy;tumor metabolism;tumor progression;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE:   Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Approximately 140000 new cases and 51000 deaths are predicted for the year 2013. Although there has been some modest improvement in survival a better understanding of the molecular events leading to cancer progression and treatment resistance is needed in order to improve the prognosis of CRC patients.


application_id: 9600315
project_number: 1R03AI135592-01A1
project_title: Function and Stability of Expanded Regulatory T cells in Obese Renal Transplant Candidates
administering_ic: NIAID
award_notice_date: 2018-05-18
opportunity_number: PA-16-162
application_type: 1
activity_code: R03
ic: AI
serial_number: 135592
suffix: A1
program_official: KEHN, PATRICIA J
project_start_date: 2018-05-18
project_end_date: 2020-04-30
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 7732443
contact_pi: MARTI, FRANCESC
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Function and Stability of Expanded Regulatory T cells in Obese Renal Transplant CandidatesABSTRACTMore than two-thirds of adults in the United States are currently considered obese. The epidemic is particularlyacute in Kentucky (ranked fifth highest state in the US) as well as in Appalachian counties in adjacent statesthat make up the University of Kentucky Transplant Centers service area. In 2016 this center evaluated nearly1000 patients with end-stage renal disease (ESRD) of which 54.2% had a body mass index (BMI) equal orgreater than 30 Kg/m2 (obese status). Obesity is an increasingly common comorbidity in patients with chronicrenal diseases. In kidney transplant patients it has been associated with delayed graft function acute rejectionepisodes and graft loss. Acute cellular rejection occurs through immunologic mechanisms that include theadaptive immune response mediated by T cells. A growing body of evidence recognizes the balance betweengraft-reactive effector cells and graft-protective suppressor regulatory T cells (Tregs) as the ultimatedeterminant of long-term allograft survival. Our Transplant Center is developing a novel clinical protocol usingexpanded autologous Treg infusions to induce tolerance in renal transplant recipients with the ultimate goal ofenhancing long-term allograft function preventing rejection and reducing the overall toxicity of currentimmunosuppressive regimens. Circulating Treg cells are reduced in number and function in obese patients.Therefore the generation of sufficient numbers of clinically competent suppressive Treg cells from these obesepatients is especially challenging. In addition how the obese microenvironment may alter the functionalcompetency of adoptively transferred Treg is not known. In order to characterize the association betweenobesity-related parameters and the functional integrity of Tregs this study will (1) optimize the conditions ofprimary Treg cell expansion isolated from obese potential transplant recipients and (2) determine the tissuedistribution functional progress and lineage stability of adoptive transferred Tregs in obese recipients. Wehypothesize that the ex-vivo activation and expansion of obese Treg cells will overcome cell-intrinsicalterations and extrinsic pro-inflammatory signals associated with obesity. In Specific Aim 1 we will measurebaseline levels of Treg cells in peripheral blood from obese (BMI 35) and non-obese (BMI <25) ESRDpatients. We will also purify the Treg cells expand them ex-vivo and verify their cell phenotype expansionrates suppressor activity metabolic profile and linage stability. We will compare the data generated fromobese and non-obese patients and perform a multivariable logistic regression analysis with the parameterscollected to determine independent predictors of Treg cell expansion and function. In Specific Aim 2 we willuse a mouse model to evaluate in vivo the functional proficiency of adoptively transferred Treg cells into obeserecipients. The results will (1) characterize the population of Treg cells (baseline levels) (2) determine thefeasibility of expanding functionally competent and stable Treg cells from obese patients and (3) establish thein vivo influence of obese environment to the functional status of adoptively transferred Treg cells.

project_terms:
Acute;Address;Adoptive Cell Transfers;Adoptive Immunotherapy;Adoptive Transfer;Adult;Adverse effects;Affect;Allografting;Appalachian Region;Area;Autologous;Blood;Body mass index;Cell Count;Cells;Cessation of life;Chronic Kidney Failure;Clinical;Clinical Data;Clinical Investigator;Clinical Protocols;Collaborations;Communities;Comorbidity;Competence;County;Data;Dependence;Development;Diet;Drug or chemical Tissue Distribution;Effector Cell;End stage renal failure;Energy-Generating Resources;Environment;Epidemic;Equilibrium;FOXP3 gene;Generations;Glycolysis;Goals;Graft Survival;Graft-vs-Host Disease;Health Service Area;Immune;Immunologics;Immunology;Immunosuppressive Agents;Impairment;Incidence;Inflammatory;Infusion procedures;Insulin-Dependent Diabetes Mellitus;Kentucky;Kidney;Kidney Transplantation;Life;Logistic Regressions;Measures;Mediating;Mitochondria;Modeling;Morbidity - disease rate;Mouse Strains;Non obese;Obese Mice;Obesity;Ohio;Operative Surgical Procedures;Organ;Outcome;Overweight;Oxidative Phosphorylation;Patients;Perioperative;Perioperative complication;Pharmaceutical Preparations;Phenotype;Population;Proteins;Publishing;Quality of life;Regimen;Regression Analysis;Regulatory T-Lymphocyte;Reporting;Research;Risk Factors;Savings;Signal Transduction;Solid;Surveys;Survival Rate;T-Lymphocyte;Tennessee;Testing;Therapeutic;Toxic effect;Transplant Recipients;Transplantation;United States;Universities;Validation;Weight;West Virginia;adaptive immune response;allograft rejection;base;delayed graft function;dosage;functional status;improved;in vivo;metabolic profile;mortality;mouse model;multidisciplinary;novel;novel therapeutic intervention;peripheral blood;pre-clinical;prevent;programs;promoter;public health relevance;transplant centers

public_health_relevance:
Function and Stability of Expanded Regulatory T cells in Obese Renal Transplant CandidatesPROJECT NARRATIVEPUBLIC HEALTH RELEVANCE: This project will characterize the functional competency of Treg cellsin obese and develop the optimal conditions for the pre-clinical validation of expanded obese Tregs.


application_id: 9600052
project_number: 5R01AI123486-03
project_title: Role of the gut microbiota in shaping severity of malaria
administering_ic: NIAID
award_notice_date: 2018-12-03
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AI
serial_number: 123486
program_official: PESCE, JOHN T
project_start_date: 2017-01-11
project_end_date: 2019-05-31
study_section: Pathogenic Eukaryotes Study Section[PTHE]
contact_pi_person_id: 11178918
contact_pi: SCHMIDT, NATHAN
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Infections by parasites of the genus Plasmodium cause more than 200 million cases of malaria and kill morethan 400000 people annually the majority of whom are Plasmodium falciparum-infected children in sub-Saharan Africa. Most Plasmodium infections are either asymptomatic or cause only mild malaria. A smallproportion of infections progress to severe malaria that can be life threatening. To date the host factors thatpredispose patients to developing severe malaria are not known and it has not been possible to identify riskfactors that predict progression from asymptomatic infection to severe malaria. These knowledge gaps hinderdiscovery of new strategies for the prevention of severe malaria. Using multiple Plasmodium species andmouse strains we have recently published the novel observation that mice with distinct gut bacterialcommunities exhibit differences in the severity of malaria and humoral immune response following infectionwith Plasmodium. Mice resistant to severe malaria exhibit elevated T follicular helper (Tfh) and germinal center(GC) B cell numbers and accelerated antibody class switching following Plasmodium yoelii infection comparedto susceptible mice. When mice predicated to develop mild malaria were treated with antibodies that disruptTfh-GC B cell communication they developed high parasite burdens similar to mice that develop severemalaria. These new observations support the scientific premise of this application and suggest that gutmicrobiome-mediated modulation of the GC reaction may be a critical mechanism underlying the developmentof severe malaria. The objective of this proposal is to determine the immunological mechanisms by which thegut microbiome determines susceptibility to severe malaria and identify the specific microbes and metabolitesresponsible for this outcome. These studies will move the field of malaria pathogenesis forward in newdirections and may lead to new translational approaches to control severe malaria which could in turn savethe hundreds of thousands of lives lost to severe malaria each year. The central hypothesis of this proposalis that specific microbes and their metabolites modulate GC reactions to determine susceptibility to severemalaria. Our hypothesis will be tested through the following specific aims: Aim 1. Determine the dynamics ofgut microbiota-mediated modulation of the GC reaction in mice. Aim 2. Determine the Tfh cell- and GC B cell-intrinsic pathways modulated by the gut microbiota in mice. Aim 3. Identify the specific gut bacteria and theirmetabolites that determine resistance or susceptibility to severe malaria in mice.

project_terms:
Adoptive Transfer;Affect;Africa South of the Sahara;Anemia;Antibodies;B-Lymphocytes;Bacteria;Biological Models;CD4 Positive T Lymphocytes;Cause of Death;Cell Communication;Cell Count;Cell physiology;Cerebral Malaria;Cessation of life;Child;Clinical;Communicable Diseases;Data;Development;Disease;Evolution;Exhibits;Foundations;Future;Germ-Free;Health;Helper-Inducer T-Lymphocyte;Human;Immune response;Immunity;Immunoglobulin Class Switching;Immunologics;Immunology;Inbreeding;Individual;Infection;Integration Host Factors;Knowledge;Lead;Life;Malaria;Mediating;Metabolic;Microbe;Molecular;Morbidity - disease rate;Mouse Strains;Mus;Outcome;Parasite Control;Parasites;Parasitic infection;Pathogenesis;Pathology;Pathway interactions;Patients;Physiology;Plasmodium;Plasmodium falciparum;Plasmodium yoelii;Population;Predictive Factor;Predisposing Factor;Predisposition;Prevention strategy;Process;Publishing;Reaction;Resistance;Risk Factors;Rodent;Role;Severities;Shapes;Structure of germinal center of lymph node;Syndrome;Testing;Virus;Wild Type Mouse;bacterial community;fungus;gut bacteria;gut microbes;gut microbiome;gut microbiota;imprint;microbiota;mortality;mouse model;novel;novel therapeutics;prevent;programs;translational approach;translational study;ward

public_health_relevance:
Recent studies have shown that the trillions of microbes living on and within us profoundly influence multipleaspects of human physiology. Malaria remains a significant infectious disease causing the death of about400000 people annually. Completion of this proposal will both determine how gut microbes modulate hostimmunity to the parasite that causes malaria and identify the specific bacteria and their metabolic products thatdetermine susceptibility to severe malaria which will be important in the identification of novel therapeutics tomitigate morbidity and mortality caused by malaria.


application_id: 9599941
project_number: 1R21DA045101-01A1
administering_ic: NIDA
award_notice_date: 2018-06-29
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: DA
serial_number: 045101
suffix: A1
program_official: KAUTZ, MARY A
project_start_date: 2018-07-15
project_end_date: 2020-06-30
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 8906159
contact_pi: BABALONIS, SHANNA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Evaluating Recreational and Medical Marijuana Strains for Impairing Effects on Simulated Driving Performance

project_abstract:
Abstract:Driving under the influence of drugs of abuse is an epidemic in the United States (U.S.) and has been identifiedas a priority area of research by the National Institute on Drug Abuse and the White House Office of NationalDrug Control Policy. This public health crisis is occurring on the background of a precipitous increase in theavailability of marijuana across the U.S. However it is not clear how smoked marijuana particularly highpotency products that are commonly used for medical and recreational purposes affect driving performance.The aim of this study is to employ driving simulator methodology to characterize the impairing effects of severaltypes of smoked marijuana in a tightly controlled laboratory setting by utilizing a randomized placebo-controlled outpatient within-subject design enrolling healthy occasional marijuana smokers (n=24completers 12 M 12 F). This study will examine smoked marijuana containing: 1) high concentrations of THC(20% THC trace CBD) 2) high concentrations of CBD (10% CBD trace THC) and 3) moderateconcentrations of both CBD and THC (5% CBD 10% THC) in comparison to inactive marijuana (0% THC 0%CBD; negative control) and a dose of alcohol known to produce driving impairment (0.8 g/kg [which produces0.08% breath alcohol concentration]; positive control) on performance in a driving simulator a model that ispredictive of on-road driving ability. Secondary aims include examining the abuse liabilitycognitive/psychomotor performance and physiological effects across the dose conditions; sex differences willalso be explored. Overall this study will use state-of the-art technology to yield new empirical data ondrugged-driving performance following exposure to the most commonly abused illicit drug marijuana. Thesefindings will be highly relevant to public health and may directly inform recommendations for medical marijuanapatients and public safety regulations.

project_terms:
Accidents;Acute;Adult;Affect;Age;Alcohols;American;Area;Automobile Driving;Behavior;Body Fluids;Canada;Cannabinoids;Chronic;Cognitive;Consensus;Data;Dose;Driving While Intoxicated;Drug Controls;Drug usage;Enrollment;Epidemic;Exposure to;Formulation;Guidelines;Health;Household;Human;Illicit Drugs;Impairment;International;Intoxication;Laboratories;Laboratory Study;Lateral;Lead;Legal;Link;Liquid substance;Marijuana;Measures;Medical;Medical Marijuana;Methodology;Methods;Modeling;National Institute of Drug Abuse;Outcome;Outpatients;Participant;Patients;Performance;Pharmaceutical Preparations;Physiological;Placebos;Policies;Population;Positioning Attribute;Psychomotor Performance;Public Health;Randomized;Reaction Time;Recommendation;Recording of previous events;Regulation;Reporting;Research;Risk;Safety;Sampling;Sex Characteristics;South Africa;Speed;Statutes and Laws;Surveys;THC concentration;Technology;Testing;United States;Variant;Waxes;behavioral outcome;breath alcohol measurement;cognitive task;design;driving under influence;drug driving;drug of abuse;epidemiology study;experience;illicit drug use;impaired driving performance;marijuana smoke;marijuana smoker;marijuana use;response

public_health_relevance:
PROJECT NARRATIVEThis research will provide important public health and safety information regarding the acute effects ofcommonly used medical and recreational marijuana doses on driving performance.


application_id: 9598694
project_number: 1K99ES028734-01A1
project_title: TMAO is a biomarker of dioxin-like pollutant exposure and cardiometabolic disease
administering_ic: NIEHS
award_notice_date: 2018-08-14
opportunity_number: PA-16-193
application_type: 1
activity_code: K99
ic: ES
serial_number: 028734
suffix: A1
program_official: SCHUG, THADDEUS
project_start_date: 2018-08-15
project_end_date: 2019-09-14
study_section: Special Emphasis Panel[ZES1 LAT-D (K1)]
contact_pi_person_id: 11033651
contact_pi: PETRIELLO, MICHAEL CURTIS
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Dioxin-like organic pollutants persist in the environment and because of their bioaccumulation in adiposetissue can be detected in the blood of most individuals. Exposure to these pollutants causes diabetes and itscomplications of obesity and cardiovascular disease in animal models. These observations can likely betranslated to humans because several large longitudinal epidemiological studies have associated serum levelsof these pollutants for example polychlorinated biphenyls (PCBs) with an increased risk of cardiovasculardisease and type 2 diabetes. The variability in inter-individual responses to increased body burdens of thesepollutants observed in these epidemiological studies can likely be explained by the additional contributions ofgenetic and other environmental risk factors the most powerful of which is clearly the diet. The goal of thisproposal is to provide the applicant with mentored training and early career research support to become anindependent investigator studying interactions between diet nutrition and environmental exposures asdeterminants of human disease. To accomplish this the candidate will be mentored by an interactive group ofestablished investigators with complementary expertise in analytical chemistry multivariate statistics andpreclinical models of cardiovascular and metabolic disease. This training will be accomplished throughparticipation in an original research project studying a mechanism that could link diet and exposure to dioxin-like persistent organic pollutants to cardiovascular disease risk. Increased circulating levels of a diet derivedmetabolite trimethylamine N-oxide (TMAO) are associated with coronary artery disease and diabetes risk inhumans. The precursor of TMAO trimethylamine (TMA) is generated from dietary substrates (cholinecontaining lipids and carnitines) by the gut microbiota. TMA is oxidized to TMAO by hepatic Flavin-containingmonooxygenases predominantly the FMO3 isoform. We have found that exposure to dioxin-like PCBs stronglyincreases FMO3 expression in the liver to amplify formation of TMAO from dietary sources in animal modelsand that exposure to dioxin like pollutants positively associates with circulating TMAO levels in a highlyexposed human population. These observations lead us to propose our overarching hypothesis that inductionof FMO3 expression is a mechanism linking coplanar PCB exposure to the development of cardiovascular andrelated metabolic diseases and that circulating TMAO levels are a biomarker of systemic dioxin-like pollutantexposure in humans. We will test this hypothesis in the following aims. 1: To test the hypothesis that a diet highin TMAO precursors can exacerbate dioxin-induced cardiometabolic disease in vivo. 2: To test the hypothesisthat FMO3 and/or gut microbiota are required for dioxin-induced cardiometabolic disease in vivo. 3 To test thehypothesis that elevated TMAO levels in dioxin-like pollutant-exposed individuals result from increased FMO3activity/expression.

project_terms:
Adipose tissue;Analytical Chemistry;Animal Model;Antibiotics;Atherosclerosis;Biological Markers;Blood;Body Burden;Cardiovascular Diseases;Cardiovascular system;Carnitine;Choline;Chronic Disease;Coronary Arteriosclerosis;Dairy Products;Data;Development;Diabetes Mellitus;Diagnosis;Diet;Diet and Nutrition;Dietary Factors;Dioxins;Disease;Environment;Environmental Exposure;Environmental Risk Factor;Exposure to;FMO3;Functional disorder;Future;Genes;Genetic;Goals;Hepatic;Human;Individual;Inflammation;Intervention;Investigation;Knockout Mice;Lead;Levocarnitine;Link;Lipids;Liver;Mass Spectrum Analysis;Meat Products;Medicine;Mentors;Metabolic Diseases;Modeling;Monitor;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oxides;Pharmacology;Plasma;Polychlorinated Biphenyls;Pre-Clinical Model;Process;Protein Isoforms;Public Health;Publishing;Research Personnel;Research Project Grants;Research Support;Risk;Risk Assessment;Role;Serum;Source;Testing;Toxicant exposure;Training;Translating;Work;bioaccumulation;cardiometabolism;cardiovascular disorder risk;career;design;diabetes risk;disorder risk;epidemiology study;exposed human population;feeding;flavin-containing monooxygenase;gut microbiota;human disease;in vivo;individual response;insulin sensitivity;inter-individual variation;lipid metabolism;metabolomics;mouse model;novel marker;persistent organic pollutants;pollutant;prevent;statistics;toxicant;trimethylamine;trimethyloxamine

public_health_relevance:
PROJECT NARRATIVEWe hypothesize that dietary factors can interact with pollutant exposures to modulate associated chronicdiseases. Results from our mechanistic studies will identify biomarkers such as TMAO that link diet toxicantexposure and cardiometabolic diseases which are important within the contexts of human cumulative riskassessment and environmental public health.


application_id: 9598339
project_number: 5R01GM121660-03
project_title: Nucleophilic halogenation reagents
administering_ic: NIGMS
award_notice_date: 2019-01-29
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: 2021-11-30
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;One-Step dentin bonding system;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: 9594592
project_number: 2R01GM079684-10
project_title: The Regulation of Smoothened in Hedgehog Signaling
administering_ic: NIGMS
award_notice_date: 2018-09-05
opportunity_number: PA-16-160
application_type: 2
activity_code: R01
ic: GM
serial_number: 079684
program_official: XU, JIANHUA
project_start_date: 2008-07-01
project_end_date: 2020-08-31
study_section: Development - 1 Study Section[DEV1]
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract:Hedgehog (Hh) proteins function as morphogenes and play critical roles in patternformation and cell growth control. Aberrant Hh signaling causes diverse types of cancers.The G protein-coupled receptor (GPCR) family protein Smoothened (Smo) is required inboth insects and mammals for transduction of the Hh signal. This project uses Drosophilaas a simple and genetically tractable model system to explore the mechanisms of Smoregulation at the levels of transcription and post-translation. The long-term goal of ourresearch is to elucidate how Hh signals are sensed and transmitted to control downstreambiological events that ultimately govern cell growth and patterning. Many components in Hhpathway have been identified how the Hh signal is transduced through Patched (Ptc) toSmo is still unclear. We have discovered that Smo undergoes phosphorylation that leads toSmo cell surface accumulation and signaling activity that sumoylation induced by Hhpromotes Smo activation and that ubiquitination downregulates Smo cell surfaceaccumulation by promoting Smo endocytosis. Results from our studies have suggestedthat in response to Hh stimulation multiple steps occur in Smo regulation. However manyquestions persist regarding the mechanism controlling Smo protein expression andactivation. To address these questions we have recently discovered that Smo transcriptionis regulated in specific tissue and that a non-canonical cholesterol biosynthesis pathwayregulates Smo accumulation and activation. Our published findings and preliminary studiesprovide new tools and hypotheses for investigating the mechanisms of Smo signaling. Inthis project our central hypothesis is that reciprocal regulation of lipolysis and Hh signalingallows Smo transcription to be upregulated by a specific transcription factor and Smoprotein activity to be triggered by cholesterol. We will use a combination of genetic andbiochemical approaches in three Specific Aims: 1) to determine how Hh promotes lipolysisby regulating the expression of lipolysis genes; 2) to delineate the transcriptional regulationof Smo by a novel transcription factor; 3) to investigate how endogenous cholesterolbiosynthesis regulates Smo.

project_terms:
Address;Adipose tissue;Basal cell carcinoma;Binding;Biochemical;Biological;Biological Assay;Biological Models;Cell surface;Cholesterol;Congenital Abnormality;Development;Diagnostic;Dimerization;Drosophila genus;Drug resistance;Embryonic Development;Endocytosis;Enzymes;Erinaceidae;Event;Experimental Models;Family;Fasting;Fat Body;G-Protein-Coupled Receptors;Gene Expression;Gene Targeting;Genes;Genetic;Genetic Transcription;Genomic DNA;Goals;Hydroxymethylglutaryl-CoA reductase;In Vitro;Insecta;Investigation;Laboratories;Link;Lipase;Lipids;Lipolysis;Luciferases;Malignant Neoplasms;Mammals;Mediating;Membrane;Messenger RNA;Metabolic;Metabolic Diseases;Metabolism;Midgut;Modeling;Molecular;Mutation;Neurotensin;Obesity;Pathway interactions;Pattern;Pattern Formation;Phosphatidylinositols;Phosphorylation;Phosphotransferases;Play;Process;Production;Protein Dephosphorylation;Protein Family;Proteins;Publishing;Regulation;Reporter;Research;Role;Signal Pathway;Signal Transduction;Signaling Molecule;Site;Starvation;System;Testing;Tissues;Transcription Factor 3;Transcriptional Activation;Transcriptional Regulation;Translations;Ubiquitination;adipocyte differentiation;cancer type;cell growth;cholesterol biosynthesis;experimental study;hedgehog signal transduction;human disease;in vivo;inositol 4-phosphate;insight;interest;lamin B receptor;lipid metabolism;medulloblastoma;member;morphogens;novel;novel therapeutic intervention;prevent;promoter;protein activation;protein expression;protein function;response;smoothened signaling pathway;tool;transcription factor;transcription factor USF

public_health_relevance:
HEALTH RELEVANCEHedgehog (Hh) signaling is known for its role in directing processes such as cell growth proliferation anddifferentiation during embryogenesis. Mutations in Smoothened (Smo) a critical protein in the signal receptionsystem results in human diseases such as basal cell carcinoma and medulloblastoma. Investigation of how Hhand Smo regulates lipid metabolism and how Smo is regulated by metabolic molecules the goal of this projectwill provide insights into developmental problems and create novel concepts of Hh signaling in cancer obesityand metabolic diseases.


application_id: 9593958
project_number: 1R01HL137910-01A1
project_title: HDAC6 regulation of ICAM-1 expression and endothelial inflammatory signaling in sepsis
administering_ic: NHLBI
award_notice_date: 2018-06-14
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: HL
serial_number: 137910
suffix: A1
program_official: AGRAWAL, NITIN
project_start_date: 2018-06-15
project_end_date: 2022-04-30
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 8693493
contact_pi: FU, JIAN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Acetylation;Binding;Blood Vessels;Cell Adhesion Molecules;Cell Communication;Cell physiology;Cessation of life;Clinical Trials;Cytoplasm;Cytoskeleton;Data;Deacetylase;Deacetylation;Development;Disease;Endothelial Cells;Future;Gene Expression;HDAC4 gene;HDAC6 gene;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Intercellular adhesion molecule 1;JAK2 gene;Knockout Mice;Leukocytes;Life;Lung;Mediating;Mediator of activation protein;Microtubule Stabilization;Microtubules;Morbidity - disease rate;Multiple Organ Failure;Nuclear;Pathogenesis;Play;Regulation;Reporting;Role;STAT1 gene;STAT1 protein;Sepsis;Signal Pathway;Signal Transduction;Structure of parenchyma of lung;Survival Rate;TNF gene;Testing;Therapeutic;Therapeutic Effect;Tubulin Interaction;alpha Tubulin;experimental study;inhibitor/antagonist;knock-down;mortality;mouse model;novel;novel therapeutic intervention;novel therapeutics;overexpression;prevent;protective effect;protein function;transcription factor;tumor


application_id: 9593285
project_number: 1R13HS026357-01
administering_ic: AHRQ
award_notice_date: 2018-06-28
opportunity_number: PA-16-453
application_type: 1
activity_code: R13
ic: HS
serial_number: 026357
program_official: BURWEN, DALE R
project_start_date: 2018-07-01
project_end_date: 2019-06-30
study_section: Special Emphasis Panel[ZHS1 HSR-T (04)]
contact_pi_person_id: 15175497
contact_pi: CHAPPELL, HAZEL
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: 2018-07-01
project_title:
Reducing Antimicrobial Resistance:  Shifting the Paradigm through Antibiotic Stewardship Emphasizing Evidence-Based Practices and Interprofessional Collaboration

project_abstract:
Abstract The project goal is to host a live interprofessional conference supported by web-based learning that willprovide evidence-based information strategies guidelines and tools to assist in reducing antibiotic use throughappropriate antibiotic stewardship (AS). The specific objective of this conference is to provide information tovarious provider types that will enhance their knowledge and understanding of strategies that may be used inbuilding successful antibiotic stewardship programs (ASPs). Evidence-based strategies and tools promotejudicious antibiotic use and reduce the number of unnecessary antibiotics prescribed in Kentucky therebymaking healthcare safer reducing cost and improving overall quality. The University Of Kentucky College Of Nursing Office of Nursing Continuing Education (ONCE) will hostthe proposed conference in collaboration with key stakeholders who serve on the steering committee. Thissteering committee will identify nationally recognized experts in the field of AS who will provide information andguidance to clinicians on the practical aspects of antibiotic stewardship activities. The ONCE is requesting a project period of one (1) year to support a Dissemination and Implementationconference. The proposed conference includes a two-day in-seat regional conference for 2018 that will utilizevideo conferencing at multiple sites throughout Kentucky. The conference will include didactic sessionsdiscussion networking time and follow-up web-based learning. Invitations to the conference will be distributedto professional organizations within Kentucky and its bordering states. Various strategies utilized in thisconference will increase engagement of healthcare providers by extending capacity and outreach to those whomay not be able to attend in order to reach priority populations. The target audience will be all healthcare practitioners responsible for prescribing antibiotics as well asnon-prescribing registered nurses and pharmacists. The first day of the conference will address specific areasconcerning antibiotic use in Kentucky and the nation at large as well as methods that can be employed to buildrobust ASPs. The second day of the conference will provide information on how to increase interprofessionalcollaboration with a special emphasis on the role of non-prescribing nurses in reducing antibiotic use. The University Of Kentucky College Of Nursing Office of Nursing Continuing Education (ONCE) is in aunique position to lead efforts in interprofessional collaboration and the role of nurses and other healthcareproviders in promoting AS. The ONCE will build on previous conferences regarding AS by: (1) providing in-depthinformation to healthcare practitioners regarding strategies in developing robust ASPs through use of evidence-based practices tools and guidelines; (2) increasing capacity of attendance through multi-media platforms; (3)networking with experts in AS at the state and national level; and (4) providing a forum for exploring strategiesto increase interprofessional collaboration and the unique role of nurses in reducing unnecessary antibiotic use.

public_health_relevance:
Project Narrative The project goal is to host a live interprofessional conference supported by web-based learning that willprovide evidence-based information strategies guidelines and tools to assist in reducing antibiotic use throughappropriate antibiotic stewardship (AS).These strategies will promote judicious antibiotic use and reduce thenumber of unnecessary antibiotics prescribed for priority populations thereby making healthcare safer reducingcost and improving overall quality. The University of Kentucky College of Nursing Office of Continuing NursingEducation (OCNE) is in a unique position to lead efforts in interprofessional collaboration and the role of nursesand other healthcare providers in promoting AS.


application_id: 9593025
project_number: 5R01GM113832-05
project_title: Synthetic HDL_a potential sepsis therapy
administering_ic: NIGMS
award_notice_date: 2018-11-15
opportunity_number: RFA-HL-14-028
application_type: 5
activity_code: R01
ic: GM
serial_number: 113832
program_official: ZHAO, XIAOLI
project_start_date: 2015-01-01
project_end_date: 2022-05-31
study_section: ZHL1-CSR-O(S1)
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
other_pis: SCHWENDEMAN, ANNA
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Summary High-density lipoprotein (HDL) is key a component of circulating blood and plays essential roles in vascular endothelial cells and immunity. However the levels of HDL decrease by 40-70% in septic patients which is associated with a poor prognosis. Using ApoAI null mice as an HDL deficient model we recently reported that mice lacking HDL are susceptible to cecal ligation and puncture (CLP)-induced septic death and increase HDL levels by over expression of ApoAI protects CLP-induced septic death. These clinical and animal studies indicate that a decrease in HDL levels is a risk factor for sepsis and raising circulating HDL levels may provide an efficient therapy for sepsis. In the preliminary study we demonstrated that synthetic HDL (sHDL) treatment significantly protects mice from CLP-induced septic death indicating that sHDL is a potential effective therapy for sepsis. We hypothesize that sHDL therapy protects sepsis by restoring both HDL level and its immune- and vascular-protective functions. The objectives of this grant are to understand the mechanism(s) underlying sHDL vascular protection to use this information to tailor the sHDL composition and to optimize treatment strategy specifically for sepsis. To achieve the grant objectives we plan to: 1) determine the mechanisms of sHDL's protection against sepsis-induced vascular pathogenesis; 2) Tailor sHDL composition for increased efficacy in sepsis; and 3) Optimize the sHDL treatment regimen for sepsis and test in immunocompromised septic mice. Completion of this preclinical study will provide a body of mechanistic data for a novel sHDL-based therapeutic approach for treatment of sepsis and position it for rapid clinical translation.

project_terms:
Animals;Bacteria;Biodistribution;Biological;Biology;Biotechnology;Blood;Blood Vessels;Cessation of life;Chemicals;Clinical;Clinical Data;Data;Dose;Drops;Drug Kinetics;Effector Cell;Endothelial Cells;Endotoxins;Event;Extravasation;Frequencies;Generations;Goals;Grant;High Density Lipoprotein therapy;High Density Lipoproteins;Immune;Immunity;Immunocompromised Host;In Vitro;Industrialization;Inflammatory;Inflammatory Response;Knockout Mice;Knowledge;Lead;Lipids;Lipoprotein (a);Mediating;Modeling;Mus;Pathogenesis;Pathway interactions;Peptides;Play;Positioning Attribute;Proteins;Regimen;Reporting;Research Personnel;Risk Factors;Role;Safety;Sepsis;Shapes;Signal Transduction;Testing;Therapeutic;Treatment Protocols;Vascular Endothelial Cell;aged;base;cardiovascular disorder therapy;cecal ligation puncture;clinical translation;cytokine;design;effective therapy;endothelial dysfunction;experience;in vitro Assay;in vivo;innovation;macrophage;mortality;multidisciplinary;novel;outcome forecast;overexpression;pre-clinical;preclinical study;reconstitution;septic;septic patients;success;tool;treatment optimization;treatment strategy;vascular endothelial dysfunction

public_health_relevance:
The goal of this application is to develop synthetic HDL for sepsis therapy. Weexpect that completion of this preclinical study will provide a body of mechanistic datafor a novel synthetic HDL-based therapeutic approach for treatment of sepsis andposition it for rapid clinical translation.


application_id: 9592753
project_number: 1U01HL143508-01
administering_ic: NHLBI
award_notice_date: 2018-08-02
opportunity_number: RFA-HL-18-018
application_type: 1
activity_code: U01
ic: HL
serial_number: 143508
program_official: STONEY, CATHERINE
project_start_date: 2018-08-15
project_end_date: 2020-07-31
study_section: Special Emphasis Panel[ZHL1 CSR-H (M3)]
contact_pi_person_id: 14537492
contact_pi: LI, JING
other_pis: SMYTH, SUSAN S.;WILLIAMS, MARK V
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-08-15
project_title:
Project MISSION: Developing a multicomponent Multilevel Implementation Strategy for Syncope OptImalCare thrOugh eNgagement

project_abstract:
Project Abstract Syncope is a complex presenting symptom that requires thoughtful and efficient evaluation todetermine the etiology of a patient's loss of consciousness. Prevalence rates of syncope have been reportedas high as 41% with recurrent syncope occurring in 13.5%. A common symptom approximately 1% to 3% ofall emergency department (ED) visits (as many ED visits as atrial fibrillation) and up to 6% of all hospitaladmissions are due to syncope. The prognosis among patients with syncope depends on the etiology andunderlying cardiovascular condition. A cardiac etiology of syncope is associated with significantly higher ratesof morbidity and mortality than other causes such as vasovagal reflex mediated or orthostatic hypotension. TheFramingham study documented a doubling of the risk of death among participants with cardiac syncopecompared with those with non-cardiac syncope. Notably experiencing syncope affects patients' quality of life(QoL) and those with more frequent syncope report poorer QoL with perceptions of low overall physical andmental health and impairment in activities of daily living. The QoL among patients with recurrent syncopeappears equivalent to severe rheumatoid arthritis and chronic low-back pain in an adult population. Thoughresearch in the past 25 years provides substantial understanding of the pathophysiology of particular etiologiesof syncope the diagnostic approach to such a perplexing symptom remains difficult and efficient diagnosisremains elusive. The major challenge in the evaluation of patients with syncope is that most patients are asymptomaticat the time of their presentation. Because of concerns that patients presenting with syncope are at risk for animpending catastrophic event overuse and inappropriate use of testing and hospital admission are common.Aiming to provide guidance on optimizing the evaluation and management of syncope a collaboration of theAmerican College of Emergency Physicians Society for Academic Emergency Medicine American College ofCardiology (ACC) American Heart Association (AHA) and Heart Rhythm Society (HRS) issued a Guideline forthe Evaluation and Management of Patients with Syncope in 2017. Adopting a standardized approach tosyncope based on this guideline offers an effective opportunity for delivering high value care to patientssuffering this distressing and potentially dangerous event. Aiming for more rapid translation from guideline toclinical practice and improved health the proposed study will identify barriers and facilitators forimplementation of an evidence-based high value approach to diagnosis and management of patientspresenting with syncope. The research team will develop a multi-level multi-component implementationstrategy for evidence-based syncope evaluation and management and plan for a subsequent hybrideffectiveness-implementation trial guided by the Consolidated Framework for Implementation Research(CFIR).

project_terms:
Academic Medical Centers;Accident and Emergency department;Activities of Daily Living;Adherence;Admission activity;Adopted;Adoption;Adult;Affect;American;American Heart Association;Assessment tool;Atrial Fibrillation;Attitude;Cardiac;Cardiology;Cardiovascular system;Caring;Cessation of life;Characteristics;Chronic low back pain;Climate;Clinical;Clinical Practice Guideline;Collaborations;Community Hospitals;Complex;Dangerousness;Data;Diagnosis;Diagnostic;Distress;Effectiveness;Emergency Department Physician;Emergency Medicine;Emergency department visit;Etiology;Evaluation;Event;Functional disorder;Goals;Guidelines;Health;Hospitals;Hybrids;Impairment;Interview;Knowledge;Mediating;Medicine;Mental Health;Morbidity - disease rate;Organizational Culture;Orthostatic Hypotension;Participant;Patient-Focused Outcomes;Patients;Perception;Population;Prevalence;Process;Provider;Public Health;Quality of life;Readiness;Recommendation;Recurrence;Reflex action;Reporting;Research;Rheumatoid Arthritis;Risk;Social Environment;Societies;Standardization;Structure;Surveys;Symptoms;Syncope;System;Testing;Time;Translations;Unconscious State;Vasovagal;Work;adverse outcome;base;clinical care;clinical practice;college;common symptom;design;evidence base;experience;heart rhythm;high risk;implementation research;implementation strategy;implementation trial;improved;mortality;novel;outcome forecast;physical conditioning;social organization;tool

public_health_relevance:
Project NarrativeA growing and burdensome public health issue approximately 1% to 3% of all emergency department (ED)visits as many ED visits as atrial fibrillation and 6% of all hospital admissions were due to syncope. Thoughresearch in the past 25 years achieved substantial understanding of the pathophysiology of particularetiologies of syncope the diagnostic approach to such a perplexing symptom remains difficult and efficientdiagnosis remains elusive. Project MISSION (Developing a multicomponent Multilevel ImplementationStrategy for Syncope OptImalCare thrOugh eNgagement) will develop a multi-level multi-componentimplementation strategy for evidence-based syncope evaluation and management and plan for a subsequenthybrid effectiveness-implementation trial guided by Consolidated Framework for Implementation Research(CFIR).


application_id: 9592598
project_number: 3R01DE024509-04S1
project_title: Filifactor alocis interactions with neutrophils
administering_ic: NIDCR
award_notice_date: 2017-11-06
opportunity_number: PA-18-586
application_type: 3
activity_code: R01
ic: DE
serial_number: 024509
suffix: S1
program_official: LUNSFORD, DWAYNE
project_start_date: 2014-07-01
project_end_date: 2019-03-30
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
project_abstract:
DESCRIPTION (provided by applicant): Abstract Periodontitis is a microbial-induced chronic inflammatory disease that affects the gingival tissues supporting the tooth. With the development of high-throughput sequencing technologies and their application to the oral microbiota several newly appreciated organisms have become recognized as associated with periodontal lesions. Among these is the Gram-positive anaerobic rod Filifactor alocis which is present in high numbers in periodontal disease sites compared to healthy sites. However association does not establish causality and the challenge now is to determine the potential pathogenicity of F. alocis. Chronic inflammatory infectious diseases such as periodontitis can occur because the pathogens are able to evade or disable the innate immune system. Neutrophils are a major component of the innate host response and the outcome of the interaction between periodontal pathogens and neutrophils is a key determinant of oral health status. An understanding of both microbial and host factors is therefore essential to increase our knowledge of the periodontal disease process. The current proposal will test the hypothesis that Filifactor alocis modulates neutrophil functional responses as an immune evasion strategy to avoid killing and promote inflammation. We will test our hypothesis by the following specific aims: Aim 1: To characterize neutrophil respiratory burst response to F. alocis challenge. The goal of this aim will be to test the hypothesis that F. alocis stimulation causes dysfunction of select neutrophil responses and thus compromises bacterial killing. Aim 2: To characterize the neutrophil oxygen-independent antimicrobial response to F. alocis challenge. The goal of this aim will be to test the hypothesis that F. alocis will modulate neutrophil degranulation and thus subvert neutrophil antimicrobial mechanisms. Aim 3: To determine the effect of F. alocis on neutrophil recruitment and activation in an animal model. The goal of this aim will be to test the hypothesis that F. alocis infection will stimulate neutrophil recruitment activation and matrix metalloproteinases release to promote inflammation in vivo. The current project is a collaborative effort from a new/early stage investigator with expertise in neutrophil biology and inflammation (Dr. Uriarte) and an expert in the field of oral pathogens and host cell responses (Dr. Lamont). The proposed collaborative efforts offer an innovative and strong framework to study the interaction between F. alocis and neutrophils. Furthermore the data generated from this application are a necessary component of the information that will be required to allow the development of novel therapeutic strategies for controlling periodontal disease.

project_terms:
Adult;Affect;Anaerobic Bacteria;Animal Model;Bacteria;Bacterial Infections;Biology;Cells;Chronic;Communicable Diseases;Cytoplasmic Granules;Data;Development;Diagnostic;Disease;Enzymes;Etiology;Exocytosis;Functional disorder;Future;Gingiva;Goals;Health;Health Status;High-Throughput Nucleotide Sequencing;Human;Immune;Immune Evasion;Immune response;In Vitro;Infection;Inflammation;Inflammatory;Innate Immune System;Integration Host Factors;Intention;Knockout Mice;Knowledge;Lesion;Leukocytes;Maintenance;Matrix Metalloproteinases;Modeling;Mus;Neutrophil Activation;Neutrophil Infiltration;Oral;Oral health;Organism;Outcome;Oxygen;Particulate;Pathogenesis;Pathogenicity;Periodontal Diseases;Periodontitis;Phagosomes;Population;Porphyromonas gingivalis;Process;Research;Research Personnel;Respiratory Burst;Role;Site;Stimulus;TLR2 gene;Technology;Testing;Tissues;Tooth structure;United States;antimicrobial;combat;dysbiosis;in vivo;innovation;microbial;microbial host;neutrophil;novel therapeutic intervention;novel therapeutics;oral bacteria;oral microbial community;oral pathogen;pathogen;pathogenic bacteria;public health relevance;recruit;response;retinal rods;subcutaneous;synergism;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Project Narrative Periodontal disease is an inflammatory condition induced by oral pathogenic bacteria that affects over half of the adult population in theUnited States. Oral health status is maintained by the presence of white blood cells which are involved in killing the oral bacteria that cause periodontal disease. In the current study we propose to define the interaction between white blood cells and a newly appreciated bacterium which has been proposed as a diagnostic indicator of periodontal disease; with the intention of filling a significant gap in the understanding of which factors contribute to periodontal disease.


application_id: 9591433
project_number: 1R21DC017247-01
project_title: Mechanotransduction-Dependent Remodeling of the Stereocilia Cytoskeleton
administering_ic: NIDCD
award_notice_date: 2018-05-29
opportunity_number: PAR-16-057
application_type: 1
activity_code: R21
ic: DC
serial_number: 017247
program_official: FREEMAN, NANCY
project_start_date: 2018-07-01
project_end_date: 2021-06-30
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 12084410
contact_pi: VELEZ ORTEGA, ALEJANDRA CATALINA
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Mechanosensitivity of the inner ear hair cells depends on actin-filled cellular projections known asstereocilia. We recently found that the stability of the stereocilia cytoskeleton depends on the constantinflux of calcium ions through the mechano-electrical transduction (MET) channels that are located atthe tips of stereocilia (Velez-Ortega et al. eLife 2017). We showed that the blockage of MET channelsor the breakage of the tip links that gate these channels leads to the selective shortening of transducingstereocilia in the bundle (i.e. only the middle and short row stereocilia harbor MET channels). Once theMET blockage is removed or the tip links regenerate the shortened stereocilia regrow. An increase inintracellular calcium buffering also led to the selective remodeling of transducing stereocilia indicatingthat calcium ions are the main component of the MET current regulating the stereocilia morphology.Stereocilia remodeling in response to variations in the resting MET current represents an activity-dependent plasticity of the stereocilia actin cytoskeleton which may initiate profound changes in thehair bundle morphology in various types of hereditary or acquired hearing losses. Therefore this projectbegins the search for the molecular players involved in the MET-dependent remodeling of thestereocilia cytoskeleton. Aim 1 will determine the MET-dependent changes in the actin incorporationinto the stereocilia potential actin treadmill and actin isoform composition. Given that myosin XVdelivers the elongation machinery to the tips of stereocilia Aim 2 will test for the contribution of myosinXV isoforms in the MET-dependent regulation of the stereocilia height. This study is significantbecause it may uncover the molecular mechanisms of the fine adjustments of the staircase architectureof the hair cell bundles. Moreover stereocilia shorteningand perhaps eventual stereociliadisappearancecould occur after noise exposure (when the MET current is reduced due to tip linkbreakage) or in certain cases of congenital deafness (due to impaired MET current). Therefore thisstudy will expand our knowledge of the molecular mechanisms of various types of hearing loss.

project_terms:
Acquired Deafness;Actins;Affect;Antibodies;Architecture;Area;Auditory;Buffers;Calcium;Calcium ion;Cells;Cilia;Cytoskeleton;Exhibits;Growth;Hair;Hair Cells;Hearing;Height;Impairment;Inherited;Knowledge;Label;Labyrinth;Lead;Link;Maintenance;Molecular;Morphology;Motor;Mus;Mutation;Myosin ATPase;Natural regeneration;Noise;Noise-Induced Hearing Loss;Organelles;Plasmids;Protein Isoforms;Proteins;Regulation;Rest;Role;Sensory;Shapes;Testing;Variant;age related;beta Actin;congenital deafness;depolymerization;gamma Actin;hearing impairment;mechanotransduction;new therapeutic target;polymerization;prevent;response;treadmill

public_health_relevance:
PROJECT NARRATIVE Our sense of hearing relies on the survival of a limited number of inner ear sensory cells throughoutour entire lifetime. This project will provide clues about the molecular machinery regulating the stabilityand shape of the inner ear sensory organelles known as stereocilia. The identification of thesemolecular players might uncover novel therapeutic targets to prevent the loss of stereocilia in sometypes of age-related or noise-induced hearing loss.


application_id: 9590370
project_number: 1R15AI135924-01A1
project_title: Big data in acute renal rejection
administering_ic: NIAID
award_notice_date: 2018-05-10
opportunity_number: PA-16-200
application_type: 1
activity_code: R15
ic: AI
serial_number: 135924
suffix: A1
program_official: MINNICOZZI, MICHAEL
project_start_date: 2018-05-10
project_end_date: 2021-04-30
study_section: Special Emphasis Panel[ZRG1 SBIB-G (83)]
contact_pi_person_id: 8792882
contact_pi: EL-BAZ, AYMAN S
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: UNIVERSITY-WIDE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY Background: Acute rejection of renal transplant i.e. the immunological response of the human body to aforeign kidney is the main cause of dysfunction in renal transplant patients surpassing acute tubular necrosis(ATN) and immune drug toxicity. Over 650000 patients in the US have end-stage renal disease and renaltransplant offers the best outcome for these patients. However 15%-27% of renal transplant patients haveARTR within 5 years which if not detected and treated promptly causes renal damage and leads to renalfailure of the transplanted kidney. Currently ARTR is initially evaluated using blood tests and urine samplinge.g. plasma creatinine and creatinine clearance. However these indices have low sensitivity since asignificant change in creatinine levels is only detectable after the loss of 60% of renal function. ARTR diagnosisrequires renal biopsy (gold standard) which is invasive takes a week for diagnosis and costs up to $20000.Further needle biopsy is prone to over- or under-estimation of inflammation. The proposed study seeks todevelop and validate a new noninvasive computer-aided diagnostic (CAD) software system that can providehighly accurate (over 97% accuracy) diagnosis of ARTR at an early stage by integrating laboratory-basedbiomarkers (e.g. creatinine clearance (CrCl) and serum plasma creatinine (SPCr)) with imaging-markers thatwill be extracted from either dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) or diffusion-weighted magnetic resonance imaging (DW-MRI). Objective/Hypotheses: The primary objective of this proposal is to develop and validate a clinically usablesystem for the early detection of acute renal transplant rejection (ARTR) based on testing the following threehypotheses: (i) The perfusion of the contrast agent in the cortex of the rejected kidney is slower than theperfusion of the contrast agent in the non-rejected kidney; (ii) The estimated apparent diffusion coefficient(ADC) in the cortex of the rejected kidney is smaller than the estimated ADC in the cortex of the non-rejectedkidney; and (iii) Fusing laboratory-based biomarkers (e.g. CrCl and SPCr) with imaging-markers that will leadto novel fused indices for distinguishing rejected versus non-rejected kidneys in clinical decision-making. Specific Aims: (i) Develop a software CAD system for early detection of acute renal transplant rejectionbased on integrating/fusing the estimated physiological perfusion parameters from DCE-MRI data withlaboratory-based biomarkers for both rejected and non-rejected transplanted kidneys; (ii) Develop a softwareCAD system for early detection of acute renal transplant rejection based on integrating/fusing the estimatedphysiological diffusion parameters from DW-MRI data with laboratory-based biomarkers for both rejected andnon-rejected transplanted kidneys; and (iii) Evaluate the accuracy of the proposed image analysis softwaresystem with clinical data that will be collected at University of Louisville (Approved IRB # 16.0041) Universityof Michigan (Approved IRB # HUM00115031) and the collected MRI data at The Kidney transplant center atMansoura University with local regulatory approval. Study Design: We will develop the following image analysis techniques to accurately analyze both DCE-MRI and DW-MRI: (i) segmentation of the kidney object from the surrounding abdominal structures for eitherDCE-MRI or DW-MRI using appearance and prior shape models; (ii) a Laplace-based non-rigid registrationapproach to handle local deformations in the kidney region caused by physiological effects (e.g. intrinsicpulsatile effects breathing or transmitted effects from adjacent structures such as the bowel) during the datacollection; (iii) segmentation of the kidney cortex and generation of either the physiological perfusionparameters (e.g. wash-in slope wash-out slope time-to-peak and peak value) or physiological diffusionparameters (e.g. ADC); (iv) classification of the acute rejection versus non-rejection kidney status andevaluating the method as a diagnostic test; and (v) depiction of parametric maps of the estimated perfusion ordiffusion indices to help clinical visual assessment of the transplanted kidney. The MRI and clinical data will beobtained from patients who have undergone kidney transplantation from live donors and are available to ourresearch team via Dr. Beache and Dr. Dwyer (Radiology Department and The Kidney Transplant Center at theUniversity of Louisville respectively) and Dr. Samaniego-Picota (Director of the Kidney Transplant Programand the Transplant Ambulatory Care Unit at the University of Michigan). In addition to the data that will becollected at the University of Louisville and the University of Michigan our group has access to MRI data thathad been collected from an additional 100 subjects at Mansoura University Hospital Egypt. This data isavailable to our group through Dr. Abou El-Ghar one of the PI collaborators and it will be used to test theproposed CAD system on the data collected from another geographical area. Our preliminary diagnosticresults based on analysis of DCE-MRI data from 54 independent in-vivo cases using leave-one-subject-outapproach were 98% accurate (sensitivity = 100.00% specificity = 96% and Dice similarity coefficient (DSC) =98%). Moreover our preliminary results based on the analysis of DW-MRI data from 75 independent in-vivocases using leave-one-subject-out were 97% accurate (sensitivity = 98% specificity = 96% and DSC = 98%).These results demonstrate the potential of the proposed CAD system to complement current technologiessuch as nuclear imaging and ultrasonography to determine the type of kidney dysfunction post transplantation.

project_terms:
Abdomen;Acute;Acute Kidney Tubular Necrosis;Algorithms;Ambulatory Care;Appearance;Big Data;Biological Markers;Biopsy;Blood Tests;Breathing;Classification;Clinical;Clinical Data;Collection;Complement;Computer Assisted;Computer software;Contrast Media;Creatinine;Creatinine clearance measurement;Data;Data Collection;Data Set;Detection;Diagnosis;Diagnostic;Diagnostic tests;Diffusion;Diffusion Magnetic Resonance Imaging;Drug toxicity;Early Diagnosis;Egypt;End stage renal failure;Functional disorder;Generations;Geographic Locations;Gold;Graft Rejection;Human body;Image Analysis;Immune;Immune response;Inflammation;Institutional Review Boards;Intestines;Kidney;Kidney Failure;Kidney Transplantation;Laboratories;Lead;Machine Learning;Magnetic Resonance Imaging;Maps;Methods;Michigan;Modeling;Morbidity - disease rate;Needle biopsy procedure;Patient-Focused Outcomes;Patients;Perfusion;Physiological;Plasma;Radiology Specialty;Renal function;Research;Research Design;Resort;Sampling;Shapes;Specificity;Statistical Models;Structure;System;Systems Analysis;Techniques;Technology;Testing;Time;Tissues;Transplant Recipients;Transplantation;Ultrasonography;Universities;University Hospitals;Urine;Visual;accurate diagnosis;base;clinical biomarkers;clinical decision-making;contrast enhanced;cost;diagnostic accuracy;imaging biomarker;improved;in vivo;indexing;kidney cortex;magnetic resonance imaging biomarker;novel;nuclear imaging;programs;software systems;tool;transplant centers

public_health_relevance:
PROJECT NARRATIVEAcute renal transplant rejection (ARTR) i.e. the immunological response of the human body to a foreignkidney is the main cause of dysfunction in renal transplant patients surpassing acute tubular necrosis andimmune drug toxicity. Over 650000 patients in the US have end-stage renal disease and renal transplantoffers the best outcome for these patients. However 15%-27% of renal transplant patients have ARTR within 5years which if not detected and treated promptly causes renal damage and leads to renal failure of thetransplanted kidney. Biopsy remains the gold standard for the assessment of renal transplant dysfunction butcan lead to over- or under-estimation of the inflammation and is used as a last resort due to invasiveness highcost and potential morbidity. The proposed study seeks to provide a new noninvasive computer-aideddiagnostic (CAD) software system with the ability to make highly accurate diagnosis (>97% accuracy)at an early stage of ARTR by integrating laboratory-based biomarkers (e.g. creatinine clearance (CrCl)and serum plasma creatinine (SPCr)) with imaging-markers obtained from dynamic contrast-enhancedmagnetic resonance imaging (DCE-MRI) or diffusion-weighted magnetic resonance imaging (DW-MRI).


application_id: 9589913
project_number: 1R15GM123391-01A1
project_title: Structural Mechanisms Underlying Regulation and Substrate Specificity of Deubiquitinase A
administering_ic: NIGMS
award_notice_date: 2018-08-16
opportunity_number: PA-16-200
application_type: 1
activity_code: R15
ic: GM
serial_number: 123391
suffix: A1
program_official: BARSKI, OLEG
project_start_date: 2018-09-01
project_end_date: 2023-08-31
study_section: Macromolecular Structure and Function B Study Section[MSFB]
contact_pi_person_id: 9798314
contact_pi: LI, YING
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
project_abstract:
Deubiquitinases are proteases involved in a myriad of cellular pathways in humans. The activityof deubiquitinases is tightly regulated and deregulation leads to human diseases includingcancer neurodegenerative diseases and autoimmune diseases. The overall objective of theproposed research is to elucidate the molecular mechanisms underlying the regulation andsubstrate specificity of deubiquitinase A (DUBA) which is one of several deubiquitinasesinvolved in immune responses. Conformational dynamics is implicated in the function of manymembers of the deubiquitinase family including DUBA. The activity of DUBA is regulated byphosphorylation in the absence of significant structural changes which suggests the need tocharacterize both the structural and dynamical properties of DUBA in order to understand itsregulation mechanism. DUBA displays specificities towards more than one ubiquitin chainlinkages and the structural basis of substrate recognition is not well defined. Studies on otherdeubiquitinases suggest the importance of conformational flexibility which allows substrates ofdifferent chain topologies to be accommodated. The proposed research has two specific aims:(1) to characterize the conformational dynamics of DUBA in apo state and to define thefunctional roles of the observed conformational processes and (2) to dissect the molecularmechanism of substrate recognition. Solution NMR spectroscopy will be used as the mainexperimental technique which provides site-specific information on both structure anddynamics. NMR measurements will be combined with biochemical assays to establish therelationship between the parameters characterizing the conformational dynamics and thecatalytic rate constants of wildtype and mutants of DUBA. Structural insights gained from theproposed research can potentially aid in the design of therapeutic strategies for diseasesinvolving deregulation or malfunction of deubiquitinases.

project_terms:
Autoimmune Diseases;Binding;Biochemical;Biological Assay;Cell physiology;Crystallization;DNA Damage;Data;Disease;Event;Family;Fluorescence Spectroscopy;Future;Goals;Human;Immune response;Inflammatory;Kinetics;Knowledge;Lead;Malignant Neoplasms;Measurement;Mediating;Molecular;Molecular Conformation;NMR Spectroscopy;Neurodegenerative Disorders;Pathway interactions;Peptide Hydrolases;Phosphorylation;Polyubiquitin;Post-Translational Protein Processing;Process;Property;Proteins;Regulation;Research;Role;Serine;Site;Site-Directed Mutagenesis;Specificity;Structure;Substrate Specificity;Techniques;Therapeutic;Therapeutic Intervention;Ubiquitin;Ubiquitination;Virus Diseases;design;experimental study;flexibility;human disease;insight;member;molecular recognition;mutant;protein degradation;response;trafficking

public_health_relevance:
Malfunction and deregulation of deubiquitinases have been implicated in human diseasesincluding cancer neurodegenerative diseases inflammatory diseases and autoimmunediseases. Understanding the molecular mechanisms by which deubiquitinases are regulatedand the structural basis of substrate specificity can guide future efforts on exploitingdeubiquitinases for therapeutic interventions.!


application_id: 9589538
project_number: 1U01AA026936-01
project_title: Lipid metabolites can both potentiate and treat alcoholic hepatitis
administering_ic: NIAAA
award_notice_date: 2018-09-22
opportunity_number: RFA-AA-18-003
application_type: 1
activity_code: U01
ic: AA
serial_number: 026936
program_official: DUNTY, JR, WILLIAM
project_start_date: 2018-09-22
project_end_date: 2023-06-30
study_section: Special Emphasis Panel[ZAA1 JJ (01)]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: JOSHI-BARVE, SWATI
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:
Abstinence;Acrolein;Acute Alcoholic Hepatitis;Address;Alcoholic Hepatitis;Alcoholic liver damage;Alcohols;Aldehydes;American diet;Arachidonate 15-Lipoxygenase;Attenuated;Bacteria;Biological Markers;Blood;Butyrates;Cell Death;Cell membrane;Cessation of life;Data;Development;Diet;Diet and Nutrition;Dietary Fats;Disease;Dose;Endotoxemia;Fatty acid glycerol esters;Free Radicals;Funding;Genetic;Health Care Costs;Heavy Drinking;Hepatocyte;Human;Inflammatory disease of the intestine;Injury;Institution;Intake;Intervention;Intestinal permeability;Investigation;Laboratories;Linoleic Acids;Lipid Peroxidation;Lipids;Liver;Liver diseases;Macronutrients Nutrition;Mediating;Membrane Lipids;Metabolism;Morbidity - disease rate;Mus;National Institute on Alcohol Abuse and Alcoholism;Nutritional;Omega-3 Fatty Acids;Omega-6 Fatty Acids;Organ;Oxidative Stress;Oxides;Patient Care;Patients;Play;Polyunsaturated Fatty Acids;Production;Receptor Activation;Recovery;Research;Risk;Rodent;Rodent Model;Role;Sampling;Serum;Severities;Severity of illness;Smoking;Stress;Testing;Therapeutic;Tissues;Toll-like receptors;United States;Universities;Urine;Volatile Fatty Acids;adduct;alcohol research;cytokine;dysbiosis;gut bacteria;gut microbiota;human subject;improved;liver injury;mortality;mouse model;nutrition;oxidation;polyunsaturated fat;pre-clinical;prevent;response;tributyrin


application_id: 9588799
project_number: 5F32AG058456-02
administering_ic: NIA
award_notice_date: 2019-02-11
opportunity_number: PA-16-307
application_type: 5
activity_code: F32
ic: AG
serial_number: 058456
program_official: OPANASHUK, LISA A
project_start_date: 2018-02-01
project_end_date: 2021-01-31
study_section: Special Emphasis Panel[ZRG1-F01A-F(20)L]
contact_pi_person_id: 11123177
contact_pi: BRAUN, DAVID 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: 2019-02-01
project_title:
Vascular-associated neuroinflammation in Alzheimer's disease: differential effects on disease progression modulated by underlying amyloid burden

project_abstract:
PROJECT SUMMARY Of the modifiable factors that collectively account for over half of Alzheimers disease (AD) cases themajority are vascular risk factors (VRFs). Given that the number of AD patients is expected to double by 2040this situation presents an important opportunity to reduce negative impacts on public health. Clearerunderstanding of the precise temporal and mechanistic alterations linking VRFs to AD may enable developmentof therapeutic approaches to sever that link. The overall goal of this proposal is therefore to elucidate potentiallytargetable mechanisms underlying the connection between early vascular damage and subsequent ADpathology. Vascular inflammation is one unifying feature of many VRFs and this can induce or propagateneuroinflammatory changes in the brain. Considering the established role of neuroinflammation in ADpathogenesis it may be clinically useful to target neuroinflammatory alterations secondary to vascular insult.This proposal will therefore test the hypothesis that vascular risk factors contribute to AD primarily by increasingneuroinflammatory responses and altering subsequent amyloid pathology. For these studies I will use a well-characterized amyloid beta (Ab) overexpression mouse model of AD (APPswe/PS1dE9) along with a dietaryhyperhomocysteinemia (HHcy) model to induce vascular damage and inflammation. In Aim 1 I will induce HHcyin AD mice within a period corresponding to prodromal AD and in Aim 2 within a period corresponding to earlyAD. In both aims l will acutely treat the vascular-associated neuroinflammation in half of the animals. I willcharacterize how vascular damage and associated neuroinflammation interact with underlying Ab pathology toproduce additive cognitive deficits at different stages of AD progression. In addition both aims will includeclinically relevant neuroimaging measures to connect pathological alterations with detectable alterations incerebral blood flow (arterial spin labeling) and metabolic changes (magnetic resonance spectroscopy).Successful completion of this project will provide clinically-relevant insight into the links between VRFs and AD.Further it will provide proof-of-concept of the utility of targeting neuroinflammation secondary to vasculardamage as a means of preventing or delaying future cognitive decline. Ideally such an approach will somedaybe incorporated into a comprehensive strategy of managing AD risk. A carefully designed career developmentplan has also been formalized that includes participation in specialty workshops regular presentation of dataparticipation in scientific meetings and enhancement of non-technical science proficiencies. An experiencedmentoring group of senior scientists in a well-established institution for AD research ensure that I will haveoptimal opportunity to grow into a successful independent investigator devoted to AD therapeutic development.

project_terms:
Abeta synthesis;Acute;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease risk;Amyloid;Amyloid beta-Protein;Amyloid deposition;Animals;Anti-inflammatory;Blood - brain barrier anatomy;Blood Vessels;Brain;Cerebrovascular Circulation;Cerebrovascular Disorders;Cerebrum;Clinical;Cognitive;Cognitive deficits;Comorbidity;Data;Deposition;Development Plans;Diet;Disease Progression;Educational workshop;Ensure;Functional disorder;Future;Goals;Hyperhomocysteinemia;Hypertension;Impaired cognition;Inflammation;Inflammatory;Injury;Institution;Link;Magnetic Resonance Spectroscopy;Measures;Mediating;Memory impairment;Mentors;Metabolic;Modeling;Mus;Neuroglia;Obesity;Pathogenesis;Pathogenicity;Pathologic;Pathology;Patients;Pattern;Pharmaceutical Preparations;Process;Public Health;Research;Research Personnel;Risk;Risk Factors;Role;Science;Secondary to;Senior Scientist;Spin Labels;Testing;Training;Translating;Vascular Diseases;abeta accumulation;abeta deposition;amyloid pathology;beta amyloid pathology;brain metabolism;career development;cerebral hypoperfusion;clinically relevant;cytokine;design;epidemiology study;experience;glial activation;hypercholesterolemia;inflammatory marker;insight;medical specialties;meetings;middle age;modifiable risk;mouse model;neuroimaging;neuroinflammation;overexpression;prevent;response;stem;therapeutic development;tool;treatment strategy;vascular inflammation;vascular risk factor

public_health_relevance:
PROJECT NARRATIVEThe most prevalent modifiable risk factors for Alzheimers disease (AD) are vascular risk factors and there isstrong evidence that neuroinflammation is a crucial aspect of this risk. Successful completion of this project willclarify this relationship advance anti-inflammatory treatment strategies and hopefully help to stem the tide ofnew AD cases projected to occur in the coming decades.


application_id: 9586086
project_number: 1R03DE028031-01
project_title: A novel role for NADPH oxidase in modulating neutrophil functions in periodontal disease
administering_ic: NIDCR
award_notice_date: 2018-07-10
opportunity_number: PAR-16-409
application_type: 1
activity_code: R03
ic: DE
serial_number: 028031
program_official: CHANDER, PREETHI
project_start_date: 2018-07-10
project_end_date: 2020-06-30
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
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:
ABSTRACTPeriodontal diseases are caused by host inflammatory responses to dysbiotic oral microbiota resultingin the progressive destruction of supporting hard and soft tissues of the peridontium. It is estimated thatapproximately 50% of the US population will suffer from some form of periodontal disease. Neutrophilsare the most common anti-microbial effector myeloid cells recruited to the oral cavity under bothphysiological and pathological conditions. Although neutrophils are associated with the initiation andprogression of periodontal diseases we know little about the specific immune pathways that driveneutrophil recruitment or activation at the gingival barrier. The NADPH oxidase enzyme complex ishighly expressed in neutrophils. On activation the NADPH oxidase generates superoxide which isenzymatically or spontaneously converted to reactive oxygen species (ROS) that have antimicrobialand immuno-regulatory functions. Our preliminary data demonstrates a key role for NADPH oxidasederived-ROS in limiting neutrophilic effector functions in response to periodontal pathogens. Oxidasenull neutrophils generated excessive amounts of inflammatory mediators in response to oral bacteria.Oxidase deficiency in mice resulted in profound inflammation characterized by excessive mobilizationand tissue accrual of neutrophils. These data support a somewhat counterintuitive role for ROS inlimiting host inflammation. Our central hypothesis is that the NADPH oxidase derived-ROSindependent of their antimicrobial functions play key roles in redox modulation of neutrophil effectorfunctions in vitro and in vivo. Further we hypothesize that while excessive amounts of ROS areassociated with the pathophysiology of periodontal diseases low-level localized ROS responses areimmuno-regulatory. These hypotheses will be tested in two specific aims. 1) We will determine thespecific intracellular signaling pathways modulated by oxidants that limit neutrophil degranulation andtranscriptional responses to oral bacteria. 2) We will also investigate the role of sentinel macrophagesand ROS from microbial sources in modulating neutrophilic inflammation in vivo. The use of conditionalknockout mice that specifically lack NADPH oxidase activity in neutrophils will enable us to specificallydetermine the role of oxidants in regulation of neutrophil effector functions in a cell intrinsic manner invivo. The data generated by these studies will not only shed key mechanistic insights in neutrophilbiology but also enhance our understanding of immune pathways relevant in gingival inflammation andtheir regulation by oxidants. Further our studies are also highly relevant in understanding theimmunopathology of chronic granulomatous disease a life-threatening pediatric immuno-deficiencycaused by inherited mutations in NADPH oxidase genes.

project_terms:
Alleles;Antibiotic Therapy;Autoimmune Diseases;Biology;Cell membrane;Cell physiology;Cells;Childhood;Chronic;Chronic Granulomatous Disease;Conflict (Psychology);Data;Dendritic Cells;Diagnosis;Disease;Effector Cell;Enzymes;Functional disorder;Fusobacterium nucleatum;Generations;Genes;Genetic;Genetic Transcription;Gingiva;Goals;Immune;Immune response;Immunologic Deficiency Syndromes;In Vitro;Individual;Infection;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Inherited;Injury;Knockout Mice;Leukocytes;Life;Literature;Microbe;Multienzyme Complexes;Mus;Mutation;Myelogenous;Myeloid Cells;NADPH Oxidase;Nature;Neutrophil Activation;Neutrophil Infiltration;Oral cavity;Oral mucous membrane structure;Outcome;Oxidants;Oxidases;Oxidation-Reduction;Pathologic;Pathway interactions;Patients;Peptide Hydrolases;Periodontal Diseases;Periodontium;Physiological;Play;Population;Porphyromonas gingivalis;Production;Reactive Oxygen Species;Regulation;Reporting;Resolution;Role;Sentinel;Signal Pathway;Source;Sterility;Stimulus;Superoxides;Testing;Tissues;Tooth structure;antimicrobial;chemokine;cytokine;dysbiosis;immunopathology;immunoregulation;in vivo;insight;macrophage;microbial;mouse model;neutrophil;novel;null mutation;oral bacteria;oral microbial community;pathogen;prevent;recruit;release of sequestered calcium ion into cytoplasm;response;soft tissue;superoxide-generating NADPH oxidase

public_health_relevance:
PROJECT NARRATIVEAberrant host inflammatory responses to microbial infections or sterile injury can cause tissue damage and isan underlying factor in multiple chronic inflammatory and autoimmune disorders. The proposed studies willdetermine how oxidants generated by leukocytes play a role in dampening host inflammatory responses in theoral mucosa independent of their antimicrobial function. These studies will not only elucidate entirely novelpathways regulated by oxidants during host inflammatory responses but also shed key mechanistic insightsinto understanding the basis of profound inflammatory complications observed in chronic granulomatousdisease patients; a severe immunodeficiency caused by inherited mutations in NADPH oxidase genes.!


