# projects

application_id: 9265786
project_number: 5R01AI120244-03
project_title: Molecular and Cellular Pathogenesis of Legionella
administering_ic: NIAID
award_notice_date: 2017-04-27
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 120244
program_official: ERNST, NANCY L
project_start_date: 2015-05-01
project_end_date: 2020-04-30
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
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): In the aquatic environment Legionella pneumophila (Lp) proliferates within amoeba but upon transmission to humans it causes pneumonia with high morbidity and mortality. Within amoeba and human macrophages Lp proliferates within the Legionella-containing vacuole (LCV) which evades lysosomal fusion and is remodeled by the endoplasmic reticulum (ER). Biogenesis of the LCV is controlled by the Dot/Icm type IV secretion system which injects into the host cell ~300 protein effectors that modulate a myriad of cellular processes to enable intracellular proliferation of Lp. Very few of this large battery o Lp effectors such as AnkB and AnkH are required for the intracellular infection. To attain biological function in the host cell many injected bacterial effectors require post- translationalmodification by various host machineries. Post-translational modification of eukaryotic proteins by Asparagine (Asn) hydroxylation impacts their protein-protein interaction and has been widely studied during hypoxic conditions in inflammatory foci. It is not known whether any injected bacterial effector is post-translationally modified by the host asparagine hydroxylase FIH. The Asn hydroxylation motif has been identified within many human Ankyrin repeats-containing proteins (Ank) that have been shown to be modified by FIH. Our bioinformatics preliminary data have identified an Asn hydroxylation motif within the ankyrin repeats of the AnkB and AnkH effectors of Lp and we show that both effectors are modified by the host FIH Asparagine hydroxylase. We show that the host FIH is rapidly recruited to the LCV membrane where AnkH and AnkB are exclusively localized. Our in silico genomic analyses have identified the Asn hydroxylation motif in eight other translocated effectors of Lp. Importantly RNAi-mediated knockdown or chemical inhibition of FIH abolishes intracellular proliferation of Lp and promotes fusion of the LCV to the lysosomes. Therefore our hypothesis is: host-mediated Asn hydroxylation of Lp effectors by FIH is required for their functions in biogenesis of the LCV and intracellular proliferation of Lp. To test our hypothesis our specific aims are to characterize th following: I) Asn hydroxylation of AnkH and its role in the intracellular infection; II) Asn hydroxylation of AnkB and its role in the intracellular infection; and III) Asn hydroxylation of oter Lp effectors and its role in biogenesis of the LCV. Upon completion of our proposed studies the biological function and host targets of AnkH will be known and the ubiquitination substrates of AnkB will be identified. The role of host FIH-mediated Asn hydroxylation in the biological function of AnkH and AnkB will be uncovered. This is significant since both effectors are two of very few of the battery of ~300 Lp effectors to be required for intra-vacuolar proliferation. We wil report on our novel discovery of the acquisition of the FIH complex by a pathogen-containing vacuole and its role in modification of several Lp effectors. We will uncover the role of FIH-mediated Asn hydroxylation of several Lp effectors in lysosomal evasion by the LCV. Our proposed studies on Lp-primary hMDMs interaction and specific manipulation of the host post- translational modification by FIH are innovative with broad high impact and significance not only for Lp but for other pathogens. This is evident from our discovery of Asn hydroxylation of the YopM effector of Yersinia and potential Asn hydroxylation of the IpaH4.5 effector of Shigella and the EsxF effector of Mycobacterium.

project_terms:
Alveolar Macrophages;Amoeba genus;Ankyrin Repeat;Asparagine;Bacterial Proteins;Binding;Biogenesis;Bioinformatics;Biological Process;Cell physiology;Cells;Chemicals;Complex;Computer Simulation;Data;Disease;Endoplasmic Reticulum;Environment;Enzymes;Genetic Transcription;Genomics;Genus Mycobacterium;Human;Hydroxylation;Hypoxia;Infection;Inflammatory;Injectable;Killings;Legionella;Legionella pneumophila;Lysosomes;MMP14 gene;Mediating;Membrane;Mixed Function Oxygenases;Modification;Molecular;Morbidity - disease rate;Organism;Pathogenesis;Phagocytes;Pneumonia;Post-Translational Protein Processing;Proliferating;Proteins;Proteome;RNA Interference;Recruitment Activity;Reporting;Role;Shigella;System;Testing;Type IV Secretion System Pathway;Ubiquitination;Vacuole;Yersinia;genome-wide;innovation;knock-down;liquid chromatography mass spectrometry;macrophage;microbial;monocyte;mortality;novel;pathogen;protein protein interaction;public health relevance;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Very little is known about how intracellular pathogens evade killing by phagocytic cells through manipulation of various cellular processes to facilitate intracellular bacterial proliferation and manifestation of disease. Our proposed studies on Legionella pneumophila explores how this pathogen utilize the bacterial proteins such as AnkH and AnkB which the pathogen injects into the host cell to manipulate the host cell to enable microbial proliferation. These injected microbial proteins are modified by the host modification machineries and this modification is required for the functions of the injected bacterial effector. Our proposed studies will identify the host protein substrates that interact with these injected AnkH and AnkB effectors and the role of host-mediated modifications of the effector in intracellular proliferation of L. pneumophila. We have identified eight additional Legionella proteins that are also injected into the host and have the potential to be modified by the host and this will be investigated in our proposed studies.


application_id: 9265775
project_number: 5R01AI118814-03
project_title: Lead Optimization of ML336 a Potent VEEV Inhibitor
administering_ic: NIAID
award_notice_date: 2017-03-27
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 118814
program_official: DAVIS, MINDY I
project_start_date: 2015-05-01
project_end_date: 2020-04-30
study_section: Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section[DDR]
contact_pi_person_id: 9658299
contact_pi: CHUNG, DONGHOON
other_pis: GOLDEN, JENNIFER E.;JONSSON, COLLEEN B
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 New World alphaviruses Venezuelan (VEEV) Eastern and Western Equine Encephalitis viruses are emerging pathogens that are endemic throughout the Americas. They cause encephalitis in humans and equines thus presenting serious health and economic problems. Despite the urgent need neither approved drugs nor vaccines are available for treatment of these diseases in humans. Broad long-term objectives: The research objectives stated herein and in future studies that build upon these findings will deliver analogs of ML336 a promising lead compound as small molecule therapeutic candidates for future clinical evaluation targeting diseases caused by VEEV and other alphaviruses. Specific aims/hypothesis: The specific aims address two hypotheses. In aims 1 and 2 we hypothesize that medicinal chemical optimization of ML336 can afford a safe and specific therapeutic preclinical candidate to treat New World alphaviral diseases. In aim 3 we test the hypothesis that ML336 blocks VEEV RNA synthesis through disruption of interactions required for replicase assembly and/or directly inhibits an enzymatic activity required for viral RNA synthesis. Research design and methods: Aim 1 will derive a robust pharmacological profile suitable for in vivo efficacy through structure-activity and structure-property relationshi (SAR-SPR) studies. Specifically Dr. Golden will lead efforts to generate analogs of ML336 with an improved pharmacological profile that includes increased solubility and BBB permeability and reduced metabolic liability to improve exposure and clearance parameters. In Aim 2 Dr. Guo will assess the biodistribution and pharmacokinetics/dynamics of ML336 and 2-3 lead compounds each year showing suitable and robust pharmacological and antiviral (in vitro and in vivo) profiles. Dr. Jonsson will lead in vivo efficacy testing studies of two of the most promisinglead candidates to define the optimal dosing regimen using the VEEV Trinidad Donkey strain. Finally Dr. Chung will dissect the mechanism of action of ML336 using in vitro assays focused on replication (Aim 3) in consultation with Dr. Sawicki.

project_terms:
Address;Alphavirus;Americas;Amidines;Antiviral Agents;Asses;Biodistribution;Biotechnology;Chemicals;Chemistry;Consultations;Disease;Dose;Drug Kinetics;Encephalitis;Equus caballus;Future;Human;In Vitro;Knowledge;Lead;Metabolic;Molecular Bank;Mus;Nonstructural Protein;Outcome;Permeability;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Preclinical Drug Development;Property;RNA Viruses;RNA chemical synthesis;Regimen;Replication-Associated Process;Research;Research Design;Research Methodology;Resistance;Series;Solubility;Structure;Structure-Activity Relationship;Testing;Therapeutic;Toxic effect;Trinidad;United States National Institutes of Health;Vaccines;Venezuelan;Venezuelan Equine Encephalitis Virus;Virus Inhibitors;Western Equine Encephalitis Virus;analog;cytotoxicity;efficacy study;efficacy testing;health economics;high throughput screening;improved;in vitro Assay;in vitro activity;in vivo;insight;interest;mouse model;novel;pathogen;pre-clinical;preclinical study;public health relevance;replicase;research clinical testing;small molecule;small molecule therapeutics;therapeutic candidate;viral RNA;viral resistance

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The New World alphaviruses Venezuelan Eastern and Western Equine Encephalitis viruses are emerging pathogens that are endemic throughout the Americas. They cause encephalitis in humans and equines thus presenting serious health and economic threats. Despite the urgent need neither approved drugs nor vaccines are available for treatment of these diseases in humans. We propose to address this gap by advancing analogs of ML336 a promising small molecule as preclinical therapeutic candidates.


application_id: 9265656
project_number: 1R01NS095229-01A1
project_title: CNS Functions of Calpain 5
administering_ic: NINDS
award_notice_date: 2016-09-01
opportunity_number: PAS-15-029
application_type: 1
activity_code: R01
ic: NS
serial_number: 095229
suffix: A1
program_official: RIDDLE, ROBERT D
project_start_date: 2016-09-01
project_end_date: 2021-05-31
study_section: Special Emphasis Panel[ZRG1 MDCN-C (02)]
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W.
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Actins;Active Sites;Acute;Acute Promyelocytic Leukemia;Afferent Neurons;Affinity;Affinity Chromatography;Alzheimer's Disease;Basic Science;Binding;Binding Sites;Biotin;Brain;C2 Domain;Caenorhabditis elegans;Calcium;Calpain;Caspase;Cell Line;Cell Nucleus;Cell membrane;Cells;Cessation of life;Characteristics;Chronic;Cleaved cell;Clustered Regularly Interspaced Short Palindromic Repeats;Computer Simulation;Cysteine;Cytokinesis;Data;Dynein ATPase;EF-Hand Domain;Family;Genes;Genetic;Human;In Vitro;Knock-out;Knockout Mice;Lipids;Long-Term Potentiation;Mass Spectrum Analysis;Membrane;Membrane Lipids;Messenger RNA;Methods;Microtubules;Mitochondria;Necrosis;Nerve Degeneration;Neurodegenerative Disorders;Neurosciences;Nomenclature;Nuclear;Pentas;Peptide Hydrolases;Phenotype;Phospholipids;Physiological;Property;Proprotein Convertase 1;Proprotein Convertase 2;Protease Domain;Protein Isoforms;Proteins;Research;Role;Signal Transduction;Site-Directed Mutagenesis;Spinal Cord;Structure;Techniques;Toxic effect;Traumatic Brain Injury;Triad Acrylic Resin;abstracting;alpha Actinin;alpha Tubulin;base;beta Tubulin;calpain inhibitor;in vivo;inhibitor/antagonist;insight;interest;knock-down;member;migration;novel;overexpression;protein TDP-43;response;sensor;sex determination;stroke


application_id: 9265338
project_number: 5R01NS093920-03
project_title: Microglia responses to CNS injury: targeting p38 MAPK signaling
administering_ic: NINDS
award_notice_date: 2017-03-16
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 093920
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2015-05-01
project_end_date: 2020-04-30
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Microglia are the resident tissue myeloid cell in the brain. Acute isolation and molecular profiling of adult microglia have clearly identified a microglia-specific gene expression profile not found in other macrophage populations or other cells in the CNS. As a molecular and functionally unique population of cells microglia exhibit a remarkable ability to survey the brain and rapidly undergo a spectrum of responses to insults or tissue damage. These coordinated responses normally result in protection against injury but can be dysfunctional and exacerbate or even cause neurological disease. An added layer of complexity occurs when monocytes are recruited to the brain following disease or injury. As a functionally distinct population newly recruited monocytes/macrophages make different contributions to disease progression compared to microglia. One of the top canonical pathways in microglia/macrophages is the p38 MAPK pathway a well-established signaling pathway important in stress responses. In the last funding period we documented the importance of the p38alpha isoform in microglia proinflammatory cytokine production and found that suppression of p38alpha can prevent the inflammatory response that causes subsequent neuronal/synaptic damage. In two mouse models of diffuse traumatic brain injury (TBI) we found that deletion of p38alpha in myeloid cells was associated with decreased microglia activation and a rescue of vestibulomotor deficits cognitive impairments and synaptic protein loss. Our data demonstrating the importance of p38alpha in regulating key functions of macrophages/microglia that are altered by a brain injury provides a strong precedent for further mechanistic and translational studies. We have now developed an exceptionally specific small molecule p38alpha inhibitor (termed MW150) that is CNS- penetrant has drug-like properties and no adverse effects at very high doses. MW150 is a novel reagent with high translational relevance for future therapeutic development. As a foundation for future development we now propose to address mechanistically how to target p38alpha to improve outcomes following a TBI. To this end we need to answer: 1) When can p38alpha be targeted; i.e. what is the optimal therapeutic window after TBI? 2) Where and how can p38alpha be targeted; i.e. does p38alpha in other inflammatory cell types besides microglia (infiltrating macrophages astrocytes endothelial cells)contribute to neuroinflammatory responses after TBI? Our studies will provide key mechanistic information about how injury-induced p38alpha-dependent inflammatory responses in multiple cell types synergize and cross-talk to drive neurologic impairments. We will test the hypothesis that suppression of p38alpha signaling in appropriate therapeutic windows and appropriate cell types after CNS injury can lead to selective beneficial outcomes. Our aims are: Aim 1. Establish the post-injury therapeutic window for efficacy of our small molecule p38a inhibitor. Aim 2. Define the contribution of p38a in resident microglia versus infiltrating macrophages to TBI-induced impairments. Aim 3. Determine how p38alpha in other CNS inflammatory cell types (astrocytes and endothelial cells) contributes to injury-induced responses.

project_terms:
AD pathology;Acute;Address;Adult;Adverse effects;Alzheimer's Disease;Astrocytes;Brain;Brain Injuries;Cells;Central Nervous System Diseases;Chronic;Clinical;Cognitive deficits;Craniocerebral Trauma;Data;Dementia;Development;Diffuse;Disease;Disease Progression;Dose;Drug Kinetics;Endothelial Cells;Exhibits;Foundations;Functional disorder;Funding;Future;Gene Expression Profile;Immune response;Impaired cognition;Impairment;Inflammatory;Inflammatory Response;Injury;Intervention;Knockout Mice;Lead;MAPK14 gene;Medical;Microglia;Mitogen-Activated Protein Kinases;Modeling;Molecular;Molecular Profiling;Morbidity - disease rate;Mus;Myeloid Cells;Nervous System Physiology;Nervous System Trauma;Neuroglia;Neurologic;Neurons;Outcome;Paracrine Communication;Pathway interactions;Pharmaceutical Preparations;Phenotype;Phosphotransferases;Population;Production;Property;Protein Isoforms;Proteins;Reagent;Recruitment Activity;Reporting;Research;Risk;Role;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Site;Surveys;Synapses;Testing;Therapeutic;Therapeutic Intervention;Tissues;Traumatic Brain Injury;analog;biological adaptation to stress;cell type;central nervous system injury;clinical development;cytokine;defined contribution;effective therapy;improved outcome;inhibitor/antagonist;macrophage;mitogen-activated protein kinase p38;monocyte;mouse model;nervous system disorder;neuroinflammation;novel;prevent;public health relevance;response;small molecule;small molecule inhibitor;stressor;targeted treatment;therapeutic development;therapeutic target;translational study

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Traumatic brain injury represents a major unmet medical need for which there is no effective therapy to improve outcome and prevent the cognitive impairment long-term neurologic morbidity or increased risk of dementia and other medically intractable complications. Successful completion of these studies will define when where and how the important inflammatory kinase p38alpha can be targeted for beneficial outcomes. Our results will provide a foundation for the future clinical development of p38alpha inhibitors for head injury.


application_id: 9264944
project_number: 5F31GM117868-02
project_title: Analysis of chronic muscle weakness in post-septic mice using a novel resuscitation protocol
administering_ic: NIGMS
award_notice_date: 2017-03-15
opportunity_number: PA-14-147
application_type: 5
activity_code: F31
ic: GM
serial_number: 117868
program_official: BARSKI, OLEG
project_start_date: 2016-04-11
project_end_date: 2017-12-15
study_section: Special Emphasis Panel[ZRG1-F15-P(20)L]
contact_pi_person_id: 12654514
contact_pi: OWEN, ALLISON M.
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Sepsis is a severe life-threatening condition that damages multiple physiological systems which manifest in a devastating acute critical illness. After discharge from the hospital 70-100% of severe sepsis survivors report sustained weakness which prevents them from resuming a normal lifestyle. As the mortality rate of sepsis declines due to advancements in critical care medicine and the incidence rate increases due to an aging US population there are more than 1 million new sepsis survivors every year. It is predicted that the rate of sepsis survivors will continue to rise as the population ages and advancements continue to be made in treatment of sepsis. However despite recognition of this clinical issue the molecular mechanisms contributing to chronic muscle dysfunction after sepsis are not well understood due to the lack of an appropriate animal model. Current models are either too mild to induce muscle weakness or are too severe and cause death within a few days. To circumvent this problem I developed a clinically relevant ICU-like sepsis resuscitation protocol with which 70% of middle-aged mice are rescued from otherwise completely lethal sepsis. The Aims of this project are (1) to test whether the mice that are rescued from lethal sepsis by the ICU-like resuscitation protocol exhibit muscle weakness and (2) to identify the primary mechanism(s) responsible for muscle weakness after sepsis. Muscle functional analyses will be performed using in vivo and ex vivo strength tests at different time points after sepsis which will be carefully designed so that the presence of atrophy and/or myopathy can be detected. I have already found that animals with lethal sepsis but rescued using my resuscitation protocol have significant muscle weakness 2 weeks after sepsis induction. Although the mechanisms by which sepsis-induced muscle weakness becomes a chronic condition are unknown my preliminary data suggest that mitochondria are involved. Therefore a series of molecular analyses will be performed to assess the time course and severity of muscle dysfunction and how it may cause reduction in force generating capacity by oxidizing sarcomeric proteins. These studies will promote the development of numerous scientific skill sets including proper animal research design implementation and interpretation as well as an assortment of molecular analysis techniques. Successful completion of this project will yield an understanding of the mechanism(s) responsible for muscle weakness after sepsis which could help elucidate a novel therapeutic target to prevent sepsis-mediated from developing in patients.

project_terms:
Abdomen;Acute;Age;Aging;Animal Experimentation;Animal Model;Animals;Antioxidants;Atrophic;Biological Assay;Cause of Death;Cessation of life;Chronic;Clinical;Communities;Critical Care;Critical Illness;DNA Damage;Data;Development;Evaluation;Exhibits;Female;Fibrinogen;Focal Infection;Functional disorder;Future;Generations;Goals;Hand Strength;Health;Histologic;Hospitals;Hyperactive behavior;Immune response;Immune system;Incidence;Infection;Isometric Exercise;Life;Life Style;Longitudinal Studies;Mediating;Medicine;Mitochondria;Mitochondrial DNA;Modeling;Molecular;Molecular Analysis;Multienzyme Complexes;Mus;Muscle;Muscle Fibers;Muscle Weakness;Muscular Atrophy;Myopathy;Oxides;Pathogenesis;Patients;Peripheral Nerves;Physicians;Physiological;Polyneuropathy;Population;Process;Production;Proteins;Protocols documentation;Reactive Oxygen Species;Recovery;Reporting;Research Design;Respiration;Resuscitation;Risk;Sepsis;Series;Severities;Skeletal Muscle;Survival Rate;Survivors;System;Techniques;Testing;Time;aging population;base;clinically relevant;cytokine;design;effective therapy;enzyme activity;experimental study;falls;improved;in vivo;middle age;mortality;new therapeutic target;novel;novel therapeutics;oxidation;prevent;public health relevance;septic;sex;skills;trend

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  For decades sepsis survivors and physicians alike have reported muscle weakness that persists for years but the lack of an appropriate animal model has been a critical barrier for identifying the underlying cause of this phenomenon. In this proposal a newly optimized protocol that rescues animals from severe abdominal sepsis will be used to investigate muscle dysfunction in sepsis survivors. This will help to elucidate therapies for inhibiting the development of sepsis-mediated physical dysfunction such as a mitochondria-targeted anti-oxidant.


application_id: 9264563
project_number: 5P30GM110787-04
project_title: Pilot Grant Program
administering_ic: NIGMS
award_notice_date: 2017-05-01
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
study_section: ZGM1-TWD-C
subproject_number: 6094
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
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: 2017-05-01
budget_end_date: 2018-04-30
project_abstract:
The long-term goal of the Pilot Grant Program is to provide resources to COBRE investigators so that they can generate new preliminary data for extramural grant applications and thus expand their research programs. The Pilot Grant Program was begun in Phase I continued in Phase II and its success will be built upon in Phase III. During Phase I and II the Program was extremely successful. Awardees produced -200 publications and the success rate for gaining independent extramural funding was -80%. Many of the initial awardees have now been granted tenure. This successful program will continue in Phase III. The Pilot Grant Program will feature three grant categories all designed to further the goals of the COBRE Center for Molecular Medicine and to promote innovation by allowing meritorious investigators to explore novel ideas and develop new technologies. Category 1 grants are for newly-independent non-tenured tenure-track research faculty with no prior NIH ROI or equivalent external grant support as a principal investigator. A strong mentoring component is associated with this class of grant. Category 2 grants are for more established faculty who wish to pursue a new research area for which they do not currently have an NiH R01 or equivalent. These grants are meant to promote innovation and allow investigators to expand their research programs into new areas. Category 3 grants are available to groups of investigators planning to submit a multi-PI or Program Project grant application working collaboratively on a specific research problem and can be comprised of both junior and more established investigators. These grants are meant to promote synergistic collaborations. The grants are designed for 2 years of funding ($50000 per year) with the second year contingent on demonstrated progress. Evaluation of the grant applications and funding decisions will be made by the External Advisory Board in consultation with the Program Coordinator. All applicants regardless of funding decisions will receive a review of their proposals with a full evaluation of NIH's five criteria so that their future proposals can be improved. This Pilot Grant program has had a highly successful past and its philosophy of operation will be carried into Phase III.

project_terms:
Animal Model;Applications Grants;Area;Award;Basic Science;Categories;Cellular biology;Centers of Research Excellence;Clinical;Collaborations;Consultations;DNA;Data;Development;Diagnostic;Discipline;Evaluation;Evolution;Extramural Activities;Faculty;Feasibility Studies;Fostering;Foundations;Funding;Future;Generations;Goals;Grant;Growth;Kentucky;Knowledge;Mentors;Molecular;Molecular Medicine;Neurodegenerative Disorders;Participant;Patients;Phase;Philosophy;Pilot Projects;Positioning Attribute;Principal Investigator;Program Research Project Grants;Publications;RNA;Research;Research Personnel;Research Project Grants;Resources;Science;Signal Pathway;Sum;Technology;Therapeutic;Translational Research;United States National Institutes of Health;Universities;career;design;experience;faculty research;human disease;improved;innovation;interest;new technology;novel;operation;programs;success;tenure track;tool;trafficking;translational study

public_health_relevance:
The Pilot Grant Program promotes innovation by supporting COBRE investigators in the exploration of novel ideas and in the development of new technologies. This new knowledge will be the foundation for developing the future diagnostics tools and clinical therapeutics needed in the treatment of human disease.


application_id: 9264562
project_number: 5P30GM110787-04
project_title: Genetic Technologies Core
administering_ic: NIGMS
award_notice_date: 2017-05-01
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
study_section: ZGM1-TWD-C
subproject_number: 6093
contact_pi_person_id: 1893692
contact_pi: MENDENHALL, MICHAEL D.
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: 2017-05-01
budget_end_date: 2018-04-30
project_abstract:
The Genetic Technologies Core evolved from the Viral Core that began with funding from an ARRA supplement grant in 2009 and was incorporated into the COBRE in 2011. It was initially conceived as a central service facility for the preparation purification and titering of recombinant lentlviruses adenoviruses and adeno-associated viruses for the use of investigators associated with the Center for Molecuair Medicine and for other investigators interested in the use of recombinant viruses as a delivery tool for nucleic acids. Over the past four years the Core has steadily grown in the number of individual viral preparations that it produced and the number of investigators it served. There has evolved an interest from users for services in addition to those associated with viral production and the Core has adapted by increasing the scope of services provided necessitating the change to its new designation as the Genetic Technologies Core. At present the Genetic Technologies Core provides a broad range of services related to the manipulation and analysis of recombinant DNAs especially for those laboratories with clinical/translational interests that are not equipped for recombinant DNA work. Evolution of the Core continues as it adds capacity in genomic manipulation through the development and use of "recombineering" TALEN and piggybac technologies. These technologies will be especially valuable for the creation of cellular and animal models of human diseases that can be exploited by members of the Center for Molecular Medicine. In addition to its scientific development the Core is also expanding its outreach programs by interfacing with the expanding Masters of Medical Science program (currently over 30 students) to provide hands-on and didactic instruction in recombinant DNA technologies including viral production and assay mammalian genomic manipulation tissue culture techniques and federal regulatory and safety requirements for up to three students each semester. A parallel didactic-only class is being developed for PhD graduate students. These courses will serve as additional revenue sources to sustain this core beyond COBRE funding.

project_terms:
Adenoviruses;American;Animal Model;Biological Assay;Cell model;Cells;Centers of Research Excellence;Clinical;Complex;Consultations;DNA;DNA Sequence Alteration;DNA laboratory;Dependovirus;Development;Disease model;Doctor of Philosophy;Evolution;Exposure to;Fee-for-Service Plans;Fees;Funding;Genetic Engineering;Genome;Genomics;Grant;Individual;Institution;Instruction;Investments;Kentucky;Laboratories;Leadership;Master of Science;Medical;Medicine;Modeling;Molecular;Molecular Medicine;Nucleic Acids;Phase;Plasmids;Positioning Attribute;Preparation;Production;Reagent;Recombinant DNA;Recombinants;Recovery;Research;Research Personnel;Resources;Safety;Science;Services;Source;Speed;Students;System;Techniques;Technology;Time;Tissue Culture Techniques;Training;Training Activity;Training Programs;United States National Institutes of Health;Universities;Viral;Work;base;cost;design and construction;genetic technology;graduate student;human disease;interest;mammalian genome;member;operation;outreach program;programs;recombinant virus;tool;transcription activator-like effector nucleases

public_health_relevance:
The Genetic Technologies Core provides a wide range of services relating to the manipulation of recombinant DNAs and mammalian genomes for investigators associated with the Center for Molecular Medicine. Of particular importance are the production of recombinant viruses for the delivery of nucleic acids for experimental use and the manipulation of mammalian genomes for creation of cell-based and animalbased human disease models.


application_id: 9264561
project_number: 5P30GM110787-04
project_title: Organic Synthesis Core
administering_ic: NIGMS
award_notice_date: 2017-05-01
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
study_section: ZGM1-TWD-C
subproject_number: 6092
contact_pi_person_id: 1964895
contact_pi: WATT, DAVID STEWART
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: 2017-05-01
budget_end_date: 2018-04-30
project_abstract:
The Organic Synthesis Core prepares novel specialized organic compounds that are not readily obtainable from commercial sources for faculty in the Center for Molecular Medicine as well as other investigators at the University of Kentucky other Kentucky universities. The core has all of the appropriate equipment needed to prepare small organic compounds (< 2 kDa) along with access to appropriate analytical techniques including NMR and mass spectrometry for confirming structural assignments to characterize the final product(s) an essential element of any synthesis project. The core has synthesized and characterized novel probes for more than twenty-five investigators including photoactive drug analogs fluorescent compounds used as molecular probes modified natural products unnatural peptides and compounds used for the affinity purification of proteins. The core has developed small molecule libraries that have been effectively used for ligand and drug screening leading to the identification of novel targets and the development of therapeutics. In Phase III this core will continue to provide novel small-molecule probes for disease-relevant studies further develop and expand its libraries of small-molecules for biological screening and promote and facilitate the use of small-molecule approaches in our translational research efforts. In addition the core will provide training opportunities for students and researchers who seek to learn synthetic organic chemical techniques and apply them to their research projects. An important but potentially overlooked aspect of the Organic Synthesis Core is that it does not compete with pharmaceutical companies rather the services provided by the core complement what private enterprises do. Generally a potentially valuable new compound developed by the core in collaboration with an investigator will be patented and then licensed to a pharmaceutical company for development and testing leading ultimately to clinical trials.

project_terms:
Affinity Chromatography;Biological;Businesses;Centers of Research Excellence;Clinical Trials;Collaborations;Complement;Consult;Consultations;Detection;Deuterium;Development;Disease;Drug Industry;Elements;Equipment;Extramural Activities;Faculty;Fees;Funding;Grant;Health;Human;Institution;Investigation;Investigational Drugs;Investments;Kentucky;Label;Learning;Legal patent;Ligands;Link;Lipids;Malignant Neoplasms;Mass Spectrum Analysis;Medicine;Molecular;Molecular Medicine;Molecular Probes;Monitor;NMR Spectroscopy;National Center for Research Resources;National Institute of General Medical Sciences;Natural Products;Nature;Neurodegenerative Disorders;Organic Chemicals;Organic Synthesis;Outcome;Peptide Nucleic Acids;Peptides;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacy facility;Phase;Polymers;Positioning Attribute;Postdoctoral Fellow;Preclinical Drug Evaluation;Private Enterprises;Proteins;Publications;Research;Research Personnel;Research Project Grants;Research Support;Resources;Services;Source;Structure;Students;Techniques;Testing;Time;Training;Translating;Translational Research;Universities;X-Ray Crystallography;analog;base;college;cost;design;drug candidate;functional group;graduate student;human disease;improved;industry partner;instrumentation;molecular mass;novel;novel therapeutics;operation;outreach;programs;protein purification;radiotracer;screening;small molecule;small molecule libraries;therapeutic development;training opportunity;undergraduate student

public_health_relevance:
This Organic Synthesis core synthesizes small organic molecule use by investigators for their research projects related to understanding the molecular basis of human disease.


application_id: 9264560
project_number: 5P30GM110787-04
project_title: Protein Core
administering_ic: NIGMS
award_notice_date: 2017-05-01
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
study_section: ZGM1-TWD-C
subproject_number: 6091
contact_pi_person_id: 7875214
contact_pi: RODGERS, DAVID W
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: 2017-05-01
budget_end_date: 2018-04-30
project_abstract:
The Protein Core in the University of Kentucky Center for Molecular Medicine works with biomedical investigators to facilitate the expression purification and characterization of recombinant proteins and other macromolecules. It makes available equipment instrumentation and expertise not normally be found within individual research laboratories. The Core has fermentors bioreactors and tissue culture facilities for expressing recombinant protein in bacteria yeast insect or mammalian cells as required. It also maintains cell cracking equipment and an extensive facility for the purification of recombinant proteins. In addition a range of analytical instruments for biophysical characterization are available in the Core including dynamic light scattering spectropolarimetry fluorescence isothermal titration calorimetry high performance liquid chromatography analytical ultracentrifugation and X-ray crystallography. Crystallography facilities include instruments for automated crystallization trials in house data collection equipment and membership in a group (SER-CAT) operating a state-of-the-art data collection facility at the Advanced Photon Source located within Argonne National Laboratory. A Core staff member maintains the equipment provides training and works with researchers on their individual projects. Experienced users have direct access to Core facilities while new users are first trained by Core personnel and assisted in initial experiments. Users with more difficult projects receive additional assistance from the Core personnel. Service projects are undertaken selectively for users who lack the expertise or personnel to carry out the work on their own. The Core is used by investigators representing 50-70 research groups each year with over 4200 individual uses of instruments or facilities documented for the first four years of Phase II COBRE funding. Outreach activities include the Core web site talks given by Core associated faculty individual and group training sessions a monthly research talk series and participation in graduate courses and an NSF REU summer program. The Core is active in obtaining new instrumentation and introducing new techniques. Transition to a selfsustaining regional facility is planned over the course of Phase III COBRE funding.

project_terms:
Area;Bacteria;Behavior;Biological;Biomedical Research;Bioreactors;Calorimetry;Cells;Centers of Research Excellence;Chromatography;Collaborations;Communities;Consult;Core Facility;Core Protein;Crystallization;Crystallography;Data Collection;Equipment;Fees;Fluorescence;Fostering;Funding;Goals;Grant;Growth;High Pressure Liquid Chromatography;Human Resources;Individual;Insecta;Institution;Kentucky;Laboratories;Laboratory Research;Mammalian Cell;Mission;Molecular Medicine;Phase;Photons;Production;Protein Chemistry;Proteins;Recombinant Proteins;Recruitment Activity;Research;Research Personnel;Resources;Schedule;Series;Services;Source;Structural Biologist;Structure;Techniques;Time;Titrations;Training;Universities;Work;X-Ray Crystallography;Yeasts;analytical ultracentrifugation;biophysical properties;cell type;design;equipment acquisition;experience;experimental study;instrument;instrumentation;light scattering;macromolecule;member;mid-career faculty;operation;outreach;outreach program;structural biology;summer program;tissue culture;web site

public_health_relevance:
This Protein Core in the Center for Molecular Medicine provides a variety of services aimed at the production and characterization of proteins for investigator inflated biomedical research. The Core makes available well maintained instruments and facilities not generally found in individual research labs and provides both training in their use and expert guidence. In addition service projects carried out by Core personnel are undertaken.


application_id: 9264559
project_number: 5P30GM110787-04
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2017-05-01
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
study_section: ZGM1-TWD-C
subproject_number: 6090
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
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: 2017-05-01
budget_end_date: 2018-04-30
project_abstract:
The Administrative Core will provide the administrative oversight for the Center for Molecular Medicine and the COBRE resources designed to build and strengthen the Center. The Administrative Core under the direction of Lou Hersh the COBRE PI and Sidney Whiteheart Program Coordinator will provide leadership oversight and coordination of the various activities associated with the Ceriter and it COBRE resources. The Administrative Core will facilitate and implement the goals and objectives of this COBRE and facilitate the transition of the Center for Molecular Medicine and its associated Cores to a sustainable independent status. The Administrative Core will provide oversight of the various activities associated with the COBRE grant including its voucher program its pilot grant program its mentoring activities and its scientific cores. The Administrative Core will work with the Intemal and External Advisory Committees and the Core directors and to meet our goals and objectives. The Administrative Core will oversee the budgets associated with the COBRE coordinate the various mentoring and Advisory Board meetings track core usage prepare reports etc. The specific objectives of the Administrative Core include enhancing and sustaining the infrastructure of the Center for Molecular Medicine including its research core facilities increasing the critical mass of investigators whose research focuses on the molecular basis of human disease fostering new collaborative and novel research in the Center providing a foundation for investigators to obtain extramural research support and to expand and develop educational activities through the scientific cores. The Administrative Core will use a number of approaches to facilitate faculty mentoring especially for junior untenured faculty to enhance educational initiatives associated with the Center and its cores to optimally use the pilot grant program to enhance competitive research to facilitate programmatic grant development and to develop collaborations with other IDeA centers and institutions in the region.

project_terms:
Achievement;Advisory Committees;Basic Science;Biochemistry;Budgets;Centers of Research Excellence;Collaborations;Core Facility;Data;Department chair;Development;Educational Activities;Equipment;Extramural Activities;Faculty;Fostering;Foundations;Goals;Grant;Head;Institution;Kentucky;Leadership;Medicine;Mentors;Mission;Molecular;Molecular Medicine;Performance;Phase;Recruitment Activity;Reporting;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Running;Services;Solid;Techniques;Technology;Universities;Work;college;design;faculty mentor;human disease;meetings;new technology;novel;programs;tool;voucher

public_health_relevance:
This Administrative Core will oversee all of the activities of this COBRE including the scientific cores the voucher program and the pilot grant program.


application_id: 9264349
project_number: 7R01HL055673-19
project_title: HyperGEN: Genetics of Left Ventricular Hypertrophy
administering_ic: NHLBI
award_notice_date: 2016-07-14
opportunity_number: PA-14-078
application_type: 7
activity_code: R01
ic: HL
serial_number: 055673
program_official: JAQUISH, CASHELL E
project_start_date: 2016-07-15
project_end_date: 2019-04-30
study_section: Special Emphasis Panel[ZRG1-PSE-H(02)M]
contact_pi_person_id: 1876483
contact_pi: ARNETT, DONNA K
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 PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Left ventricular (LV) remodeling and hypertrophy occurs frequently in the general population and is a strong predictor of myocardial infarction heart failure and stroke. Data previously collected in the HyperGEN and GENOA studies of the Family Blood Pressure Program (FBPP) have pointed to genetic loci contributing to LV hypertrophy and dimensional traits through linkage studies and genome-wide association studies. Despite these advances a large portion of variation in LV traits is unaccounted for. We hypothesize that in part rare variants account for this variation. We propose the following aims.Aim 1. Whole exome sequence (WES) 1200 AA unrelated hypertensives with extreme values for echocardiographic LV mass/hgt2.7 to identify rare and low-frequency variants contributing to LV mass and related structural and functional phenotypes. We will select unrelated individuals from the top and bottom quartile of LV mass index. Because the distribution of LV mass/hgt2.7 in the FBPP is shifted to higher values than the general population the cutpoint for the upper quartile is approximately equal to the definition of LVH. We will sequence at a density sufficient to capture rare variants. We will conduct extreme phenotype-based analysis weighted by function and conservation to identify high-impact coding variants. A gene list will be ranked for selection in Aim 2 based on evidence from statistical and bioinformatic analyses and expression experiments in induced pluripotent stem cell- (iPSC-)derived cardiomyocytes. Aim 2. Validate variants detected in Aim 1 by resequencing 40 candidate genes in all AA HyperGEN/GENOA family members and subsequently validate 768 most significant variants in external cohorts. We will sequence all exons and regulatory regions in the remainder of the FBPP families and siblings not sequenced in Aim 1 (n=2266). We will conduct association analysis followed by bioinformatic filtering to identify high-impact coding variants and rank the 768 most significant variants for further external replication. We will genotype these in 9160 AA (5623 hypertensive) participants from population-based studies using Illumina assays (ie JHS CARDIA ARIC CHS WUSTL). Gene-based associations will be examined within and meta-analyzed among cohorts. Genes will be ranked by statistical and biological evidence to move to Aim 3. Aim 3. Use human iPSC cardiomyocytes to functionally validate variants replicated in Aim 2. Using hypertrophy-induced cardiomyocytes we will test the direction of effect and clinical characterization of associated genes with rare variants from Aim 2. We will use siRNA transfections to test whether knock down of candidate genes influences hypertrophy in the cell-based model. The research proposed herein if successful will continue the success of HyperGEN and GENOA in identifying novel genes contributing to LV hypertrophy and evaluate their relevance in a cell-based system to identify new pathways for future treatment.

project_terms:
Accounting;African American;Ancillary Study;Arterial Disorder;Award;Behavioral;Bioinformatics;Biological;Biological Assay;Biological Models;Blood;Blood Pressure;Candidate Disease Gene;Cardiac Myocytes;Cardiomegaly;Cardiovascular Diseases;Cardiovascular system;Cells;Cessation of life;Code;Complex;DNA Resequencing;Data;Diagnosis;Echocardiography;Exons;Family;Family Study;Family member;Frequencies;Functional disorder;Future;General Population;Genes;Genetic;Genetic Programming;Genomics;Genotype;Grant;Health;Heart;Heart failure;Human;Hypertension;Hypertrophy;Individual;Intervention;Lead;Left;Left Ventricular Hypertrophy;Left Ventricular Mass;Left Ventricular Remodeling;Left ventricular structure;Measures;Meta-Analysis;Methods;Modeling;Myocardial Infarction;Nature;Nucleic Acid Regulatory Sequences;Participant;Pathway interactions;Persons;Phenotype;Protocols documentation;Pump;Race;Reading;Research;Resources;Risk;Sampling;Sequence Analysis;Siblings;Small Interfering RNA;System;Testing;Transfection;Variant;Ventricular;Weight;Work;base;blood pressure reduction;cardiovascular disorder risk;cardiovascular risk factor;clinical effect;cohort;density;effective therapy;exome sequencing;gene discovery;genetic association;genetic epidemiology;genetic variant;genome wide association study;hypercholesterolemia;indexing;induced pluripotent stem cell;innovation;knock-down;member;new therapeutic target;next generation sequencing;novel;population based;programs;rare variant;research study;stomach cardia;stroke;success;trait

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Black people tend to have an enlarged left ventricle (the heart chamber that pumps oxygenated blood throughout the body) more commonly than those in other race groups putting them at greater risk for having potentially fatal cardiovascular diseases. Enlarged left ventricles are caused at least in part by a person's genes. This study seeks to discover which genetic factors may cause an enlarged heart; this may ultimately lead to new diagnoses and treatments to help lower cardiovascular disease risk in blacks.


application_id: 9264214
project_number: 2R01NS045954-11A1
project_title: Neuropeptidergic Inhibition of Spinal Pain Transmission
administering_ic: NINDS
award_notice_date: 2016-12-08
opportunity_number: PA-13-118
application_type: 2
activity_code: R01
ic: NS
serial_number: 045954
suffix: A1
program_official: OSHINSKY, MICHAEL L
project_start_date: 2002-09-10
project_end_date: 2021-11-30
study_section: Special Emphasis Panel[ZRG1 IFCN-B (03)]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Nerve injury dramatically increases NPY expression in sensory neurons and NPY receptor-mediatedanalgesia yet this is underappreciated as a potential pain relief mechanism that might prevent the transitionfrom acute to chronic pain. Among 35 original research articles reviews and a book published during theprevious funding cycle (28 as first or senior authors) our work published in PNAS discovered that intrathecalNPY receptor antagonists or conditional genetic NPY depletion reinstated hyperalgesia even when appliedmonths after nerve injury or inflammation. Our overall hypothesis is that injury induces a sustained release ofNPY and activation of NPY Y1 receptor signaling that opposes the transition to a chronic state of lasting painvulnerability. However whether tissue- or nerve-injury induced increases in spinal NPY Y1 receptor (Y1R)signaling is associated with a tonic increase in the releasable pool of NPY has been difficult to determine. Toaddress this gap we developed a new in situ assay of functional NPY release (Y1R internalization). Our newdata indicate that Y1R internalization is greater with nerve injury after high frequency electrical stimulation ofdorsal horn slices or after in vivo non-noxious stimulation of the hindpaw. Specific Aim 1 will use this novelmethod to test the hypothesis that non-noxious stimulus-evoked release of NPY from A-fibers will remainprimed for weeks and even months after nerve injury. We now report that NPY produces an outward currentand inhibits action potentials evoked by dorsal root stimulation (DRS) in Y1-EGFP labeled neurons. To test thehypothesis that injury increases synaptic inhibition by NPY Specific Aim 2A will patch-clamp lamina IIneurons and conduct Fura-2 [Ca2+]i imaging at peak of hyperalgesia after injury. We predict that Y1R agonistswill inhibit stimulus-evoked responses and their concentration-response curves will be left-shifted by injury. Ourprogress with NPY saporin-conjugated neurotoxin indicates that Y1R-expressing dorsal horn neuronscontribute to neuropathic pain and new double-label immunohistochemistry and patch-clampelectrophysiology data in Y1R-EGFP mice support the concept that Y1R-positive neurons are excitatory. Totest the hypothesis that Y1R-expressing neurons maintain LS after inflammation or nerve injury but are held incheck by NPY Specific Aim 2B will evaluate the effects of Y1 receptor antagonists on [Ca2+]i mobilization andNMDA or AMPA receptor currents in Y1R-expressing neurons upon dorsal root stimulation or laser-directedNMDA/AMPA uncaging. Specific Aim 3 will then use an intrathecal pharmacology approach to determinewhether NPY silences pronociceptive GluN AC1 Epac signaling on Y1R-expressing dorsal horn neuronsand TRPA1 TRPV1 signaling on central afferents terminals. Completion of this project will bring us closer toour long-term goal of alleviating chronic pain by either: a) facilitating endogenous NPY analgesia thusrestricting pain within a state of remission; or b) extinguishing spinal neuron sensitization altogether forexample with a selective AC1 or Epac1 inhibitor.

project_terms:
AMPA Receptors;Absence of pain sensation;Action Potentials;Acute;Address;Adenylate Cyclase;Affect;Afferent Neurons;Agonist;American;Analgesics;Biological Assay;Books;Chronic;Confocal Microscopy;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Data;Disease remission;Electric Stimulation;Electrophysiology (science);Evoked Potentials;Failure;Fiber;Frequencies;Funding;Fura-2;Genetic;Goals;Hyperalgesia;Image;Immunohistochemistry;In Situ;Inflammation;Injury;Interneurons;Intrathecal Injections;Label;Lasers;Left;Mediating;Methods;Molecular;Mus;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;Neurons;Neuropeptide Y Receptor;Neurotoxins;Nociceptors;Pain;Peripheral nerve injury;Pharmacology;Physical Function;Physiologic pulse;Posterior Horn Cells;Productivity;Proteins;Public Health;Publishing;Quality of life;Receptor Activation;Receptor Signaling;Reporting;Research;Signal Transduction;Site;Slice;Spinal;Spinal Cord;Spine pain;Stimulus;Synapses;TRPV1 gene;Testing;Tissues;Traumatic injury;Work;central sensitization;chronic pain;cost;dorsal horn;excitatory neuron;in vivo;inflammatory neuropathic pain;inhibitor/antagonist;knock-down;mental function;nerve injury;neuropeptide Y;neuropeptide Y-Y1 receptor;novel;painful neuropathy;patch clamp;prevent;public health relevance;receptor;receptor internalization;response;small molecule inhibitor;somatosensory;spinal nerve posterior root;synaptic inhibition;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE STATEMENTChronic pain is a public health problem which affects the physical and mental functioning quality oflife and productivity of over 100 million Americans costing $600 billion dollars annually. Our recentwork suggests that our body's own natural pain killers (namely neuropeptide Y) exert an extremelypowerful and very long-lasting ability to put chronic pain in remission. This project seeks to elucidatenot only the molecular mechanisms that cause painful suffering following chronic inflammation or atraumatic injury but also the compensatory mechanisms in the spinal cord that prevent the transition tochronic pain.


application_id: 9264023
project_number: 5R01NS084823-05
project_title: Mechanisms of Homocysteine-Induced Fibrinogen-Amyloid Plaque Formation
administering_ic: NINDS
award_notice_date: 2017-05-05
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: NS
serial_number: 084823
program_official: CORRIVEAU, RODERICK A
project_start_date: 2013-07-01
project_end_date: 2019-04-30
study_section: Special Emphasis Panel[ZRG1-VH-B(03)]
contact_pi_person_id: 6869069
contact_pi: LOMINADZE, DAVID
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The plaques in the brain during Alzheimer's diseases (AD) are primarily composed of amyloid- (A) peptide. Although a strong association between A fibrinogen (Fg) and elevated level of homocysteine (Hcy) i.e. hyperhomocysteinemia (HHcy) during AD is well- documented the mechanism of amyloid plaque formation is unclear. The long-term goal of this project is to understand the mechanisms of cerebrovascular permeability leading to amyloid plaque formation. We have shown that elevated levels of Hcy and Fg i.e. hyperfibrinogenemia (HFg) increase cerebrovascular permeability and Fg can cross vascular endothelial cell (EC) layer secondary to activation of matrix metalloproteinase-9 (MMP-9). In addition increased levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) which enhances collagen content in subendothelial matrix (SEM) are associated with AD. In pilot studies we found that while HHcy enhances vascular permeability through mainly the paracellular pathway HFg activates mainly the transcellular transport. We also found that blood level of Fg is increased during HHcy. Therefore Fg can have an additive effect in HHcy-induced cerebrovascular permeability. We found that HHcy increases collagen level in SEM and Fg and A depositions in brain vasculature. While HHcy increases MMP-9 activity and enhances the paracellular transport as well as homocyteinylates Fg (making fibrin clots more rigid) Fg enhances the transcellular transport through caveolin-1 (Cav-1) signaling (via phosphorylation of Cav-1). However the role of Hcy and Fg in Hcy-Fg-A-collagen complex formation is unclear. The hypothesis of this proposal is that HHcy increases vascular permeability by primarily affecting the endothelial cell (EC) junction proteins and activating MMP-9 and indirectly by increasing blood content of Fg which enhances transcellular transport leading to an enhanced Hcy- Fg-A-collagen complex formation. We will test this hypothesis with three specific aims: 1) To determine whether the HHcy instigates cerebrovascular permeability via paracellular transport leading to enhanced cerebrovascular crossing of fibrinogen 2) To determine whether the fibrinogen deposition enhances cerebrovascular permeability mainly through caveolar transcytosis via Cav-1 signaling secondary to MMP-9 activation 3) To determine whether the HHcy increases fibrinogen-A-collagen complex accumulation in mouse brains secondary to increasing tissue inhibitor of metalloproteinase-1. To define specific causative effects of Hcy Fg MMP-9 Cav-1 and TIMP-1 in Fg-Ab-collagen complex formation the studies will be done on pial vessels of wild type (WT) Cystathionine -Synthase heterozygote (CBS+/-) mice (a model of HHcy) MMP-9 gene knockout (MMP9-/-) CBS and MMP-9 double knockout (CBS+/-/MMP9-/-) Cav-1 gene knockout (Cav1-/-) Fg -chain-deficient (Fg-/-) CBS+/-/Fg-/- HFg transgenic (HFg) HFg/MMP9-/- CBS+/-/Cav1-/-/MMP9-/- CBS+/- /HFg CBS+/-/HFg/MMP9-/- TIMP-1 gene knockout (TIMP1-/-) CBS+/-/TIMP1-/- double knockout Fg-/-/MMP1-/- and CBS+/-/Fg-/-/TIMP1-/- mice using a newly developed dual-tracer probing method that allows separation of paracellular from transcellular transport. Formation of Fg-A-collagen complex in brain cortex will be assessed with immunohistochemical analysis. The results of the proposed research should uncover the molecular mechanisms regulating Hcy-Fg-A-collagen complex formation and lead to effective strategies for the treatment of cerebrovascular complications during diseases such as AD.

project_terms:
Affect;Aging;Alzheimer's Disease;Amyloid beta-Protein;Binding;Blood;Brain;CAV1 gene;Caveolae;Cerebrovascular system;Coagulation Process;Collagen;Complex;Cystathionine beta-Synthase;Dementia;Deposition;Development;Disease;Endothelial Cells;Extravasation;Fibrin;Fibrinogen;Gelatinase B;Goals;Heterozygote;Homocysteine;Hyperhomocysteinemia;Immunohistochemistry;Intercellular Junctions;Interstitial Collagenase;Knock-out;Knowledge;Lead;MMP9 gene;Matrix Metalloproteinases;Measures;Methods;Mission;Modeling;Molecular;Mus;Neurodegenerative Disorders;Pathogenicity;Pathway interactions;Peptides;Permeability;Phosphorylation;Pilot Projects;Presenile Alzheimer Dementia;Proteins;Public Health;Research;Role;Sampling;Secondary to;Senile Plaques;Signal Transduction;TIMP1 gene;Testing;Therapeutic;Tissue Inhibitor of Metalloproteinase-1;Tracer;Transgenic Organisms;United States National Institutes of Health;Vascular Endothelial Cell;Vascular Permeabilities;abeta deposition;cadherin 5;caveolin 1;cerebrovascular;design;knockout gene;novel;occludin;public health relevance;transcytosis;treatment strategy;venule

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Alzheimer's Disease (AD) is the most common form of dementia and it is not a normal part of aging. Up to 5 percent of people with the disease have early onset AD. The plaques in the brain during AD are primarily composed of amyloid- (A) peptide. Although a strong association between A fibrinogen (Fg) and homocysteine (Hcy) is well-documented the mechanism is unclear. Our findings show that at elevated levels Hcy increases cerebrovascular permeability to proteins leading to Fg deposition in brain cortical vessels. We also found that this Fg is associated with increased levels of A and collagen in brain vasculature. These effects of Hcy and Fg were diminished in the absence of matrix metalloproteinase-9 (MMP-9) activity. The long-term goal of this project is to understand mechanisms leading to brain Fg-A-collagen complex formation. The knowledge of mechanisms that control the amyloid plaque formation will lead to the design of therapeutic strategies for the control of this devastating neurodegenerative disease. The proposed research is relevant to public health and to the mission of NIH because it will clarify a novel pathogenic causal relationship into the role of Hcy Fg and MMPs in development of AD.


application_id: 9263686
project_number: 5F31DC015400-02
project_title: TrkB-expression divides taste neurons into subtypes
administering_ic: NIDCD
award_notice_date: 2017-05-10
opportunity_number: PA-14-148
application_type: 5
activity_code: F31
ic: DC
serial_number: 015400
program_official: RIVERA-RENTAS, ALBERTO L
project_start_date: 2016-06-01
project_end_date: 2018-05-31
study_section: ZDC1-SRB-Y(53)
contact_pi_person_id: 12153137
contact_pi: RIOS-PILIER, JENNIFER
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Peripheral sensory neurons of the visual and somatosensory systems can be divided into different types based on molecular morphological and functional characteristics. These various neuron types contribute to "parallel pathways" that code different aspects of sensation. The taste receptor cells which transduce the chemicals in the food we eat exist as types. It is unclear whether there are types of geniculate ganglion neurons which carry this information from taste buds to the brainstem. Differential expression of the neurotrophin receptor TrkB in half of the taste neurons could be an indicator that these neurons do exist as different types. If this is the case TrkB-expressing taste neurons should be developmentally functionally and morphologically distinctive from neurons that lack TrkB. The goal of this study is to examine this possibility using genetic labeling electrophysiology conditional knockout mice taste nerve labeling and tract tracing. I will use these approaches to determine 1) if adult TrkB expressing neurons arise differently during development than TrkB-negative taste neurons; 2) if adult TrkB-expressing neurons have a specific function; 3) if adult TrkB-neurons have specific projections to the NTS. Together these experiments will test the hypothesis that that TrkB expression divides gustatory neurons in half and that these two groups of taste neurons differ in their development function and CNS projections. If my proposed hypothesis is correct this would provide the first evidence that gustatory neurons can be divided into types based on intrinsic criteria. Understanding how the taste system develops and is organized in adulthood is imperative for taste system repair following disruption. For example both middle ear surgeries and basal cell carcinoma treatment disrupt gustatory structure and function. This study could contribute to the design of improved treatment that will offer better quality of life to patients with taste disturbances.

project_terms:
Adult;Afferent Neurons;Axon;Basal cell carcinoma;Biological Preservation;Brain;Brain Stem;Brain-Derived Neurotrophic Factor;Characteristics;Chemicals;Code;Development;Eating;Electrophysiology (science);Esthesia;Excision;Exhibits;Fiber;Food;Genetic;Goals;Hair;Imagery;Individual;Injection of therapeutic agent;Knockout Mice;Label;Ligands;Molecular;Morphology;Mus;Nerve;Nerve Growth Factor Receptors;Neuraxis;Neuronal Differentiation;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 2;Nucleus solitarius;Otologic Surgical Procedures;Palate;Pathway interactions;Patients;Pattern;Peripheral;Prevention;Quality of life;Receptor Cell;Signal Transduction;Sodium Chloride;Spinal Ganglia;Stimulus;Structure;Structure of geniculate ganglion;Synapses;System;Tamoxifen;Taste Buds;Taste Perception;Testing;Tongue;Visual;base;chorda tympani;design;differential expression;experience;experimental study;improved;middle ear;public health relevance;repaired;response;segregation;somatosensory;taste stimuli;taste system;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Preservation of the chorda tympani nerve function is important for prevention of taste disturbances in patients that experience middle ear surgeries and basal cell carcinoma treatment. Understanding how TrkB-expression defines the development and function of geniculate ganglion neurons is important for the design of treatment that will offer better quality of life to patients with taste disturbances.


application_id: 9263401
project_number: 1R21AI129522-01
project_title: Pathogenesis of Borrelia mayonii infection
administering_ic: NIAID
award_notice_date: 2017-07-24
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AI
serial_number: 129522
program_official: ILIAS, MALIHA R
project_start_date: 2017-07-24
project_end_date: 2019-06-30
study_section: Special Emphasis Panel[ZRG1 IDM-R (02)]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTBorrelia mayonii is the causative agent of a newly-recognized tick-borne disease. First reported in the upperMidwest during February 2016 the geographic range of this emerging public health threat is not yet known.Although B. mayonii is related to the classic Lyme disease agent Borrelia burgdorferi the two species exhibitsubstantial genetic differences. We hypothesize that those differences are responsible for the distinct featuresof B. mayonii infection. A striking difference between the two diseases is the high spirochetemia that has beenobserved only in patients infected with B. mayonii. Other symptoms of B. mayonii infection include macularrashes across the body myalgia and neurological signs with some patients requiring hospitalization. Threecritical questions about B. mayonii and its associated disease are being addressed by our studies: (1) Whatare the extents of spirochetemia tissue pathology and other infectious qualities in untreated mammalian B.mayonii infection? (2) What is responsible for the high-level spirochetemia that occurs during B. mayoniiinfection but not during B. burgdorferi infection? and (3) What antigenic proteins are produced during B.mayonii infection but not during B. burgdorferi infection that can be used for diagnosis of this emergingdisease? Results from our studies will provide valuable insight on the pathogenic properties of B. mayonii andlay important groundwork for diagnosis and treatment.

project_terms:
Address;Affinity;Amino Acids;Antigens;Bacteremia;Bacterial Adhesins;Blood Vessels;Borrelia;Borrelia burgdorferi;Chromosomes Human 4-5;Clinical;Complement;Development;Diagnosis;Diffuse;Disease;Employee Strikes;Event;Exanthema;Exhibits;Genes;Genetic;Geography;Goals;Hospitalization;Human;Inbred Mouse;Infection;Lyme Disease;Membrane Proteins;Midwestern United States;Modeling;Molecular;Mus;Myalgia;Neurologic Signs;Orthologous Gene;OspC protein;Pathogenesis;Pathogenicity;Pathologic;Pathology;Patients;Property;Proteins;Proteomics;Public Health;Reporting;Surface Antigens;Symptoms;Tick-Borne Diseases;Ticks;Tissues;Virulence Factors;insight;macula;mouse model;novel;outer surface lipoprotein;pathogen;tool

public_health_relevance:
PROJECT NARRATIVEBorrelia mayonii is a newly-identified tick-borne pathogen of humans in the USA. Symptoms of B. mayoniiinfection include high-level bacteremia and diffuse macular rashes which are distinct from those of its relativeBorrelia burgdorferi the Lyme disease agent. The proposed studies focus on elucidating the molecularmechanisms responsible for the unique pathogenic properties of B. mayonii.


application_id: 9263192
project_number: 1UG1HD090904-01
project_title: The Kentucky Pediatric Clinical Trials Rural/Urban Partnership
administering_ic: NICHD
award_notice_date: 2016-09-21
opportunity_number: RFA-OD-16-001
application_type: 1
activity_code: UG1
ic: HD
serial_number: 090904
program_official: TAMBURRO, ROBERT F
project_start_date: 2016-09-21
project_end_date: 2016-09-22
study_section: Special Emphasis Panel[ZHD1 DRG-S (55)]
contact_pi_person_id: 2311234
contact_pi: SULLIVAN, JANICE E
other_pis: WATSON, SARA E
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT As a predominantly rural state Kentucky leads the nation in many pediatric and adult chronic andenvironmentally-related diseases and ranks nationally in low educational achievement. These adverse factorscombine to make Kentuckians especially unhealthy residents with a high prevalence of obesity diabetessmoking alcohol use heart disease stroke lung cancer etc. Many of these diseases are environmentallyrelated to poor nutrition obesity smoking drug abuse and work-place exposures. Kentucky also leads thenation in the percentage of pediatric populations with special health care needs. Prior work has shown thatmost adult diseases begin in childhood and some begin during intrauterine exposure making childhood theideal time for intervention with the goal of improving health outcomes into adulthood. Improving healthcare outcomes and wellness in children is contingent on expanding high quality clinicalresearch to include more diverse populations. Pediatricians at the University of Louisville (UofL) with ourHealthcare Partners serve a highly diverse patient population that includes the rural and urban poor a uniqueAppalachian community refugees and numerous ethnic minorities. In order to better serve this population wepropose to build upon our current programs expand our bidirectional community engagement effortscollaborate with other institutions on pediatric clinical trials through the IDeA Pediatric Trials Network andcollaborate with ECHO and CHEAR sites to advance healthcare for children. The Kentucky-Pediatric IDeA Research Center (K-PIRC) as part of the IDeA States Pediatric Clinical TrialNetwork will make it possible for 1) underserved rural and urban infants children and adolescents toparticipate in clinical research; 2) junior investigators to be trained in clinical research and communityengagement improve the health of both children and adults in Kentucky through this research and developtheir academic career; and 3) create a regional network of partners to sustain this clinical research initiative.The four primary focus areas of research are 1) upper and lower airway disease; 2) obesity; 3) pre- peri- andpostnatal outcomes; and 4) neurodevelopmental outcomes. These primary focus areas have a highprevalence in Kentucky therefore K-PIRC will enable strengthening current collaborations and accelerate thedevelopment of new networks within the state through bidirectional community engagement and feedback tosupport pediatric clinical research. Ultimately through these efforts the health outcomes of Kentucky childrenand adults will improve and a sustainable pediatric clinical research workforce locally and nationally will beestablished.

project_terms:
Address;Adolescent;Adult;Alcohol consumption;Applications Grants;Area;Assessment tool;Autistic Disorder;Child;Childhood;Chronic;Clinic;Clinical;Clinical Research;Clinical Trials;Clinical Trials Network;Collaborations;Communities;Development;Diabetes Mellitus;Disease;Drug abuse;Educational Status;Enrollment;Environmental Health;Etiology;Faculty;Feedback;Goals;Health;Health Benefit;Healthcare;Heart Diseases;High Prevalence;Individual;Infant;Institution;Intervention;Kentucky;Leadership;Malignant neoplasm of lung;Medical;Mentors;Mentorship;National Institute of Child Health and Human Development;National Institute of General Medical Sciences;Neonatal;Neurodevelopmental Disorder;Obesity;Outcome;Outcomes Research;Perinatal;Physicians;Population;Population Heterogeneity;Preparation;Preventive healthcare;Primary Health Care;Program Development;Program Research Project Grants;Provider;Publications;Refugees;Research;Research Infrastructure;Research Personnel;Resources;Rural;Rural Population;Scientist;Site;Smoking;Talents;Teacher Professional Development;Time;Training;Training Programs;Underserved Population;Universities;Urban Population;Work;Workplace;career;community based participatory research;community partnership;ethnic minority population;faculty research;fetal;improved;interest;life-long learning;member;nervous system disorder;next generation;novel strategies;nutrition;outreach;patient population;pediatrician;postnatal;programs;stroke;success;underserved rural area;urban area

public_health_relevance:
PROJECT NARRATIVEThe Kentucky-Pediatric IDeA Research Center (K-PIRC) as part of the IDeA States Pediatric Clinical TrialNetwork will make it possible for: 1) underserved rural and urban infants children and adolescents toparticipate in clinical research; 2) junior investigators to be trained in clinical research and communityengagement improve the health of both children and adults in Kentucky through this research and developtheir academic career; and 3) create a regional network of partners to sustain this clinical research initiative.The four primary focus areas are 1) upper and lower airway disease; 2) obesity; 3) pre- peri- and postnataloutcomes; and 4) neurodevelopmental. These primary focus areas are highly prevalent in Kentucky thereforethe efforts of the K-PIRC in collaboration with our community partners will improve the health outcomes ofKentucky children and adults.


application_id: 9262871
project_number: 5R01CA131075-07
project_title: Defining the contribution of ATR to MC1R-enhanced DNA repair in melanocytes
administering_ic: NCI
award_notice_date: 2017-03-17
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 131075
program_official: JOHNSON, RONALD L
project_start_date: 2010-07-01
project_end_date: 2021-03-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN A
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
A kinase anchoring protein;ATR gene;Address;Adenylate Cyclase;Affect;American;Ataxia;Binding;Biological Assay;Cancer Etiology;Cells;Cessation of life;Co-Immunoprecipitations;Complex;Coupled;Coupling;Cutaneous;Cyclic AMP;Cyclic AMP Receptors;Cyclic AMP-Dependent Protein Kinases;DNA;DNA Binding;DNA Damage;DNA Repair;Defect;Development;Diagnosis;ERCC1 gene;Event;Funding;GTP-Binding Protein alpha Subunits Gs;Generations;Genetic Polymorphism;Genome;Goals;Gravin;Incidence;Individual;Inherited;Laboratories;Left;Ligation;Link;Maintenance;Malignant Neoplasms;Measures;Mediating;Melanins;Melanocortin 1 Receptor;Melanocyte stimulating hormone;Melanoma Cell;Membrane;Modeling;Molecular;Mus;Mutagenesis;Mutagens;Mutation;Nuclear;Nucleotide Excision Repair;Oligonucleotides;Pathway interactions;Pharmacology;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Pigmentation physiologic function;Population;Positioning Attribute;Post-Translational Protein Processing;Prevention strategy;Preventive therapy;Production;Protein Kinase;Protein Phosphatase 2A Regulatory Subunit PR53;Proteomics;Public Health;Radiation therapy;Receptor Signaling;Recruitment Activity;Regulation;Repair Complex;Reporting;Resistance;Retrieval;Risk;Risk Factors;Role;Seminal;Signal Transduction;Skin;Skin Cancer;Surface;Surgical incisions;Time;Tissues;UV Radiation Exposure;UV response;Ultraviolet Rays;United States;Woman;Xeroderma Pigmentosum;base;cell type;chemotherapy;defined contribution;design;experimental study;high risk;loss of function;melanocyte;melanoma;men;mortality;prevent;receptor;repaired;response;therapy development;ultraviolet;ultraviolet damage


application_id: 9262052
project_number: 5F32AR069985-02
project_title: Enhancing myoblast fusion in muscular dystrophy
administering_ic: NIAMS
award_notice_date: 2017-03-30
opportunity_number: PA-14-149
application_type: 5
activity_code: F32
ic: AR
serial_number: 069985
program_official: BOYCE, AMANDA T
project_start_date: 2016-04-01
project_end_date: 2019-03-31
study_section: Special Emphasis Panel[ZRG1-F10B-B(20)L]
contact_pi_person_id: 11651573
contact_pi: HINDI, SAJEDAH M
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is a devastating genetic muscle disorder. Augmenting the regeneration potential of endogenous muscle progenitor cells is one of the potential approaches to attenuate disease progression in DMD. Moreover introduction of exogenous muscle stem cells can be used as an approach to restore dystrophin levels in DMD patients. However transplantation of muscle stem cells into dystrophic muscles typically results in minimal engraftment which is attributed at least in part o the poor fusion of the introduced myogenic cells with injured myofibers. While the mechanisms of myoblast fusion remain less understood enhancing fusion of endogenous or introduced myogenic cells has enormous potential for the development of novel cellular therapies for DMD patients. Ongoing studies in my laboratory have identified myeloid differentiation primary response gene 88 (Myd88) as a major positive regulator of myoblast fusion. Our preliminary studies have shown that levels of Myd88 are increased during muscle regeneration and upon induction of differentiation in cultured myoblasts. Genetic deletion of Myd88 specifically inhibits
myoblast fusion without affecting their proliferation and differentiation. While our preliminary studies clearly demonstrate that Myd88-mediated signaling promotes myoblast fusion it remains unknown whether augmenting the levels of Myd88 in myoblasts can stimulate myofiber regeneration and improve engraftment of introduced myoblasts in DMD. In this project we have proposed to investigate the effects of myoblast-specific ablation and overexpression of Myd88 on disease progression in a preclinical mouse model of DMD. Our hypothesis and specific aims are: AIM I: Investigate the effects of myoblast-specific deletion of Myd88 in myopathy of mdx mice. Hypothesis I: Myoblast-specific deletion of Myd88 will inhibit repair of injured myofibers and exaggerate myopathy in mdx mice. AIM II: Investigate the effects of myoblast-specific overexpression of Myd88 in the pathogenesis of mdx mice. Hypothesis IIa: Overexpression of Myd88 in exogenous myoblasts (before transplantation) will improve their engraftment in dystrophic muscle of mdx mice; and Hypothesis IIb: Myoblast-specific transgenic overexpression of Myd88 will enhance myofiber regeneration and mitigate myopathy in mdx mice. Successful completion of this work will provide basis for considering Myd88 as therapeutic target in preclinical trials for patients with DMD. Furthermore the project will provide me outstanding new training to achieve my goal of becoming a tenure-track faculty in an academic institution.

project_terms:
Ablation;Adult;Affect;Alpha Cell;Attenuated;Caliber;Cell Therapy;Cells;Cessation of life;Complementary DNA;Defect;Development;Disease Progression;Duchenne muscular dystrophy;Dystrophin;Engraftment;Faculty;Fibrosis;Fluorescence;Future;Gene Expression;Genes;Genetic;Genomics;Goals;Hereditary Disease;Impairment;In Vitro;Inbred mdx Mice;Individual;Injury;Institution;Interleukin-1;Knock-out;Knockout Mice;Laboratories;Lentivirus Vector;Life;Mediating;Messenger RNA;Mus;Muscle;Muscle Fibers;Muscle function;Muscle satellite cell;Muscular Atrophy;Muscular Dystrophies;Myelogenous;Myoblasts;Myopathy;Natural regeneration;Pain;Pathogenesis;Pathway interactions;Patients;Phenotype;Physiological;Pre-Clinical Model;Process;Proteins;Proteomics;Reporting;Role;Signal Pathway;Signal Transduction;Signaling Protein;Skeletal Muscle;Small Interfering RNA;Stem cells;Toll-like receptors;Training;Transgenic Mice;Transgenic Organisms;Transplantation;WNT Signaling Pathway;Wild Type Mouse;Work;barium chloride;disability;gain of function;improved;injured;interleukin-18 receptor;knock-down;loss of function;molecular targeted therapies;mouse model;muscle regeneration;muscle transplantation;novel;overexpression;pre-clinical;preclinical trial;premature;promoter;public health relevance;reduced muscle strength;repaired;response;tenure track;therapeutic target;tibialis anterior muscle

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Duchenne muscular dystrophy (DMD) is the most prevalent form of muscular dystrophy which involves severe muscle-wasting fibrosis and premature death of afflicted individuals. We have identified Myd88 as a major regulator of myoblast fusion. We will investigate whether enhancing the levels of Myd88 in myoblasts can improve their fusion and improve regeneration of myofibers in preclinical models of DMD. Our proposed studies will provide strong basis whether Myd88 can be used as novel molecular target for treatment of DMD patients in future therapies.


application_id: 9261875
project_number: 1R01CA213990-01
project_title: Transcriptional Regulation of Immunosuppressive Macrophages by c-Maf in Cancer
administering_ic: NCI
award_notice_date: 2017-02-06
opportunity_number: PA-13-302
application_type: 1
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_terms:
Agonist;Anti-Inflammatory Agents;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;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;Natural immunosuppression;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;T-Lymphocyte;TNF gene;Testing;Transcriptional Regulation;Tumor Burden;Vascular Endothelial Growth Factors;Yeasts;arginase;bZIP Domain;base;beta-Glucans;c-myc Genes;cancer immunotherapy;chemotherapeutic agent;chemotherapy;cytokine;dectin 1;density;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


application_id: 9261469
project_number: 5F30AI114194-03
project_title: Elucidating binding fusion and entry of HMPV in cell culture and host tissue
administering_ic: NIAID
award_notice_date: 2017-03-24
opportunity_number: PA-14-150
application_type: 5
activity_code: F30
ic: AI
serial_number: 114194
program_official: KIM, SONNIE
project_start_date: 2015-05-01
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1-F13-C(20)L]
contact_pi_person_id: 12024712
contact_pi: KLIMYTE, EDITA MARIA
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): Human metapneumovirus (HMPV) is a recently discovered respiratory pathogen in the Paramyxoviridae family that infects nearly 100% of the world population. This enveloped virus causes severe viral respiratory disease in infants the elderly and immunocompromised patients worldwide. In fact HMPV is estimated to be the second most common cause of pediatric lower respiratory illness following the closely related respiratory syncytial virus. Furthermore the rate of hospitalization for respiratory disease caused by HMPV in adults over the age of 65 is near that of influenza. Despite its clinical significance there is no antiviral treatment or vaccine available at this time. Since its discovery several key factors have been identified to play a role in HMPV entry but much of the mechanisms of binding fusion and entry remain unsolved. It has been previously shown by our group that heparan sulfate is a required moiety for HMPV binding and infectivity; however it is not known if heparan sulfate proteoglycans (HSPGs) serve as a receptor or mediate other necessary cellular factors on the plasma membrane. Furthermore the route of entry has not been identified for HMPV. Thus to elucidate the role of HSPGs we will utilize a collection of currently available HMPV strains from laboratory strains and clinical isolates to determine the effects of heparan sulfate blocking molecules and knockdown studies on specific HSPGs; in order to identify the route of entry we will utilize viral particles with fluorescent labeled envelopes to track if membrane fusion is occurring at the plasma membrane or within intracellular compartments. Finally we propose to study HMPV entry in the context of traditional cell culture utilizing physiologically relevant cell lines derived from human lung tissue such as Beas-2B Calu-3 and A549 as well as novel human airway epithelial tissue to elucidate important details about its life cycle in this model and identify potential factors that may affectHMPV infection in vivo. We hypothesize heparan sulfate proteoglycans specifically the syndecan moieties serve as an attachment factor for HMPV which is required for internalization and membrane fusion occurs in intracellular compartments. We expect heparan sulfate is also critical for viral infectivity in human airway epithelium. We also anticipate tissus derived from patients with chronic respiratory disease will show an increased permissibility to HMPV infection.

project_terms:
A549;Address;Adult;Adult Acute Lymphocytic Leukemia;Affect;Antigens;Antiviral Agents;Area;Asthma;Binding;Biological Models;Bronchiolitis;Caveolins;Cell Culture Techniques;Cell Line;Cell membrane;Cells;Chemicals;Child;Childhood;Chimeric Proteins;Chronic;Chronic Disease;Clathrin;Clinical;Collection;Complex;Dendrimers;Dependence;Development;Disease;Dynamin;Elderly;Endocytosis;Endosomes;Epithelial;Epithelium;Escherichia coli;Excision;Family;Glycoproteins;HIV;Heparan Sulfate Proteoglycan;Heparitin Sulfate;Hospitalization;Human;Human Metapneumovirus;Immunocompromised Host;Infant;Infection;Influenza;Intervention;Label;Laboratories;Life Cycle Stages;Lipids;Lung;Lung diseases;Mediating;Membrane Fusion;Modeling;Molecular;Mucous body substance;Paramyxoviridae;Paramyxovirus;Pathway interactions;Patients;Peptides;Physiological;Play;Pneumonia;Pneumovirinae;Population;Predisposition;Production;RNA Viruses;Respiratory Signs and Symptoms;Respiratory Tract Diseases;Respiratory syncytial virus;Role;Route;Site;Structure of parenchyma of lung;Surface;System;Time;Tissue Model;Tissues;Trypsin;Unspecified or Sulfate Ion Sulfates;Vaccines;Viral;Virus;Virus Replication;airway epithelium;airway hyperresponsiveness;cell type;cellular targeting;clinically significant;human disease;in vivo;inhibitor/antagonist;knock-down;member;monolayer;mortality;novel;older patient;particle;pathogen;public health relevance;receptor;reconstitution;respiratory;syndecan;uptake;virus envelope

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Human metapneumovirus is a prevalent cause of respiratory disease in children and adults all over the world. It is important to understand how the virus getsinto the cells of the lungs in order to develop treatments and vaccines for this virus.


application_id: 9261099
project_number: 1R13AI129382-01
project_title: Autumn Immunology Conference
administering_ic: NIAID
award_notice_date: 2016-11-01
opportunity_number: PA-13-347
application_type: 1
activity_code: R13
ic: AI
serial_number: 129382
program_official: MILLER, LARA R
project_start_date: 2016-11-01
project_end_date: 2018-10-31
study_section: Special Emphasis Panel[ZAI1 TC-M (S2)]
contact_pi_person_id: 1864845
contact_pi: SNOW, ERNEST CHARLES
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Allergic Disease;Applied Research;Autoimmunity;Award;Basic Science;Cancer Biology;Collaborations;Communicable Diseases;Data;Discipline;Education;Educational workshop;Equilibrium;Feedback;Fostering;Funding;Gender;Goals;Grant;Immune System Diseases;Immunology;Individual;Inflammation;Institution;Mentors;Midwestern United States;National Institute of Allergy and Infectious Disease;Oral;Participant;Pathogenesis;Postdoctoral Fellow;Preparation;Recruitment Activity;Request for Applications;Request for Proposals;Research;Research Personnel;Scholarship;Science;Scientist;Travel;Underrepresented Minority;United States;United States National Institutes of Health;Vendor;Woman;career;career development;design;interest;meetings;minority scientist;posters;prevent;programs;racial and ethnic;symposium;undergraduate student;vaccine development

public_health_relevance:
Project NarrativeThis application requests funding for an annual scientific conference called theAutumn Immunology Conference. The purpose of this meeting is to exchangeand disseminate information and to explore contemporary problems in the fieldof Immunology. Thus it is consistent with the fiscal and programmatic priorities ofthe National Institutes of Allergy and Infectious Diseases (NIAID) which is toconduct and support basic and applied research to better understand treat andultimately prevent infectious immunologic and allergic diseases.


application_id: 9261019
project_number: 1R13DC015972-01
project_title: International Society of Neurogastronomy 2106 Conference
administering_ic: NIDCD
award_notice_date: 2016-09-13
opportunity_number: PA-13-347
application_type: 1
activity_code: R13
ic: DC
serial_number: 015972
program_official: SULLIVAN, SUSAN L
project_start_date: 2016-09-13
project_end_date: 2017-08-31
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe objective of this conference grant request is to provide support for certain aspects ofthe 2nd annual meeting of the International Society of Neurogastronomy (ISN). ISN is anew society whose composition of scientists clinicians nutritionists food serviceprofessionals and chefs naturally predisposes it to focus on translational issuesfundamental to how the chemical senses impact human health. The first two specificobjectives are to provide a venue and opportunity that brings these groups together andfacilitates the synergies that arise when distinctly different fields interact productively. Thethird specific objective is to attract and stimulate the young scientists that are the future ofthe field of neurogastronomy. The fourth specific objective is to ensure that this new fieldembraces a culture of diversity weaving this principle into its early development byrecruiting persons of diverse backgrounds to the conference.

project_terms:
Agriculture;Appalachian Region;Area;Chemicals;Clinical;Development;Diet Habits;Disabled Persons;Education;Ensure;Environment;Equation;Equilibrium;Event;Flavoring;Food;Food Services;Fostering;Funding;Future;Goals;Grant;Health;Human;International;Knowledge;Life;Mission;Neurosciences;Nutritional;Nutritionist;Perception;Persons;Policies;Quality of life;Recruitment Activity;Rural;Science;Scientist;Societies;Structure;Training;Underrepresented Groups;Veterans;Work;citizen science;design;ethnic minority population;improved;interest;meetings;member;nutrition;preference;racial and ethnic;social;sound;symposium


application_id: 9260882
project_number: 5R01DE012505-20
project_title: Molecular Aspects of Oral Plaque Formation
administering_ic: NIDCR
award_notice_date: 2017-04-24
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DE
serial_number: 012505
program_official: LUNSFORD, DWAYNE
project_start_date: 1998-09-01
project_end_date: 2018-04-30
study_section: Special Emphasis Panel[ZRG1-MOSS-B(02)M]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: DEMUTH, DONALD R
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): Periodontal disease one of the most common infections of humans has a polymicrobial etiology whereby groups of microorganisms exhibit synergistic pathogenicity. As a model system for the study of polymicrobial synergy we are investigating P. gingivalis-S. gordonii interactions. S. gordonii an early colonizer of the plaquebiofilm provides an attachment substratum for the more pathogenic later colonizer P. gingivalis. Contact dependent signaling and metabolite perception initiate further accumulation of P. gingivalis and the development of a dual species community. Interspecies coadhesion is mediated by the short fimbriae (comprised of the Mfa1 structural subunit) of P. gingivalis that engage the Ssp surface proteins of S. gordonii. Within SspB several amino acid motifs within a region spanning residues 1167-1193 (designated BAR) dictate binding activity and specificity. Development and later constraint of community development depends on the balance of tyrosine phosphorylation (through the kinase Ptk1) and dephosphorylation (through the phosphatase Ltp1) within P. gingivalis which controls expression of community effectors such as Mfa1 and LuxS. This tyrosine (de)phosphorylation dependent signal transduction pathway also converges on the expression genes encoding proteases and a dual species community of P. gingivalis and S. gordonii is more pathogenic compared to either species alone in a murine alveolar bone loss model. The objectives of this study are to: i) characterize the structural and functional motifs of Mfa1 that interact with the BAR domain of SspB; ii) define the role of the P. gingivalis tyrosine kinase Ptk1 in regulatory networks that control heterotypic community development with S. gordonii; and iii) determine the responses of P. gingivalis to the streptococcal metabolite 4-aminobenzoate (pABA) that regulate community development and pathogenic potential. Successful completion of these objectives will provide novel structure and function information on the P. gingivalis Mfa1 fimbrial adhesin. In addition we will unravel the interplay between tyrosine kinase (Ptk1) and phosphatase (Ltp1) activities in the signal transduction events that regulate community development. We will also generate novel information regarding metabolite sensing and its role in both community development and pathogenic potential. Our broad long-term goal is to translate this fundamental mechanistic information into the identification of novel targets for therapeutic intervention directed toward pathogenic community inhibition. As single target intervention can have limited utility and has yet to yield any significant advances in periodontal therapeutic options interference with multiple components of pathogenic community development including adhesive and maturation events may have a greater likelihood of success.

project_terms:
Adherence;Adhesives;Affect;Alveolar Bone Loss;Amino Acid Motifs;Bacteria;Bacterial Infections;Bacteroides;Binding;Biochemical;Biological Models;Catalytic Domain;Cell Communication;Cells;Communication;Communities;Community Developments;Complex;Coupled;Development;Disease;Disease Progression;Equilibrium;Etiology;Event;Exhibits;Fimbrial Adhesins;Gene Expression;Gene Expression Regulation;Genes;Goals;Human;Infection;Intercept;Intervention;Maps;Mediating;Membrane Proteins;Metabolic;Microbial Biofilms;Modeling;Molecular;Molecular Models;Mono-S;Mus;Oral;Oral cavity;Organism;Pathogenesis;Pathogenicity;Peptide Hydrolases;Perception;Periodontal Diseases;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Porphyromonas gingivalis;Process;Production;Protein Dephosphorylation;Protein Tyrosine Kinase;Protein Tyrosine Phosphatase;Proteins;Regulation;Role;Severities;Signal Transduction;Signal Transduction Pathway;Specificity;Streptococcus gordonii;Structure;Surface;System;Testing;Therapeutic;Therapeutic Intervention;Tooth structure;Toothpaste;Translating;Tyrosine;Tyrosine Phosphorylation;Virulence;base;bone loss;microbial;microbial community;microorganism;microorganism culture;molecular modeling;mutant;new therapeutic target;novel;oral plaque;pathogen;prevent;protein metabolite;public health relevance;response;success;synergism;yeast two hybrid system

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Information that will be obtained from this study has the potential to be translated into the development of toothpastes or mouthrinses that can prevent disease causing organisms from accumulating on the teeth. These would reduce the ability of disease causing bacteria to persist in the mouth and consequently prevent or reduce the severity of gum disease.


application_id: 9260876
project_number: 5R21EB022185-02
project_title: Vascularized cell-based device for restoring physiological homeostasis
administering_ic: NIBIB
award_notice_date: 2017-01-05
opportunity_number: PA-12-284
application_type: 5
activity_code: R21
ic: EB
serial_number: 022185
program_official: RAMPULLA, DAVID
project_start_date: 2016-04-15
project_end_date: 2018-12-31
study_section: Bioengineering, Technology and Surgical Sciences Study Section[BTSS]
contact_pi_person_id: 8307477
contact_pi: BOYD, NOLAN LEE
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_abstract:
DESCRIPTION (provided by applicant): Cell source and vascularization are two challenges to successful cell-based therapy. In this proposal we present an enabling technology for the vascularization of physiologically restored parenchymal cells derived from genetically deficient induced pluripotent stem cells (iPSC). As a proof-of-principle we have restored the low-density lipoprotein receptor (LDLR) feedback endocytosis in Familial Hypercholesterolemia (FH) iPSC. We will derive restored hepatocyte-like cells (HLC) and combine them with a unique stromal and vascularization cell source isolated from adipose tissue known as the stromal vascular fraction (SVF). The objective of this proposal is to determine the capacity of an ectopic cell-based apheresis and metabolism device to modulate circulating LDL cholesterol (LDL-C) under hypercholesterolemic conditions. We will pursue this objective through the following Specific Aims: Aim 1: Determine the apheresis device LDL-C metabolism function. In this Aim we will investigate our device design for LDL-C internalization and metabolism parenchymal cell survival device vascularization and residual pluripotent cell elimination. Aim 2: Determine the apheresis device capacity to modulate circulating LDL-C. In this Aim we will investigate the capacity of the device to engraft modulate LDL-C levels and produce human circulating proteins.

project_terms:
Address;Adipocytes;Adipose tissue;Affect;Alpha Cell;Apolipoprotein A-I;Apolipoprotein E;Autologous;Bile Acid Biosynthesis Pathway;Bile Acids;Blood Circulation;Blood Coagulation Factor;Blood Component Removal;Blood Vessels;Cell Fraction;Cell Survival;Cell Therapy;Cells;Cholesterol Homeostasis;Complex;Data;Development;Device Designs;Device Removal;Devices;Diet;Digestion;Drug Implants;Endocytosis;Endothelium;Engraftment;Excision;Familial Hypercholesterolemia;Feedback;Functional disorder;Genetic;Genomic DNA;Hepatocyte;Homeostasis;Human;Immune;Implant;LDL Cholesterol Lipoproteins;Lipids;Liver;Location;Low Density Lipoprotein Receptor;Low-Density Lipoproteins;Mediating;Mesenchymal;Metabolism;Microcirculation;Modeling;Modification;Organ;Organoids;Pathology;Patients;Pericytes;Physiological;Plasma;Plasmids;Population;Production;Proteins;Publishing;Rag1 Mouse;Residual state;Retrieval;Source;Stream;System;Technology;Technology Transfer;Teratoma;Therapeutic;Tissue Engineering;Toxin;Triglycerides;Vascularization;base;cancer cell;cardiovascular disorder risk;chylomicron remnant;collagenase;disorder risk;gene product;implantation;in vivo;induced pluripotent stem cell;macromolecule;mouse model;public health relevance;receptor;receptor expression;receptor mediated endocytosis;restoration;subcutaneous;vector

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cell-based technologies could be used for removing circulating toxins or providing missing biomolecules due to genetic deficiencies. Induced pluripotent stem cells (iPSC) could provide an unparalleled autologous cell source for therapeutic applications; however they may require modification to restore physiological function. Additionally engineered tissues are challenged by poor vascularization. In this project we propose to develop a vascularized cell-based enabling technology that is functionally modifiable to the patient's requirements. As a proof-of-principle we will deliver hepatocyte-like cells (HLC) derived from low-density lipoprotein receptor (LDLR) deficient Familial Hypercholesterolemia iPSC that have receptor mediated endocytosis feedback control restored. The FH-HLC-LDLR will be combined with a unique vascularization cell source isolated from adipose tissue. The implant will function as an ectopic device for removal and metabolism of excess circulating LDL to reduce the risk of cardiovascular disease development.


application_id: 9260447
project_number: 1P42ES023716-01A1
project_title: Characterizing Urban- and Finer-Scale Spatial Variability for Select VOC Superfund Compounds
administering_ic: NIEHS
award_notice_date: 2017-09-01
opportunity_number: RFA-ES-15-019
application_type: 1
activity_code: P42
ic: ES
serial_number: 023716
suffix: A1
study_section: Special Emphasis Panel[ZES1 LKB-K (S)]
subproject_number: 5123
contact_pi_person_id: 10828196
contact_pi: TURNER, JAY ROBERT
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-08-15
project_terms:
Air;Automobile Driving;Benzene;Categories;Complex;Coupled;Data;Data Analyses;Data Quality;Development;Disease;Disease Progression;Ecology;Environment;Environmental Engineering technology;Environmental Exposure;Equipment and supply inventories;Etiology;Exhibits;Exposure to;Future;Gases;Geography;Goals;Green space;Health;Heart;Housing;Human;Industrialization;Location;Measurement;Modeling;Monitor;Neighborhoods;Nitrogen Dioxide;Participant;Particulate Matter;Pattern;Proxy;Research Project Grants;Resolution;Route;Sampling;Scheme;Seasons;Site;Small-Area Variations;Source;Superfund;Testing;Time;Variant;Work;density;design;design and construction;field study;insight;land use;metropolitan;miniaturize;mobile computing;model building;novel;pollutant;portability;remediation;sample collection;spatial relationship;study population;superfund chemical;tool;urban area;urinary;volatile organic compound


application_id: 9260446
project_number: 1P42ES023716-01A1
project_title: Development of Novel Ultrasensitive Devices for the Measurement of VOCs
administering_ic: NIEHS
award_notice_date: 2017-09-01
opportunity_number: RFA-ES-15-019
application_type: 1
activity_code: P42
ic: ES
serial_number: 023716
suffix: A1
study_section: Special Emphasis Panel[ZES1 LKB-K (S)]
subproject_number: 5122
contact_pi_person_id: 9972311
contact_pi: NANTZ, MICHAEL H
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-08-15
project_terms:
13-Butadiene;Acrolein;Acute;Adsorption;Air;Benzene;Biomedical Research;Butadiene;Chemicals;Chronic;Complex;Coupled;Custom;Detection;Development;Devices;Disease;Ecology;Electrodes;Engineering;Environmental Exposure;Environmental Monitoring;Environmental Pollutants;Exposure to;Face;Gas Chromatography;Gases;Goals;Gold;Health;High Pressure Liquid Chromatography;Human;Insulin Resistance;Ions;Liquid substance;Mass Spectrum Analysis;Measurement;Measures;Methods;Modification;Normal Range;Oxidants;Pattern;Process;Research;Research Project Grants;Security;Signal Transduction;Silicon;Site;Sulfhydryl Compounds;Superfund;Surface;System;Techniques;Technology;Temperature;Tube;Vinyl Chloride;Work;adduct;air sampling;base;carbonyl compound;cost;design;functional group;glycolaldehyde;improved;mass spectrometer;metal oxide;microsensor;miniaturize;nanoparticle;new technology;novel;sensor;simulation;superfund site;vascular inflammation;volatile organic compound


application_id: 9260445
project_number: 1P42ES023716-01A1
project_title: Molecular and Cellular Mechanisms of Cardiometabolic Toxicity of VOCs
administering_ic: NIEHS
award_notice_date: 2017-09-01
opportunity_number: RFA-ES-15-019
application_type: 1
activity_code: P42
ic: ES
serial_number: 023716
suffix: A1
study_section: Special Emphasis Panel[ZES1 LKB-K (S)]
subproject_number: 5121
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-08-15
project_terms:
ATF6 gene;Acids;Acrolein;Adipose tissue;Adult;Affect;Aldehydes;Apoptosis;Atherosclerosis;Attenuated;Benzene;Biochemical Pathway;Biological;Biological Markers;Blood Vessels;Body Burden;Butyric Acids;Cardiovascular Diseases;Cardiovascular system;Carnosine;Cell Respiration;Chemical Exposure;Chemical Injury;Chemicals;Chronic Disease;Data;Deposition;Development;Diabetes Mellitus;Diet;Disease;Disease Resistance;Dyslipidemias;Endoplasmic Reticulum;Endothelial Cells;Environmental Exposure;Environmental Impact;Enzymes;Exposure to;Fatty Liver;Fatty acid glycerol esters;Functional disorder;Goals;Hazardous Chemicals;Hazardous Substances;Health;Hepatic;High Prevalence;Individual;Inflammatory;Injury;Insulin Resistance;Investigation;Lead;Link;Lipids;Measures;Mediator of activation protein;Metabolic;Metabolism;Molecular;Molecular Chaperones;Mus;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Nutritional status;Obesity;Organic Chemicals;Oxidative Stress;Parents;Particulate;Particulate Matter;Pathway interactions;Pharmacology;Phase;Plants;Plasma;Poisons;Polyvinyl Chloride;Process;Production;Proteins;Protocols documentation;Reporting;Risk;Role;Series;Signal Transduction;Stress;Superfund;Surveys;Symptoms;Testing;Therapeutic;Tissues;Tobacco smoke;Toxic effect;Vinyl Chloride;Work;aldehyde dehydrogenases;ambient air pollution;cardiovascular disorder risk;cardiovascular health;design;endoplasmic reticulum stress;global health;insight;insulin sensitivity;metabolomics;mouse model;novel;overexpression;oxidized lipid;prevent;protein folding;response;stroke;superfund site;tauroursodeoxycholic acid;therapeutic evaluation;therapy design;toxicant;urinary;vascular inflammation;volatile organic compound;western diet


application_id: 9260444
project_number: 1P42ES023716-01A1
project_title: Environmental Exposure and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2017-09-01
opportunity_number: RFA-ES-15-019
application_type: 1
activity_code: P42
ic: ES
serial_number: 023716
suffix: A1
study_section: Special Emphasis Panel[ZES1 LKB-K (S)]
subproject_number: 5120
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-08-15
project_terms:
Air;Area;Arsenic;Attention;Benzene;Biochemical Pathway;Biological Markers;Blood;Blood Coagulation Factor;Blood Platelets;Cardiac Death;Cardiovascular Diseases;Cardiovascular system;Case-Control Studies;Cause of Death;Cell physiology;Cessation of life;Chronic;Clinical;Collaborations;Communities;Cross-Sectional Studies;Cytokeratin 18;Data;Databases;Death Certificates;Development;Disease;Disease Progression;Dyslipidemias;Endocrine Disruptors;Endothelial Cells;Enrollment;Environment;Environmental Exposure;Environmental Pollutants;Environmental Risk Factor;Event;Exposure to;Fatty Liver;Geography;Glucose Intolerance;Goals;Heart;Heart Diseases;Hot Spot;Human;Impact evaluation;Individual;Industrialization;Industry;Inflammation;Injury;Insulin;Insulin Resistance;Lipids;Liver diseases;Longitudinal prospective study;Measures;Medical;Medical History;Metabolic;Metabolic Marker;Metabolism;Modeling;Monitor;Non obese;Non-Insulin-Dependent Diabetes Mellitus;Nutritional status;Obesity;Occupational;Occupational Exposure;Outcome Measure;Participant;Particulate;Pathogenicity;Pathway interactions;Plants;Plasma;Population;Prevalence;Process;Prospective Studies;Publishing;Research;Resources;Retrospective Studies;Risk;Rodent;Role;Sampling;Serum;Severities;Specimen;Stem cells;Superfund;Testing;Time;Toxicology;Toxin;Urine;Vinyl Chloride;Work;adipokines;animal data;atherogenesis;base;biobank;blood glucose regulation;cardiovascular disorder risk;cardiovascular injury;cohort;cytokine;data management;endoplasmic reticulum stress;endothelial dysfunction;exposed human population;insulin signaling;monocyte;novel;novel marker;nutrition;pollutant;primary outcome;prospective;superfund chemical;superfund site;translational study;urinary;volatile organic compound


application_id: 9260443
project_number: 1P42ES023716-01A1
project_title: Sample and Data Management Core
administering_ic: NIEHS
award_notice_date: 2017-09-01
opportunity_number: RFA-ES-15-019
application_type: 1
activity_code: P42
ic: ES
serial_number: 023716
suffix: A1
study_section: Special Emphasis Panel[ZES1 LKB-K (S)]
subproject_number: 5119
contact_pi_person_id: 9753394
contact_pi: RAI, SHESH N.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-08-15
project_terms:
Animals;Annual Reports;Archives;Basic Science;Bioinformatics;Biological;Biometry;Biostatistical Methods;Cataloging;Catalogs;Clinical Investigator;Clinical Research;Clinical Trials;Collaborations;Collection;Communities;Consultations;Continuing Education;Data;Data Analyses;Development;Dimensions;Disease;Educational workshop;Elements;Ensure;Environment;Environmental Exposure;Evaluation;Experimental Designs;Exposure to;Faculty;Fostering;Future;Goals;Hazardous Chemicals;Hazardous Substances;Health;Human Resources;Individual;Journals;Metabolism;Methods;Modeling;Outcome;Population Analysis;Postdoctoral Fellow;Preparation;Prevention;Procedures;Productivity;Protocols documentation;Publications;Records;Reproducibility;Research;Research Activity;Research Design;Research Personnel;Resources;Risk;Risk Assessment;Sampling;Scientist;Services;Signal Recognition Particle;Source;Specimen;Statistical Data Interpretation;Statistical Methods;Students;Superfund;System;Technology;Testing;Tissues;Toxic effect;Training;Translational Research;Universities;Work;base;biobank;career development;cohesion;cohort;data archive;data management;design;disorder risk;efficacy testing;epidemiology study;experience;experimental analysis;graduate student;innovation;meetings;member;novel;operation;pollutant;preclinical study;programs;quality assurance;radio frequency;repository;statistical service;tool;usability


application_id: 9260442
project_number: 1P42ES023716-01A1
project_title: Metabolism and Toxicity Core
administering_ic: NIEHS
award_notice_date: 2017-09-01
opportunity_number: RFA-ES-15-019
application_type: 1
activity_code: P42
ic: ES
serial_number: 023716
suffix: A1
study_section: Special Emphasis Panel[ZES1 LKB-K (S)]
subproject_number: 5118
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-08-15
project_terms:
Address;Analytical Chemistry;Animals;Biochemistry;Biological Assay;Biological Markers;Biology;Cells;Charge;Chemical Exposure;Clinical;Communities;Complex;Continuing Education;Data;Detection;Development;Disease;Ensure;Environmental Exposure;Equipment;Extramural Activities;Faculty;Felis catus;Flow Cytometry;Future;Goals;Histologic;Human;Human Resources;Informatics;Measurement;Metabolic;Metabolism;Mission;Mus;Pathologic;Pathology;Physiological;Population;Postdoctoral Fellow;Procedures;Property;Proteomics;Protocols documentation;Research;Research Infrastructure;Research Personnel;Resolution;Resources;Role;Sampling;Services;Signal Transduction;Superfund;Techniques;Technology;Testing;Therapeutic Intervention;Toxic effect;Toxicology;Toxin;Training;Universities;Validation;career development;flexibility;graduate student;interest;investigator training;meetings;member;metabolomics;novel;operation;response;success;superfund chemical;systemic toxicity;volatile organic compound


application_id: 9260441
project_number: 1P42ES023716-01A1
project_title: Research Translation Core
administering_ic: NIEHS
award_notice_date: 2017-09-01
opportunity_number: RFA-ES-15-019
application_type: 1
activity_code: P42
ic: ES
serial_number: 023716
suffix: A1
study_section: Special Emphasis Panel[ZES1 LKB-K (S)]
subproject_number: 5117
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-08-15
project_terms:
Administrator;Affect;Area;Awareness;Basic Science;Cardiovascular Diseases;Chemical Exposure;Chemicals;Collaborations;Communication;Communities;Consequentialism;Data;Decision Making;Detection;Development;Devices;Diabetes Mellitus;Disease;Education;Educational Activities;Educational Materials;Educational Technology;Effectiveness;Emergency response;Engineering;Ensure;Environment;Environmental Exposure;Environmental Health;Evaluation;Exposure to;Federal Government;General Population;Goals;Government;Government Agencies;Government Officials;Health;Health Policy;Health Professional;Human;Human Resources;Information Dissemination;Institution;Intellectual Property;Kentucky;Knowledge;Learning;Link;Liver diseases;Local Government;Medical emergency;Methods;National Institute of Environmental Health Sciences;Newsletter;Organic Chemicals;Participant;Pathway interactions;Policies;Policy Maker;Population;Process;Public Health;Regulation;Research;Research Activity;Research Personnel;Risk Estimate;Science;Scientist;State Government;Students;Superfund;Technology;Technology Transfer;Time;Training;Translating;Translational Research;Work;base;effectiveness research;experience;federal policy;health organization;innovation;interest;meetings;member;news;novel;programs;public health relevance;social media;superfund chemical;superfund site;symposium;tailored messaging;tool;web site;webinar


application_id: 9260440
project_number: 1P42ES023716-01A1
project_title: Community Engagement Core
administering_ic: NIEHS
award_notice_date: 2017-09-01
opportunity_number: RFA-ES-15-019
application_type: 1
activity_code: P42
ic: ES
serial_number: 023716
suffix: A1
study_section: Special Emphasis Panel[ZES1 LKB-K (S)]
subproject_number: 5116
contact_pi_person_id: 11775218
contact_pi: HEBERLE, LAUREN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-08-15
project_terms:
Address;Adult;Affect;African American;Age;Air;Air Pollution;Area;Awareness;Back;Belief;Centers for Disease Control and Prevention (U.S.);Child;Chronic;Chronic Disease;Code;Communities;Dangerousness;Data;Death Rate;Development;Diabetes Mellitus;Disease;Elements;Ensure;Environment;Environmental Exposure;Environmental Health;Equipment;Evaluation;Exposure to;Fatty Liver;Feedback;Future;Goals;Government;Grant;Green space;Growth;Health;Health Food;Health Sciences;Heart Diseases;Hepatic;Home environment;Hospitals;Hot Spot;Housing;Hypertension;Industrialization;Industry;Intervention;Kentucky;Knowledge;Liver diseases;Love;Malignant Neoplasms;Marines;Measures;Medical;Monitor;Natural Sciences;Neighborhoods;Obesity;Participant;Perception;Plants;Play;Policy Maker;Population;Poverty;Prevention;Preventive Intervention;Process;Public Health;Recording of previous events;Recruitment Activity;Research;Research Personnel;Research Project Grants;Resources;Risk;Role;Scientist;Social Sciences;Source;Superfund;Surveillance Program;Syndrome;Testing;Toxic effect;Training;Transcend;Translational Research;Transportation;Trees;Vinyl Chloride;Work;attributable mortality;biological systems;community center;fighting;health care delivery;health disparity;landfill;meetings;member;pollutant;public health relevance;racial disparity;social;superfund site;therapy design;toxicant


application_id: 9260439
project_number: 1P42ES023716-01A1
project_title: Administrative Core
administering_ic: NIEHS
award_notice_date: 2017-09-01
opportunity_number: RFA-ES-15-019
application_type: 1
activity_code: P42
ic: ES
serial_number: 023716
suffix: A1
study_section: Special Emphasis Panel[ZES1 LKB-K (S)]
subproject_number: 5115
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-08-15
project_terms:
Administrator;Advisory Committees;Collaborations;Communication;Communities;Consultations;Core Facility;Counseling;Data;Development;Development Plans;Diabetes Mellitus;Discipline;Disease;Ensure;Environment;Environmental Exposure;Evaluation;Focus Groups;Funding;Future;Goals;Hazardous Chemicals;Heart Diseases;Human Resources;IACUC;Individual;Institutional Review Boards;Leadership;Link;Liver diseases;Logistics;Mentors;Monitor;National Institute of Environmental Health Sciences;Productivity;Progress Reports;Protocols documentation;Quality Control;Reagent;Regulation;Research;Research Personnel;Research Project Grants;Research Training;Resource Sharing;Resources;Scientific Evaluation;Selection Criteria;Signal Recognition Particle;Specimen;Students;Superfund;Time;Training;Training Activity;Training and Education;Translational Research;Universities;Work;effectiveness research;experimental study;meetings;member;operation;programs;tool;training opportunity;web site


application_id: 9260437
project_number: 1P42ES023716-01A1
project_title: Environmental Exposure and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2017-09-01
opportunity_number: RFA-ES-15-019
application_type: 1
activity_code: P42
ic: ES
serial_number: 023716
suffix: A1
program_official: CARLIN, DANIELLE J
project_start_date: 2017-09-01
project_end_date: 2022-03-31
study_section: Special Emphasis Panel[ZES1 LKB-K (S)]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Action Research;Acute;Advanced Development;Affect;Animal Experiments;Animal Model;Animals;Area;Attenuated;Awareness;Biological;Biological Markers;Cardiovascular Diseases;Cause of Death;Chemical Exposure;Chemicals;Chemistry;Chronic;Communities;Community Outreach;Complement;Cost Measures;Critical Pathways;Data;Decision Making;Detection;Development;Devices;Diabetes Mellitus;Disease;Disease Pathway;Ecology;Education and Outreach;Ensure;Environment;Environmental Exposure;Epidemic;Epidemiology;Etiology;Evaluation;Exposure to;Fatty Liver;Foundations;Future;Goals;Hazardous Chemicals;Hazardous Substances;Hazardous Waste Sites;Health;Heart Diseases;Human;Incidence;Industrialization;Injury;Investigation;Knowledge;Liver diseases;Mass Spectrum Analysis;Measures;Medical;Metabolism;Methods;Molecular;Monitor;Non-Insulin-Dependent Diabetes Mellitus;Nutritional;Nutritional status;Obesity;Organic Chemicals;Pathway interactions;Population;Postdoctoral Fellow;Predisposition;Prevalence;Private Sector;Public Health;Public Sector;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Research Training;Resources;Risk;Sampling;Science;Severities;Site;Superfund;Technology;Testing;Therapeutic Intervention;Time;Tissue Sample;Toxic effect;Toxicity Tests;Toxicology;Training;Training Programs;Translational Research;Universities;Validation;Work;animal tissue;base;biobank;computer code;data archive;data management;experience;graduate student;human population study;human tissue;innovation;interest;member;metabolomics;multidisciplinary;new technology;novel marker;outreach program;planetary Atmosphere;pollutant;programs;remediation;repository;resilience;response;sharing data;superfund chemical;superfund site;technique development;tool;translational medicine


application_id: 9260020
project_number: 5R01HL122676-03
project_title: Cardiovascular Toxicity of Tobacco Products and Constituents
administering_ic: NHLBI
award_notice_date: 2017-05-18
opportunity_number: RFA-OD-13-011
application_type: 5
activity_code: R01
ic: HL
serial_number: 122676
program_official: ITURRIAGA, ERIN
project_start_date: 2015-07-01
project_end_date: 2020-04-30
study_section: Special Emphasis Panel[ZRG1-AARR-J(56)R]
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cardiovascular Toxicity of Tobacco Products The Family Smoking Prevention and Tobacco Control Act grants the FDA the authority to regulate tobacco products to protect public health. However to set standards for tobacco products it is important to know which components of conventional new and emerging tobacco products induce cardiovascular injury so as to provide toxicity thresholds for harmful and potentially harmful constituents (HPHC) in tobacco products. However to identify HPHC toxicity it is important to determine how this toxicity could be identified and associated with disease risk and what assays best compare the toxic properties of different tobacco products. Although for toxicological profiling a high-throughput in vitro method is preferable CVD is a complex disease that develops from the dysfunction of several organ systems. Therefore the cardiovascular toxicity of tobacco products cannot be estimated in simple in vitro systems. Hence we will use an animal model and determine the relative toxicity of major HPHCs in cigarette smoke and electronic cigarette aerosol determine the toxicity profile of individual HPHCs specifically aldehydes and assess how the toxicity of an individual HPHC is modified by other HPHCs and nicotine. To validate this toxicity profile in humans we will examine the relationship between exposure to different HPHCs and cardiovascular toxicity in a well-characterized cohort. Successful completion of this project will lead to quantitative and rigorous evaluation of the cardiovascular toxicity of the major HPHCs in tobacco products and to the validation of an association between exposure to individual HPHCs and cardiovascular toxicity in humans. These findings will provide new information regarding the contribution of individual aldehydes in HPHC mixtures to the cardiovascular toxicity of tobacco smoke and as such will be useful in developing informed threshold limits and the policies needed to regulate HPHC levels in cigarettes electronic cigarettes smokeless tobacco as well as in other emerging tobacco-derived products.

project_terms:
Acetaldehyde;Acrolein;Address;Adult;Aerosols;Affect;Aldehydes;Animal Model;Animals;Biological Assay;Biological Markers;C57BL/6 Mouse;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Chronic Disease;Cigarette;Complex;Complex Mixtures;Cotinine;Creatinine;Data;Disease;Dose;Dyslipidemias;Electronic cigarette;Evaluation;Exposure to;Family Smoking Prevention and Tobacco Control Act;Female;Formaldehyde;Functional disorder;Future;Grant;Guidelines;Human;In Vitro;Individual;Injury;Insulin Resistance;Knowledge;Lead;Lipids;Measures;Mediating;Metabolism;Methods;Modification;Mus;Nicotine;Non-smoker;Plasma;Policies;Property;Public Health;Risk;Risk Factors;Smokeless Tobacco;Smoker;Smoking;System;Thrombosis;Tobacco;Tobacco smoke;Tobacco use;Toxic effect;Toxicology;Validation;Variant;authority;body system;cardiovascular disorder risk;cardiovascular injury;cigarette smoke;cigarette smoking;cohort;disorder risk;environmental tobacco smoke exposure;experimental study;male;primary outcome;public health relevance;response;secondary outcome;tobacco exposure;urinary

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cardiovascular Toxicity of Tobacco Products Project Narrative Although the rates of smoking have declined in the recent past nearly 1 billion people continue to smoke and cigarette smoking remains the most important cause of preventable deaths worldwide. Smoking and the use of tobacco products are associated with increased risk of developing multiple chronic diseases; however roughly half of all smoking-related illnesses are due to cardiovascular disease (CVD). Cigarette smoking and potentially the use of smokeless tobacco are associated with an increase in CVD risk factors. Nonetheless tobacco constituents that mediate the cardiovascular toxicity of tobacco use remain unknown and therefore it is unclear how tobacco products could be regulated to reduce cardiovascular injury or how Potential Reduced Exposure Tobacco Products (PREPs) such as electronic cigarettes could be evaluated for cardiovascular toxicity. This project will address this gap in knowledge regarding the toxicity of harmful and potentially harmful constituents (HPHCs) in tobacco products.


application_id: 9259955
project_number: 5R33DA035641-05
project_title: Buprenorphine Treatment and Health Reform: Availability Utilization and Quality
administering_ic: NIDA
award_notice_date: 2017-03-28
opportunity_number: RFA-DA-13-001
application_type: 5
activity_code: R33
ic: DA
serial_number: 035641
program_official: DUFFY, SARAH Q
project_start_date: 2013-05-01
project_end_date: 2020-04-30
study_section: NSS
contact_pi_person_id: 8146786
contact_pi: KNUDSEN, HANNAH
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:
Although its implementation is likely to vary across states due to the recent Supreme Court decision passage of the Affordable Care Act (ACA) is expected to dramatically impact the delivery of substance use disorder (SUD) treatment through changes to treatment financing and greater integration of mainstream health care and SUD treatment. The evolving system of buprenorphine treatment for opioid use disorders (OUDs) is a prime example of integration. While this system has grown substantially in the past decade research is limited regarding how physicians are implementing this lifesaving treatment and whether they are delivering HIVrelated services. It is unknown how the ACA will impact the delivery of buprenorphine treatment. The proposed study seeks 1 year of R21 support to establish study feasibility and 4 years of R33 support to conduct a longitudinal study of buprenorphine implementation that integrates multi-level data on state-level variations in ACA implementation with longitudinal surveys of buprenorphine-prescribing physicians. The primary aim of the R21 phase is to determine the feasibility of conducting a longitudinal study that integrates physician-level and state-level data collection through research procedures linked to 4 milestones encompassing the construction of the physician sample survey development through qualitative and cognitive interviews and generation of a protocol for longitudinal collection of state-level data on ACA implementation. The three specific aims of the proposed R33 study are: (1) To estimate cross-sectional and longitudinal models of buprenorphine utilization as well as the implementation of high-quality clinical practice behaviors (CPBs) and HIV-related services in buprenorphine treatment in the context of states implementation of the ACA; (2) To examine the relative importance of patient payment source (e.g. Medicaid private insurance or out-of-pocket) and other patient characteristics on physician decision-making during buprenorphine treatment; and (3) To model the state-level associations between the implementation of the ACA and two state-level outcomes: utilization of buprenorphine within Medicaid and the number of physicians holding the X-license for prescribing buprenorphine. These aims will be accomplished through ongoing collection of policy and administrative data at the state-level with 4 annual surveys of a nationally representative sample of 1200 physicians who hold the X-license to prescribe buprenorphine. This longitudinal survey design will support fielding four unique conjoint analyses each addressing a key domain of physician decision-making while also collecting data on CPBs over time. Data analysis will include cross-sectional multivariate models of decision-making and multi-level longitudinal analyses of CPB adoption and implementation to test theory-driven hypotheses. By measuring the quality availability and utilization of buprenorphine treatment in the US this research may identify treatment gaps for which interventions may be developed to improve treatment quality for OUDs while contributing to scientific knowledge regarding the impact of the ACA on US treatment services.

project_terms:
Address;Adoption;Affordable Care Act;Behavior;Buprenorphine;CCL4 gene;Characteristics;Clinical;Cognitive;Collection;Data;Data Analyses;Data Collection;Decision Making;Development;District of Columbia;Drug Utilization;Feasibility Studies;Future;Generations;Growth;Guidelines;HIV;HIV risk;Health;Health Care Reform;Healthcare;Individual;Insurance;Insurance Carriers;Intervention;Interview;Knowledge;Licensing;Link;Longitudinal Studies;Longitudinal Surveys;Mainstreaming;Measurement;Measures;Medicaid;Methodology;Modeling;Monitor;Opiate Addiction;Opioid;Outcome;Patient Selection;Patients;Persons;Pharmaceutical Preparations;Phase;Physicians;Policies;Privatization;Procedures;Protocols documentation;Quality of Care;Research;Sampling;Services;Source;Statutes and Laws;Substance Use Disorder;Supreme Court Decisions;Surveys;System;Technology;Testing;Time;Variant;base;clinical care;clinical decision-making;clinical practice;court;design;improved;innovation;longitudinal analysis;longitudinal design;medical specialties;multilevel analysis;opioid use disorder;payment;theories

public_health_relevance:
This research will provide significant information about the implementation of buprenorphine for the treatment of opioid dependence by physicians in the context of the Affordable Care Act including clinical decisionmaking and treatment quality. Measuring the quality of buprenorphine treatment may identify important targets for future interventions to improve the quality of care received by opioid-dependent patients while providing vital information regarding how health care reform is impacting this sector of the US treatment system.


application_id: 9259915
project_number: 5R01CA125454-10
project_title: Regulation of Snail in breast cancer progression and metastasis
administering_ic: NCI
award_notice_date: 2017-06-13
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 125454
program_official: AULT, GRACE S
project_start_date: 2007-09-13
project_end_date: 2019-04-30
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Basal-like breast cancer (BLBC) exhibits an aggressive clinical history with development of recurrence distant metastasis shorter survival and usually occurs in young women. BLBC intrinsically possesses many epithelial-mesenchymal transition (EMT) characteristics and cancer stem cell (CSC)-like features suggesting that activation of EMT program generates high-grade invasive cells with CSC-like traits in BLBC. Our long-term goal is to discover the intrinsic factors within tumor cells and the extrinsic signals from tumor microenvironments that regulate EMT and to identify molecules that may serve as druggable targets for treating this deadly disease. In the last several years we have systematically studied the role of Snail and the molecular mechanism by which Snail represses E-cadherin expression in BLBC. Our study clearly indicates that Snail is one of the key intrinsic factors within tumor cells responsible for EMT; our study also implies that the inflammatory tumor microenvironment provides an extrinsic signal for EMT. However how the extrinsic tumor milieu of BLBC is initiated and built up despite its paramount importance remains unaddressed. Recently we found that expression of the X-box binding protein (XBP1) was significantly reduced in BLBC from human breast tumor samples and mouse breast cancer tissues. Snail suppressed XBP1 expression and resulted in a significant upregulation of CCL2 a major chemokine for tumor associated macrophages (TAMs) and lymphocytes. XBP1 is a key molecule in the most conserved "unfolded-protein response" (UPR) signaling pathway that cells use to cope with environmental and cellular stresses in endoplasmic reticulum (ER). Loss of XBP1 results in "unresolved ER stress" which signals endogenous cellular injury triggering leukocyte infiltration and a significant boost of inflammatory responses in target tissues. We hypothesize that the loss of XBP1 by Snail-mediated repression ignites an "inside out" signal for recruiting TAMs and lymphocytes which establish an inflammatory/wound stroma to further boost EMT and cultivate CSC-like traits in BLBC by providing additional cytokines and growth factors. The objective of this proposal is to characterize the repression of XBP1 by Snail and explore therapeutic interventions that will disrupt this vicious cycle and thereby restore ER homeostasis using a newly developed specific Snail inhibitor. Guided by strong preliminary data we will test this hypothesis by pursuing three specific aims: (1) to determine the molecular mechanisms responsible for Snail-mediated XBP1 repression in BLBC; (2) to delineate why loss of XBP1 enhances inflammation in BLBC; and (3) to elucidate the functional roles of XBP1 in vivo. Our proposal is innovative and significant because it will not only open a new paradigm that significantly affects our views on the co- evolvement of tumor cells and their microenvironments in breast cancer progression and metastasis but will also lay groundwork for developing new therapeutic strategies against this disease.

project_terms:
Address;Affect;BRCA1 gene;Binding Proteins;Brain;Breast;Breast Cancer Cell;CCL2 gene;Caenorhabditis elegans;Cancer cell line;Cells;Cellular Stress;Characteristics;Chromatin;Clinical;Complex;Data;Development;Disease;Distant Metastasis;Down-Regulation;E-Cadherin;Endoplasmic Reticulum;Environment;Enzymes;Epithelial;Exhibits;Fostering;Gene Silencing;Glycogen Synthase Kinase 3;Goals;Growth Factor;Homeostasis;Human;IL8 gene;Immune;Infiltration;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Interleukin-6;Intervention;Intestines;Intrinsic factor;KDM1A gene;Knowledge;Leukocytes;Location;Lung;Lymphocyte;Malignant Neoplasms;Mammary Neoplasms;Mediating;Medical Oncologist;Mesenchymal;Molecular;Mus;Mutation;Neoplasm Metastasis;Outcome;Pathologist;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Play;Proteins;Public Health;Reagent;Recording of previous events;Recruitment Activity;Recurrence;Regulation;Repression;Research;Role;Sampling;Signal Pathway;Signal Transduction;Site;Snails;Stromal Neoplasm;Talents;Testing;Therapeutic Intervention;Tissues;Up-Regulation;cancer stem cell;cancer subtypes;cancer therapy;cell injury;chemokine;chromatin modification;cytokine;endoplasmic reticulum stress;experimental study;gene repression;genome wide association study;in vivo;inhibitor/antagonist;innovation;insight;macrophage;malignant breast neoplasm;multidisciplinary;neoplastic cell;novel;novel therapeutic intervention;outcome forecast;paracrine;prevent;programs;promoter;protein expression;public health relevance;response;snail protein;success;targeted treatment;trait;tumor;tumor microenvironment;tumor progression;ubiquitin isopeptidase;ubiquitin-protein ligase;wound;young woman

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Our proposal is innovative since we will have a significant impact to public health through its potential to influence cancer treatment. The knowledge gained will expand our understanding of the co-evolvement between tumor cells and their microenvironments in tumor progression and metastasis. When successfully completed these studies will provide insights for the development of novel interventions to prevent and treat metastatic basal-like breast cancer.


application_id: 9258458
project_number: 5R01HL073085-13
project_title: Angiotensin - A link between obesity and hypertension
administering_ic: NHLBI
award_notice_date: 2017-04-23
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 073085
program_official: OH, YOUNGSUK
project_start_date: 2003-06-03
project_end_date: 2020-04-30
study_section: Special Emphasis Panel[ZRG1-VH-F(02)M]
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The prevalence of obesity is rising in Kentucky and the nation. Prior to the obesity epidemic hypertension prevalence was lower in females than males until menopause when both obesity and hypertension increase. The most recent NHANES data demonstrate the surprising finding that the prevalence of hypertension is rising at a faster rate in females than males. This competing renewal focuses on mechanisms contributing to obesity-induced hypertension in males versus females a highly significant topic since obesity is a primary cause of hypertension in both genders. We have examined whether an activated adipocyte renin-angiotensin system (RAS) is a link between obesity and hypertension. During the current period we demonstrated that deficiency of adipocyte-derived angiotensinogen (AGT) prevented elevations in adipose and systemic angiotensin II (Ang II) concentrations and abolished the development of hypertension in obese male mice. We also demonstrated that adipocytes express angiotensin converting enzyme 2 (ACE2) which cleaves Ang II to form the vasodilator peptide angiotensin-(1-7) (Ang-(1-7)). In male obese hypertensive mice exhibiting increased adipose-derived systemic Ang II adipose ACE2 expression was reduced and systemic Ang-(1-7) concentrations plummeted. These results suggest that reductions in ACE2 in an expanded adipose mass make Ang II the predominant adipose-derived RAS peptide contributing to hypertension in obese male mice. In contrast to males obese female mice were totally resistant to the development of hypertension despite greater adiposity. Remarkably female normotensive obese mice exhibited increased adipose ACE2 activity associated with elevated plasma Ang-(1-7) concentrations. Deficiency of ACE2 converted obese females to a hypertensive phenotype. Removal of ovarian sex hormones reduced adipose ACE2 activity and plasma Ang- (1-7) concentrations and resulted in robust obesity-induced hypertension. Moreover estrogen markedly stimulated ACE2 mRNA abundance in 3T3-L1 adipocytes. We hypothesize that differential regulation of adipocyte ACE2 in obese males versus females determines whether adipose tissue produces Ang II or Ang-(1- 7) in the development of hypertension. Aim 1 tests the hypothesis that adipocyte ACE2 deficiency promotes hypertension in obese female mice while ACE2 activation prevents hypertension in obese males through an adipocyte ACE2-dependent mechanism. Aim 2 tests the hypothesis that estrogen promotes adipocyte ACE2 expression and protects male and ovariectomized female obese mice from hypertension. Aim 3 tests the hypothesis that DIZE-induced ACE2 activation reduces blood pressure in male and ovariectomized female obese hypertensive mice through an Ang-(1-7)/MasR-dependent mechanism. The impact of these studies is definition of mechanisms for the development of hypertension in obese males versus females. We will also develop ACE2 activation as a novel therapy to treat hypertension in obese males and/or menopausal females.

project_terms:
Adipocytes;Adipose tissue;Angiotensin II;Angiotensinogen;Angiotensins;Blood Pressure;Body mass index;Castration;Cleaved cell;Data;Development;Epidemic;Equilibrium;Estrogen Therapy;Estrogens;Excision;Exhibits;Female;Gender;Gonadal Steroid Hormones;Hypertension;Kentucky;Knock-out;Left;Link;Mediator of activation protein;Menopause;Messenger RNA;Modeling;Mus;NHANES;Obese Mice;Obesity;Ovarian;Peptides;Peptidyl-Dipeptidase A;Pharmacotherapy;Phenotype;Plasma;Prevalence;Production;Regulation;Renin-Angiotensin System;Resistance;Source;Testing;Translating;Vasodilator Agents;angiotensin I (1-7);blood pressure reduction;male;new therapeutic target;normotensive;novel therapeutics;prevent;public health relevance;receptor;transgender

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Obesity is at epidemic proportions in the US and may eventually overcome previously ascribed protection of females against the development of hypertension. These studies focus on the renin-angiotensin system of adipocytes as a mediator of obesity-hypertension in males versus females. Since obesity is the primary cause of hypertension in the US and the prevalence of hypertension is increasing more rapidly in females than males our studies will define mechanisms for these differences and uncover novel targets for drug therapy.


application_id: 9257365
project_number: 5R01CA188118-03
project_title: Determine the Functional Role Dub3 in Breast Cancer Progression and Metastasis
administering_ic: NCI
award_notice_date: 2017-03-13
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 188118
program_official: AULT, GRACE S
project_start_date: 2015-04-01
project_end_date: 2020-03-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Basal-like breast cancer (BLBC) presents with an aggressive clinical history development of recurrence distant metastasis shorter survival and usually occurs in young women. BLBC has an activated epithelial-mesenchymal transition (EMT) program which provides cells with the increased phenotypic and cellular plasticity required during embryonic development tissue remodeling wound healing and metastasis. Our long-term goal is to discover the molecular circuitry that governs the functional plasticity of BLBC cells in metastasis and to identify molecules that may serve as druggable targets for treating this deadly disease. In the last nine years we have systematically studied the function of Snail and the molecular mechanism by which Snail represses E-cadherin expression in BLBC. Our studies clearly indicate that Snail levels are regulated predominantly through protein ubiquitination. High levels of Snail due to protein stabilization contribute significantly to theincreased invasion therapeutic resistance CSC-like properties and tumor recurrence. However the mechanism by which Snail escapes ubiquitination and degradation remains unknown; uncovering this mechanism is crucially important for the development of novel approaches to treat BLBC. Recently we discovered that Dub3 is a bona fide deubiquitinase of Snail and contributes to Snail stabilization in breast cancer. Dub3 is evolutionarily conserved from Drosophila to humans. Dub3-knockout downregulated Snail and disrupted gastrulation (an event that requires EMT) in Drosophila. Elevated expression of Dub3 correlates unequivocally with Snail expression in BLBC samples and cell lines. Overexpression of Dub3 in luminal breast tumor MCF7 and T47D cell lines which contain no detectable endogenous Dub3 and Snail induces transformation to a basal-like phenotype; whereas Dub3-knockdown downregulates Snail and suppresses cell migration. Intriguingly Dub3 was an early response gene that appeared after exposure to inflammatory cytokines. We hypothesize that Dub3 is the long-sought "missing molecule" that regulates cellular plasticity by controlling the level of Snail durig EMT and metastasis. The objective of this proposal is to characterize the function and regulation of the Dub3-Snail axis and explore the clinical value of Dub3 as a prognostic biomarker and a druggable target for treating metastatic breast cancer. Guided by strong preliminary data we will test this hypothesis by pursuing three specific aims: (1) to delineate th molecular mechanism by which Dub3 controls EMT; (2) to determine the function and regulation of Dub3 in breast cancer; and (3) to define the function and therapeutic efficacy of Dub3 in vivo. Our proposal is innovative and significant because it will not only uncover a new paradigm that significantly increases our understanding of the regulation of cellular plasticity during tumor progression and metastasis but also leads to the development of specific Dub3 inhibitors for treating metastatic breast cancer.

project_terms:
Address;Brain;Breast;Breast Cancer Cell;Breast cancer metastasis;Cell Line;Cells;Chromatin;Clinical;Coupled;Crystallization;Data;Deubiquitination;Development;Diagnosis;Disease;Distant Metastasis;Drosophila genus;E-Cadherin;ERG gene;Embryonic Development;Environment;Enzymes;Epithelial;Event;Exposure to;Genes;Goals;Growth;Human;Inflammatory;Intrinsic factor;Investigation;KDM1A gene;Knock-out;Knowledge;Libraries;Location;Lung;MCF7 cell;Malignant Neoplasms;Mammary Neoplasms;Mass Spectrum Analysis;Mesenchymal;Metabolic;Metastatic breast cancer;Modeling;Molecular;Mus;Neoplasm Metastasis;Oncologist;Pathologist;Pharmaceutical Preparations;Phase;Phenotype;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Prognostic Marker;Property;Proteins;Public Health;Reagent;Recording of previous events;Recruitment Activity;Recurrence;Regulation;Research;Role;Sampling;Signal Transduction;Site;Small Interfering RNA;Snails;Specimen;Stromal Neoplasm;Structural Biologist;Structure;T47D;Talents;Testing;Therapeutic;Tissues;Treatment Efficacy;Tumor Cell Invasion;Ubiquitination;Validation;Wound Healing;Xenograft procedure;aerobic glycolysis;base;beta-Transducin Repeat-Containing Proteins;cancer stem cell;cancer therapy;cell growth regulation;cell motility;cytokine;diagnostic biomarker;experimental study;functional plasticity;gastrulation;glycogen synthase kinase 3 beta;in vivo;inhibitor/antagonist;innovation;knock-down;loss of function;macrophage;malignant breast neoplasm;multidisciplinary;neoplastic cell;new therapeutic target;novel strategies;outcome forecast;overexpression;prevent;prognostic;programs;promoter;public health relevance;screening;success;targeted biomarker;targeted treatment;therapy resistant;tumor;tumor microenvironment;tumor progression;ubiquitin-protein ligase;virtual;young woman

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Our proposal is innovative since we will have a significant impact to public health through its potential to influence cancer treatment. The knowledge gained will expand our understanding of the molecular mechanism in controlling early-phase of tumor cell invasion dissemination and metastasis. When successfully completed these studies will offer new therapeutic target and diagnostic biomarker to prevent and treat metastatic basal- like breast cancer.


application_id: 9257360
project_number: 5R01CA175105-05
project_title: Targeting Translation Dependence in Colorectal Cancer Progression
administering_ic: NCI
award_notice_date: 2017-03-13
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 175105
program_official: AULT, GRACE S
project_start_date: 2013-04-01
project_end_date: 2019-11-30
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 10534129
contact_pi: SHE, QING-BAI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Mutational activation of the RAS/RAF/MEK/ERK and PI3K/AKT pathways is associated with colorectal cancer (CRC) progression and metastasis. Several small molecularly-targeted PI3K AKT RAF and MEK inhibitors have been tested in the clinic for the treatment of CRC but have shown only limited activity as a single agent. We have recently discovered that inhibition of both the ERK and AKT pathways exhibits potent synergistic anti-CRC effects both in vitro and in vivo by effectively inhibiting eIF4E-initiated cap-dependent translation. Our overarching hypothesis is that the activation of cap-dependent translation by cooperative ERK and AKT signaling can selectively upregulate key oncoproteins that confer CRC progression and metastasis. By characterizing the molecular details of the activation of cap-dependent translation by cooperative ERK and AKT signaling we aim to understand the molecular mechanisms underlying translational activation for CRC metastatic progression and to explore the therapeutic applications of targeting translational regulation for CRC treatment. Our Specific Aims are: Aim 1. Determine the biologic and therapeutic consequences of translational activation by cooperative ERK and AKT signaling in CRC. We will determine 1) the extent to which the mTOR kinase integrates the function of ERK and AKT signaling in translational regulation of CRC cell growth and motility; 2) how mTOR inhibition-induced feedback activation of ERK and AKT deregulates cap-dependent translation and causes mTOR-independence; and 3) the molecular basis of metastatic progression-modulated translational activity using our well-established orthotopic metastastic model of CRC. Aim 2. Characterize the molecular mechanism of translational activation by cooperative ERK and AKT signaling for CRC progression and metastasis. We demonstrate that survivin is a key translational target of the ERK and AKT pathways. We will explore the possible mechanism by which the translationally-regulated survivin acts as an important growth/metastasis-promoting effector of these pathways. We will use combined polysome profiling and proteomic approaches to systematically identify other mRNAs that are selectively recruited to polysomes and translated by cooperative ERK and AKT signaling and characterize in detail the functional importance of these genes in CRC progression and metastasis. Aim 3. Evaluate the in vivo utility of combined inhibition of the MEK/ERK and AKT/mTOR pathways and targeting the convergence of their signals on translation initiation for enhancing CRC therapy. We will use both the mouse orthotopic model of CRC and the patient tumor-derived xenograft model to determine the effectiveness of MEK AKT and mTOR inhibitors alone and in combination and to characterize the ability of the translation initiation inhibitor 4EGI-1 to prevent tumor progressio and metastasis. The expression and modulation of eIF4E 4E-BP1 and survivin and their correlation with the mutational activation status of ERK and AKT pathways will also be characterized in response to the targeted therapies and in clinical specimens.

project_terms:
AKT Signaling Pathway;Address;Animal Model;Biochemical;Biology;Biometry;Cancer Cell Growth;Clinic;Clinical;Colonic Neoplasms;Colorectal Cancer;Data;Dependence;Disseminated Malignant Neoplasm;EIF4EBP1 gene;Effectiveness;Exhibits;FRAP1 gene;Feedback;Genes;Goals;Growth;Human;In Vitro;Knowledge;MEK inhibition;MEKs;Messenger RNA;Modeling;Molecular;Molecular Target;Mus;Mutation;Neoplasm Metastasis;Oncoproteins;Operative Surgical Procedures;PI3K/AKT;PTEN gene;Pathogenesis;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Play;Polyribosomes;Proteomics;Proto-Oncogene Proteins c-akt;Ras/Raf;Recruitment Activity;Research Infrastructure;Resistance;Role;Signal Transduction;Solid;Specimen;Techniques;Testing;Therapeutic;Translating;Translation Initiation;Translational Activation;Translational Regulation;Translational Repression;Translations;Tumor-Derived;Tyrosine Kinase Receptor Inhibition;Xenograft Model;cancer therapy;cell motility;clinically relevant;colon cancer cell line;colon cancer patients;in vivo;inhibitor/antagonist;insight;interdisciplinary collaboration;mTOR Inhibitor;mTOR inhibition;metastatic colorectal;new therapeutic target;novel;novel marker;novel therapeutics;pre-clinical;prevent;public health relevance;response;survivin;targeted treatment;tumor;tumor growth;tumor progression;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The great majority of patients with metastatic colorectal cancer (CRC) is unresponsive to currently known therapy. This proposal aims to lay the groundwork for understanding the molecular mechanisms involved in the translational control of metastatic progression and treatment of CRC and is therefore of clinical relevance in itself since new therapy for metastatic CRC is urgently needed. The overarching high impact of this proposal lies in the proof-of-concept that will be established for discovery of novel biomarkers and therapeutic targets for CRC.


application_id: 9256484
project_number: 5F30ES025099-03
project_title: Xenobiotic Receptors Modulate PCB-induced Steatohepatitis
administering_ic: NIEHS
award_notice_date: 2017-03-29
opportunity_number: PA-14-150
application_type: 5
activity_code: F30
ic: ES
serial_number: 025099
program_official: SCHUG, THADDEUS
project_start_date: 2015-04-15
project_end_date: 2020-04-14
study_section: Special Emphasis Panel[ZRG1-F06-S(20)L]
contact_pi_person_id: 12058438
contact_pi: CLAIR, HEATHER B
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is intimately associated with obesity diabetes and the metabolic syndrome. Traditionally NAFLD has been associated with caloric excess on a susceptible genetic background however recent studies from our laboratory and others have pointed out a role for environmental toxicants including polychlorinated biphenyls (PCBs) in the etiology of steatosis and steatohepatitis particularly inthe context of hypercaloric diet coexposure. Our proposed study uses exposure parameters informed by our recent analysis of serum samples from a previously-described cohort of individuals residing in Anniston AL who were exposed to high levels of PCB-containing waste. Although many of these individuals have serum levels of PCBs above that found in the general population of the US their exposures remain well below the levels implicated in acute liver injury. Nevertheless these individuals have significantly elevated biomarkers of liver injury as well as elevated inflammatory cytokines elevated prevalence of diabetes and increased BMI when compared to an unexposed population. A frustrating finding of previous toxicity studies has been the very different pathological response of mice and humans to such subacute chronic and environmentally relevant PCB exposures. Our preliminary data in a mouse model of subacute PCB exposure shows paradoxical elevations of liver injury biomarkers fatty change and inflammatory cytokines at lower exposure vs. higher exposure to a PCB mixture (20mg Aroclor 1260/kg body weight vs. 200mg/kg body weight Aroclor 1260). In two knockout mouse models that lack the constitutive androstane receptor (CAR) or the pregnane and xenobiotic receptor (PXR) our laboratory has found differential transcription of the gene targets of these receptors in response to Aroclor 1260 and high-fat diet exposure. These patterns of pathological and phenotypic responses are consistent with a transcription-factor based mechanism of PCB toxicity. The differences in disease endpoints may therefore be due to differences in ligand specificity and target gene cohort between the human and mouse forms of these receptors. We therefore propose to expand our investigation of receptor-based mechanisms of PCB toxicity with the use of a novel triple-transgenic mouse model expressing human forms of AhR PXR and CAR. We hypothesize that using both an acute-exposure primary hepatocyte culture and a whole animal chronic exposure model we will find that differences in the structure and function of these receptors will drive a differential transcriptioal response to PCBs and ultimately differences in PCB-associated disease endpoints.

project_terms:
AHR gene;Acute;Address;Adolescent;Adult;Affect;Affinity;Animals;Aryl Hydrocarbon Receptor;Biological Markers;Body Weight;Cessation of life;Chemicals;Chronic;Cirrhosis;Comorbidity;Complex;Computer Simulation;Data;Diabetes Mellitus;Diet;Disease;Dose;Energy Intake;Environmental Exposure;Environmental Risk Factor;Enzymes;Etiology;Exposure to;Fatty Change;Fatty Liver;Gene Expression;Gene Targeting;General Population;Genes;Genetic;Genetic Transcription;Hepatic;Hepatocyte;High Fat Diet;Human;Individual;Industrialization;Inflammation;Inflammatory;Insulin Resistance;Investigation;Knockout Mice;Laboratories;Ligands;Lipids;Liver;Liver diseases;Mediating;Metabolic Diseases;Metabolic syndrome;Metabolism;Microarray Analysis;Modeling;Molecular Weight;Mus;NHANES;Nutritional;Obesity;Odds Ratio;Overweight;Participant;Pathologic;Pathway interactions;Pattern;Pharmaceutical Preparations;Phenotype;Pollution;Polychlorinated Biphenyls;Population;Pregnanes;Prevalence;Primary carcinoma of the liver cells;Receptor Activation;Research;Role;Sampling;Serum;Specificity;Steatohepatitis;Structure;Testing;Toxic Environmental Substances;Toxic effect;Transcript;Transgenic Mice;Transplantation;Wild Type Mouse;Xenobiotics;acute liver injury;base;carbohydrate metabolism;cardiovascular risk factor;cohort;constitutive androstane receptor;cytokine;design;exposed human population;improved;liver injury;mRNA Expression;mouse model;non-alcoholic fatty liver;nonalcoholic steatohepatitis;novel;persistent organic pollutants;population based;public health relevance;receptor;receptor function;response;transcription factor;transcriptome;transcriptomics;wasting

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Traditionally non-alcoholic fatty liver disease has been associated with high caloric intake however recent studies from our laboratory and others have pointed out a role for environmental toxicants including polychlorinated biphenyls (PCBs) in the etiology of fatty liver and liver disease. This application studies the connection of pollution andliver disease.


application_id: 9256478
project_number: 5P42ES007380-20
project_title: Chloro-Organic Degradation by Polymer Membrane Immobilized Iron-Based Particle Sy
administering_ic: NIEHS
award_notice_date: 2017-03-24
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7485
contact_pi_person_id: 8534525
contact_pi: BHATTACHARYYA, DIBAKAR
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: 2017-04-01
budget_end_date: 2018-03-31
project_terms:
Address;Adsorption;Aftercare;Attention;Benign;Biological Sciences;Carbon;Chemicals;Chemistry;Chlorine;Collaborations;Development;Diffusion;Drug Metabolic Detoxication;Engineering;Environment;Environmental Health;Free Radicals;Funding;Generations;Health;Heating;High temperature of physical object;Human;Hydrogen Peroxide;Hydroxyl Radical;Immobilization;Individual;Inflammatory;Iron;Kentucky;Knowledge;Laboratories;Laboratory Research;Lead;Manufacturer Name;Medical;Membrane;Metals;Methods;Modeling;Mono-S;Nanostructures;Nature;Outcome Study;Palladium;Pathway interactions;Phase;Plants;Poisons;Polychlorinated Biphenyls;Polymers;Production;Public Health;Reaction;Research;Risk;Risk Management;Science;Scientist;Site;Soil;Solvents;Source;Structure;Superfund;System;Techniques;Technology;Temperature;Testing;Toxic effect;Toxicity Tests;Translational Research;Trichloroethylene;United States Environmental Protection Agency;Vinyl Chloride;Water;Work;aryl hydrocarbon receptor ligand;base;chemical stability;contaminated water;cost;cost effective;dechlorination;demineralization;design;drinking;drinking water;global environment;hazard;hydrodynamic flow;innovation;iron oxide;metal oxide;microbial;nanoparticle;nanoscale;nanosized;nanostructured;novel;nutrition;oxidation;particle;pollutant;prevent;remediation;scaffold;superfund chemical;superfund site;technology validation;treatment strategy


application_id: 9256477
project_number: 5P42ES007380-20
project_title: Biomimetic Magnetic Nanocomposites as a Platform Technology for the Capture and S
administering_ic: NIEHS
award_notice_date: 2017-03-24
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7484
contact_pi_person_id: 8239234
contact_pi: HILT, JAMES ZACH
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: 2017-04-01
budget_end_date: 2018-03-31
project_terms:
Address;Affinity;Antibodies;Binding;Binding Proteins;Biodistribution;Biological;Biomimetics;Characteristics;Chemistry;Coupled;Detection;Dioxins;Engineering;Environment;Environmental Health;Environmental Pollution;Excision;Flavonoids;Fluorescence;Goals;Health;Human;Kentucky;Light;Magnetic nanoparticles;Magnetism;Mass Fragmentography;Membrane Microdomains;Methods;Milk;Molecular;Phenols;Plants;Poisons;Polychlorinated Biphenyls;Polymers;Process;Production;Property;Proteins;Reporting;Research;Resources;Risk;Sampling;Sensitivity and Specificity;Soil;Solubility;Specificity;Superfund;Surface;System;Techniques;Technology;Testing;Thick;Time;Toxic effect;Tryptophan;Tyrosine;Universities;Work;aqueous;base;bisphenol A;chemical stability;design;disorder prevention;evidence base;exposed human population;exposure route;fundamental research;global environment;imprint;nanocomposite;nanomaterials;nanoscale;novel;novel strategies;nutrition;pi bond;pollutant;polyphenol;rapid detection;remediation;screening;superfund chemical;superfund site;tool


application_id: 9256475
project_number: 5P42ES007380-20
project_title: Postnatal Complications of Perinatal Polychlorinated Biphenyl Exposure - Project
administering_ic: NIEHS
award_notice_date: 2017-03-24
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7482
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
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: 2017-04-01
budget_end_date: 2018-03-31
project_terms:
Adipose tissue;Adult;Adult Children;Aryl Hydrocarbon Receptor;Attenuated;Beta Cell;Biochemical;Body Composition;Breast;Child;Chlorinated Hydrocarbons;Data;Development;Diabetes Mellitus;Discipline of Nursing;Disease;Dose;Environment;Environmental Health;Environmental Impact;Environmental Pollutants;Environmental Pollution;Epidemic;Erythroid;Etiology;Euglycemic Clamping;Exercise;Exposure to;Fatty acid glycerol esters;Female;Fostering;Functional disorder;Funding;Gender;Glucose Intolerance;Goals;Gold;Health;High Fat Diet;Human Milk;Impairment;Inflammation;Inflammatory;Insulin;Insulin Resistance;Intervention;Laboratories;Life;Life Cycle Stages;Lipids;Long-Term Effects;Measures;Messenger RNA;Metabolism;Methods;Molecular;Mus;Neonatal;Nuclear;Nurses;Obesity;Outcome;Oxidative Stress;Paper;Partner in relationship;Perinatal;Perinatal Exposure;Placenta;Play;Polychlorinated Biphenyls;Predisposition;Pregnancy;Prevalence;Principal Investigator;Public Health;Research;Risk;Role;Running;Serum;Source;Techniques;Testing;Thinness;Tissues;Toxic effect;Toxin;United States;Weaning;Work;blood glucose regulation;chemical stability;cost effective;critical period;cytokine;exposed human population;fasting glucose;fetal;glucose tolerance;healthy pregnancy;impaired glucose tolerance;improved;in utero;in vivo Model;innovation;insight;insulin sensitivity;insulin signaling;lifestyle intervention;liver inflammation;mouse model;novel;nutrition;offspring;perinatal complications;pollutant;postnatal;pregnant;prenatal;prenatal exposure;sedentary;superfund chemical;trait;trend


application_id: 9256474
project_number: 5P42ES007380-20
project_title: Superfund Chemicals Nutrition and Endothelial Cell Dysfunction - Project 1
administering_ic: NIEHS
award_notice_date: 2017-03-24
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7481
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
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: 2017-04-01
budget_end_date: 2018-03-31
project_terms:
Address;Affect;Agonist;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Arterial Fatty Streak;Aryl Hydrocarbon Receptor;Atherosclerosis;Biological Assay;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Catechin;Cause of Death;Caveolae;Caveolins;Cells;Chemicals;Chronic;Complement;Data;Development;Diet;Dietary Fats;Dietary Intervention;Dietary Polyphenol;Disease;Ecology;Endocrine disruption;Endothelial Cells;Endothelium;Environment;Environmental Health;Environmental Pollutants;Epigallocatechin Gallate;Erythroid;Event;Exposure to;Flavonoids;Foundations;Functional disorder;Genes;Green tea;Hazardous Waste Sites;Health;Health Food;Human;Hypertriglyceridemia;In Vitro;Inflammation;Inflammatory;Investigation;Kentucky;Knockout Mice;Link;Lipids;Mediating;Membrane;Methodology;Modeling;Nuclear;Nutritional;Nutritional status;Omega-3 Fatty Acids;Omega-6 Fatty Acids;Oxidation-Reduction;Plants;Play;Poisons;Polychlorinated Biphenyls;Preventive measure;Process;Proteins;Public Health;Regulation;Research;Risk;Risk Assessment;Risk Factors;Role;Severities;Signal Pathway;Signal Transduction;Small Interfering RNA;Structural Protein;Superfund;Technology;Testing;Time;Toxic effect;United States;Universities;Vascular Diseases;Vascular Endothelial Cell;Work;bioactive food component;caveolin 1;chemical stability;cost;design;disorder risk;exposed human population;genetic manipulation;global environment;heme oxygenase-1;in vivo;lipophilicity;mouse model;novel;nutrition;organic contaminant;pollutant;polyphenol;prevent;programs;protective effect;remediation;response;stressor;superfund chemical;superfund site;toxicant;trafficking;vascular inflammation


application_id: 9256473
project_number: 5P42ES007380-20
project_title: Training Core - Core E
administering_ic: NIEHS
award_notice_date: 2017-03-24
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7480
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
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: 2017-04-01
budget_end_date: 2018-03-31
project_terms:
Address;Affect;Clinical Sciences;Communication;Communities;Complex;Detection;Dimensions;Discipline;Ecology;Education;Educational workshop;Environment;Environmental Health;Ethics;Fostering;Foundations;Future;Generations;Goals;Grant;Health;Human;Individual;Institution;Interdisciplinary Study;Internships;Intervention;Kentucky;Knowledge;Leadership;Life;Link;Measures;Medical Ethics;Mentors;Methods;Mission;Policies;Problem Solving;Public Health;Public Health Education;Recruitment Activity;Research;Research Personnel;Research Training;Science;Scientific Advances and Accomplishments;Series;Signal Recognition Particle;Solid;Students;Superfund;Targeted Research;Toxic effect;Toxicology;Training;Training Activity;Training Programs;Translational Research;Underrepresented Groups;Universities;Writing;base;biomedical scientist;career;career development;college;graduate student;health knowledge;improved;interdisciplinary collaboration;knowledge integration;meetings;nutrition;outreach;pollutant;programs;remediation;responsible research conduct;skill acquisition;skills;skills training;social;socioeconomics;success;superfund chemical;superfund site;symposium;tool;web page


application_id: 9256472
project_number: 5P42ES007380-20
project_title: Community Engagement Core - Core D
administering_ic: NIEHS
award_notice_date: 2017-03-24
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7479
contact_pi_person_id: 8535399
contact_pi: GAETKE, LISA M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-04-01
budget_end_date: 2018-03-31
project_terms:
Affect;Appalachian Region;Area;Attitude;Chronic Disease;Collaborations;Communication;Communities;Community Actions;Community Services;County;Diet;Dietitian;Environmental Health;Environmental Pollutants;Evaluation;Exposure to;Family;Feedback;Food;Fostering;Funding;Hazardous Waste Sites;Health;Health Professional;Health Status;Health behavior;Human Resources;Individual;Kentucky;Knowledge;Life Style;Location;Methods;Nurses;Nutritional;Outcome;Outcome Measure;Outcomes Research;Physicians;Poisons;Population;Prevalence;Process;Public Health;Recommendation;Research;Research Personnel;Resources;Risk;Services;Site;Superfund;Toxic effect;Translating;Trust;United States Environmental Protection Agency;Work;base;design;disease registry;evidence base;health knowledge;improved;interest;nutrition;programs;response;superfund chemical


application_id: 9256471
project_number: 5P42ES007380-20
project_title: Research Translation Core - Core C
administering_ic: NIEHS
award_notice_date: 2017-03-24
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7478
contact_pi_person_id: 8535916
contact_pi: ORMSBEE, LINDELL E
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: 2017-04-01
budget_end_date: 2018-03-31
project_terms:
Address;Advisory Committees;Appalachian Region;Area;Behavior Therapy;Cardiovascular system;Chemicals;Clinical Sciences;Collaborations;Communication;Communities;County;Decision Making;Department of Energy;Diffusion;Documentation;Ecology;Educational workshop;Electronic Mail;Engineering;Ensure;Environment;Environment and Public Health;Environmental Health;Event;Exercise;Exposure to;Family;Fostering;Future;Goals;Health;Home environment;Housing;Human Resources;Information Dissemination;Interdisciplinary Study;Kentucky;Laboratory Research;Lead;Leadership;Maintenance;Medicine;Mentors;Mentorship;National Institute of Environmental Health Sciences;Outcome;Outcomes Research;Output;Pharmacology;Physiological;Plants;Poisons;Polychlorinated Biphenyls;Positioning Attribute;Process;Productivity;Program Development;Public Health;Public Policy;Reporting;Research;Research Activity;Research Infrastructure;Research Institute;Research Project Grants;Research Support;Resources;Risk;Risk Management;Role;Scientist;Series;Services;Site;Superfund;Targeted Research;Toxic effect;Toxicology;Training;Translating;Translational Research;Translations;Trichloroethylene;United States Environmental Protection Agency;Universities;University resources;Water;Work;base;community center;disease registry;experience;implementation science;innovation;meetings;nano;new technology;nutrition;pollutant;practice-based research network;program dissemination;programs;success;superfund chemical;technology validation;web site;webinar


application_id: 9256470
project_number: 5P42ES007380-20
project_title: Research Support Core - Core B
administering_ic: NIEHS
award_notice_date: 2017-03-24
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7477
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-04-01
budget_end_date: 2018-03-31
project_terms:
Address;Advanced Development;Animal Model;Animals;Area;Basic Science;Bioinformatics;Biological Markers;Biology;Biometry;Calibration;Cardiovascular Diseases;Cell model;Cells;Center for Translational Science Activities;Clinical;Clinical Research;Cultured Cells;Data;Data Analyses;Data Base Management;Data Set;Detection;Development;Dose;Drug Metabolic Detoxication;Ecology;Ensure;Experimental Designs;Funding;Gene Expression Profiling;Generations;Health Hazards;Health Services Research;High Pressure Liquid Chromatography;Individual;Inflammation;Informatics;Intervention;Investments;Kentucky;Laboratories;Life Style;Mass Fragmentography;Mass Spectrum Analysis;Mediator of activation protein;Metabolic;Metabolic Diseases;Methods;Monitor;Nutritional;Nutritional Study;Outcome;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Polychlorinated Biphenyls;Productivity;Proteomics;Public Health;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Services;Superfund;Suspensions;Systems Biology;Technology;Toxic effect;Toxin;Training;Universities;Validation;base;biomarker discovery;biomarker identification;case control;computer infrastructure;data acquisition;data management;design;diphenyl;experimental study;exposed human population;instrumentation;metabolomics;nutrition;programs;remediation;sensor;sharing data;small molecule;superfund chemical;translational scientist


application_id: 9256469
project_number: 5P42ES007380-20
project_title: Administrative Core - Core A
administering_ic: NIEHS
award_notice_date: 2017-03-24
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7476
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
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: 2017-04-01
budget_end_date: 2018-03-31
project_terms:
Address;Advisory Committees;Area;Benign;Cardiovascular system;Chemicals;Collaborations;Communication;Communities;Discipline;Documentation;Ecology;Educational workshop;Engineering;Ensure;Environment;Environmental Health;Environmental Pollution;Event;Exercise;Exposure to;Federal Government;Fostering;Future;Goals;Health;Housing;Human Resources;Individual;Inflammatory;Information Centers;Interdisciplinary Study;Kentucky;Leadership;Life Style;Maintenance;Medicine;Mentors;Mentorship;Modeling;National Institute of Environmental Health Sciences;Outcome;Output;Pharmacology;Physiological;Polychlorinated Biphenyls;Positioning Attribute;Private Sector;Process;Productivity;Program Development;Public Health;Reporting;Research;Research Activity;Research Infrastructure;Research Project Grants;Research Support;Research Training;Resources;Risk;Role;Science;Scientist;Superfund;Targeted Research;Technology;Toxic effect;Toxicology;Training;Translational Research;Translations;Universities;base;experience;innovation;meetings;nano;nutrition;pollutant;programs;remediation;superfund chemical;superfund site;training project


application_id: 9256466
project_number: 5P42ES007380-20
project_title: Nutrition and Superfund Chemical Toxicity
administering_ic: NIEHS
award_notice_date: 2017-03-24
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
program_official: HENRY, HEATHER F
project_start_date: 1997-04-07
project_end_date: 2019-03-31
study_section: ZES1-LKB-K(S)
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adipose tissue;Affinity;Atherosclerosis;Binding;Biological;Biological Markers;Biology;Biomedical Research;Biomimetics;Blood Vessels;Chemicals;Collaborations;Communities;Coupled;Detection;Diabetes Mellitus;Diet;Diffusion;Disease;Drug Metabolic Detoxication;Ecology;Education;Environment;Environmental Health;Exercise;Exposure to;Health;Human;Immobilization;In Vitro;Inflammation;Inflammatory;Insulin Resistance;Iron;Kentucky;Lead;Learning;Life Style;Longevity;Mass Spectrum Analysis;Mediator of activation protein;Membrane;Mentorship;Methods;Modeling;Monitor;Nanostructures;National Institute of Environmental Health Sciences;Nutritional;Obesity;Outcome;Oxidation-Reduction;Oxidative Stress;Pigments;Plants;Policies;Policy Developments;Polychlorinated Biphenyls;Polymers;Population;Populations at Risk;Prevention strategy;Primary Prevention;Process;Production;Public Health;Recommendation;Research;Research Design;Research Project Grants;Research Support;Research Training;Risk;Risk Assessment;Risk Management;Role;Rotation;Scientist;Site;Statutes and Laws;Students;Superfund;System;Techniques;Technology;Technology Transfer;Tissues;Toxic effect;Toxin;Training;Translational Research;Translations;Trichloroethylene;United States Environmental Protection Agency;Universities;Work;base;biomedical scientist;chemical stability;computer infrastructure;cytokine;data management;dechlorination;development policy;evidence base;experience;fetal;global environment;improved;in vivo Model;innovative technologies;insight;lifestyle intervention;manufacturing process;nanomaterials;nanostructured;novel;nutrition;organic contaminant;particle;pollutant;programs;public health relevance;remediation;science education;sensor;superfund chemical;superfund site;technology development;tool;toxicant;translational engagement


application_id: 9256396
project_number: 5R01AG033649-08
project_title: A healthy brain aging strategy to restore insulin signaling and Ca homeostasis
administering_ic: NIA
award_notice_date: 2017-04-17
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AG
serial_number: 033649
program_official: WISE, BRADLEY C
project_start_date: 2009-08-01
project_end_date: 2020-03-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 8361727
contact_pi: THIBAULT, OLIVIER
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    Peripheral metabolic dysregulation appears to increase the risk for cognitive decline with aging and susceptibility to dementing neurodegenerative disorders such as Alzheimer's disease. However the pathways and mechanisms underlying the relationship between metabolic dysregulation and age-related cognitive impairment are not clearly defined. Here we propose that insulin resistance in the brain can destabilize tightly regulated processes which maintain normal calcium homeostasis in neurons resulting in neuronal dysfunction and impaired cognition. Age-related neuronal calcium dysregulation is a well-recognized mechanism contributing to neurologic dysfunction and cognitive decline and we and others have extensively characterized this dysfunction in brain structures important for learning and memory. Interestingly peripheral tissues that are insulin resistant also show calcium dysregulation and provide supporting evidence for a similar relationship in the brain. In the prior funding cycle weidentified a previously unrecognized link between metabolic dysregulation and altered calcium signaling in hippocampal neurons. Together these findings provide support for the notion that overcoming insulin resistance in the hippocampus with insulin-raising strategies will reestablish neuronal calcium homeostasis. Several innovative approaches will be used to increase brain insulin signaling in aging. Specifically we will 1) utilize intranasal insulin delivery to increas insulin availability at the brain insulin receptor in vivo 2) increase insulin receptor signaling n the brain via AAV-mediated expression of a constitutively active human insulin receptor mutant ( subunit) and 3) increase endogenous insulin receptor trafficking through the use of a novel pharmacologic strategy. Using these approaches in the F344 rat model of aging we will investigate cognitive functions using different behavioral paradigms. In hippocampal tissue from these animals we will use single cell electrophysiology/imaging to directly measure calcium status (recordings of calcium-dependent potentials and calcium imaging) and complement these studies with molecular/biochemical assays. To determine whether increasing insulin in the brain affects other pathways independent of Ca2+ we will also quantify p-Akt signaling tyrosine phosphorylation glucose homeostasis (glucose imaging) and adiponectin levels. Type 2 diabetes has reached epidemic proportions among older adults accounting for approximately 26 million people and a $175 billion dollar toll to our health care system (CDC statistics). Our studies are designed to determine whether enhancing insulin action in the brain reduces the burden of cognitive decline in aging and helps to maintain healthy cognitive function. The outcomes from our studies will inform related clinical studies and may have significant impact for the aging population especially for those at increased risk for neurodegenerative diseases such as Alzheimer's disease. This work is clinically-oriented and directly addresses one of the missions of the NIA by establishing novel targets for the treatment of cognitive decline and/or dementia in brain aging.

project_terms:
Accounting;Address;Affect;Age;Age-associated memory impairment;Aging;Alzheimer's Disease;Alzheimer's disease model;Animal Model;Animals;Area;Behavior;Behavioral;Behavioral Paradigm;Biochemical;Biological Assay;Brain;Calcium;Calcium Signaling;Cell membrane;Cells;Centers for Disease Control and Prevention (U.S.);Clinical;Clinical Research;Complement;Dementia;Diabetes Mellitus;Disease;Dorsal;Elderly;Electrophysiology (science);Epidemic;Event;Exhibits;Formulation;Functional disorder;Funding;Gap Junctions;Glucose;Healthcare Systems;Hippocampus (Brain);Homeostasis;Human;Hypothalamic structure;Image;Imaging Techniques;Impaired cognition;Inbred F344 Rats;Insulin;Insulin Receptor;Insulin Resistance;Intervention;Kinetics;Learning;Ligands;Link;Measures;Mediating;Memory;Metabolic;Mission;Modeling;Modification;Molecular;Neurodegenerative Disorders;Neurologic Dysfunctions;Neuronal Dysfunction;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Outcome Measure;Pathologic;Pathway interactions;Patients;Peripheral;Pharmacology;Physiological;Positioning Attribute;Predisposition;Process;Receptor Signaling;Regulation;Research;Risk;Risk Factors;Role;Satiation;Signal Transduction;Slice;Structure;Synapses;Techniques;Testing;Time;Tissues;Tyrosine Phosphorylation;Viral;Visceral;Work;adeno-associated viral vector;adiponectin;age related;aged;aging brain;aging population;animal tissue;base;blood glucose regulation;clinical effect;clinically relevant;cognitive function;cognitive performance;cognitive process;design;feeding;improved;in vivo;innovation;insight;insulin sensitivity;insulin signaling;male;morris water maze;mutant;neuronal excitability;novel;novel therapeutics;pre-clinical;public health relevance;receptor;response;sensory cortex;sigma-2 receptor;statistics;trafficking;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    Our work will test if the mechanism of insulin actions in the brain modulates calcium-related functions inside cells. We will focus on one area of the brain that is known for its role in memoryfunction the hippocampus. We propose new ways to increase insulin signals in the brain.


application_id: 9255783
project_number: 2R44AI112048-02
administering_ic: NIAID
award_notice_date: 2017-02-24
opportunity_number: PA-15-269
application_type: 2
activity_code: R44
ic: AI
serial_number: 112048
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2014-12-15
project_end_date: 2019-02-28
study_section: Special Emphasis Panel[ZRG1 IDM-X (10)]
contact_pi_person_id: 11949039
contact_pi: KELLY, PATRICK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 780816091
primary_uei: F873ZJEX7615
duns_number: 780816091
uei: F873ZJEX7615
fips: US
organization_id: 10027931
organization_name: MOSQUITOMATE, INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40502
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-03-01
project_title:
Phase II: Feasibility assessment of a novel tool for mosquito vector control: Auto-Dissemination Augmented by Males (ADAM)

project_abstract:
Project summary/abstract Mosquito control remains the primary tool for combating many mosquito-vectored diseases such asDengue Chikungunya Zika and West Nile because no approved vaccine therapeutant or prophylaxis iscurrently available for use. Key deficiencies of existing vector control methods include resistance to existinginsecticides and the inability to find and treat cryptic breeding sites which provide refuge to immaturemosquitoes and allow for the rapid recovery of mosquito populations following conventional control efforts. Theself-delivering method known as `auto-dissemination' addresses this deficiency by using mosquitoes as thevehicle to deliver a potent mosquito growth regulator to cryptic breeding sites. The Phase 1 results haveincluded pilot laboratory and field work as a proof-of-principle against both Aedes aegypti and Aedesalbopictus. The epidemiology of Zika has led to an urgent need for preemptive vector control approaches.Specifically a majority of Zika virus infections in humans are not detected quickly. Delayed detection canundermine a public health protection plan that is based on reactive approaches i.e. a strategy of initiatingintensive vector control only after the detection of an epidemic because by the time of detection a largeproportion of the human population can be infected already. The approach being developed in the proposedwork is ideal as a preemptive approach because (1) it requires small amounts of chemical i.e. lessenvironmental impact and (2) the artificially-reared mosquito carriers can be delivered at any time e.g. beforean indigenous vector population reaches dangerous levels. The Auto-Dissemination Augmented by Males (ADAM) is based on mass-producing male mosquitoeswhich do not bite or transmit pathogens. The ADAM method can utilize wild type mosquitoes Wolbachia-infected mosquitoes or Genetically Modified mosquitoes. Integration with existing mosquito mass rearingprograms can speed the uptake of the ADAM technology. Adult ADAM males are treated with an Insect GrowthRegulator (IGR) and then released to deliver lethal doses of the IGR to oviposition sites. Phase I workincluded: 1) laboratory development 2) regulatory work e.g. approval of a Research Authorization from theCalifornia Department of Pesticide Regulation 3) field trials in KY against Ae. albopictus and 4) field trials incollaboration with the Consolidated Mosquito Abatement District (CMAD) to test the ADAM approach againstAe. aegypti. The laboratory results show that Ae. albopictus Ae. aegypti and Culex pipiens males can: 1)tolerate the IGR with negligible cost to the male carriers 2) directly deliver larvicide to breeding sites and 3)cross-contaminate females with IGR doses that are subsequently lethal to larvae. Field trials with both Ae.aegypti and Ae. albopictus show the ADAM method to cause significant larval mortality and significantreductions in the adult population when compared to the non-treated sites. Phase 1 work also included animprovement of methods for the mass manufacturing of adult male mosquitoes. In the proposed Phase II work we will conduct work to replicate and expand field trials against Ae.aegypti and Ae. albopictus from proof-of-principle trials to a scale that is adequate for operational use bymosquito abatement districts. By performing field trials with multiple abatement districts from different statesour proposed Phase II work will satisfy an EPA requirement for commercial registration i.e. that efficacy andsafety be demonstrated in multiple ecological contexts. In addition to the EPA the data will be submitted to theWorld Health Organization (WHO) Vector Control Advisory Group (VCAG) which serves as an advisory bodyon new forms of vector control. WHO approval is anticipated to increase international uptake of the ADAMtechnology. Additional Phase II work will extend Phase I work with Cx. pipiens an important vector of WestNile Virus. Specifically one or more field trials will provide efficacy data for use against this additionalimportant mosquito species which is another focus of abatement districts' vector control efforts.

project_terms:
Abate;Address;Adult;Aedes;Affect;Animals;Attention;Authorization documentation;Behavior;Blood;Breeding;California;Chemicals;Chikungunya virus;Collaborations;Culex (Genus);Culex pipiens;Culicidae;Dangerousness;Data;Dengue;Dengue Virus;Detection;Disease;Disease Vectors;Dose;Environmental Impact;Epidemic;Epidemiology;Face;Female;Florida;Flowers;Goals;Growth;Health protection;Human;Indigenous;Insecta;Insecticide Resistance;Insecticides;International;Juvenile Hormones;Killings;Laboratories;Larva;Lead;Measurement;Measures;Methods;Minor;Monitor;Mosquito Control;Mosquito-borne infectious disease;Native-Born;Outcome;Oviposition;Partner in relationship;Pesticides;Phase;Plant Leaves;Population;Practice Management;Production;Prophylactic treatment;Public Health;Recommendation;Recovery;Regulation;Research;Resistance;Risk;Safety;Site;Speed;Sterility;Techniques;Technology;Testing;Time;Trees;Vaccines;Virus Diseases;Visit;Water;West Nile virus;Wolbachia;Work;World Health Organization;Zika Virus;base;chikungunya;combat;commercialization;cost;drinking water;experimental study;feeding;laboratory development;male;meetings;milliliter;mortality;novel;pathogen;programs;success;tool;uptake;vector;vector control;vector mosquito;wasting

public_health_relevance:
NarrativeVector control remains the only means to combat many mosquito borne diseases including those caused byZika West Nile Dengue Chikungunya viruses and other pathogens. There is a need to develop additionaltools that target immature mosquito populations that remain hidden or protected within cryptic breeding sitesand that are inaccessible to conventional control techniques. The proposed work will further develop a novel`self delivering' approach that is based on the release of adult male mosquitoes as vehicles to deliver apowerful and safe Insect Growth Regulator.


application_id: 9254208
project_number: 5F30DE025543-03
project_title: Characterization of P. gingivalis minor fimbrial accessory proteins
administering_ic: NIDCR
award_notice_date: 2017-04-28
opportunity_number: PA-14-150
application_type: 5
activity_code: F30
ic: DE
serial_number: 025543
program_official: FRIEDEN, LESLIE A
project_start_date: 2015-06-01
project_end_date: 2019-05-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 11948429
contact_pi: LEE, JAE YONG
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): Periodontitis is a chronic inflammatory disease affecting around half the adults over 35 in the United States. Clinical outcomes include damage to periodontal tissues and alveolar bone loss with eventually exfoliation of the teeth. Porphyromonas gingivalis is a keystone pathogen in adult periodontitis and the organism possesses a number of virulence factors that enable colonization of the periodontal area confer resistance to host immunity and mediate destruction of periodontal tissues. P. gingivalis colonization of antecedent oral communities is facilitated by binding to common oral bacteria such as S. gordonii. Attachment of P. gingivalis to S. gordonii is mediated by the short/minor fimbriae of P. gingivalis which interact with the SspA/B streptococcal surface proteins. Communities of P. gingivalis and S. gordonii are more pathogenic in a mouse model of alveolar bone loss compared to either organism alone. The minor/short fimbriae are comprised of the Mfa1 structural subunit and the mfa1 gene is part of a cluster that contains mfa1 mfa2 mfa3 pgn0290 and pgn0291. Mfa2 is an anchoring and length regulating protein. Mfa3 is an accessory protein localized to the fimbrial tip and necessary for the integration of proteins derived from pgn0290 and pgn0291 (which we designate Mfa4 and Mfa5 respectively) into the fimbrial structure. Beyond this however little is known regarding protein interactions supramolecular structure and the functions of Mfa3 4 and 5. We propose 3 specific aims to address these topics: To determine the location of Mfa4 and Mfa5 on the Mfa fimbriae and characterize the binding interactions among Mfa3 4 and 5; to determine the role of Mfa3 Mfa4 and Mfa5 in P. gingivalis co-adhesion to S. gordonii; and to determine the role of Mfa3 Mfa4 and Mfa5 in polymicrobial synergy in vivo. The findings from this study will provide novel structural and functional detail of an important virulence factor of P. gingivalis. This has the potential to lead to the design of new therapeutics to target the effector molecules of P. gingivalis colonization and prevent the accumulation of P. gingivalis into polymicrobially synergistic communities.

project_terms:
Address;Adhesions;Adult;Affect;Alveolar Bone Loss;Anaerobic Bacteria;Animals;Area;Binding;Binding Proteins;Biogenesis;Biological Assay;Cell surface;Chronic;Chronic Disease;Clinical;Communities;Complement;Complex;Development;Disease;Electron Microscopy;Epithelial Cells;Exhibits;Filament;Gene Cluster;Genes;Goals;Homeostasis;Immune;Immune response;Immunity;Individual;Infection;Inflammatory;Lead;Left;Length;Location;Mediating;Membrane Proteins;Minor;Molecular;Mouth Diseases;Oral;Oral cavity;Oral health;Organism;Outcome;Pathogenesis;Pathogenicity;Periodontitis;Population;Porphyromonas gingivalis;Process;Protein Subunits;Proteins;Recombinant Proteins;Research;Resistance;Role;Severities;Streptococcus gordonii;Structure;Surface;Testing;Therapeutic Studies;Tissues;Tooth Exfoliation;Tooth Loss;United States;Virulence Factors;bone loss;co-infection;design;immunoregulation;improved;in vivo;mouse model;mutant;new therapeutic target;novel;novel therapeutics;oral bacteria;pathogen;prevent;protein complex;public health relevance;synergism;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Periodontitis is a prevalent oral disease that can ultimately lead to tooth loss. In this project we shall study the means by which one of major causative agents of periodontitis establishes itself in the mouth. This has the potential to identify therapeutic targets which in turn can be included in oral health products designed to mitigate the severity of periodontitis.


application_id: 9253592
project_number: 5U01NS090408-04
project_title: The Center for SUDEP Research (CSR) Informatics and Data Analytics Core (IDAC)
administering_ic: NINDS
award_notice_date: 2016-08-10
opportunity_number: RFA-NS-14-004
application_type: 5
activity_code: U01
ic: NS
serial_number: 090408
program_official: STEWART, RANDALL R
project_start_date: 2016-02-27
project_end_date: 2019-07-31
study_section: ZNS1-SRB-B(40)
contact_pi_person_id: 7938505
contact_pi: ZHANG, GUO-QIANG
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:
DESCRIPTION (provided by applicant): Project Summary The goal of SUTRA (SUDEP Translational Research Alliance) Center Without Walls is to better understand the brainstem mechanisms responsible for SUDEP and elucidate the role of cortical influences thereon using a data-driven systems-biology-based approach. This understanding requires a strategy that shares research resources and infrastructure to make good and efficient use of a spectrum of prospectively collected data encompassing clinical electrophysiological biochemical genetic and neuropathological domains. A critical aspect of SUTRA is the process and infrastructure facilitating the sharing of clinical and research data across centers. In our NINDS-funded center- planning award Prevention and Risk Identification of SUDEP Mortality (PRISM; 1P20- NS076965) a team of world-class epileptologists computer scientists biomedical informaticians and data analytics experts has developed an informatics infrastructure for sharing research data using the Multi-Modality Epilepsy Data Capture and Integration System (MEDCIS). The main goal of this Informatics and Data Analytics U01 Core (IDAC) is to build on the paradigm-changing progress already achieved through PRISM's MEDICS infrastructure and expand and broaden the sharing and utilization of research resources among SUTRA partners. With access to biospecimen materials and alliances with stakeholder organizations including Dup15q the North American SUDEP Registry Courtagen GW Pharma and CURE SUTRA will continuously boost materials and data collection. IDAC will promote and facilitate SUDEP research by expanding an integrated clinical and translation data resource for epilepsy; providing coordinated services and support for SUTRA members; empowering investigator with web-based cohort search interface for data mining and hypothesis generation; data analytics and statistical support for in-depth analyses of multi-modal data collected in the shared and expanding SUTRA Data Repository.

project_terms:
Address;Algorithms;American;Animals;Award;Big Data;Biochemical Genetics;Biological;Blood Pressure;Brain;Brain Stem;Clinical;Clinical Research;Cloud Computing;Collection;Computers;Consultations;Coupling;Data;Data Analyses;Data Analytics;Data Collection;Data Set;Databases;Development;Electrocardiogram;Electroencephalography;Electrophysiology (science);Enrollment;Epilepsy;Event;Feedback;Formalin;Freezing;Funding;Galvanic Skin Response;Generations;Goals;Health;Imagery;Informatics;Institution;Intervention;Modality;Motion;National Institute of Neurological Disorders and Stroke;Online Systems;Ontology;Oxygen;Patients;Performance;Phenotype;Prevention;Prevention Measures;Process;Registries;Research;Research Design;Research Infrastructure;Research Personnel;Resources;Respiration;Rest;Risk;Role;Seizures;Services;Signal Transduction;Statistical Data Interpretation;Structure;Surveys;System;Systems Biology;Systems Integration;Technology;Terminology;Translational Research;Translations;Visual;Work;base;biomedical scientist;cohort;computerized tools;crosslink;data management;data mining;demographics;design;empowered;evidence base;genetic resource;improved;informatics infrastructure;member;mortality;neuropathology;open source;phenotypic data;quality assurance;respiratory;satisfaction;signal processing;sleep epilepsy;sudden unexpected death in epilepsy;tool;user-friendly

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Project Narrative The main goal of this Informatics and Data Analytics Core a part of the SUDEP Translational Research Alliance is to expand and broaden the sharing and utilization of research resources across centers to accelerate the understanding of biological mechanisms responsible for SUDEP and to develop intervention and prevention measures to reduce SUDEP mortality.


application_id: 9253568
project_number: 2R42AG044187-02A1
project_title: Commercialization of a Novel Therapeutic for Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2017-09-22
opportunity_number: PA-16-092
application_type: 2
activity_code: R42
ic: AG
serial_number: 044187
suffix: A1
program_official: MARTIN, ZANE
project_start_date: 2012-09-30
project_end_date: 2019-05-31
study_section: Special Emphasis Panel[ZRG1 ETTN-M (11)]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 841834083
primary_uei: JK7PN2MFXEU2
duns_number: 841834083
uei: JK7PN2MFXEU2
fips: US
organization_id: 10022006
organization_name: COPLEX THERAPEUTICS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
project_abstract:
ABSTRACTTraditional mon-therapeutic target driven approaches to drug development for Alzheimersdisease (AD) are becoming increasingly expensive and in many cases disappointinglyunsuccessful. Based on preliminary in vitro and in vivo studies we have identified a novel smallmolecule (methyl 24-dimethyl-5-oxo-56-dihydrobenzo[c][27]naphthyridine-1-carboxylate;(BNC-1)) that significantly decreases neuroinflammation and production of A42 in mousemodels of AD pathology through Elk-1 mediated transcriptional repression of presenilin-1 butnot presenilin-2. Although our preliminary data show BNC-1 effectively modulates 2 of the mainpathologic features of AD without the adverse effects associated with current mono-therapeutics there is a need for characterization of its basic pharmacology/toxicity and foridentification of the most efficacious treatment regimen in a well characterized mouse model ofA deposition and neuroinflammation (5X FAD mice). If successful the data obtained in thisproposal will provide necessary pharmacology/safety toxicology data to de-risk the drug forpotential corporate partners thus increasing the likelihood of successful commercialization.

project_terms:
APP-PS1;Abeta synthesis;Adrenal Glands;Adverse effects;Age;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Anti-Inflammatory Agents;Anti-inflammatory;Autopsy;Biological Availability;Blood specimen;Body Weight;Brain;Chromosome abnormality;Clinical;Clinical Chemistry;Clinical Pathology;Clinical Services;Clinical Trials;Collaborations;Data;Deposition;Development;Diet;Disease;Dose;Drug Kinetics;Female;Formic Acids;Future;Guidelines;Hematology;High Pressure Liquid Chromatography;Histopathology;In Vitro;Inflammatory;Intestines;Intravenous;Isotope Labeling;Kentucky;Kidney;Learning;Legal patent;Liver;Maximum Tolerated Dose;Mediating;Memory;Methods;Modeling;Mono-S;Mus;Mutation;Naphthyridines;Oral;Outcome;PS2 protein (alzheimer-associated);Pancreas;Pathogenesis;Pathogenicity;Pathologic;Pathology;Pathway interactions;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Pharmacology and Toxicology;Phase;Phenotype;Positioning Attribute;Presenile Alzheimer Dementia;Prevention;Production;Proteins;Radial;Rattus;Recovery;Regimen;Risk;Rivers;Role;Safety;Series;Spleen;Sprague-Dawley Rats;Tail;Testing;Therapeutic;Time;Toxic effect;Toxicokinetics;Toxicology;Transcription Repressor/Corepressor;Treatment Protocols;Universities;Veins;Water;amyloid formation;animal resource;arm;base;behavior measurement;carboxylate;commercialization;cytokine;drug development;drug efficacy;efficacy testing;familial Alzheimer disease;food consumption;gamma secretase;gene repression;improved;in vivo;inhibitor/antagonist;male;mouse model;mutant;neuroinflammation;notch protein;novel;novel therapeutics;object recognition;pre-clinical;presenilin-1;respiratory;small molecule;therapeutic target

public_health_relevance:
NarrativeIn preliminary studies we identified a novel small molecule (methyl 24-dimethyl-5-oxo-56-dihydrobenzo[c][27]naphthyridine-1-carboxylate; (BNC-1) that lowers beta amyloid (A) production andpro-inflammatory cytokines but increases anti-inflammatory cytokines and significantly improvesbehavioral measures in a mouse model of Alzheimers disease. Future studies described in thisproposal aim to determine the pharmacokinetics and toxicology of BNC-1 and to test the efficacy forprevention of beta amyloid (A) formation and deposition and neuroinflammation in a well-establishedalternative mouse model of A pathology (5X FAD mice). Together these studies will help de-risk BNC-1 for potential partners and better position the compound for further commercialization.


application_id: 9253077
project_number: 1R44AA025804-01
project_title: Mutant transgenic plant cells as a novel source of drugs
administering_ic: NIAAA
award_notice_date: 2016-09-22
opportunity_number: PAR-14-088
application_type: 1
activity_code: R44
ic: AA
serial_number: 025804
program_official: FERTIG, JOANNE
project_start_date: 2016-09-22
project_end_date: 2018-08-31
study_section: Special Emphasis Panel[ZRG1 IMST-L (10)]
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:
AbstractThe objective is further development of a biotechnology that evolves biosynthesis in a plant species towardbioactive metabolites with a specific molecular target. In wild-type plants bioactive metabolites have generallyevolved by mutation and natural selection over millennia [1] whereas here target-directed evolution canchange the active metabolite profile in mutant plant cells within months. Proof of concept has been obtained inLobelia cardinalis which contains the complex alkaloid lobinaline. This is a novel inhibitor of the dopaminetransporter (DAT) [2] a molecular target in Parkinson's Disease and drug dependence [34 ]. First hairy rootcultures of this species were transformed to express the human DAT. This made these transgenic (hDAT)plant cells highly susceptible to toxicity induced by the neurotoxin MPP+ which is accumulated intracellularlyby activity of the DAT. Gain of function mutants of these transgenic cells were then generated in aconcentration of MPP+ that is lethal to non-mutants. This selection procedure favors survival of mutants thatoverproduce metabolites that inhibit the DAT. As a result more than half the >100 MPP+-resistant mutantswere significantly overproducing DAT inhibitory activity relative to controls. In the majority of these mutantsenhanced DAT inhibition could be ascribed to lobinaline or other known active metabolites but 25 mutantscontain unknown DAT inhibitors. In these mutants there are 9 novel HPLC peaks that are not observed inwild-type and these all contain DAT inhibitory activity. The first specific aim is to separate sufficient quantitiesof these metabolites for chemical identification and pharmacological analysis (DAT inhibition in vitro and invivo). This will establish whether novel DAT inhibitory metabolites with therapeutic potential exist in thesemutants. Many of the remaining MPP+-resistant population (mutants that do not overproduce DAT inhibitors)appear to overproduce metabolites that inhibit the intracellular mechanism of MPP+. Extracts from thesemutants protect the dopaminergic cell line SH-SY5Y against MPP+ and so may contain novel neuroprotectivemetabolites. The second specific aim is to separate and analyze these also using the same approach basedon separation and analysis of novel HPLC peaks so that their potential therapeutic value can be ascertained.Successful completion of these aims will establish proof of application for the technology as a platform for plantdrug discovery. The same approach can also be used to generate overproducing mutants to becomebiosynthetic production systems and as a means of optimizing biosynthesis of therapeutic metabolites inmedicinal plants. In addition although this proposal uses the human DAT and L. cardinalis as examples thetechnology can be applied to many other targets and plant species. If adopted by the global pharmaceuticalindustry this could be a transformative technology. The applicants intend to pursue this in phase III by seekingpartnerships with major pharmaceutical and/or biotechnology companies. Thus the main purpose of theproposal is technology development to be achieved by demonstrating that this approach is capable ofdiscovering novel active metabolites with therapeutic potential in mutant transgenic plant cells.

project_terms:
1-Methyl-4-phenylpyridinium;Adopted;Alkaloids;Anabolism;Biotechnology;Carbon;Cell Line;Cells;Chemicals;Complex;Development;Directed Molecular Evolution;Dopaminergic Cell;Drug Addiction;Drug Industry;Evaluation;Freeze Drying;High Pressure Liquid Chromatography;Human;In Vitro;Industry;Lobelia;Mass Fragmentography;Mass Spectrum Analysis;Medicinal Plants;Methanol;Methodology;Molecular Target;Mutation;N-Methylaspartate;Natural Selections;Neurons;Neurotoxins;Nuclear Magnetic Resonance;Parkinson Disease;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Plant Roots;Plants;Population;Procedures;Production;Proteins;Protons;Resistance;Resolution;Source;Spectrometry;Spectrum Analysis;Structure;Synapses;System;Technology;Testing;Therapeutic;Toxic effect;Toxin;Traditional Medicine;Transgenic Organisms;Transgenic Plants;Work;abstracting;aqueous;base;chemical synthesis;commercialization;cytotoxicity;dopamine transporter;drug discovery;drug production;gain of function;gain of function mutation;in vitro activity;in vivo;inhibitor/antagonist;mutant;novel;novel therapeutics;technology development;therapeutic target;uptake

public_health_relevance:
Project narrativeThe company is developing a technology which enables us to tell mutant cells of a plant species what kind ofdrug we want them to make. This proposal applies the technology to drugs that may be of value in Parkinson'sDisease or drug dependence. The main objective is to show that the technology works so that it can beadopted by the industry as an alternative to chemical synthesis as a source of new drugs.


application_id: 9251728
project_number: 5R01AG045775-04
project_title: Translating CD33 genetic mechanism into a novel Alzheimers therapeutic
administering_ic: NIA
award_notice_date: 2017-03-20
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AG
serial_number: 045775
program_official: REFOLO, LORENZO
project_start_date: 2014-04-15
project_end_date: 2018-11-30
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 1859637
contact_pi: ESTUS, STEVEN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overarching theme of this proposal is that polymorphisms identified by recent Alzheimer's disease (AD) genome wide association studies biologically define rate-limiting steps in AD pathways. Hence elucidating their mechanism of action will identify robust pharmacologic targets. Notably a SNP with modest molecular actions may reduce AD risk by 10% but a drug that acts strongly at the same target may have a large effect on AD risk. This proposal will elucidate the mechanism of action of rs3865444 (rs444) an AD-associated SNP in CD33 and translate this mechanism into a proof of concept AD treatment. In our highly compelling preliminary results we associate the AD-protective minor allele of rs444 with (i) a robust increase in the proportion of CD33 lacking exon 2 (D2-CD33) which appears critical to CD33 function. Large pharma have developed humanized monoclonal antibodies against CD33 for acute myeloid leukemia (AML); these antibodies and their derivatives have potential AD relevance as CD33 antagonists. This leads to our global hypothesis: Reduced CD33 function decreases AD risk whether CD33 inhibition is due to genetics or pharmacologic agents. To test our hypothesis we will (i) Elucidate the mechanism underlying the CD33 AD SNP (ii) Compare CD33 and D2- CD33 function especially relative to AD pathogenic mechanisms and (iii) Translate CD33 genetics into a novel AD therapeutic mimic. Overall this focused proposal will develop our compelling mechanistic genetic results elucidate the differences in D2-CD33 and CD33 function and begin to translate these changes into an AD-preventive agent. In work beyond the scope of this focused proposal we anticipate that these therapeutic agents will be tested in "AD" murine models that are transgenic for human CD33 and eventually humans.

project_terms:
Acute Myelocytic Leukemia;Alleles;Alzheimer disease prevention;Alzheimer's Disease;Alzheimer's Disease Pathway;Alzheimer's disease risk;Antibodies;Apolipoprotein E;Apoptotic;Asses;Binding;Biological;Brain;Critical Pathways;Exons;Fab Immunoglobulins;Family member;Foundations;Future;Genes;Genetic;Genetic Polymorphism;Genotype;Goals;Half-Life;Human;Immunoglobulins;In Vitro;Individual;Lectin;Length;Ligands;Mediator of activation protein;Messenger RNA;Microglia;Minor;Molecular;Mutate;NR0B2 gene;Neurons;Odds Ratio;PTPN11 gene;Pathogenicity;Phagocytosis;Pharmaceutical Preparations;Pharmacology;Preventive;Process;Production;Protein Isoforms;Proteins;Public Health;RNA Splicing;Reporting;Sialic Acids;Signal Transduction;Single Nucleotide Polymorphism;Staging;Testing;Therapeutic;Therapeutic Agents;Transgenic Model;Translating;Work;cohort;cytokine;genome wide association study;humanized monoclonal antibodies;in vivo;inhibitor/antagonist;mouse model;novel;novel therapeutics;pre-clinical;public health relevance;receptor;sulfated glycoprotein 2;targeted agent;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The significance of this proposal to public health is that we will identify the mechanism whereby a genetic factor modulates the risk of Alzheimer's disease. We will then perform studies to identify agents that target this mechanism as proof-of-concept pre- clinical Alzheimer's disease prevention studies.


application_id: 9250350
project_number: 7R01HL091357-06
project_title: Genomewide Association Study of Lipid Response to Fenofibrate and Dietary Fat
administering_ic: NHLBI
award_notice_date: 2016-07-15
opportunity_number: PA-14-078
application_type: 7
activity_code: R01
ic: HL
serial_number: 091357
program_official: JAQUISH, CASHELL E
project_start_date: 2008-09-05
project_end_date: 2019-02-28
study_section: Special Emphasis Panel[ZRG1-PSE-Q(90)S]
contact_pi_person_id: 1876483
contact_pi: ARNETT, DONNA K
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Dyslipidemias remain a critical determinant of cardiovascular disease risk. Effective dietary and therapeutic interventions to reduce dyslipidemia including elevated triglycerides (TGs) and high non-HDL-cholesterol exist yet there is much variation in lipid and lipoprotein level's response to these interventions. Genetics partially explain this variation. We hypothesize that by using improved lipid phenotyping techniques we will be able further characterize this interindividual variation of lipids in respone to diet and drug. Recent advances in mass spectrometry-based techniques allow metabolomic characterization in large populations. Detailed and precise measurement of lipid molecular species a field known as "lipidomics" now offers an unprecedented picture of lipid metabolism. The Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study provides an ideal context in which to pursue this work. GOLDN is the largest family study conducted to date that has sought to identify genetic factors that explain response to two short-term interventions one to raise lipids (i.e. ingestion of a high-fat meal the "post-prandial lipemia" (PPL) intervention and one to lower lipids (i.e. treatment with fenofibrate (FFB)). The goal of the "Genomewide Association Study (GWAS) of Lipid Response to Fenofibrate and Dietary Fat" (Arnett PI R01-HL091357) was to identify the common genetic variants that explain response to the interventions. In addition to this GOLDN is also conducting a genome- wide epigenomics study and exome sequencing through the NIH Pharmacogenomics Research Network (PGRN). The proposed work will leverage this wealth of genomic data in the context of state-of-the-art lipidomic phenotypes specifically phospholipids neutral lipids and sterols to identify rare andcommon variants and epigenetic marks that determine response to GOLDN's diet and drug interventions. Specifically we aim to: (1) Quantify pre- and post-FFB treatment/PPL response of 350 metabolites. GOLDN recruited and examined 1048 Caucasians from 186 families. Participants were given an 83% fat meal and three weeks of FFB treatment 250 mg/d. Blood was drawn at fasting and 6-hr post ingestion and again after 3 wk of FFB treatment. Plasma from each of these time points will be analyzed with for 350 lipidomic species. PPL response (estimated as the 6-hr TG response adjusted for baseline) and fenofibrate response (estimated by the ratio of post/pre TG values) of the new lipidomic phenotypes will be calculated. Responsive and heritable metabolites will be moved forward to Aim 2. (2) Test the association of these small molecules with (a) common (GWAS) and rare (WES) variants (b) methylation at CpG sites (EWAS). (3) Replicate PPL findings in 500 subjects selected from extremes of the PPL response in the HAPI Heart Study. (4) Use induced pluripotent stem cell- derived hepatocytes to functionally validate fenofibrate response variants identified in Aim 2. If successful GOLDN will identify novel lipidomic biomarkers to predict efficacy and adverse responses to a high-fat meal and fenofibrate treatment leading to more personalized approaches to diet and pharmacologic treatment.

project_terms:
Aftercare;Age;Biological Assay;Biological Markers;Biological Models;Blood;Body Surface Area;Calcium-Activated Potassium Channel;Calories;Caucasians;Chemicals;Cholesterol;Data;Diet;Dietary Fats;Dietary Intervention;Disease;Drug Prescriptions;Drug Targeting;Dyslipidemias;Eating;Epigenetic Process;Family;Family Study;Fasting;Fatty Acids;Fatty acid glycerol esters;Fenofibrate;Fibrates;Funding;Genes;Genetic;Genome;Genomics;Goals;Health;Heart;Hepatic;Hepatocyte;Heritability;Human;Hypertension;Hypertriglyceridemia;Ingestion;Institutes;Intervention;Link;Lipids;Lipoproteins;Mass Spectrum Analysis;Measurement;Measures;Metabolism;Methodology;Methylation;Modeling;Molecular;Myocardial Infarction;Nuclear;PPAR alpha;Participant;Pharmaceutical Preparations;Pharmacogenomics;Phase;Phenotype;Phospholipids;Plasma;Population;Process;Protocols documentation;Recruitment Activity;Reporting;Research;Sample Size;Sampling;Signal Transduction;Sister;Site;Steroids;Sterols;Techniques;Testing;Therapeutic Intervention;Time;Triglycerides;United States National Institutes of Health;Universities;Validation;Variant;Washington;Work;base;blood lipid;cardiovascular disorder risk;density;epigenome-wide association studies;epigenomics;exome sequencing;gene environment interaction;genetic pedigree;genetic variant;genome wide association study;genome-wide;genomic data;improved;induced pluripotent stem cell;inter-individual variation;lipid metabolism;member;metabolic profile;metabolomics;novel;personalized approach;prevent;programs;rare variant;response;sex;small molecule;stroke;tandem mass spectrometry;trait

public_health_relevance:
PUBLIC HEALTH RELEVANCE: People differ in the ways their bodies process dietary fats and in the ways they respond to drugs meant to lower elevated blood lipids (such as cholesterol and triglycerides factors that can increase the risk of cardiovascular disease). By studying the building blocks of lipids and the chemicals that lipids are broken down into this project seeks todetermine which genetic factors influence people's blood lipid concentrations after eating a high-fat meal or after taking a lipid- lowering drug. Ultimately this research may help doctors more accurately assess people's risk of cardiovascular disease and more effectively prescribe drugs to prevent disease.


application_id: 9250286
project_number: 7R01HL104135-05
project_title: Epigenetic Determinants of Lipid Response to Dietary Fat and Fenofibrate
administering_ic: NHLBI
award_notice_date: 2016-06-28
opportunity_number: PA-14-078
application_type: 7
activity_code: R01
ic: HL
serial_number: 104135
program_official: JAQUISH, CASHELL E
project_start_date: 2016-06-30
project_end_date: 2018-05-31
study_section: Special Emphasis Panel[ZRG1-PSE-J(03)M]
contact_pi_person_id: 1876483
contact_pi: ARNETT, DONNA K
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:
Dyslipidemias play a large role in the occurrence of cardiovascular disease which has fueledinterest to better understand environmental factors responsible for dyslipidemias especiallyhypertriglyceridemia. Epigenetic variations may affect triglyceride (TG) metabolism andresponse to environmental challenges. Our goal is to conduct the first experiments that willcomprehensively scan the epigenome for determinants of TG and other dyslipidemic responsesto two environmental interventions one to raise TGs (a high-fat meal) and one to lower TGs(3-week fenofibrate treatment). These experiments will be conducted in the NHLBI Program inGene-Environment Interaction Network's Genetics of Lipid Lowering and Diet (GOLDN) study.GOLDN recruited family members from field centers in Minnesota and Utah and phenotypedthem extensively for enzymatic and NMR lipids and inflammatory markers in response to thetwo interventions. The proposed study will build upon this unique resource using previouslycollected samples to implement the following aims: (1) Conduct genome-wide CpG methylationanalysis using next generation sequencing method specifically Reduced RepresentationBisulfite Sequencing in 1048 individuals from 184 families to identify epigenetic variationcontributing to the response of TGs and TG-related phenotypes to a fat meal fenofibrate and afat meal in the context of fenofibrate treatment. From these results we will select 20 candidategenes with the best evidence for further characterization in Aim 2. (2) Characterize themethylation state of these 20 genes using bisulfite sequencing of promoters and other regionsof interest in all 1048 family members. (3) Replicate significant findings from Aims 1 and 2 inexternal cohorts. (4) Conduct gene expression studies to identify the functional impact ofmethylation findings from Aims 1-3 since DNA methylation may affect the expression of nearbygenes in a variety of ways including transcription rates alternative splicing microRNAinhibition or allele specific expression. We will apply next-generation sequencing to bothmRNA and microRNA from 150 subjects using a method called RNAseq. If successful we willidentify novel epigenetic variations that predict individuals who respond poorly to dietary fat orfavorably to fenofibrate which will lead to the development of targeted interventions to moreeffectively prevent and treat hypertriglyceridemia.

public_health_relevance:
Epigenetics is a relatively new area of study which seeks to understand how gene activity rather than genestructure influences people's traits. Epigenetic factors may explain why the levels of fat and cholesterol insome people's blood change dramatically after eating a high-fat meal or after taking fat-lowering drugs whilefat and cholesterol levels in other people change very little under the same conditions. This study aims todiscover the epigenetic factors that cause people's bodies to respond so differently to diet and drugs withthe belief that such knowledge could ultimately help lower people's risk for cardiovascular disease.


application_id: 9249967
project_number: 5R01CA186661-04
project_title: Small molecule targeting of MIF as a novel melanoma therapeutic
administering_ic: NCI
award_notice_date: 2017-03-16
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 186661
program_official: ALLEY, MICHAEL C
project_start_date: 2014-04-03
project_end_date: 2019-03-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 7360475
contact_pi: MITCHELL, ROBERT A
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):  Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are critically important determinants of solid tumor immunosuppression neovascularization and metastatic dissemination. Despite intensive efforts aimed at identifying TAM/MDSC regulatory effectors very few have been identified that can orchestrate this process and be effectively targeted.  Macrophage migration inhibitory factor (MIF) is one the oldest cytokine activities described and is a centrally important mediator of monocyte/macrophage immune responses. TAMs and MDSCs from melanoma bearing MIF-deficient mice exhibit a unique reversion in their "polarization" state resulting in a switch from n immunosuppressive angiogenic phenotype (MIF+/+ TAM/MDSC) into an immunostimulatory non-angiogenic phenotype (MIF-/- TAM/MDSC) which results in significant reductions in primary and metastatic melanoma disease progression. Intriguingly our previously discovered MIF small molecule antagonist - 4-iodo-6- phenylpyrimidine (4-IPP) - fully recapitulates MIF-deficiency both in vitro and in vivo and serves to attenuate TAM and MDSC alternative activation immunosuppression neoangiogenesis and melanoma disease progression [1601]. We very recently discovered that 4-IPP functionally inhibits MIF by dramatically reducing intracellular MIF protein levels in a proteasome-dependent manner. However relatively high 4-IPP IC50 values and a lack of information on its mechanism of action bioavailability and chronic toxicity dictate that much more study is needed to fully identify optimize and characterize lead MIF-degradation inducing compounds before moving forward with small molecule MIF targeting in a clinical setting. To fulfill the stated objectives of this application the following aims areproposed: Aim 1: Delineate the mechanisms of action of 4-IPP and MIF-dependent TAM/MDSC polarization Aim 2: Characterize TAM/MDSC modulatory in vivo bioavailability toxicity and anti-tumor activities of existing and newly identified MIF inhibitor scaffolds and Aim 3: Evaluatethe therapeutic potential of lead MIF small molecule antagonists as individual and combinatorial modalities against established melanoma.

project_terms:
5'-AMP-activated protein kinase;American;Antibody Therapy;Attenuated;Binding;Biological Availability;Cancer Center;Cancer Patient;Cells;Chemotherapy-Oncologic Procedure;Chimeric Proteins;Chronic;Clinical;Clinical Trials;Cytotoxic T-Lymphocyte-Associated Protein 4;Denileukin Diftitox;Diagnosis;Disease Progression;Distal;Drug Targeting;Effector Cell;Exhibits;Future;Gene Expression;Goals;Growth;IL2 gene;IL2RA gene;Immune;Immune response;Immunosuppressive Agents;Immunotherapeutic agent;Immunotherapy;In Vitro;In complete remission;Individual;Innate Immune Response;Invaded;Lead;Lesion;Lifetime Risk;Ligands;Malignant Neoplasms;Mediator of activation protein;Melanoma Cell;Metastatic Melanoma;Migration Inhibitory Factor;Modality;Molecular Profiling;Mus;Myelogenous;Natural immunosuppression;Neoplasm Metastasis;Outcome;Pathway interactions;Patients;Phenotype;Population;Process;Proteins;Quantitative Structure-Activity Relationship;Regulatory T-Lymphocyte;Resistance;Role;Signal Pathway;Skin Cancer;Solid;Solid Neoplasm;Specificity;Stromal Cells;Suppressor-Effector T-Lymphocytes;Survival Rate;Testing;Therapeutic;Toxic effect;Tumorigenicity;United States;analog;angiogenesis;base;cancer cell;clinical efficacy;combinatorial;cytokine;design;efficacy study;immunoregulation;improved;in vivo;inhibitor/antagonist;insight;lung metastatic;macrophage;melanoma;monocyte;mouse model;multicatalytic endopeptidase complex;neovascularization;novel;novel therapeutics;partial response;phenylpyruvate tautomerase;polarized cell;prevent;public health relevance;receptor;scaffold;small molecule;small molecule inhibitor;subcutaneous;therapeutic target;therapy resistant;tumor;tumor microenvironment;tumorigenic

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Malignant melanoma is the most deadly form of skin cancer due in large part to its aggressive ability to locally invade and distally metastasize. One in 50Americans has a lifetime risk of developing melanoma and nearly 69000 people in the United States were diagnosed with it last year. The five year survival rate for those diagnosed with stage IV metastatic melanoma remains unacceptably low at only 5 - 10%. Despite the advent of new immunotherapies designed to enhance the patient's immune response to attack melanocytic cancer cells no appreciable improvements have been observed in overall patient survival percentages. Our recent studies now demonstrate that small molecule targeting of macrophage migration inhibitory factor (MIF) induces substantial resistance to implantable subcutaneous and lung metastatic melanoma. Studies described in this proposal seek to fully delineate the mechanism(s) by which small molecule MIF antagonists induce intracellular degradation of MIF thereby reverting immunosuppressive pro-angiogenic TAM/MDSC cell populations into immunostimulatory non-angiogenic innate immune effector cells. These studies will rigorously characterize and refine the clinical efficacy of small molecule MIF targeting as both an individual and combinatorial therapeutic modality targeting malignant melanoma.


application_id: 9249527
project_number: 5K01DK096042-05
project_title: Enhancement of NAFLD risk by vinyl chloride: interaction of gut-liver-adipose axi
administering_ic: NIDDK
award_notice_date: 2017-03-23
opportunity_number: PAR-12-020
application_type: 5
activity_code: K01
ic: DK
serial_number: 096042
program_official: SASLOWSKY, DAVID E
project_start_date: 2013-04-01
project_end_date: 2018-03-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 10438358
contact_pi: BEIER, JULIANE I
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Obesity and its metabolic complications are major health problems in the United States and worldwide. A major disease associated with obesity is non-alcoholic fatty liver disease (NAFLD). Indeed obesity may influence individual susceptibility to other environmental exposures such as vinyl chloride (VC). Specifically we hypothesize that experimental NAFLD sensitizes the liver to VC as a 2nd hit. Recent studies indicate that intestinal barrier function and GI tract flora play a key role in the development of NAFLD. Supplementation with probiotics has been shown to decrease induced gut permeability and liver injury. We therefore propose that VC via altering intracellular signaling cascades impairs barrier function integrity in NAFLD and that probiotic supplementation [Lactobacillus rhamnosus Gorbach-Goldin (LGG)] will attenuate these effects. Aim 1. To test the hypothesis that VC exposure exacerbates liver injury caused by HFD. It is well-known that liver injury is increased by high fat (HFD) diet. It has been shown that VC is hepatotoxic. We propose here that VC exposure will exacerbate liver injury caused by experimental NAFLD (HFD) in mice. Subaims will determine: a) the minimal low dose VC exposure conditions that exacerbate fatty liver due to HFD; b) potential mechanisms by which VC exposure enhances liver damage caused HFD. Aim 2. To determine mechanisms by which VC accentuates fatty liver disease caused by HFD. It is known that there is a critical crosstalk between the GI tract the adipose tissue and the liver tha plays an important role in the development of NAFLD (i.e. the 'gut-liver-adipose axis'). The purpose of this Aim is to determine the effect of VC metabolites on responses in in vitro paradigms of the gut-liver-adipose axis. Subaims will characterize the response of: a) hepatocytes to cytotoxic stimuli b) response of macrophages to inflammatory stimuli and c) stimulus of adipocytes to produce adipogenic mediators. Aim 3. To test the hypothesis that VC exposure exacerbates intestinal permeability caused by HFD. It is known that intestinal permeability is increased after HFD feeding. The barrier function of the intestinal epithelium is also dependent on the gut microbiota profile. Probiotic microorganisms have been shown to improve barrier integrity of the intestinal epithelium. We propose here that VC exposure will exacerbate gut permeability due to HFD in mice and that gut microbiota play an important role in gut permeability and VC-induced toxicity in HF-fed mice. We will further determine if probiotics [e.g. lactobacillus rhamnosus GG (LGG)] will decrease VC-induced toxicity in HF-fed mice via improvement of gut permeability and TJ integrity. Subaims will determine: a) the combined effect of VC and HFD on intestinal integrity in vivo (mice) and in vitro (Caco-2 cells); b) the effct of VC and dietary fatty acids on mRNA and surface expression of key tight junction proteins and the role of SAPK signaling in this process in Caco-2 cells; c) if HFD and VC synergistically impair TJ barrier functions in vivo; and d) the protective effect of probiotic LGG on HFD and VC-induced gut permeability.

project_terms:
Adipocytes;Adipose tissue;Attenuated;Caco-2 Cells;Chemicals;Data;Development;Diet;Dietary Fatty Acid;Disease;Dose;Endotoxemia;Environmental Exposure;Environmental Pollutants;Fatty Liver;Fatty acid glycerol esters;Gastrointestinal tract structure;Health;Hepatocyte;Hepatotoxicity;High Fat Diet;Human;Impairment;In Vitro;Individual;Inflammatory;Inflammatory Response;Intestines;Lactobacillus casei rhamnosus;Liver;Liver diseases;Mediating;Mediator of activation protein;Messenger RNA;Metabolic;Modeling;Mus;Nutrient;Obesity;Permeability;Play;Population;Predisposition;Probiotics;Process;Production;Proteins;Relative Risks;Risk;Risk Factors;Role;SAPK;Safety;Signal Transduction;Stimulus;Surface;Testing;Tight Junctions;Toxic effect;Toxin;Treatment Protocols;United States;Vinyl Chloride;Work;cytokine;cytotoxic;disorder risk;feeding;gut microbiota;improved;in vivo;in vivo Model;intestinal epithelium;liver development;liver injury;macrophage;microbiota;microorganism;non-alcoholic fatty liver;nonalcoholic steatohepatitis;novel;probiotic supplementation;protective effect;public health relevance;response;toxicant

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  We propose that vinyl chloride exposure even below levels that are overtly hepatotoxic may increase the stimulated inflammatory response in the liver potentially adding another risk factor to the development of liver disease associated with obesity (i.e. non-alcoholic fatty liver disease). The project will focus on the individual and combined effects of vinyl chloride and diet on gut-liver-adipose axis in experimental NAFLD.


application_id: 9249099
project_number: 5F31HL126403-03
project_title: Bringing Advanced Heart MRI to Pediatric Clinics Using an Interactive Videogame
administering_ic: NHLBI
award_notice_date: 2017-04-21
opportunity_number: PA-14-147
application_type: 5
activity_code: F31
ic: HL
serial_number: 126403
program_official: SCOTT, JANE
project_start_date: 2015-04-20
project_end_date: 2017-07-21
study_section: Special Emphasis Panel[ZRG1-F15-P(20)L]
contact_pi_person_id: 12104869
contact_pi: HAMLET, SEAN MICHAEL
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Congenital heart disease (CHD) affects roughly 2 million people in the US and remains responsible for twice as many years of life lost as all of childhood cancer combined. Cardiac magnetic resonance (CMR) imaging has become the gold standard technique that clinicians use to monitor cardiovascular function in patients over time. Advanced CMR techniques offer incredible potential for improving our ability to diagnose and treat patients with CHD but currently require long acquisition times that limit their feasibility n the clinic. Our overall goal is to make these advanced CMR techniques clinically feasible through dramatically reducing the time required to acquire the image data. We propose a new CMR system which we call videogame interface for diaphragm location (VIDLoc) that can reduce acquisition times by 50%. VIDLoc works by advising children how to alter their breathing patterns in real-time during CMR in order to dramatically reduce the total time required to acquire CMR data. Because the heart moves up and down on the diaphragm as children breathe imaging can only be performed when the diaphragm is within a narrow region called the "acceptance window". Since children breathe very erratically the amount of time they spend in the acceptance window is often as low as 20% (thus imaging can only be performed 1/5th of the time). VIDLoc overcomes this by imaging the child's diaphragm location in real-time and using this to generate a videogame showing a car on a road. The car's location relative to the road represents the diaphragm location relative to the acceptance window. VIDLoc will provide instructions to children to guide their diaphragm (or car) to be within the acceptance window (or road) where the heart can be imaged. We hypothesize that using VIDLoc will increase the amount of time spent in the acceptance window and therefore dramatically reduce CMR acquisition times. This will make advanced CMR techniques clinically feasible in patients with CHD. We will first optimize VIDLoc by adding extra features such as text and voice feedback of breathing instructions which will be tested by children with CHD to determine each feature's effectiveness. Then we will test VIDLoc against conventional free breathing for acquisition time and quality of data derived. Twenty children with CHD will undergo an advanced CMR technique to image three-dimensional cardiac motion. Lastly we will quantify the acquisition time and quality of data derived from VIDLoc with and without pre-CMR training in a simulator. A simulated version of the VIDLoc system outside of the scanner will use a sensor to quantify chest wall excursion as a proxy for diaphragm location. Twenty children with CHD will be randomized to undergo advanced CMR using VIDLoc with or without pre-CMR training in the simulator. Acquisition times and image quality will be used to determine the efficacy of pre-CMR training. The overall goal of this proposal is to use VIDLoc to reduce CMR acquisition time so that we can start using advanced CMR techniques in the clinic to ultimately improve the lives of patients with congenital heart disease.

project_terms:
Adult;Affect;Automobile Driving;Benchmarking;Blood;Breathing;Cardiac;Cardiovascular Physiology;Chest wall structure;Child;Childhood;Clinic;Clinical;Data;Data Quality;Decision Making;Diagnosis;Dimensions;Effectiveness;Feedback;Future;Goals;Gold;Heart;Heart Abnormalities;Heart Diseases;Image;Imaging Techniques;Imaging technology;Instruction;Ionizing radiation;Location;Magnetic Resonance;Magnetic Resonance Imaging;Malignant Childhood Neoplasm;Measures;Monitor;Motion;Operative Surgical Procedures;Patients;Pattern;Positioning Attribute;Proxy;Randomized;Reproducibility;Respiratory Diaphragm;Role;Scanning;System;Techniques;Testing;Text;Time;Training;Voice;Work;base;congenital heart disorder;cost;heart dimension/size;heart function;heart imaging;heart motion;improved;mortality;public health relevance;repaired;sensor;time use;years of life lost

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Advanced imaging techniques for quantifying heart function in children born with heart defects require long imaging times that reduce their clinical feasibility.This project's interactive videogame system has the ability to reduce the imaging times required to perform advanced heart imaging by over 50%. The overall goal of this project is to use this imaging technology to improve our understanding of heart function in order to guide appropriate treatments in children and in the future adults with heart disease.


application_id: 9249092
project_number: 5R01HL120507-03
project_title: Lipid phosphate phosphatase 3 as a novel atherosclerosis suppressor
administering_ic: NHLBI
award_notice_date: 2017-03-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 120507
program_official: HASAN, AHMED A K
project_start_date: 2015-04-01
project_end_date: 2019-03-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: MORRIS, ANDREW J
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:
DESCRIPTION (provided by applicant): Lysophosphatidic acid (LPA) is an essential bioactive phospholipid mediator that regulates a range of developmental and physiological processes which are emerging as targets for a new class of molecular therapeutics. In the cardiovascular system LPA is poised to serve as a mediator of atherothrombotic disease: it is abundant in atherosclerotic plaque increases during acute myocardial infarction triggers phenotypic responses in smooth muscle cells and disrupts endothelial integrity. We and others have demonstrated that LPA promotes both the development of intimal hyperplasia following injury and atherosclerosis in experimental models. Lipid phosphate phosphatase 3 (LPP3) encoded by the PPAP2B gene is an integral membrane enzyme that regulates the bioavailability of LPA. We have recently demonstrated that LPP3 is an intrinsic negative regulator of vascular inflammation suppresses smooth muscle cell proliferation and promotes endothelial barrier function likely by limiting LPA signaling. Analysis of data from a series of genome-wide association studies of coronary artery disease (CAD) identified a striking association between the PPAP2B locus and myocardial infarction. We provide evidence that CAD-risk associated PPAP2B variant disrupts an intronic enhancer that increases transcription of the gene and LPP3 expression in ox-LDL stimulated macrophages. These findings suggest the testable hypothesis that LPP3 functions as an atherosclerosis suppressor and that reduced PPAP2B gene expression aggravates cellular events underlying atherosclerosis and increases the likelihood of myocardial infarction. In this proposal we will define the role of LPP3 in the development of atherosclerosis provide insight into the molecular mechanism(s) involved and validate the predicted risk allele associated with CAD in humans. We are uniquely well-prepared to achieve these goals based on our expertise in bioactive lipid signaling and the tools we have amassed to study LPP3. Completion of these studies promises to provide valuable insight into the mechanism(s) by which extracellular bioactive lipid mediators influence the development of atherosclerosis and provide novel and innovative targets to predict prevent and treat CAD.

project_terms:
Acute myocardial infarction;Alleles;Arterial Fatty Streak;Atherosclerosis;Attenuated;Binding;Biological Availability;Blood Cells;Blood Vessels;CCAAT-Enhancer-Binding Proteins;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell Proliferation;Cell Survival;Cell model;Cell surface;Cells;Clinical;Complement;Coronary Arteriosclerosis;Coronary artery;Cultured Cells;Data Analyses;Deposition;Development;Developmental Process;Diagnosis;Disease;Drosophila genus;Employee Strikes;Enhancers;Enzymes;Event;Experimental Models;Family;Gene Expression;Genes;Genetic;Genetic Polymorphism;Genetic Transcription;Genetic Variation;Goals;Homologous Gene;Human;Human Genetics;Hyperplasia;Inflammatory;Injury;Introns;Investigation;Knowledge;Lipids;Lysophospholipids;Mass Spectrum Analysis;Mediating;Mediator of activation protein;Membrane;Molecular;Mus;Myocardial Infarction;Myocardial Ischemia;Phenotype;Phospholipids;Phosphoric Monoester Hydrolases;Physiological Processes;Positioning Attribute;Predisposition;Publishing;Reagent;Recording of previous events;Research;Research Project Grants;Resolution;Risk;Risk Factors;Role;Series;Signal Transduction;Single Nucleotide Polymorphism;Site;Site-Directed Mutagenesis;Smooth Muscle Myocytes;Stable Isotope Labeling;Stimulus;Testing;Therapeutic;Tissues;United States;Up-Regulation;Variant;Work;base;cardiovascular disorder risk;cell motility;disorder risk;extracellular;genetic variant;genome wide association study;improved;innovation;inorganic phosphate;insight;lipid mediator;lipid metabolism;lipid phosphate phosphatase;lysophosphatidic acid;macrophage;monocyte;mortality;mouse model;novel;novel therapeutic intervention;oxidized low density lipoprotein;prevent;public health relevance;response;risk variant;tool;vascular inflammation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Ischemic heart disease is a leading cause of death in the United States. Genetic variation in the gene encoding lipid phosphate phosphatase 3 (LPP3) an enzyme that regulates the bioavailability of lysophospholipids was recently identified to predict the development of coronary artery disease and acute myocardial infarction. We propose that LPP3 functions as an atherosclerosis suppressor. Completion of our work will define mechanism(s) involved and may implicate bioactive lipid mediators in the development of ischemic heart disease which will ultimately provide novel and innovative targets to predict prevent and treat coronary artery disease.


application_id: 9249005
project_number: 5R01CA205400-02
project_title: Distinct Redox Mechanism in Normal and Cancer Cells as a Novel Therapeutic Target
administering_ic: NCI
award_notice_date: 2017-03-03
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 205400
program_official: BERNHARD, ERIC J
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_terms:
Acute;Address;Adverse effects;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;Evaluation;Exhibits;Experimental Animal Model;FDA approved;Family;Gene Targeting;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 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;base;cancer cell;cancer diagnosis;clinical practice;cytotoxic;expectation;gene product;hormone refractory prostate cancer;hormone therapy;improved;in vivo;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;treatment effect;treatment response;tumor


application_id: 9248788
project_number: 5K23AR062069-05
project_title: Prolonged alterations to muscle following knee surgery and physical therapy
administering_ic: NIAMS
award_notice_date: 2017-01-25
opportunity_number: PA-11-194
application_type: 5
activity_code: K23
ic: AR
serial_number: 062069
program_official: BOYCE, AMANDA T
project_start_date: 2013-02-01
project_end_date: 2018-02-28
study_section: ZAR1-CHW(M1)
contact_pi_person_id: 10137938
contact_pi: NOEHREN, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This is a K23 award application for Dr. Brian Noehren an Assistant Professor of Physical Therapy at the University of Kentucky. Dr. Noehren is establishing himself as a young investigator focused on patient orientated clinical research dedicated to the study of how rehabilitation strategies restore muscle function in patients to ultimately improve their long term functional outcomes. The K-23 award would provide Dr. Noehren the needed support to become a productive independent scientist who is able to measure the cellular and morphological properties of muscle in response to injury and subsequent physical therapy. Development of these skills will allow him in future studies to assess the effectiveness of new and novel rehabilitation treatments to improve muscle function and joint loading. To achieve these goals Dr. Noehren has assembled a mentorship team of acknowledged leaders in their respective fields. This team is led by the senior mentor Dr. Charlotte Peterson Associate Dean of Research College of Health Sciences and three co-mentors: Dr. Karyn Esser an expert in muscle health and disease Dr. Bruce Damon who is an expert in muscle structure and biophysics and Dr. Leslie Crofford an expert clinical trialist.  Quadriceps strength reductions after an anterior cruciate ligament reconstruction of greater than 20- 40% occur at a critical time when physical therapy is ending and the individual begins to return to activities that require higher muscular demands. The reduction in quadriceps strength during this period of time has been associated with poorer outcomes. The measurement of muscular strength after rehabilitation to date has been limited to gross measurements with little known of how the individual heads of the quadriceps such as the Vastus Lateralis respond to surgery. Therefore we propose two specific aims: (Aim 1) Assess the quadriceps muscle (vastus lateralis) fascicle length pennation angle and physiological cross sectional area before and after rehabilitation for ACL reconstruction. (Aim 2) Characterize muscle morphology through quantification of quadriceps muscle fiber type fiber cross sectional area and fibrosis after completing rehabilitation for an ACL reconstruction. In Aim 1 Dr. Noehren will use DTI-MRI established by one his mentors Dr. Damon to measure muscle properties strongly linked to maximum force production. In Aim 2 he will perform histo and immuno-histiochemical analysis in Dr. Peterson's laboratory of muscle biopsies taken from the Vastus Lateralis of the same group from Aim 1 to categorize the adaptations to muscle fiber cross sectional area fiber type as well as fatty in-growth and fibrosis. Dr. Esser will assist with training for this aim and the interpretation of the results. The aims will couple data from non invasive imaging with detailed cellular analysis of muscle which will inform rehabilitative practice. In addition Dr. Crofford wil provide the training of translating the results into clinical research clinical trials and data analysis.

project_terms:
Address;Anterior;Architecture;Area;Award;Biology;Biomechanics;Biophysics;Biopsy;Cellular Morphology;Clinical;Clinical Research;Clinical Trials;Coupled;Data;Data Analyses;Degenerative polyarthritis;Diffusion;Disease;Effectiveness;Fascicle;Fiber;Fibrosis;Future;Goals;Growth;Head;Health;Health Sciences;Individual;Joints;Kentucky;Knee;Laboratories;Leg;Length;Ligaments;Link;Magnetic Resonance Imaging;Measurement;Measures;Mechanics;Mentored Patient-Oriented Research Career Development Award;Mentors;Mentorship;Methods;Molecular;Morphology;Muscle;Muscle Fibers;Muscle Weakness;Muscle function;Operative Surgical Procedures;Outcome;Patient Outcomes Assessments;Patients;Physical therapy;Physiological;Positioning Attribute;Process;Production;Property;Protocols documentation;Reconstructive Surgical Procedures;Recovery;Rehabilitation therapy;Research;Research Design;Research Personnel;Scientist;Senior Scientist;Structure;Testing;Therapeutic Intervention;Time;Tissues;Training;Translating;United States National Institutes of Health;Universities;anterior cruciate ligament reconstruction;clinically significant;cohort;college;evidence base;experience;follow-up;functional outcomes;improved;innovation;interest;joint loading;muscle physiology;muscular structure;non-invasive imaging;novel;professor;public health relevance;quadriceps muscle;reconstruction;rehabilitation strategy;response to injury;skill acquisition;strength training;vastus lateralis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Identification of the underlying cellular and myofiber adaptations that contribute to the loss of quadriceps strength after an ACL reconstruction is essential to develop improved physical therapy interventions and functional outcomes.


application_id: 9248759
project_number: 1R25ES027684-01
project_title: Summer Research in Environmental Health Sciences
administering_ic: NIEHS
award_notice_date: 2017-04-28
opportunity_number: PAR-15-184
application_type: 1
activity_code: R25
ic: ES
serial_number: 027684
program_official: HUMBLE, MICHAEL C
project_start_date: 2017-05-01
project_end_date: 2022-04-30
study_section: Special Emphasis Panel[ZES1 LKB-J (R)]
contact_pi_person_id: 1883439
contact_pi: SWANSON, HOLLIE ISABEL
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:
Address;Affect;Appalachian Region;Area;Communities;Critical Thinking;Development;Ecology;Economics;Educational workshop;Elevator;Engineering;Environment;Environmental Health;Ethics;Evaluation;Faculty;Film;Future;Goals;Individual;Interview;Kentucky;Laboratories;Life;Measures;Mentors;Mission;National Institute of Environmental Health Sciences;Nature;Oral;Outcome;Play;Population Heterogeneity;Postdoctoral Fellow;Professional Competence;Recruitment Activity;Reporting;Research;Research Project Grants;Research Training;Role;Safety;Science;Scientist;Speech;Students;Surveys;Technology;Training;Training Programs;Underrepresented Students;United States;Universities;Work;career;collaborative environment;college;design;experience;experimental study;faculty mentor;global health;hands on research;improved;interest;member;movie;multidisciplinary;outreach;peer;peer coaching;posters;programs;research facility;retention rate;skills;social;student mentoring;student participation;success;summer program;summer research;undergraduate education;undergraduate research;undergraduate student


application_id: 9247321
project_number: 3R01OH010425-02S1
project_title: Home healthcare hazard training through virtual simulation
administering_ic: NIOSH
award_notice_date: 2016-03-22
opportunity_number: PAR-10-188
application_type: 3
activity_code: R01
ic: OH
serial_number: 010425
suffix: S1
program_official: FREDERICK, LINDA J
project_start_date: 2013-09-01
project_end_date: 2016-08-31
study_section: Safety and Occupational Health Study Section[SOH]
contact_pi_person_id: 11844758
contact_pi: POLIVKA, BARBARA J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Healthcare provided in the home is increasing resulting in a greater number of professional caregivers providing in-home services for ill and disabled persons. The number of home health aides is expected to increase dramatically. The unique physical environment of each home results in challenges to worker safety and health. Sixty percent of all injuries experienced by home health aides occurred inside patient homes and were due to patient handling tasks medical devices equipment and other environmental factors. Given the increase in health care provided in homes and the hazards faced by home healthcare workers it is critical that workers across disciplines have the ability to identify assess and respond to home hazards.  The proposed project will (1) Develop a virtual simulation training system (VSTS) using an interdisciplinary participatory design approach; (2) Assess the usability usefulness and desirability of the VSTS across multiple professional disciplines; and (3) Evaluate the efficacy of the VSTS in preparing home healthcare professionals to recognize assess and respond to hazards in the home health environment using appropriate risk perception and decision-making processes.  The project will use an iterative participatory design approach to develop the VSTS and a randomized design to determine its efficacy for training home healthcare professionals (Home Health Aides Nurses Occupational Therapists and Physical Therapists). The VSTS will contain a Training Environment (TE) and an Evaluation Environment (EE). The TE will provide training in hazard identification assessment and response as well as training in risk assessment and decision-making. The EE will allow an assessment of an individual's ability to identify assess and respond to hazards appropriately as well as an assessment of the decision- making processes used to evaluate risks in the home. To develop the VSTS we will recruit 90 participants representing seven professions involved with the provision in home healthcare (nurses home health aides occupational therapists physical therapists agency educators nurse managers and health and safety experts). These professionals will participate in focus groups interviews and ultimately VSTS testing to ensure development of a relevant accessible and comprehensive training program. To test the efficacy of the training we will recruit 90 additionalparticipants who will be randomly assigned to either the training (TE) or the control condition. Differences in performance and risk assessment will be evaluated through descriptive and inferential statistical analysis as well as qualitative "think aloud" techniques.  Unique to thisstudy is the use of virtual simulation as a training technique a participatory design approach and the integration of decision making and risk perception measures into the training and evaluation. The impact of this work will be the development of a broadly available easily disseminated and accessible health and safety training system for home healthcare workers across multiple disciplines.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The demand for home healthcare services is rapidly increasing. This has resulted in a need for trained home healthcare professionals to care for and support ill and disabled persons in their personal residences. However home healthcare workers are at serious and substantial risk for work-related injury and illness associated with providing healthcare services in the challenging and variable home environment. This project will develop test and evaluate a virtual simulation training system designed to train home healthcare professionals in the identification of assessment of and response to health and safety hazards in the home. This project has the potential to translate into reductions in the burden of substantial occupational injury and illness among this large population of workers.


application_id: 9247152
project_number: 5R01CA203257-02
project_title: Natural product-based modulators of 4E-BP1 phosphorylation
administering_ic: NCI
award_notice_date: 2017-03-17
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 203257
program_official: FU, YALI
project_start_date: 2016-04-01
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZRG1-BCMB-D(02)M]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: SHE, QING-BAI
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Antineoplastic Agents;Binding;Biological Assay;CCI-779;Colorectal Cancer;Complex;Development;Disease;Disease Progression;Drug Kinetics;Drug resistance;EIF4EBP1 gene;FRAP1 gene;Generations;Genetic;Genetic Translation;Goals;In Vitro;Knowledge;MEKs;Malignant Neoplasms;Maximum Tolerated Dose;Mediating;Messenger RNA;Modeling;Molecular;Molecular Probes;Mutation;Naphthoquinones;Natural Products;Neoplasm Metastasis;Oncogenes;Oncogenic;Oncoproteins;PI3K/AKT;PTEN gene;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Pharmacotherapy;Phosphorylation;Phosphotransferases;Production;Property;Protein Inhibition;Proteins;Proteomics;Proto-Oncogene Proteins c-akt;Ras/Raf;Reactive Oxygen Species;Reporter;Research;Resistance;Ribosomes;Signal Pathway;Signal Transduction;Testing;Therapeutic;Therapeutic Index;Toxic effect;Translation Initiation;Translational Regulation;Translations;Treatment Efficacy;Work;Xenograft procedure;analog;base;cancer cell;cancer therapy;cell growth;clinical efficacy;drug development;effective therapy;expectation;in vitro Assay;in vivo;inhibitor/antagonist;interest;mTOR Inhibitor;mTOR inhibition;metastatic colorectal;mouse model;mutant;novel;novel strategies;novel therapeutic intervention;pre-clinical;prevent;public health relevance;targeted treatment;tumor;tumor growth;tumor progression;tumor xenograft;tumorigenesis;upstream kinase


application_id: 9247106
project_number: 5R01AG046116-05
project_title: Pain and Well-being in Older Women: The Roles of Activity and Motivation
administering_ic: NIA
award_notice_date: 2017-03-31
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AG
serial_number: 046116
program_official: NIELSEN, LISBETH
project_start_date: 2013-07-01
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZRG1-BBBP-T(03)M]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
other_pis: CROFFORD, LESLIE J
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:
DESCRIPTION (provided by applicant): The prevalence of chronic pain in older adults is high and prevalence increases with increasing age. Although adverse effects of pain on hedonic well-being (HWB) are well documented there is less evidence that pain has a direct effect on aspects of eudaemonic well-being (EWB) such as autonomy and social satisfaction. Evidence suggests that some older adults with high physical pain nonetheless maintain high EWB whereas others with low physical pain have low EWB. The present study tests a model in which qualities of the goal-directed and physical activities of older women determine whether and how pain affects EWB. When activity is externally motivated by guilt or control pain will inhibit activity and activity will adversely affect EWB; when activity is autonomously motivated by interest or self-definition pain will not inhibit activity and activity will enhance EWB. Furthermore when activities are accorded more time these effects will be stronger. A second aim tests effects of activity and EWB on biomarkers including diurnal cortisol and inflammation as measured by interleukin-6 and its soluble receptor. A third aim will test these relationships controlling for individual differences in personality genotype fitness and pain sensitivity. Oldr women (N = 300 aged 50-75) with varying levels of pain will be recruited from an existing registry to complete 7-day diary periods at 3-month intervals over 9 waves to test day- wave- and person-level relationships. Daily measures will include goal-directed and physical activities (including motivation for and time spent in the activities) cortisol slope subjective health pai pain interference HWB and psychological need satisfaction as a measure of day-level EWB. Wave-level measures will include the Scales of Psychological Well-Being HWB interleukin-6 and interleukin-6 receptor. Person-level measures will include optimism COMT polymorphism VO2max and sensory testing. Multi-level modeling will test for between-person and within-person relationships and lagged effects. The co-PIs bring expertise in pain goals well-being and physiology to these aims and have successfully completed longitudinal studies of older adults and pain patients including a diary study. The study will advance understanding of how a common age-relevant experience - physical pain - affects EWB and physical health.

project_terms:
Adverse effects;Affect;Age;Aging;Area;Arthritis;Back Pain;Biological Markers;Elderly;Feeling;Female;Genetic Polymorphism;Genotype;Goals;Guilt;Headache;Health;High Prevalence;Hydrocortisone;Immunologics;Individual;Individual Differences;Inflammation;Interleukin 6 Receptor;Interleukin-6;Link;Literature;Longitudinal Studies;Measures;Modeling;Moods;Motivation;Musculoskeletal Pain;Neurosecretory Systems;Outcome;Pain;Pain interference;Patients;Personality;Persons;Physical activity;Physiological;Physiology;Prevalence;Recruitment Activity;Registries;Reporting;Sensory;Severities;Testing;Time;VO2max;Woman;Women's Role;aged;chronic pain;diaries;experience;fitness;heart rate variability;hedonic;improved;interest;multilevel analysis;negative affect;older women;optimism;physical conditioning;prognostic;psychologic;psychosocial;public health relevance;receptor;resilience;satisfaction;sex;social

public_health_relevance:
PUBLIC HEALTH RELEVANCE: As people age they are more likely to experience physical pain. However some older adults are able to maintain high feelings of well-being about themselves and their lives despite pain whereas some do not maintain well-being although they have little pain. This study tests whether daily activities determine whether pain does or does not result in decrements in well-being and whether activity and well-being affect immunological and neuroendocrine correlates of health.


application_id: 9247018
project_number: 5R21CA205778-02
administering_ic: NCI
award_notice_date: 2017-07-13
opportunity_number: PAR-13-146
application_type: 5
activity_code: R21
ic: CA
serial_number: 205778
program_official: LI, JERRY
project_start_date: 2016-08-01
project_end_date: 2019-01-31
study_section: ZCA1-SRB-X(J1)
contact_pi_person_id: 10631406
contact_pi: WANG, CHI
other_pis: MOSELEY, HUNTER NATHANIEL
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: 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
budget_start_date: 2017-08-01
project_title:
Statistical Detection and Biochemical Classification of Cancer Driver Mutation Patterns in Biological Networks

project_abstract:
DESCRIPTION (provided by applicant): Cancer arises from somatically acquired genetic and epigenetic alterations. While large consortia like The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) have profiled genomic somatic mutations of thousands of tumor samples from various cancer types based on whole-genome/exome sequencing meaningful mechanistic interpretation of these gene variation results are still very limited. One basic yet challenging task is to distinguish driver mutations which are causally implicated in cancer development from passenger mutations which occur randomly with neutral effect. Another critical task is to map trace and interpret the functional impact of drivr mutations within biological networks. In a network context driver mutations associated with genes within a pathway often show a mutually exclusive pattern meaning that each patient carries exactly one mutation in the pathway which is sufficient to perturb the function of that pathway. Another prominent pattern is that driver mutations of genes from several different pathways may co-occur since perturbation of multiple pathways is required for tumor formation. Screening for mutual exclusivity and co-occurrence patterns can greatly facilitate the identification of novel sets of related driver gene mutations their associated driver pathways and functional relationships between these driver pathways. Although several de novo driver mutation gene set discovery methods have been proposed in the past few years they have major limitations due to computational feasibility an inability to deal with mutational heterogeneity across patients and lack of biochemical interpretation.  The overall goal of this proposal is to develop and combine advance sequence variation analyses with complementary biological network analyses into a highly novel systems biology approach that will: i) detect sets of related mutations in driver regulatory/signaling pathways ii) classify these pathways as stimulated inhibited or mixed with respect to their role in the tumor development process and iii) predict direct metabolic outcomes of these perturbed pathways. Our specific aims are: 1) to develop a statistical method for de novo discovery of mutually exclusive and co-occurrent sets of driver mutations; and 2) to develop a pathway mapping and classification method for related sets of driver mutations. The identification and biochemical interpretation of aggregated tumor mutations from driver mutation gene sets to inhibited/stimulated pathways to perturbed biological network will provide new mechanistic insights in tumor progression at a systems level. Also with this information potential drug targets in the detected driver pathways can be classified as requiring agonist or antagonist drug development making drug target evaluation and prioritization much more effective. Furthermore identification of co-occurrence between specific genes and pathways may aid in the development of multi- therapeutic cancer treatments that are optimized to groups of patients showing the same mutational patterns of co-occurrence.

project_terms:
Agonist;Biochemical;Biological;Classification;Computing Methodologies;Data;Detection;Development;Drug Targeting;Effectiveness;Epigenetic Process;Evaluation;Gene Mutation;Genes;Genetic;Goals;Heterogeneity;Human;Individual;International;Knowledge;Malignant Neoplasms;Maps;Markov chain Monte Carlo methodology;Metabolic;Methods;Mutate;Mutation;Outcome;Pathway Analysis;Pathway interactions;Patients;Pattern;Process;Role;Sampling;Signal Pathway;Somatic Mutation;Statistical Methods;System;Systems Biology;Testing;The Cancer Genome Atlas;Therapeutic;Variant;actionable mutation;antitumor drug;base;biological systems;cancer classification;cancer genome;cancer therapy;cancer type;drug development;exome sequencing;genome-wide analysis;genomic profiles;innovation;insight;interest;novel;public health relevance;screening;success;tool;tumor;tumor progression;whole genome

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The objective of this proposed project is to develop statistical and systems biology methods to identify classify and interpret sets of somatically mutated genes that drive cancer development. The success of this project will provide new mechanistic insights in tumor progression at a systems level and enhance the effectiveness of antitumor drug target evaluation and prioritization.


application_id: 9246698
project_number: 3R43CA192850-01S1
project_title: Large Volume Intratumoral Injection Device for Therapeutic Liver Infusions
administering_ic: NCI
award_notice_date: 2016-07-12
opportunity_number: PA-16-019
application_type: 3
activity_code: R43
ic: CA
serial_number: 192850
suffix: S1
program_official: NARAYANAN, DEEPA
project_start_date: 2016-07-01
project_end_date: 2017-10-31
contact_pi_person_id: 8714039
contact_pi: STICE, JIM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079228773
duns_number: 079228773
fips: US
organization_id: 10035571
organization_name: TWIN STAR TDS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071968
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-10-31
project_abstract:
DESCRIPTION (provided by applicant): The objective of this proposal is to demonstrate the feasibility of an innovative injection device (proposed product) to improve upon intratumoral delivery of liver therapeutics as compared to standard injection needles currently used. Hepatocelluar carcinoma (HCC) will become an increasing burden on economic resources in the coming years as the prevalence of cirrhosis due to multiple disease processes in the general population increases. Transplant and surgical treatment are well established and have provided satisfactory overall survival for eligible patients however only a small minority of HCC patients are eligible for these therapies. Therefore considerable efforts have been directed toward developing alternative minimally invasive treatments. HCC therapeutic delivery by direct injection has the potential to significantly reduce the expense and morbidity of current therapeutics or those in development. Though direct injection is a seemingly straightforward approach to the problem limited ability to inject tumors greater than 3cm in diameter and uneven distribution of the therapeutic after injection are significant drawbacks to direct injectin. In contrast to conventional injection needles the proposed injection device is porous along the entire length of the targeted anatomy; therefore the surface area of tissue in contact with infusate is considerably increased. Hypothesis: Improved infusate delivery will lead to a larger area and more uniform distribution of infusate within the tumor tissue and lend itself to enhanced therapeutic direct intratumoral injection protocols for various chemoablative and anti- neoplastic infusates. Preliminary Data: We have demonstrated that porous injection devices have significantly improved in vivo distribution of ethanol within normal canine prostates and other studies have demonstrated the unique performance benefits of applicant's porous injection device. Specific Aim: This project entails preclinical testing of the porous injection device for eventual application to human patients with intrahepatic tumors. Aim 1. Demonstrate that the porous injection device provides broader distribution of an infusate compared to a standard needle. Task 1 - Transfer of VX-2 Cells and growth of tumor in rabbit for tumor implant tissue. Task 2 - Determine the preferred flow rate for infusate into the VX-2 tumor in rabbit liver Task 3 - Comparison of concentration and distribution of infusate components after infusion into VX-2 tumor with porous device and standard needle. Milestone: The porous injection device will show 50% greater distribution as compared to needle injection.

project_terms:
Ablation;Anatomy;Animal Model;Animals;Area;Caliber;Canis familiaris;Carcinoma;Catheters;Chemicals;Chemoembolization;Cirrhosis;Clinical;Cytotoxic agent;Data;Development;Devices;Diagnosis;Disease;Doxorubicin;Drug Delivery Systems;Drug resistance;Economics;Encapsulated;Ensure;Ethanol;Fiber;Gadopentetate Dimeglumine;General Population;Health;Hepatitis C;Human;Implant;Incidence;Infusion procedures;Injection of therapeutic agent;Lead;Length;Link;Liver;Liver neoplasms;Malignant neoplasm of liver;Methodology;Minority;Modeling;Morbidity - disease rate;Needles;New Zealand;Operative Surgical Procedures;Oryctolagus cuniculus;Partial Hepatectomy;Patients;Penetration;Performance;Phase;Preclinical Testing;Prevalence;Primary carcinoma of the liver cells;Process;Prostate;Protocols documentation;Radioembolization;Recurrence;Regulatory Pathway;Research;Resources;Solid Neoplasm;Surface;Survival Rate;System;Technology;Therapeutic;Therapeutic Agents;Tissues;Transplantation;Treatment Efficacy;Tumor Pathology;Tumor Tissue;United States;cancer cell;cell growth;chemotherapeutic agent;commercialization;contrast imaging;curative treatments;cytotoxic;drug distribution;improved;in vivo;innovation;interest;intrahepatic cancer;liver transplantation;minimally invasive;neoplastic;novel;standard of care;treatment planning;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Effective drug delivery of therapeutic agents directly into avascular regions of solid tumors is challenging with current clinical methodologies. The Applicants have developed novel porous hollow fiber catheters which have the potential to demonstrate more uniform and better distribution of an infusate into solid tumor tissue than standard of care needles. In this project animal studies will be conducted to compare the PHFC to standard needle for infusate delivery into a liver cancer animal model.


application_id: 9246502
project_number: 5U01DE025833-02
project_title: Oral Health Promotion (OHPROM) Strategy for Persons with Intellectual & Developmental Disabilities
administering_ic: NIDCR
award_notice_date: 2017-03-24
opportunity_number: PAR-15-059
application_type: 5
activity_code: U01
ic: DE
serial_number: 025833
program_official: RICE, ELISE
project_start_date: 2016-04-01
project_end_date: 2021-03-31
study_section: ZDE1-CF(05)
contact_pi_person_id: 7034912
contact_pi: BINKLEY, CATHERINE J
other_pis: JOHNSON, KNOWLTON WILLIAM
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Applications Grants;Area;Behavior;Behavioral;Behavioral Research;Caregivers;Caring;Classification;Cognitive;Communities;Consent;Contracts;Data;Dementia;Dental;Dental General Practice;Dental Hygiene;Dentistry;Dentists;Developmental Disabilities;Devices;Diagnosis;Diet;Dietary Practices;Diffusion;Disabled Persons;Elderly;Ensure;Evaluation;Exhibits;Expectancy;Future;General Anesthesia;General Population;Group Homes;Health;Health Care Costs;Health Planning;Health Policy;Health Promotion;Health Status;Health behavior;Healthcare;Home environment;Hygiene;Impaired cognition;Indiana;Individual;Intervention;Journals;Kentucky;Learning;Link;Literature;Location;Longitudinal Studies;Medical Records;Modeling;Oral;Oral health;Organizational Policy;Outcome;Parents;Participant;Periodontal Diseases;Persons;Phase;Physical environment;Pilot Projects;Pneumonia;Population;Prevention strategy;Preventive;Procedures;Process;Provider;Psychological reinforcement;Public Health;Publishing;Randomized;Randomized Controlled Trials;Recruitment Activity;Research;Research Infrastructure;Risk;Risk Factors;Sampling;Self Efficacy;Services;Severities;Site;Social Environment;Systemic disease;Target Populations;Testing;Tissues;Tooth Extraction;Tooth Loss;United States;base;behavioral health;community setting;design;developmentally disabled;dosage;effective intervention;efficacy study;efficacy testing;efficacy trial;environmental adaptation;health disparity;health literacy;health related quality of life;improved;intervention effect;member;post intervention;posters;programs;public health relevance;social;theories


application_id: 9246017
project_number: 1R01AI128862-01
project_title: Biosynthesis and medicinal chemistry of the capuramycin antimycobacterial antibiotics
administering_ic: NIAID
award_notice_date: 2016-12-07
opportunity_number: RFA-AI-16-006
application_type: 1
activity_code: R01
ic: AI
serial_number: 128862
program_official: BOYCE, JIM P
project_start_date: 2017-01-01
project_end_date: 2021-12-31
study_section: Special Emphasis Panel[ZRG1 IDM-W (50)]
contact_pi_person_id: 9509796
contact_pi: VAN LANEN, STEVEN GARY
other_pis: THORSON, JON SCOTT
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Achievement;Acids;Address;Anabolism;Antibiotics;Antimycobacterial Agents;Antitubercular Agents;Applied Research;Biological;Biological Availability;Cell Wall;Cessation of life;Chemicals;China;Clinical;Collaborations;Communicable Diseases;Country;Development;Disease;Drug resistance;Drug resistance in tuberculosis;Engineering;Enzymes;Family;Fostering;Funding Mechanisms;Future;Goals;Health;Hexuronic Acids;Human;In Vitro;Incidence;India;Individual;Killings;Lead;Libraries;Modification;Multi-Drug Resistance;Multidrug-Resistant Tuberculosis;Mus;Mycobacterium tuberculosis;Natural Products;Nucleosides;Open Reading Frames;Peptidoglycan;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Phosphotransferases;Population;Preparation;Production;Property;Reaction;Recovery;Reporting;Research;Resistance;Rifampin;Series;Source;Structure;Substrate Specificity;Sugar Substitute;System;Technology;Therapeutic;Toxic effect;Treatment Protocols;Tuberculosis;United States;Uridine;World Health Organization;analog;bactericide;chemical function;clinical development;drug development;drug discovery;extensive drug resistance;fighting;fundamental research;glycosyltransferase;improved;in vitro activity;in vivo;inhibitor/antagonist;innovation;isoniazid;nanomolar;novel;pathogen;permissiveness;pharmacophore;resistance mechanism;resistant strain;scaffold;sugar;tool;translocase;tuberculosis drugs;tuberculosis treatment;virtual


application_id: 9246000
project_number: 2R01AI065530-12
project_title: Type III exported effectors of Chlamydia trachomatis
administering_ic: NIAID
award_notice_date: 2016-11-04
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: AI
serial_number: 065530
program_official: VINCENT, LEAH REBECCA
project_start_date: 2005-06-01
project_end_date: 2021-10-31
study_section: Special Emphasis Panel[ZRG1 IDM-R (02)]
contact_pi_person_id: 7726964
contact_pi: FIELDS, KENNETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute Disease;Address;Alleles;Animal Model;Animals;Attenuated;Biochemical;Biological Assay;Cell physiology;Cells;Cellular biology;Chlamydia;Chlamydia Infections;Chlamydia trachomatis;Chronic Disease;Communities;Data;Defect;Development;Disease;Epithelial Cells;Event;Fluorescence;Funding;Genes;Genetic;Goals;Grant;Health;Human;Individual;Infection;Infection prevention;Integration Host Factors;Lead;Maintenance;Mediating;Membrane;Methods;Microbiology;Modeling;Molecular;Mus;Mutagenesis;Pathogenesis;Pathology;Pathway interactions;Phenotype;Physiological;Prevalence;Process;Proteins;Proteome;Recruitment Activity;Reporting;Role;Science;Sexually Transmitted Agents;Techniques;Testing;Time;Type III Secretion System Pathway;United States;Vacuole;Virulence;Work;base;comparative;design;genetic manipulation;member;mutant;novel;novel therapeutic intervention;null mutation;obligate intracellular parasite;pathogen;socioeconomics;success;suicide vector;tissue culture


application_id: 9245465
project_number: 1R21AG052050-01A1
project_title: Optimal Vitamin D Status as a Strategy to Rescue Cognitive Aging
administering_ic: NIA
award_notice_date: 2016-09-23
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AG
serial_number: 052050
suffix: A1
program_official: WAGSTER, MOLLY V
project_start_date: 2016-09-30
project_end_date: 2018-04-30
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 7875396
contact_pi: PORTER, NADA MICOVIC
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Optimal Vitamin D Status as a Strategy to Rescue Cognitive Aging NIA PA-13-303SUMMARY/ABSTRACTBecause the numbers of older adults are increasing dramatically there is an urgent need to identify interventionsthat may alleviate the personal/socioeconomic burdens associated with age-related memory impairment. Onesuch potential intervention is treatment with vitamin D. Lower serum vitamin D levels are linked to several age-related disorders including cognitive decline and aging individuals are especially susceptible to vitamin Ddeficiency. For these reasons and because we previously found that vitamin D can reduce severalneurophysiological markers of brain aging we recently undertook a major vitamin D intervention study in malerats. For 6 months we fed aging male rats different amounts of vitamin D in an attempt to model serum levelsof vitamin D found in humans ranging from deficient to sufficient. We found that rats with higher serum levelsof vitamin D considered in the optimal range for humans had superior long term memoryoutperforming rats with lower vitamin D on a complex memory task (spatial reversal in the water maze).Additional electrophysiological and gene expression analyses showed that hippocampal synaptic function andmultiple synaptic markers were altered with higher serum levels of vitamin D including gene expression forNr4a2 an immediate early gene and transcription factor that appears to selectively promote long-term memory.Interestingly our preliminary results from a separate study show that Nr4a2 is expressed in a sex-dependentmanner in the hippocampus. Because women are more than twice as likely to be vitamin D deficient and because the consequences ofcognitive aging are greater in women our goal is to determine whether vitamin D intervention in aging femalescan offset cognitive decline as it does in males. Therefore in Aim 1 we directly compare mid-aged male andfemale F344 rats treated with diets containing standard or higher vitamin D3 to test the hypothesis that higherserum levels of vitamin D will prevent declining memory function in females as in males. This Aim uses asystems-level approach that includes behavioral testing of multiple forms of memory in the Morris water mazeand molecular analyses (gene expression microarrays and immunohistochemistry) to assess processespertaining to memory. Aim 2 compares males and females on the high vitamin D3 diet to test the novelhypothesis that Nr4a2 is necessary for the cognition enhancing effects of vitamin D. F344 rats will receive intra-hippocampal injections of a viral vector containing shNr4a2 to knockdown Nr4a2 activity. Outcome measureswill be the same as in Aim 1. This proposal builds on recent NIH initiatives to investigate sex as a relevantbiological variable in order to appropriately tailor therapies/interventions. As the F344 rat is a relevant model ofhuman aging for both sexes our results also will provide pertinent mechanistic information regarding vitamin Daction in the brain. Further studies on Nr4a2 which selectively promotes long-term memory and appears to beboth vitamin D- and sex-dependent stand to significantly move the field of cognitive aging forward.

project_terms:
Address;Affect;Aging;Animals;Biological;Blood;Brain;Candidate Disease Gene;Canis familiaris;Cell Communication;Cholecalciferol;Cognition;Cognitive;Cognitive aging;Complex;Diet;Disease;Dose;Early Gene Transcriptions;Elderly;Electrophysiology (science);Female;Gene Chips;Gene Expression;Genes;Goals;Hippocampus (Brain);Human;Immediate-Early Genes;Immunohistochemistry;Impaired cognition;Inbred F344 Rats;Individual;Injection of therapeutic agent;Intervention;Intervention Studies;Learning;Link;Longevity;Mediating;Mediator of activation protein;Memory;Memory Loss;Memory impairment;Modeling;Molecular;Mus;Nuclear Orphan Receptor;Outcome Measure;Pathway interactions;Pattern;Performance;Predisposition;Process;Rattus;Serum;Sex Characteristics;Staging;Study models;Synapses;Synaptic Transmission;System;Technology;Testing;Therapeutic Intervention;Time;Treatment Efficacy;United States National Institutes of Health;Viral Vector;Vitamin D;Vitamin D Deficiency;Vitamins;Water;Woman;abstracting;age related;aged;aging brain;aging hippocampus;base;behavior test;bone health;brain tissue;cerebral atrophy;cognitive function;cognitive performance;dosage;feeding;improved;knock-down;long term memory;male;middle age;morris water maze;neurophysiology;novel;population based;precision medicine;prevent;sex;small hairpin RNA;socioeconomics;synaptic function;transcription factor

public_health_relevance:
Project Narrative:The goal of this proposal is to determine if the therapeutic efficacy of dietary vitamin D inpreserving cognitive function in aging is sex dependent. Animals will receive either a standardor high vitamin D diet beginning at middle-age for six months because this time period has thegreatest potential for preserving cognitive function. Aged rats 18 months old will be evaluatedon a learning and memory task and gene expression from brain tissue will be analyzed.


application_id: 9245436
project_number: 1R21DA041755-01A1
project_title: Social Cues and Drug Relapse
administering_ic: NIDA
award_notice_date: 2017-01-13
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: DA
serial_number: 041755
suffix: A1
program_official: SU, SHELLEY
project_start_date: 2017-02-01
project_end_date: 2019-01-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY One of the most difficult problems facing drug abuse practitioners is the continuing high rate of relapsefollowing treatment. While there are multiple internal states and external cues that may trigger relapse onecommon factor is to re-associate with drug-using social peers. Although some recent preclinical work hasexamined the role of social influence on acquisition and maintenance of drug self-administration there isessentially no information about the role of social cues in reinstatement of drug seeking. The overall hypothesisof this project is that self-administering social peers will serve as a cue to induce drug seeking in a controlledpreclinical laboratory setting. Separate from discrete cues (light tone) and contextual cues (tactile and visualcues time of day) these studies will determine if social peers also are able to reinstate extinguishedresponding for drug. In addition these studies will provide definitive information about the potential interactiveeffects of social and contextual cues in reinstatement. Two specific aims are proposed. First we willdetermine if there are sex differences in discriminative social cue-induced reinstatement and if social cuespotentiate the ability of contextual cues to reinstate drug seeking. Second in these of behavioral experimentsc-Fos protein immunoreactive cells will be quantitated in various brain regions to determine if neural activationfollowing social cues differs between males and females or if activation by social cues differs from contextualcues. If social cues prove to be a trigger for drug seeking this would provide evidence that informspsychosocial treatments which emphasize skill-building to avoid deviant peers.

project_terms:
Beer;Behavioral;Brain;Brain Diseases;Brain region;Cells;Chronic;Cocaine;Cues;Discrimination;Drug abuse;Drug abuser;Drug usage;Environment;Exposure to;Extinction (Psychology);FOS Protein;FOS gene;Female;Goals;Individual;Intervention;Laboratories;Light;Lighting;Measures;Modeling;Odors;Patient Self-Report;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Play;Pre-Clinical Model;Predisposing Factor;Prevention strategy;Procedures;Process;Rattus;Relapse;Reporting;Role;Saline;Self Administration;Self-Administered;Sex Characteristics;Syringes;System;Tactile;Testing;Time;Training;Treatment Efficacy;Visual;Work;cocaine use;community setting;craving;deviant;disorder later incidence prevention;drug maintenance;drug relapse;experimental study;immunoreactivity;male;peer;pre-clinical;psychosocial;relating to nervous system;response;skills;social;treatment program

public_health_relevance:
Relapse rates following drug treatment programs continue to be high. Treatment seeking individuals oftenreport that interacting with drug-using peers is a trigger for relapse. While exposure to discrete cues (syringecrack pipe beer bottle) or contextual cues (drug environment) are known to trigger craving and relapse thecurrent application will use a preclinical model to determine if social cues also trigger relapse.


application_id: 9245148
project_number: 1R21AG051945-01A1
project_title: Astrocytic connexin 43 modulation in AD
administering_ic: NIA
award_notice_date: 2016-12-02
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AG
serial_number: 051945
suffix: A1
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2016-12-15
project_end_date: 2018-11-30
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
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:
7. Project Summary/AbstractAstrocytes are vital to brain metabolism and help to optimize synaptic function and promote neuronal health.Direct coupling of astrocytes to the extracellular milieu via unapposed hemichannels (uHCs)made up ofconnexin 43 (Cx43) proteinsappears to be increased under a variety of pathological conditions. Elevatedlevels of amyloid- (A) peptides and pro-inflammatory cytokines characteristic of Alzheimers disease (AD)lead to greater uHC permeabilitywhich in turn impairs neuronal function and viability. In this project we willtest the novel hypothesis that A-dependent changes in uHCs are mediated in part by aberrant activation ofthe protein phosphatase calcineurin (CN) shown by our lab and others to drive several critical components ofthe activated astrocyte phenotype. Aim 1 will use a combination of adenoviral vectors and pharmacologicalagents in addition to Western blot ethidium bromide uptake patch-clamp electrophysiology and a variety ofbiochemical assays to determine whether CN and Cx43 are necessary and sufficient for the effects of A onthe functional status of HCs in primary astrocytes. In addition this aim will determine the feasibility of using anovel peptide-based reagent 43Gap52 to selectively disrupt CN/Cx43 interactions without inhibiting CN activityper se. This aim will establish whether aberrant CN/Cx43 interactions in astrocytes are a direct outcome of Apathology. Aim 2 will use adeno-associated virus (AAV) bearing astrocyte-specific promoters and CNactivators (active CN fragment) or CN inhibitors (CN-autoinhibitory peptide or 43Gap52) to selectively modulateastrocytic CN/Cx43 interactions in an intact mouse model of AD. The functional status of astrocytic uHCs willbe investigated in acutely prepared brain slices using an EtBr uptake assay as described for Aim 1. Inaddition slice electrophysiology will be used to assess the impact of CN/Cx43 interactions on hippocampalsynaptic strength and plasticity. This Aim will validate Aim 1 results in a commonly used animal model of ADen route to determining the extent to which CN/Cx43 interactions in astrocytes disrupt synaptic function duringthe progression of A pathology. These studies will shed light on the role of astrocytic HCs in ADpathophysiology and determine whether disruption of the CN/Cx43 interaction is a feasible strategy forameliorating neurologic dysfunction due to AD and other types of neurodegenerative disease.

project_terms:
APP-PS1;Acute;Adenovirus Vector;Adenoviruses;Age-Months;Aging;Alzheimer's Disease;Alzheimer's disease model;Amyloid;Amyloid beta-Protein;Animal Model;Astrocytes;Award;Biochemical;Biochemical Pathway;Biological Assay;Brain;Calcineurin;Calcineurin inhibitor;Cell membrane;Cells;Characteristics;Cognitive;Connexin 43;Coupling;Custom;Data;Dependovirus;Deposition;Development;Disease;Drug Targeting;Electrophysiology (science);Excitatory Neurotoxins;Functional disorder;Generations;Glutamates;Health;Hippocampus (Brain);Homidium Bromide;Human;Impairment;Inflammatory;Injection of therapeutic agent;Injury;Ion Channel;Lead;Light;Mediating;Mediator of activation protein;Membrane;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurologic Dysfunctions;Neurons;Neurophysiology - biologic function;Outcome;PPP3CA gene;Pathologic;Pathology;Peptides;Permeability;Pharmacology;Phenotype;Phosphorylation Site;Process;Property;Protein Dephosphorylation;Protein phosphatase;Proteins;Radial;Reagent;Role;Route;Signal Transduction;Site;Slice;Surface;Synapses;Tail;Testing;Vascular Diseases;Water;Western Blotting;Wild Type Mouse;adeno-associated viral vector;arm;base;brain metabolism;calcineurin phosphatase;cytokine;design;experimental study;extracellular;fluorescence imaging;functional outcomes;functional status;glial activation;hydrophilicity;mild cognitive impairment;mouse model;neuroinflammation;novel;overexpression;patch clamp;prevent;promoter;protein activation;protein protein interaction;pup;relating to nervous system;solute;synaptic function;transcription factor;transgene expression;uptake

public_health_relevance:
8. Project NarrativeThis project will investigate novel interactions between intracellular mediators of glial activation (i.e. calcineurin)and specialized membrane channels (hemichannels) used for coordinating astrocyte network activity. Novelreagents will be used to validate a new astrocyte-based drug target for disrupting Alzheimers pathophysiology.


application_id: 9245140
project_number: 1R01AI128818-01
project_title: Regulation of dermal gammadelta T cells by microbial pathogens/commensals in health and psoriasis
administering_ic: NIAID
award_notice_date: 2017-04-14
opportunity_number: RFA-AI-16-006
application_type: 1
activity_code: R01
ic: AI
serial_number: 128818
program_official: ROTHERMEL, ANNETTE L
project_start_date: 2017-04-20
project_end_date: 2022-03-31
study_section: Special Emphasis Panel[ZRG1 IDM-W (50)]
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_terms:
Address;Biology;CCL20 gene;Cell Proliferation;Cells;Chronic;Chronic small plaque psoriasis;Clinical;Data;Dermal;Dermis;Development;Disease;Health;Homeostasis;Human;Immune;Immunologic Surveillance;In Vitro;Individual;Infection;Infiltration;Inflammation;Inflammatory;Interleukin-1;Interleukin-1 beta;Interleukin-12;Interleukin-17;Interleukins;Laboratories;Leukocytes;Memory;Modeling;Mus;Pathogenesis;Pathogenicity;Patients;Phase II Clinical Trials;Phenotype;Play;Population;Production;Psoriasis;Recurrent disease;Regulation;Role;SCID Mice;Signal Pathway;Signal Transduction;Skin;Source;Streptococcal Infections;Symbiosis;T-Lymphocyte;T-Lymphocyte Subsets;Testing;Treatment Efficacy;Xenograft Model;base;chemokine;chronic inflammatory skin;cytokine;individual patient;insight;interleukin-23;keratinocyte;microbial;microorganism;neglect;novel;pathogen;peripheral blood;receptor;skin disorder;skin lesion;skin microbiota;trafficking; T cells


application_id: 9244982
project_number: 1R21NS095299-01A1
project_title: The role of G3BP1 in mutant SOD1-mediated familial ALS
administering_ic: NINDS
award_notice_date: 2016-08-15
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: NS
serial_number: 095299
suffix: A1
program_official: GUBITZ, AMELIE
project_start_date: 2016-08-15
project_end_date: 2018-07-31
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 12058145
contact_pi: GAL, JOZSEF
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Abstract Amyotrophic lateral sclerosis also known as Lou Gehrig's disease or ALS is a progressive and fatalneurodegenerative disease with no cure available. In order to develop effective preventive measures or cureswe have to gain a better understanding of the molecular pathogenesis of ALS. A general symptom of ALS ismuscle wasting caused by motor neuron loss. In familial ALS the disease is caused by inherited genemutations. The first gene whose mutations were identified to cause ALS encodes the Cu/Zn superoxidedismutase SOD1. It is still not fully understood how the mutations in SOD1 cause toxicity in ALS. Several othergenes whose mutations cause ALS encode RNA metabolism regulators whose known functions are seeminglyunrelated to that of SOD1. The convergence of these two pathogenic pathways in ALS is still unclear. The Ras GTPase-activating protein-binding protein G3BP1 is known to regulate the stability andtranslation of messenger RNAs. It is also a critical regulator of stress granule dynamics. Stress granules formin response to challenges such as oxidative stress and heat shock. Stress granules sequester temporarilydispensable messenger RNAs in translationally inactive form freeing up ribosomes for the translation oftranscripts that are essential to survive the stress. ALS mutants of SOD1 form cytoplasmic inclusions. We found that the mutant SOD1 inclusionscontained G3BP1. We also found an RNA independent interaction between mutant SOD1 and G3BP1. Ourhypothesis is that G3BP1 represents a critical link between the ALS mutations in SOD1 and thepathological alterations in RNA metabolism. Aim 1 of the grant proposal will determine the molecular details of the ALS mutant SOD1-G3BP1interaction in cell culture and in vitro models. Aim 2 will determine the effect of ALS mutants of SOD1 on stressgranule dynamics and G3BP1 RNA binding in cell culture and transgenic mouse models. Aim 3 will test therole of G3BP1 and the Drosophila G3BP1 homolog Rasputin/Rin in the toxicity of transgenic human SOD1 in afly model. The findings are expected to provide important insight into the mechanism by which SOD1 mutationscause toxicity and perturb RNA metabolism.

project_terms:
Address;Amyotrophic Lateral Sclerosis;Appearance;Applications Grants;Binding Proteins;Biological Models;Cell Culture Techniques;Co-Immunoprecipitations;Collaborations;Cuprozinc Superoxide Dismutase;Cytoplasmic Granules;Cytoplasmic Inclusion;Data;Defect;Disease;Drosophila genus;Etiology;Future;Gene Mutation;Genes;Genetic;Heat-Shock Response;Homologous Gene;Human;Immunoprecipitation;In Vitro;Inherited;Link;Mediating;Messenger RNA;Metabolism;Modeling;Molecular;Motor Neurons;Muscle Weakness;Muscular Atrophy;Mutagenesis;Mutate;Mutation;Neurodegenerative Disorders;Outcome;Oxidative Stress;Pathogenesis;Pathway interactions;Patients;Phenotype;Play;Preventive measure;Process;Proteins;RNA;RNA Binding;Reagent;Reporting;Research;Resolution;Ribonucleosides;Ribosomes;Role;SCA2 protein;SOD2 gene;Sampling;Spinal Cord;Stress;Surface;Symptoms;Testing;Time;Toxic effect;Transcript;Transgenic Mice;Transgenic Organisms;Translations;abstracting;base;crosslink;design;fly;in vitro Model;in vivo;insight;matrin 3;motor neuron degeneration;mouse model;mutant;neuron loss;novel;overexpression;protein TDP-43;ras GTPase-Activating Proteins;research study;response

public_health_relevance:
Project narrative Amyotrophic lateral sclerosis or ALS is a fatal neurodegenerative disease with no known cure.Mutations in the SOD1 Cu/Zn superoxide dismutase are among the most frequent causes of the familial formof ALS. This project will determine the role of the G3BP1 protein in the toxicity of SOD1 mutants.


application_id: 9242070
project_number: 5U01HL127518-03
project_title: The ExCITE Program: Expediting Commercialization Innovation Translation & Entrepreneurship
administering_ic: NHLBI
award_notice_date: 2017-04-13
opportunity_number: RFA-OD-14-005
application_type: 5
activity_code: U01
ic: HL
serial_number: 127518
program_official: ROUSCHE, KATHLEEN T
project_start_date: 2015-03-20
project_end_date: 2020-02-28
study_section: ZHL1-CSR-O(F1)
contact_pi_person_id: 6663799
contact_pi: BATES, PAULA J.
other_pis: MILLER, DONALD M.
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): The overarching goal of this project is to increase the success rate and speed with which the results of basic biomedical research are translated into products that have a positive impact on human health. To do this we propose to create a commercialization program at the University of Louisville (UofL) with a structure that is designed to overcome the many obstacles that currently impede translation. Though UofL is a relatively small institution in an IDeA state it has invested in talent and infrastructure for translational research in order to create a pro-entrepreneurial culture. This has already paid dividends and UofL has been awarded numerous major grants including three current COBRE awards a Coulter Translational Partnership the NIH Cardioprotection Consortium the NIH-UofL RBL (a BSL-3 facility) and multiple P-/U- series grants. Moreover UofL discoveries have led to interventions that have already benefited patients such as a first-in- class anticancer drug a method to prevent transplant rejection and a protocol that has allowed paraplegic patients to stand again. Many more UofL innovations are now on their way to clinical trials including new vaccines and minimally invasive devices to detect cancer. The proposed UofL REACH program will be known as "the ExCITE Hub" to reflect its function as a central resource for Expediting Commercialization Innovation Translation and Entrepreneurship. The hub is designed to fulfill the goals of the FOA (RFA-OD- 14-005) but is tailored to match UofL's specific strengths and needs. In short the university will supply a robust pipeline of diverse technologies and the infrastructure/expertise required for translational research whereas the Hub will deliver the necessary funding education and access to business expertise to bridge the gap between a great idea and the marketplace. The ExCITE Hub has three major aims: (1) identify the most promising technologies and provide funding for product definition studies (2) promote commercialization of selected products and transition to a self-sustaining ExCITE program and (3) expand educational experiential and networking opportunities for stakeholders. Our approach includes innovative features: (1) a geographically focused program to expedite operations and maximize impact on the local eco-system (2) an innovative governance structure to integrate the three main goals and avoid silos (3) a proactive rather than passive approach to education (4) a mentored technology development grant program that requires early interactions between scientists tech transfer staff and industry consultants and (5) an emphasis on improving academia-industry relationships by increasing mutual understanding ensuring robust technologies and being responsive to industry needs. Institutional and regional commitment to the ExCITE Hub is evident from the >$3.1M in matching funds and 40 letters of support. Success in this project will have a major economic impact on the region and will speed the delivery of innovative new products to the patients that need them.

project_terms:
Academia;Antineoplastic Agents;Award;Back;Basic Science;Biomedical Research;Businesses;Centers of Research Excellence;Clinical Trials;Complement;Development;Development Plans;Devices;Economic Development;Ecosystem;Education;Educational process of instructing;Ensure;Entrepreneurship;Environment;Evaluation;Faculty;Federal Government;Funding;Geography;Goals;Graft Rejection;Grant;Health;Human;Income;Incubators;Industry;Institution;Intellectual Property;Intervention;Investments;Kentucky;Knowledge;Leadership;Letters;Malignant Neoplasms;Marketing;Mentors;Mentorship;Methods;Mission;Monitor;Nature;Paraplegia;Patients;Positioning Attribute;Private Sector;Problem Solving;Protocols documentation;Research;Research Infrastructure;Research Personnel;Resources;Scientist;Series;Source;Speed;Structure;Talents;Technology;Technology Transfer;Testing;Time;Translating;Translational Research;Translations;United States National Institutes of Health;Universities;Work;base;bench to bedside;biosafety level 3 facility;clinically relevant;commercialization;design;economic impact;education access;experience;human disease;improved;infrastructure development;innovation;member;minimally invasive;novel vaccines;operation;prevent;programs;public-private partnership;success;technology development

public_health_relevance:
The federal government invests billions of dollars per year in basic research which has led to great advances inunderstanding human diseases but it is difficult to translate these discoveries into new treatments or tests thathelp patients. This is mainly because university scientists generally do not know how to convert their greatideas into useful products plus there is relatively little funding for product-driven research. This project willattempt to solve this problem by providing grants for technology development and teaching researchers aboutbusiness.


application_id: 9241702
project_number: 1R01NS100093-01
project_title: Nrf2-Antioxidant Response Element Neuroprotection in TBI
administering_ic: NINDS
award_notice_date: 2016-08-10
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: NS
serial_number: 100093
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2016-08-15
project_end_date: 2021-05-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
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_terms:
3-nitrotyrosine;4 hydroxynonenal;Acute;Antioxidants;Attention;Attenuated;Biological Preservation;Brain;Brain Injuries;Broccoli - dietary;Buffers;Calcium;Calpain;Cell Culture Techniques;Chronic;Defense Mechanisms;Diffuse;Dose;Drops;Elements;Evaluation;Experimental Designs;Failure;Female;Free Radical Scavengers;Free Radical Scavenging;Free Radicals;Future;Gender;Gene Expression;Genes;Herb;Hippocampus (Brain);Homeostasis;Injury;Lipid Peroxidation;Lipids;Mediating;Membrane Lipids;Messenger RNA;Mitochondria;Modeling;Motor;Mus;Nerve Degeneration;Nervous System Trauma;Neurodegenerative Disorders;Neurologic;Neurons;Nuclear;Oxidoreductase;Pathway interactions;Pharmaceutical Preparations;Proteins;Quinones;Reactive Oxygen Species;Recovery of Function;Respiratory physiology;Response Elements;Rosemary;Severities;Speed;Sulforaphane;Surrogate Endpoint;Surrogate Markers;Testing;Therapeutic;Time;Tissues;Traumatic Brain Injury;Treatment Efficacy;Water;Weight;base;body system;brain tissue;cognitive recovery;cohort;comparative;controlled cortical impact;design;drug discovery;expectation;glutathione peroxidase;heme oxygenase-1;improved;injured;interest;mRNA Expression;male;motor recovery;mouse model;neuroprotection;nitration;novel;object recognition;oxidative damage;prevent;protective effect;prototype;research study;respiratory;response;salvin;therapeutic target;transcription factor;young adult


application_id: 9241565
project_number: 1R01DK112282-01
project_title: The activation of brown and beige fat and role in insulin sensitivity
administering_ic: NIDDK
award_notice_date: 2016-09-15
opportunity_number: RFA-DK-15-031
application_type: 1
activity_code: R01
ic: DK
serial_number: 112282
program_official: LAUGHLIN, MAREN R
project_start_date: 2016-09-15
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZDK1 GRB-7 (O2)]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
There has been much interest in exploiting brown adipose tissue (BAT) and beige adiposetissue for the treatment of obesity and related complications. Although brown and beigeadipocytes are derived from different precursors and display unique patterns of gene expressionmarkers both cells have increased mitochondrial content and express UCP1 which uncouplesoxidative respiration to generate heat. In addition both brown and beige adipocytes requirePPAR for their development and both cell types are induced through the -adrenergic receptor(AR)/PKA pathway. BAT and beige fat are activated through the sympathetic nervous systemor by the use of AR agonist drugs. Adipose tissue contains 3AR and there have beenattempts to treat obesity with 3 agonists. Currently mirabegron (Myrbetriq Astellas) is ahighly specific 3 agonist marketed for overactive bladder with minimal side effects at therecommended dose. In addition the diabetes drug pioglitazone is a PPAR agonist whichreduces inflammation and improves insulin sensitivity. We hypothesize that the combination ofpioglitazone and mirabegron will be more effective than either drug alone at activating both BATand beige adipose tissue and in improving insulin sensitivity. We hypothesize that themechanism of this improvement in insulin sensitivity will result from an increased partitioning oflipid into oxidative pathways improved metabolic flexibility and decreased adiposeinflammation.Hypothesis 1. Chronic treatment of insulin resistant subjects with a 3 agonist will result inincreased mass and activity of BAT and beige adipose tissue along with increased restingmetabolic rate.Hypothesis 2. The combined treatment with both a TZD (PPAR agonist) and a 3 agonist willresult in an additional stimulation of BAT and beige adipose mass and activity.Hypothesis 3. The activation of BAT and beige adipose tissue will be associated with reducedskeletal muscle lipotoxicity and improvements in adipose tissue inflammation.Hypothesis 4. The activation of BAT and beige adipose tissue by combined TZD and 3agonists will result in a greater improvement in insulin sensitivity than by monotherapy alone.These studies are important because the repurposing of these common drugs couldsynergistically improve many of the metabolic dysfunctions in obese individuals.

project_terms:
Adipocytes;Adipose tissue;Adrenergic Receptor;Adverse effects;Agonist;Basal metabolic rate;Biogenesis;Brown Fat;CREB1 gene;Cells;Chronic;Combined Modality Therapy;Cyclic AMP-Dependent Protein Kinases;Development;Diabetes Mellitus;Dose;Energy Metabolism;Fatty acid glycerol esters;Figs - dietary;Functional disorder;Gene Expression Profile;Heart Diseases;Heating;Human;Individual;Inflammation;Insulin Resistance;Lead;Link;Lipids;Lipolysis;Mammals;Marketing;Metabolic;Metabolism;Mitochondria;Mus;Obesity;Overactive Bladder;Oxidative Phosphorylation;PET/CT scan;PPAR gamma;Pathway interactions;Pharmaceutical Preparations;Phosphorylation;Pioglitazone;Respiration;Role;Skeletal Muscle;Sympathetic Nervous System;Thermogenesis;Tissues;cell type;flexibility;improved;insulin sensitivity;interest;natural hypothermia;obesity treatment;prevent;therapeutic target;transcription factor;uncoupling protein 1

public_health_relevance:
Obesity is closely linked with insulin resistance diabetes and heart disease. Brown and beigeadipose tissue can increase energy expenditure and help prevent obesity complications. Thisproposal examines two common drugs which may synergistically increase brown/beige fatwhich could lead to improvement the metabolic dysfunction in adipose tissue and improveinsulin sensitivity.


application_id: 9241384
project_number: 5T35DK072923-12
project_title: Summer Endocrine Research Training Program
administering_ic: NIDDK
award_notice_date: 2017-04-17
opportunity_number: PA-14-016
application_type: 5
activity_code: T35
ic: DK
serial_number: 072923
program_official: CASTLE, ARTHUR
project_start_date: 2006-05-01
project_end_date: 2021-04-30
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Animals;Authorship;Brain;Clinical;Conflict of Interest;Data;Diabetes Mellitus;Diabetic Nephropathy;Educational Curriculum;Endocrine;Endocrinology;Environment;Funding;Goals;Institutional Review Boards;Journals;Laboratories;Malignant Neoplasms;Medical Students;Mentors;Mentorship;Metabolism;NCI Scholars Program;National Institute of Diabetes and Digestive and Kidney Diseases;Outcome;Peer Review;Persons;Physicians;Pituitary Gland;Plagiarism;Publications;Publishing;Regulation;Research;Research Personnel;Research Project Grants;Research Training;Scientist;Structure;Student recruitment;Students;Testing;Training;Training Programs;Training Support;Translational Research;Universities;Vertebrates;Work;base;career;design;ethnic disadvantage;ethnic minority population;experience;faculty research;hormone regulation;human subject;medical schools;meetings;non-alcoholic fatty liver;peer;peer coaching;peptide hormone;posters;programs;responsible research conduct;skills;summer research


application_id: 9237980
project_number: 1R21NS096983-01A1
project_title: Molecular regulation of myelin development and repair by Ick kinase
administering_ic: NINDS
award_notice_date: 2016-09-23
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: NS
serial_number: 096983
suffix: A1
program_official: MORRIS, JILL A
project_start_date: 2016-09-30
project_end_date: 2018-08-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 1906514
contact_pi: QIU, MENGSHENG
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
project_abstract:
Oligodendrocytes are myelin-forming macroglia found in all regions of the centralnervous system. The major function of myelin sheaths is to ensure the rapid andfaithful transmission of electrical signals. During development oligodendrocytesprecursor cells (OPCs) have to go through a series of morphological and molecularchanges before they become fully differentiated into mature myelinatingoligodendrocytes. The differentiation and myelination processes of oligodendrocytesare regulated by protein tyrosine phosphorylation. Recently we found that Ickcytoplasmic serine/threonine kinase is selectively up-regulated in differentiatingOPCs and disruption of Ick resulted a significant inhibition of OL differentiation. Inthis application we hypothesize that Ick enhances OPC differentiation and axonalmyelination by Ick during development and enhance myelin repair followingdemyelination insults. The first aim of this application is to examine whether Ickexpression is required for myelin development in Ick conditional mutant mice andinduced expression of Ick protein in OPCs promotes developmental myelination ininducible transgenic mice. In the second aim we will test the hypothesis that Ickexpression is also required for axonal remyelination in adult animals andoverexpression of Ick in inducible transgenic mice can promote myelin recoveryfollowing demyelination This line of study could help us understand molecular mechanisms thatcontrol axonal myelination process and provide insights into the development ofmolecular approaches to stimulate oligodendrocyte regeneration and remyelination indemyelinating diseases.

project_terms:
Address;Animal Model;Axon;Birth;Cell Communication;Cell Differentiation process;Cells;Cuprizone;Demyelinating Diseases;Demyelinations;Development;Developmental Process;Ensure;In Situ;Injury;Intestines;Knock-out;Knockout Mice;Knowledge;Ligands;Molecular;Mus;Myelin;Myelin Sheath;Natural regeneration;Nature;Neuraxis;Neurologic;Oligodendroglia;Patients;Pattern;Phenotype;Phosphorylation;Phosphotransferases;Play;Process;Protein Kinase;Protein-Serine-Threonine Kinases;Proteins;Recovery;Regulation;Role;SHH gene;Series;Signal Transduction;Spinal Cord;Spinal cord injury patients;Surface;Testing;Time;Transducers;Transgenic Mice;Tyrosine Phosphorylation;axon regeneration;base;conditional mutant;insight;macroglia;mature animal;mutant;myelination;neonatal death;oligodendrocyte precursor;overexpression;postnatal;precursor cell;receptor;remyelination;repaired;screening;smoothened signaling pathway;transmission process

public_health_relevance:
The proposed studies will provide important information on the functional role of Ickcytoplasmic serine/threonine kinase in the control of oligodendrocyte differentiationmyelin development and repair in the developing central nervous system. Knowledgeobtained from this study will yield important insights into the development of molecularstrategies for promoting oligodendrocyte regeneration and axonal remyelination inneurological patients and spinal cord injury patients.


application_id: 9237939
project_number: 3R43AI112048-01A1S1
administering_ic: NIAID
award_notice_date: 2016-04-14
opportunity_number: PA-14-077
application_type: 3
activity_code: R43
ic: AI
serial_number: 112048
suffix: A1S1
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2014-12-15
project_end_date: 2017-02-16
contact_pi_person_id: 10420394
contact_pi: BRELSFOARD, COREY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 780816091
primary_uei: F873ZJEX7615
duns_number: 780816091
uei: F873ZJEX7615
fips: US
organization_id: 10027931
organization_name: MOSQUITOMATE, INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40502
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-06-29
project_title:
Feasibility assessment of a novel tool for mosquito vector control: Auto-Dissemination Augmented by Males (ADAM)

project_abstract:
DESCRIPTION (provided by applicant): Vector control remains the only means to combat many important mosquito-borne pathogens including the viruses responsible for West Nile Dengue and Chikungunya. A key deficiency of existing vector control methods is the inability to affect cryptic breeding sites which provide refugia to immature mosquitoes and allow for the rapid recovery of mosquito populations following conventional control efforts. The self-delivering method known as 'auto-dissemination' promises to address this deficiency by using mosquitoes as the vehicle to deliver powerful larvicides to cryptic breeding sites. However current auto-dissemination methods rely upon the indigenous mosquito population to become contaminated at a device that is attractive to mosquitoes and then to transmit the larvicide as they encounter breeding sites; thus models predict that a robust mosquito population is required for the method to work effectively i.e. without mosquitoes to act as vehicles the larvicide will not leave the introduced/attractive device. The auto-dissemination approach is based on an active ingredient classified as a 'reduced risk pesticide' by the US EPA. It is potent: 1/1000th of the dry weight o a mosquito adult is adequate to treat a 200ml breeding site and there is no resistance in mosquitoes. A novel paradigm shift to the auto-dissemination approach is employing as the larvicide vehicle: mass- produced larvicide-treated adult male mosquitoes which do not bite or transmit disease. We refer to this approach as "Auto-Dissemination Augmented by Males" (ADAM). By no longer relying on the indigenous mosquito population the ADAM approach can be used as a preventative tool i.e. treating cryptic sites in advance of the normal population increase (e.g. in early spring). Furthermore using the ADAM approach the number of introduced larvicide treated males can be sustained despite a reduced indigenous population. Preliminary data from laboratory tests show that males in the ADAM approach can (1) contaminate females with dosages that are subsequently lethal to larvae ('Sexually Transmitted Larvicide') and (2) directly deliver larvicide to breeding sites. The outcome of a small field tria demonstrates that introduced oviposition sites experienced significant larval mortality relative to
control sites up to 150m from a release site that received ADAM male introductions at a rate of 4500/week over four weeks. Methods for the mass manufacturing of adult male mosquitoes are previously developed as part of an ongoing Wolbachia-biopesticide project at MosquitoMate. In the proposed work (Aims 1-3) we will examine the feasibility of the ADAM approach against Culex pipiens Aedes aegypti and Ae. albopictus first in laboratory trials and subsequently under field conditions. In Aim 4 we will prepare for a pre-registration meeting with the US EPA toward obtaining an Experimental Use Permit required for large-scale Phase 2 trials.

project_terms:
Address;Adult;Aedes;Affect;Animals;Area;Attention;Behavior;Bite;Blood;Breeding;Businesses;Chikungunya virus;Culex pipiens;Culicidae;Data;Dengue;Dengue Virus;Devices;Disease;Dose;Face;Female;Goals;Human;Indigenous;Insecta;Insecticides;Investments;Killings;Laboratories;Larva;Lead;Left;Measures;Methods;Modeling;Mosquito-borne infectious disease;Names;Native-Born;Outcome;Oviposition;Partner in relationship;Pesticides;Phase;Phase II Clinical Trials;Plant Leaves;Population;Preparation;Production;Recovery;Resistance;Risk;Site;Sterility;Techniques;Testing;Trees;Virus;Water;Weight;West Nile virus;Wolbachia;Work;base;chikungunya;combat;commercialization;dosage;experience;feeding;field study;male;mathematical model;meetings;milliliter;mortality;novel;pathogen;public health relevance;research study;success;tool;vector;vector control;vector mosquito;wasting

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Vector control remains the only means to combat many mosquito borne diseases including those caused by West Nile Dengue Chikungunya viruses and other pathogens. A critical existing gap in vector control is the inability to affect the immature proportion of the mosquito population that remains hidden/protected within cryptic breeding sites and inaccessible to conventional control tools. The proposed work will test the feasibility of a novel 'self-delivering' approach which will employ manufactured adult male mosquitoes as the vehicle for treating cryptic sites with a potent larvicide.


application_id: 9237917
project_number: 3R01ES025515-03S1
project_title: Oxidative stress Cr(VI) carcinogenesis and prevention
administering_ic: NIEHS
award_notice_date: 2017-03-03
opportunity_number: PAR-14-050
application_type: 3
activity_code: R01
ic: ES
serial_number: 025515
suffix: S1
program_official: SHAUGHNESSY, DANIEL
project_start_date: 2015-05-01
project_end_date: 2020-01-31
study_section: Special Emphasis Panel[ZRG1 DKUS-N (50)]
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
project_abstract:
Natural compound-mediated activation of inducible Nrf2 enhances the cellular antioxidant levels andsuppresses ROS which can be used as a strategy to inhibit Cr(VI)-induced malignant transformationrepresenting the first stage of Cr(VI) carcinogenesis. Our preliminary studies from the parent R01 grant showthat after transformation these cells exhibit constitutive Nrf2 activation which up-regulates its target proteinsincluding SOD and Bcl-2 leading to cell survival and tumorigenesis signifying the second stage of metal orCr(VI) carcinogenesis. Thus our data indicate that Nrf2 can be an important target for prevention againstCr(VI) carcinogenesis at both stages. The parent R01 proposal investigates the protection of a naturalcompound against Cr(VI)-induced cell transformation Cr(VI)-transformed cells-induced tumorigenesis andCr(VI)-induced angiogenesis and tumor formation with overall theme focused on endpoints of the protectionaganist Cr(VI)-induced carcinogenesis. This ViCTER application expands the scope of the parent R01 throughdeveloping new transdisciplinary collaboration by engaging with experts in the areas of autophagy metalcarcinogenesis and mechanism-based cancer prevention to focus on mechanistic aspect on Cr(VI)-inducedcarcinogenesis and its protection using a natural compound. This study is based on our following majorfindings. (a) EGFR is constitutively activated in Cr(VI)-transformed BEAS-2B cells and in lung tissues fromanimals and a cancer patient exposed to Cr(VI). (b) EGFR activation initiates autophagy and causesautophagy deficiency by blocking the fusion between autophagosomes and lysosomes leading to p62accumulation and constitutive Nrf2 activation in Cr(VI)-transformed cells. (c) Piperlongumine a naturalcompound activates inducible Nrf2 in normal cells and inhibits constitutive activations of EGFR and Nrf2 inCr(VI)-transformed cells. The central hypothesis is that piperlongumine activates inducible Nrf2 leading todecreased level of ROS and inhibition of malignant transformation of normal cells and that this compoundinhibits EGFR activation resulting in blockages of autophagy process constitutive activations of p62 and Nrf2and tumorigenesis of Cr(VI)-transformed cells. Aim 1 will test the hypothesis that EGFR activation initiatesautophagy by activating TFEB which up-regulates Beclin 1 and p62 and generates autophagosomes. Aim 2will test the hypothesis that EGFR down-regulates LAMP2a resulting in inhibition of the fusion betweenautophagosomes and lysosomes leading to accumulation of p62 and constitutive Nrf2 activation at cellularanimal and human levels. Aim 3 will demonstrate (a) piperlongumine activates inducible Nrf2 decreases ROSand inhibits Cr(VI)-induced malignant transformation of normal cells; (b) this natural compound inhibits EGFRactivation autophagy initiation and autophagy deficiency constitutive activations of p62 and Nrf2 andtumorigenesis of Cr(VI)-transformed cells; and (c) piperlongumine protects from tumor formation in animalsexposed to Cr(VI).

project_terms:
Animals;Antioxidants;Area;Autophagocytosis;Autophagosome;BCL2 gene;Binding;Cancer Patient;Carcinogenesis Mechanism;Cell Survival;Cells;Data;Data Analyses;Diet;Elements;Ensure;Epidermal Growth Factor Receptor;Epithelial;Exhibits;Experimental Designs;Goals;Grant;Human;Lung;Lung Neoplasms;Lysosomes;Malignant - descriptor;Mediating;Membrane Proteins;Metal Carcinogenesis;Metals;Normal Cell;Oxidative Stress;Parents;Play;Prevention;Process;Promoter Regions;Proteins;Reactive Oxygen Species;Receptor Activation;Role;Structure of parenchyma of lung;Superoxide Dismutase;Testing;Tumor Tissue;activating transcription factor;angiogenesis;animal tissue;base;cancer cell;cancer prevention;carcinogenesis;carcinogenicity;cell transformation;chromium hexavalent ion;interdisciplinary collaboration;novel strategies;nuclear factor-erythroid 2;prevent;response;tumor;tumorigenesis

public_health_relevance:
PROJECT NARRATIVE This application focuses on mechanistic aspect of Cr(VI)-induced carcinogenesis and its prevention bypiperlongumine a natural compound. Piperlongumine prevents from Cr(VI)-induced carcinogenesis byactivating inducible Nrf2 leading to decreased level of ROS and inhibition of malignant transformation ofnormal cells and by inhibiting EGFR activation resulting in blockages of autophagy process constitutiveNrf2 activation and tumorigenesis of Cr(VI)-transformed cells.


application_id: 9237767
project_number: 1R01ES026657-01A1
project_title: Microenvironment and Arsenic Lung Tumorigenesis
administering_ic: NIEHS
award_notice_date: 2017-09-18
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: ES
serial_number: 026657
suffix: A1
program_official: HUMBLE, MICHAEL C
project_start_date: 2017-09-30
project_end_date: 2022-08-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 10212779
contact_pi: CHEN, GANG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
A/J Mouse;Animal Model;Animals;Antibodies;Arsenic;Binding;CD4 Positive T Lymphocytes;CD4/CD8 ratio procedure;CD8B1 gene;Cancer Patient;Cell Count;Cell membrane;Cells;Cellular Structures;Chronic;Data;Development;Dose;Environmental Exposure;Environmental Risk Factor;Epithelial Cells;Equilibrium;Flow Cytometry;Functional disorder;Genes;Human;Immune;Immune Checkpoint;Immune system;Immunity;Immunologic Monitoring;Immunologic Surveillance;In Vitro;Incidence;Injection of therapeutic agent;Interleukin-6;Investigation;Knock-out;Lead;Lung;Lung Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;Mediating;Modeling;Monitor;Mus;Outcome;PDCD1LG1 gene;Pathway interactions;Pharmacologic Substance;Play;Process;Receptor Inhibition;Regulation;Reporting;Role;STAT3 gene;Skin Cancer;T-Lymphocyte;T-Lymphocyte Subsets;Tumor Escape;Tumor Immunity;Up-Regulation;cell transformation;cell type;cytotoxic;genetic approach;immune activation;in vivo;inhibiting antibody;inhibitor/antagonist;innovation;lung carcinogenesis;lung tumorigenesis;mouse model;neoplastic cell;novel;novel strategies;prevent;promoter;tumor;tumor initiation;tumorigenesis


application_id: 9237746
project_number: 3R15DE025388-01S1
project_title: Treg regulation and its role in gingival inflammation during pregnancy (Administrative Supplements)
administering_ic: NIDCR
award_notice_date: 2016-09-23
opportunity_number: PA-16-066
application_type: 3
activity_code: R15
ic: DE
serial_number: 025388
suffix: S1
program_official: CHANDER, PREETHI
project_start_date: 2016-07-15
project_end_date: 2020-01-14
contact_pi_person_id: 9846210
contact_pi: LIANG, SHUANG
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): Pregnant women are more prone to develop exacerbated gingival inflammation which is known as pregnancy gingivitis. Inflammation and oral pathogenic bacteria infiltration during pregnancy are detrimental to pregnant women's health and negatively impact on their life quality and can cause adverse pregnancy outcomes in some cases. Using a modified ligation induced periodontal disease model our preliminary data implies that the gingival inflammation during pregnancy is linked with lower number of Tregs one subset of T cells critical for host immune regulation. This proposal hypothesizes that host Tregs proliferate in response to pathogen infection to prevent excessive immune responses but the process is down-regulated during pregnancy. This down-regulation of Treg development is responsible for the disrupted immune homeostasis and gingival inflammation. This notion will be tested using in vitro analysis and in vivo mouse model. In Aim 1 we will determine the effect of pregnancy on pathogen-induced Treg number and function. Pregnant mice will be ligated and infected with pathogens to determine the number as well as the immune suppressive function of induced Tregs; detailed mechanisms of the regulation on Treg proliferation will also be determined. Aim 2 is expected to investigate the role of Tregs in the gingival inflammation during pregnancy. Depletion of Tregs as well as adoptive transfer of Tregs into pregnant mice will reveal the effect of Tregs on the gingival inflammation. The objective is to reveal the regulation of infection-induced Treg development by pregnancy status and the effect of this regulation on gingival inflammation during pregnancy. The goal of the project is to not only pinpoint the critical cell type in the disease but also provide information for the pathogenesis and future cure of the disease therefore significantly improving woman health. Moreover another goal of current proposal is to enhance the research and training environment for the students in our school by exposing more students to the concept and technologies for oral biology research and foster next generation of scientists.

project_terms:
Administrative Supplement;Adoptive Transfer;Affect;Animal Model;Bacteria;Cells;Communicable Diseases;Data;Development;Disease;Disease model;Down-Regulation;Environment;Flow Cytometry;Fostering;Funding;Future;Gingiva;Gingivitis;Goals;Health;Hemorrhage;Homeostasis;Immune;Immune response;Immunity;In Vitro;Infection;Infiltration;Inflammation;Knockout Mice;Ligation;Link;Lymphocyte Subset;Mus;Natural Immunity;Oral;Pathogenesis;Pathway interactions;Patients;Periodontal Diseases;Pregnancy;Pregnant Women;Prevalence;Process;Proliferating;Quality of life;Regulation;Regulatory T-Lymphocyte;Research;Research Training;Role;School Dentistry;Schools;Scientist;Students;T-Cell Proliferation;T-Lymphocyte;T-Lymphocyte Subsets;Technology;Testing;Thymus Gland;Tissues;Universities;Women's Health;Work;adaptive immunity;adverse pregnancy outcome;cell type;improved;in vivo;insight;mouse model;next generation;novel;oral bacteria;oral biology;oral immunology;pathogen;pathogenic bacteria;pregnant;prevent;programs;response;therapeutic target;transcription factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Pregnant women are prone to more prevalent and more severe gingival inflammation. This application proposes to investigate the regulation of infection-driven Treg development during pregnancy and its role in gingival inflammation. This work is expected to pinpoint the role of dysregulation of Treg development in the gingival inflammation during pregnancy.


application_id: 9237694
project_number: 3R44AI098179-03S1
project_title: Biological vector control reducing arboviruses including Dengue and Chikungunya
administering_ic: NIAID
award_notice_date: 2016-04-06
opportunity_number: PA-14-077
application_type: 3
activity_code: R44
ic: AI
serial_number: 098179
suffix: S1
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2012-06-01
project_end_date: 2018-05-31
contact_pi_person_id: 11545088
contact_pi: MAINS, JAMES WILLIAM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 780816091
primary_uei: F873ZJEX7615
duns_number: 780816091
uei: F873ZJEX7615
fips: US
organization_id: 10027931
organization_name: MOSQUITOMATE, INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40502
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In the absence of effective approved drugs or vaccines vector control remains the only means of intervention for many against mosquito-borne diseases. This problem grows more complex with the recent establishment of multiple exotic mosquito species and mosquito-borne pathogens. Furthermore changing climate conditions are predicted to alter the traditional range for native mosquitoes. A notable example is Aedes albopictus the Asian Tiger mosquito introduced into the USA in the mid-1980s this invasive species has spread throughout the southeast and with warmer winters its range is now moving into New York and other northern states where it has become the primary biting mosquito. A stable infestation was discovered in California in 2011 which persists despite an ongoing elimination campaign. The cryptic biology of this mosquito makes it difficult to find and treat using traditional insecticidal approaches. In addition to its importance as a biting nuisance A. albopictus is a competent vector of over twenty pathogens. Epidemiological models show risk of returning travelers infected with chikungunya virus infecting A. albopictus and starting localtransmission. This hypothesized event would be similar to recent epidemics that have occurred in Europe India Sri Lanka and La Reunion. Our discussions with major mosquito control districts around the country (California Florida New York) demonstrate the need and commercial opportunity for new approaches against A. albopictus and an interest in the our product. Our Phase I results demonstrate feasibility of a Wolbachia biopesticide approach. Repeated releases of Wolbachia- infected males cause a form of conditional sterility capable of eliminating an A. albopictus population within eight weeks. In the proposed Phase II work we will continue the research and development of the Wolbachia biopesticide approach with the major goals of (1) demonstrating a prototype mass production unit (2) providing field performance data for Wolbachia-infected A. albopictus males and (3) measuring the pesticidal effect of Wolbachia- infected A. albopictus males against an indigenous field population.

project_terms:
Adult;Aedes;American Samoa;Arboviruses;Asians;Bacteria;Biological;Biological Assay;Biology;Bite;California;Chikungunya virus;Collaborations;Complex;Country;Culicidae;Data;Dengue;Disease;Disease Vectors;Environment;Epidemic;Epidemiologist;Europe;Event;Female;Florida;Goals;Grant;Health;India;Indigenous;Insecticides;Intervention;Kentucky;Legal patent;Licensing;Longevity;Los Angeles;Marketing;Measures;Medical;Methods;Modeling;Monitor;Mosquito Control;Mosquito-borne infectious disease;Native-Born;New York;Partner in relationship;Performance;Pharmaceutical Preparations;Phase;Population;Positioning Attribute;Practice Management;Preparation;Production;Recommendation;Regulatory Pathway;Risk;Site;Sri Lanka;Sterility;System;Technology;Tigers;Time;Vaccines;Vision;Wolbachia;Work;chikungunya;climate change;commercialization;cost;density;design;effective therapy;epidemiological model;fitness;improved;interest;male;manufacturing process;novel strategies;pathogen;prototype;research and development;sex;tool;transmission process;vector;vector control;vector mosquito

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Effective control tools are needed against the invasive disease vector mosquito Aedes albopictus (Asian Tiger mosquito). Contained trials in Phase I have shown that the repeated release of males infected with Wolbachia bacteria can cause sterility and eliminate A. albopictus populations. The proposed Phase II work will (1) demonstrate efficacy of the control approach in the field against an established population and (2) improve product production to improve the overall production levels and reduce downstream cost.


application_id: 9237298
project_number: 5R01HL131925-02
project_title: Role of IKK in obesity and atherosclerosis
administering_ic: NHLBI
award_notice_date: 2017-02-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 131925
program_official: KIRBY, RUTH
project_start_date: 2016-04-01
project_end_date: 2020-02-29
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Obesity is associated with a state of chronic inflammation that is thought to be a major contributor to diabetes and atherosclerosis. Many inflammatory pathways that contribute to the development of insulin resistance and atherosclerosis are regulated by IKK/NF-B signaling. However the role of IKK in metabolic disorders and atherosclerosis remains elusive. Our initial studies showed that IKK deficiency (driven by a SM22Cre-IKK- flox system) in smooth muscle cells (SMCs) rendered mice resistant to the development of diet-induced obesity metabolic disorders and atherosclerosis. We made the novel finding that SM22 is expressed in primary adipose stromal vascular (SV) cells and IKK positively regulates adipogenesis indicating that chronic inflammation might be an important initial trigger for the adipocyte differentiation in response to high-fat diet consumption. Our central hypothesis is that IKK is essential for adipogenesis and atherogenesis and that high-fat diet-induced IKK activation promotes adipocyte differentiation and adipose inflammation leading to increased obesity insulin resistance and atherosclerosis. Three specific aims are proposed: (1) Define the role of IKK in the regulation of murine and human adipocyte differentiation in response to overnutrition; (2) Determine the contribution of adipocyte IKK to the development of obesity-associated insulin resistance and atherosclerosis; and (3) Determine the impact of pharmacological inhibition of IKK by antisense oligonucleotides on diet-induced obesity and atherosclerosis. The proposed studies will define the role of IKK in adipogenesis and atherogenesis and will reveal a critical link between overnutrition inflammation and cardiometabolic disease. Our studies will also provide strong evidence for use of appropriate IKK inhibitors as an innovative therapeutic strategy to treat obesity and cardiometabolic disease.

project_terms:
Ablation;Adipocytes;Adipose tissue;Antisense Oligonucleotides;Atherosclerosis;Blood Vessels;Cells;Chronic;Consumption;Country;Development;Diabetes Mellitus;Diet;Disease;Epidemic;Goals;High Fat Diet;Human;Immune response;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Insulin Resistance;Link;Metabolic Diseases;Molecular;Mus;Myelogenous;Natural Immunity;Obesity;Overnutrition;Pathway interactions;Pharmacology;Phosphotransferases;Regulation;Reporting;Resistance;Role;Signal Transduction;Smooth Muscle Myocytes;System;Testing;Therapeutic;adipocyte differentiation;atherogenesis;gain of function;in vivo;inhibitor/antagonist;innovation;interest;lipid biosynthesis;loss of function;macrophage;mouse model;novel;novel strategies;population health;precursor cell;progenitor;public health relevance;response;therapeutic target;vascular inflammation

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Obesity is a rapidly growing epidemic representing a serious threat to the health of the population in almost every country around the world. There is an urgent need to understand the mechanisms underlying the diet- induced obesity and associated cardiometabolic disease. The proposed study will investigate a novel mechanism that links overnutrition to obesity and metabolic disorders.


application_id: 9236730
project_number: 1R01HL131782-01A1
project_title: Monomeric G-proteins and Cardioprotection from Heart Failure
administering_ic: NHLBI
award_notice_date: 2016-12-20
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: HL
serial_number: 131782
suffix: A1
program_official: SCHWARTZ, LISA
project_start_date: 2017-09-01
project_end_date: 2020-08-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 7875430
contact_pi: SATIN, JONATHAN
other_pis: ANDRES, DOUGLAS ALLEN
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Monomeric G-proteins and Cardioprotection from Heart FailureHeart failure incidence in the United States is steadily increasing with annual costs in excess of $30 billion andthe cost is expected to increase 127% between now and 2030. Heart failure with reduced ejection fraction(HFrEF) occurs in ~45% of HF patients and is associated with longer survival compared to HF with preservedejection fraction; however treatment options are poor and are limited to increasing survival without improvingsystolic function. Success of agents such as -blockers to prolong lifespan (not necessarily quality of life) ofHFrEF draws attention away from the fundamental principle that in HFrEF the heart defect is failure to contractwith sufficient force to meet demand. This new proposal is motivated by our findings of a novel cardiacphenotype caused by deletion of the Rad-GTPase. Rad-null mice (Rad-/-) show increased cardiac contractilitythat persists well into senescence and out-performs age- and gender-matched animals. Rad-/- mice also showcardioprotection against chronic catecholamine stimulation and against chronic pressure overload. In thisproposal we will test two classes of potentially related but mutually exclusive mechanistic hypothesis. First wewill evaluate the contribution of altered Ca2+ homeostasis in response to Rad ablation; and second we willassess Rad contributions to the -adrenergic receptor (-AR) signaling axis. Three complementary Aims guideour studies. First we will test the hypothesis that Rad-ablation confers enhanced function via sarcolemmalCa2+ influx. These experiments will traverse scales of function from molecular to whole organ. Cardiacmagnetic resonance imaging (CMR) and echocardiography will also be used to measure in vivo heart function.Second we will evaluate the hypothesis that Rad deletion contributes to cardioprotection via enhancement ofintracellular Ca2+ synchrony and preservation of -AR signaling. Again assessments of heart structure andfunction will traverse scales from molecular to cellular to organ level and in vivo function. Our third aimfocuses on Rad-deletion as a potentially beneficial therapeutic approach. Overall this proposal tests a novelmechanism of augmentation of cardiac function that confers cardioprotection against sustained pressureoverload and chronic stress signaling.

project_terms:
ADRBK1 gene;Ablation;Acute;Adrenergic Receptor;Age;Agonist;Animal Model;Animals;Attention;Biological Preservation;Cardiac;Cardiac Myocytes;Catecholamines;Chronic;Chronic stress;Contracts;Data;Development;Disease;EFRAC;Echocardiography;Failure;Gender;Goals;Guanosine Triphosphate Phosphohydrolases;Health;Heart;Heart Abnormalities;Heart Hypertrophy;Heart failure;Homeostasis;Hypertrophy;Incidence;Knockout Mice;Laboratories;Longevity;Magnetic Resonance Imaging;Measures;Molecular;Monomeric GTP-Binding Proteins;Mus;Myocardial;Myocardium;Organ;Pathologic;Pathway interactions;Patients;Phenotype;Quality of life;RNA Interference;Reducing Agents;Regulation;Risk Factors;Signal Transduction;Stress;Structure;Symptoms;System;Testing;Therapeutic;Time;Tissues;United States;Ventricular Remodeling;Viral;base;cost;experimental study;genetic manipulation;heart function;improved;in vivo;innovation;molecular scale;novel;pressure;response;senescence;success

public_health_relevance:
Heart failure is a major health problem in the United States and a major risk factor is old age.By definition heart failure involves the inability of the heart to generate sufficiently forcefulcontractions - defined as an insufficient inotropic response. This proposal tests a novel putativetherapeutic direction that provides positive inotropic support to the failing myocardium along withprotection against stress-induced remodeling.


application_id: 9236502
project_number: 1R01NR016262-01A1
project_title: Corazn de la Familia (Heart of the Family)
administering_ic: NINR
award_notice_date: 2017-03-02
opportunity_number: PA-14-142
application_type: 1
activity_code: R01
ic: NR
serial_number: 016262
suffix: A1
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
project_terms:
Acculturation;Address;Adult;Affect;Age;Behavior;Behavior Therapy;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;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;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


application_id: 9235659
project_number: 3R01DK100892-04S1
project_title: The role of hepatic insulin resistance on SR-BI dependant HDL cholesterol uptake
administering_ic: NIDDK
award_notice_date: 2016-08-23
opportunity_number: PA-16-066
application_type: 3
activity_code: R01
ic: DK
serial_number: 100892
suffix: S1
program_official: SILVA, CORINNE M
project_start_date: 2013-09-20
project_end_date: 2018-08-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8553632
contact_pi: GRAF, GREGORY A
other_pis: VAN DER WESTHUYZEN, DENEYS REM
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:
DESCRIPTION (provided by applicant): The overall objective of this proposal is to examine the extent to which impaired insulin signaling alters HDL- mediated reverse cholesterol transport (RCT). A key cardioprotective function of HDL is the delivery of excess cholesterol from plasma and tissues to the liver for elimination from the body via RCT. SR-BI is the major hepatic HDL receptor and mediates the selective uptake of HDL cholesterol esters (HDL-CE). Compared to other circulating lipoproteins cholesterol carried on HDL particles is preferentially secreted int bile in an SR-BI dependent manner. In addition to SR-BI's role in trans-hepatic sterol transport both gain and loss-of-function studies have established that SR-BI is a determinant of hepatic cholesterol metabolism including cholesterol synthesis biliary cholesterol secretion rates and the incorporation of cholesterol into VLDL. Both HDL-CE uptake and biliary cholesterol secretion have been shown to be negatively affected by impaired insulin signaling a key contributing element to the Metabolic Syndrome (MetS) and the increased risk for cardiovascular disease. Our published and preliminary data indicate that insulin signaling regulates SR-BI by a novel post-translational mechanism that promotes SR-BI expression on the plasma membrane. We hypothesize that insulin resistance reduces HDL-CE uptake and alters SR-BI-dependent delivery of cholesterol to hepatic regulatory and secretory pools through mechanisms that include the redistribution of SR-BI to an intracellular compartment. Specific Aim 1 will determine the effect of hepatic insulin signaling and insulin resistance on SR-BI mediated sterol traffickingto secretory and regulatory hepatic cholesterol pools. Hepatic insulin signaling will be disrupted by selective depletion of insulin receptors or by expression of a dominant negative phosphatidylinositol-3 kinase (AdnilPI3K) and the extent to which hepatic insulin resistance reduces SR-BI mediated HDL-C selective cholesterol ester uptake determined. Studies will also determine how reduced SR-BI function alters steady-state hepatic cholesterol synthesis and secretion in the setting of impaired insulin signaling? Specific Aim 2 will test the hypothesis tha transhepatic (THCE) elimination of HDL cholesterol in bile is reduced in the setting of hepatic insulin resistance and hypertriglyceridemia. This will be accomplished by a) determining whether reduced SR-BI function diminishes THCE of HDL-C b) determining whether hepatic IR decreases macrophage to feces RCT in an SR-BI dependent manner and c) examining whether changes in HDL particle composition disrupt THCE of HDL-C and synergize with SR-BI dysfunction to reduce HDL RCT function. Specific Aim 3 will determine the molecular mechanisms by which insulin signaling regulates SR-BI cell surface localization in hepatocytes. The effect of insulin-dependent PI3K signaling on SR- BI subcellular distribution will be examined in cultured hepatocytes together with the identity of the intracellular compartment(s) in which SR-BI accumulates as a result of impaired insulin signaling. The responsible insulin- dependent signaling pathways will be defined and studies will be performed to identify the determinants on SR- BI necessary for its regulation by insulin signaling.

project_terms:
1-Phosphatidylinositol 3-Kinase;Affect;Back;Bile fluid;Biliary;Cardiovascular Diseases;Cell membrane;Cell surface;Cholesterol;Cholesterol Esters;Cholesterol Homeostasis;Data;Dependence;Dominant-Negative Mutation;Elements;Excretory function;Feces;Functional disorder;Future;HDL cholesteryl ester;HDL receptor;Health;Hepatic;Hepatocyte;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Hypertriglyceridemia;Insulin;Insulin Receptor;Insulin Resistance;Liver;Low Density Lipoprotein Receptor;Mediating;Metabolic syndrome;Metabolism;Molecular;Mus;Mutagenesis;Obesity;Outcome;Pathway interactions;Peripheral;Plasma;Play;Process;Publishing;Regulation;Role;Signal Pathway;Signal Transduction;Sterols;Testing;Therapeutic;Tissues;Very low density lipoprotein;cardiovascular disorder risk;cardiovascular risk factor;design;insulin signaling;lipoprotein cholesterol;loss of function;macrophage;mouse model;novel;particle;reverse cholesterol transport;trafficking;translational approach;treatment strategy;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This proposal examines the effects of insulin resistance on the functionality of hepatic SR-BI. SR-BI is the primary liver receptor for HDL and plays a key role in liver uptake and elimination of excess cholesterol delivered from peripheral tissues. This process called reverse cholesterol transport underlies a key cardioprotective function of HDL. The completion of this proposal will further our understanding of the impact of obesity and insulin resistance on the cardioprotective effects of HDL and guide current and future therapeutic strategies that target HDL in the treatment of cardiovascular disease.


application_id: 9235482
project_number: 2U01DK074007-11
project_title: University of Louisvilles Clinical Center in Gastroparesis Clinical Research Consortium
administering_ic: NIDDK
award_notice_date: 2016-09-23
opportunity_number: RFA-DK-16-010
application_type: 2
activity_code: U01
ic: DK
serial_number: 074007
program_official: HAMILTON, FRANK A
project_start_date: 2006-04-15
project_end_date: 2021-08-31
study_section: Special Emphasis Panel[ZDK1 GRB-8 (O2)]
contact_pi_person_id: 8264660
contact_pi: ABELL, THOMAS LYMAN
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:
Abdominal Pain;Affect;Anatomy;Ancillary Study;Area;Brain;Chronic;Clinical;Clinical Research;Complex;Data;Databases;Devices;Digestive System Disorders;Disease;Effectiveness;Electric Stimulation;Electrolytes;Enteral;Etiology;Functional disorder;Gastric Emptying;Gastroparesis;Goals;Grant;Health;Homeostasis;Inflammatory;Insulin Infusion Systems;Knowledge;Learning;Life;Liquid substance;Malnutrition;Measures;Methods;Mission;Motor;Motor Activity;Multicenter Studies;Natural History;Nausea;Nausea and Vomiting;Nortriptyline;Nutritional Support;Nutritional status;Outcome;Pain;Pathogenesis;Patient-Focused Outcomes;Patients;Peripheral;Physical Function;Physicians;Psychological Impact;Publications;Publishing;Quality of life;Recommendation;Recruitment Activity;Registries;Research;Safety;Sensory;Series;Severities;Signal Transduction;Stomach;Symptoms;Syndrome;Therapeutic;Time;Tissue Sample;United States National Institutes of Health;Universities;Visceral;Vomiting;Work;aprepitant;base;disability;early satiety;effective therapy;glucose monitor;improved;meetings;motor disorder;novel strategies;response;treatment strategy;young woman


application_id: 9235145
project_number: 5P01CA163223-05
project_title: Stable Isotope Resolved Metabolomics Analytical Shared Core
administering_ic: NCI
award_notice_date: 2017-02-21
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
project_end_date: 2020-02-29
study_section: ZCA1-RPRB-0
subproject_number: 7605
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
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: 2017-03-01
project_abstract:
PROJECT SUMMARY (See instructions): The Stable Isotope Resolved (SIRM) Analytical Shared Core will provide high information throughput (HIT) bioanalytical support for the groups with special emphasis on stable isotope-based metabolic pathway tracing. The basis for this Core already exists in the form of the NSF-initiated UofL Center for Regulatory and Environmental Analytical Metabolomics (CREAM) established expressly for SIRM metabolomic bioanalytical services and collaborations on sample preparation and handling high field NMR mass spectrometry and biochemoinformatics since 2002. CREAM houses state of the art instrumentation that has profoundly influenced experimental design for several research groups. Therefore many Core interactions are by their nature long-standing collaborative efforts. The main goals of the SIRM Shared Core are to provide a set of shared resources for all three Research Projects and seamlessly integrate experimental design data collection and data analysis spanning tissue culture mouse models and human subjects. The Core will provide a combination of experimental methods to determine metabolic phenotypes of cancerous and non-cancerous lung cells and tissue using our state of the art analytical platforms in both NMR and mass spectrometry. In consultation with individual project leaders specific experimental design for stable isotope analysis will be tailored to individual project needs but with consistency across projects to facilitate integrated analyses. We have 3 specific aims to achieve our goals: Specific Aim 1. Provide infrastructure and expert sample handling that ensures consistent handling processing and archiving of samples across all three Research Projects; Specific Aim 2. Provide access and expertise across a wide range of NMR and MS technologies to the three Research Projects: A) Provide access to instrumentation and expertise for robust and consistent SIRM-based analytical experimental design and B) Provide expert data collection and analysis across a wide range of NMR and MS technologies. Specific Aim 3. Provide data analytical support to the Research Projects including data metabolic pathway and biochemical mechanism analyses that include: A) Implement a web-based platform for data reduction quality control and data analytical support; B) Provide methodologies for identifying and quantifying metabolites; C) Provide a bridge between the Projects data acquisition and biochemical analysis in Gore A. Core B provides extensive interoperability handling and advising all aspects of sample preparation data collection data analysis & quality control ensuring consistency of data across all 3 research projects.

project_terms:
Animal Model;Archives;Biochemical;Biochemistry;Biological;Biometry;Cancerous;Cells;Cessation of life;Collaborations;Collection;Computers and Advanced Instrumentation;Consultations;Data;Data Analyses;Data Analytics;Data Collection;Data Quality;Early Diagnosis;Ensure;Experimental Designs;Goals;Human;Individual;Informatics;Instruction;Knowledge;Lipids;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Metabolic Marker;Metabolic Pathway;Methodology;Methods;Modeling;Nature;Non-Small-Cell Lung Carcinoma;North America;Online Systems;Paper;Pathway Analysis;Pathway interactions;Persons;Preparation;Publishing;Quality Control;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resource Sharing;Sampling;Services;Software Tools;Statistical Data Interpretation;Structure of parenchyma of lung;Study Subject;Supervision;Support Groups;System;Technology;Time;Tissues;Validation;Water;base;cancer cell;cancer subtypes;data acquisition;data reduction;human subject;improved;instrumentation;interoperability;metabolic phenotype;metabolomics;mouse model;novel strategies;operation;outcome forecast;stable isotope;stem;tissue culture

public_health_relevance:
RELEVANCE (See instructions): Deaths from lung cancer are the highest among all cancers in North America and cure rates remain low. We seek to gain a deeper understanding of lung cancer biochemistry using a novel approach we developed. Improved knowledge will have direct impact on early diagnosis and prognosis. The biochemical differences between lung cancer subtypes can be related to appropriate treatments.


application_id: 9235144
project_number: 5P01CA163223-05
project_title: Administration Bioinformatics and Biostatistics Core
administering_ic: NCI
award_notice_date: 2017-02-21
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
project_end_date: 2020-02-29
study_section: ZCA1-RPRB-0
subproject_number: 7604
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
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: 2017-03-01
project_abstract:
In this Program Project "Systems Biochemistry in Lung Cancer: toward a mechanistic understanding of NSCLC" we aim to achieve a better understanding of the basic biochemistry of lung cancers as a prerequisite to mechanism-based reliable early detection of the disease and to improved approaches to treatment. The role of the Administrative Bioinformatics and Biostatistics Core is to provide overall administration and oversight to the project directors and core leaders (T. W-M. Fan Ph.D. Project 1; J. Yan M.D. Ph.D. Project 2; A. N. Lane Ph.D. Project 3; R. M Higashi Ph.D. Core B Analytical) on this Program Project. In addition Biostatistics and Informatics support (leaders S. N. Rai Ph.D. and H. N. B Moseley Ph.D.) for the Projects will be provided through this Core. To ensure smooth interoperability of the program the administrative core will be responsible for maintaining the budgets and cost reporting of the projects and cores as well as coordinating annual reports regular meetings among the project personnel and the internal and external advisory committees. The primary objective of the Bioinformatics / Biostatistics portion of this core is to provide support for investigators performing translational research and Informatics for biochemical pathway reconstruction and flux modeling. The core services are matched to the needs of each project and cover a full range of services from collaboration and routine service; protocol preparation and review; development of informatics approaches to ensure interoperability; and biochemical network analysis.

project_terms:
Advisory Committees;Annual Reports;Biochemical;Biochemical Pathway;Biochemistry;Bioinformatics;Biometry;Biostatistics Core;Budgets;Cessation of life;Collaborations;Data;Data Analyses;Data Quality;Data Set;Development;Disease;Doctor of Medicine;Doctor of Philosophy;Early Diagnosis;Ensure;Experimental Designs;Human Resources;Ice;Informatics;Instruction;Knowledge;Laboratories;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Non-Small-Cell Lung Carcinoma;North America;Pathway Analysis;Preparation;Protocols documentation;Quality Control;Reporting;Research Personnel;Role;Services;Statistical Data Interpretation;System;Translational Research;Universities;Validation;base;cancer subtypes;cost;data management;data visualization;improved;interoperability;meetings;model building;novel strategies;operation;outcome forecast;programs;reconstruction

public_health_relevance:
RELEVANCE (See instructions): Deaths from lung cancer are the highest among all cancers in North America and cure rates remain low. We seek to gain a deeper understanding of lung cancer biochemistry using a novel approach we developed. Improved knowledge will have direct impact on early diagnosis and prognosis. The biochemical differences between lung cancer subtypes can be related to appropriate treatments.


