# projects

application_id: 8776908
project_number: 5R01AI095032-04
project_title: Cooperation of CD8+ T cells and phagocytes to eliminate Toxoplasma cysts
administering_ic: NIAID
award_notice_date: 2014-11-26
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AI
serial_number: 095032
program_official: PESCE, JOHN T
project_start_date: 2012-01-01
project_end_date: 2015-12-31
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 1882071
contact_pi: SUZUKI, YASUHIRO
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:
DESCRIPTION (provided by applicant): Toxoplasma gondii establishes an important chronic infection capable of causing life-threatening toxoplasmic encephalitis in AIDS patients and other immunocompromised individuals. The basis of persistence of the infection is the tissue cyst which remains largely quiescent for the life of the host but can reactivate and cause disease. This stage of the parasite is not affected by any of the current drug treatments and it has been generally regarded as untouchable. However our recent studies revealed that the immune T cells are able to eliminate T. gondii cysts from the brains of infected hosts when the T cells are transferred into infected immunodeficient animals that have already developed large numbers of the cysts. This T cell-mediated immune process is associated with accumulation of mononuclear cells primarily microglia and macrophages morphologically around tissue cysts. Since the accumulated phagocytes penetrate within the cyst these cells appear to be the main effector cells that destroy the cysts and eliminate them from the brain after initiation of this process by immune T cells. CD8+ immune T cells possess a potent activity to initiate this anti-cyst immune process and the protective activity of the T cells requires perforin. The overall goalof this research project is to determine the molecular mechanisms by which perforin-mediated activity of CD8+ immune T cells cooperates with the phagocytes to remove T. gondii cysts from the brain. In the first aim we will determine if CD8+ immune T cells accumulate and attach to the cyst-containing cells in the brain. We will also determine if the CD8+ T cells lyse cyst-containing cells in a perforin-dependent manner in vitro and whether the perforin- mediated activity of CD8+ T cells induces the accumulation of phagocytes around the cysts in the brain. In the second aim we will determine the MHC class I molecule(s) critical for recognition of cyst-containing cells by CD8+ T cells. We will then determine the T. gondii cyst epitope(s) presented by the identified MHC class I molecule for recognition by the CD8+ T cells by screening predicted bradyzoite epitope peptides and/or bradyzoite cDNA library. The third aim is to determine the mechanisms by which phagocytes eliminate T. gondii cysts after initiation of the immune process by CD8+ T cells. We will examine the roles of inducible nitric oxide synthase and autophagy in killing of bradyzoites and elimination of cysts using mice lacking a molecule required for each mechanism. The information generated from the studies in these three specific aims all together will provide the essential basis for developing a novel method(s) to activate CD8+ T cells and phagocytes to eliminate T. gondii cysts that can reactivate and cause toxoplasmic encephalitis.

project_terms:
Acquired Immunodeficiency Syndrome;Acute;Address;Affect;Animals;Antigens;Autophagocytosis;Brain;CD8-Positive T-Lymphocytes;CD8B1 gene;Cells;Chronic;Cyst;Cytolysis;Cytotoxic T-Lymphocytes;Disease;Effector Cell;Encephalitis;Epitopes;Excision;Genes;Goals;Health;Histocompatibility Antigens Class I;Hybridomas;Immune;Immune system;Immunocompromised Host;In Vitro;Inbred BALB C Mice;Individual;Infection;Interferons;Killings;Knockout Mice;Life;Mediating;Mediator of activation protein;Methods;Microglia;Microscopy;Molecular;Mononuclear;Mus;Nitric Oxide;Parasites;Patients;Peptides;Phagocytes;Pharmaceutical Preparations;Play;Process;Production;Research Project Grants;Resistance;Risk;Role;Staging;Surface;T-Lymphocyte;Tissues;Toxoplasma;Toxoplasma gondii;base;cDNA Library;cytotoxic;human NOS2A protein;in vitro Model;in vivo;macrophage;novel;perforin;prevent;screening;two-photon

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Reactivation of chronic infection with Toxoplasma gondii causes life-threatening toxoplasmic encephalitis in AIDS patients and other immunocompromised individuals. The proposed studies are to analyze how T cells and phagocytes cooperate to eliminate the persisting cyst stage of T. gondii which can reactivate and cause the disease. These studies will provide the information essential for developing a novel method(s) to eliminate the persisting cyst stage of the parasite and prevent or reduce the risk of developing toxoplasmic encephalitis.


application_id: 8776907
project_number: 5K99AG044445-02
project_title: Involvement of myelin integrity in Alzheimer's disease pathogenesis
administering_ic: NIA
award_notice_date: 2014-11-28
opportunity_number: PA-11-197
application_type: 5
activity_code: K99
ic: AG
serial_number: 044445
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2013-12-01
project_end_date: 2016-04-30
study_section: Basic Neuroscience of Aging Study Section[NIA-N]
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
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_terms:
Alzheimer's Disease;Amyloid beta-Protein Precursor;Animal Model;Area;Automobile Driving;Autopsy;Biochemistry;Brain;Brodmann's area;Central Nervous System Diseases;Cerebrum;Cessation of life;Chronic;Clinical;Cognitive;Communication;Data;Deterioration;Development Plans;Diffusion Magnetic Resonance Imaging;Disease;Disease Progression;Educational process of instructing;Environment;Enzyme-Linked Immunosorbent Assay;Event;Exhibits;Genes;Genetic;Goals;Growth;Health;Human;Human Biology;Immunoblotting;Immunohistochemistry;Induced Mutation;Inflammation;Inflammatory;Inflammatory Response;International;Kentucky;Late Onset Alzheimer Disease;Measures;Medial;Mediating;Mental disorders;Mentors;Methods;Microglia;Mus;Mutation;Myelin;Myelin Proteins;Neocortex;Neuregulin 1;Neurodegenerative Disorders;Neurofibrillary Tangles;Neuroglia;Neurons;Oligodendroglia;Pathogenesis;Pathologic;Pathology;Pathway interactions;Phase;Phosphorylation;Research;Research Personnel;Research Project Grants;Resources;Role;Sampling;Scientist;Senile Plaques;Structure;Synapses;Temporal Lobe;Testing;Tissues;Training;Tumor Necrosis Factor-alpha;Universities;Work;Writing;axon injury;beta-site APP cleaving enzyme 1;brain tissue;burden of illness;career;career development;collaborative environment;cytokine;design;digital;feeding;frontal lobe;genetic risk factor;gray matter;hTau Mice;human tissue;hyperphosphorylated tau;improved;inhibitor/antagonist;insight;lipid transport;meetings;mild cognitive impairment;mouse model;myelination;neuroinflammation;neuron loss;neuropathology;pre-clinical;response;skills;tau Proteins;white matter;white matter change;young adult


application_id: 8774254
project_number: 5R01HL111932-03
project_title: Effects of Anti-miR-33 on Atherosclerosis Regression and RCT in Nonhuman Primates
administering_ic: NHLBI
award_notice_date: 2014-11-13
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 111932
program_official: LIU, LIJUAN
project_start_date: 2013-02-01
project_end_date: 2017-11-30
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 2186060
contact_pi: TEMEL, RYAN EUGENE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
ATP-Binding Cassette Transporters;Affect;American;Antisense Oligonucleotides;Aorta;Apolipoprotein A-I;Apolipoprotein E;Apolipoproteins;Arterial Fatty Streak;Arteries;Atherosclerosis;Binding (Molecular Function);Cells;Cercopithecus pygerythrus;Characteristics;Cholesterol;Clinical Treatment;Clinical Trials;Collagen;Complex;Coronary artery;Coronary heart disease;Feces;Fiber;Foam Cells;Future;Gene Targeting;Genes;Hepatic;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Homeostasis;Human;Implant;In Vitro;Inflammation;Introns;Lipids;Liver;Macaca fascicularis;Magnetic Resonance Imaging;Measures;Mediating;MicroRNAs;Molecular Sieve Chromatography;Monkeys;Mus;Patients;Process;Protein Isoforms;Proteins;Response Elements;Risk;Risk Factors;Role;Spectrometry Mass Electrospray Ionization;Sterols;Testing;Time;Translational Repression;fatty acid oxidation;inflammatory marker;laser capture microdissection;mRNA Transcript Degradation;macrophage;nonhuman primate;novel therapeutics;oxidation;pre-clinical;protective effect;reverse cholesterol transport;very low density lipoprotein triglyceride


application_id: 8773989
project_number: 1R01EB019036-01
project_title: Cancer specific and organ-avoiding RNA architectures for quantitative imaging
administering_ic: NIBIB
award_notice_date: 2014-07-01
opportunity_number: PAR-13-185
application_type: 1
activity_code: R01
ic: EB
serial_number: 019036
program_official: TUCKER, JESSICA
project_start_date: 2014-07-01
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1 SBIB-Z (58)]
contact_pi_person_id: 1878565
contact_pi: GUO, PEIXUAN
other_pis: EVERS, BERNARD MARK;QUINN, THOMAS P.
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Development of image-guided drug delivery systems for real-time monitoring quantifying and validating the delivery and therapeutic action is very important for both research and clinical applications. Various multifunctional nanoparticles of different materials have been investigated over the last decade as prospective imaging and therapeutic platforms; however effective strategies to quantitatively evaluate delivery of therapeutic payloads to tumors and metastatic cancer cells in vivo are challenging due to low efficiency in specific cancer targeting and non-specific trapping in vital organs such as liver an lungs. Our goal is to adopt an innovative RNA nanotechnology approach to construct ultrastable multifunctional RNA Beacons and RNA Dendrimers as image-guided agents for quantitative real-time assessment of tumor and metastatic cancer targeted therapeutic delivery distribution uptake and response. We have shown that our RNA nanoparticles are non-toxic non-immunogenic and capable of penetrating across heterogeneous biological barriers to deliver high doses of therapeutics specifically to solid tumors and metastatic cells in mice with little accumulation in normal organs. This provides an ideal platform for non-invasive imaging of cancer therapeutics in vivo. Our multifunctional RNA nanoparticles will be designed to harbor: (1) imaging modules: NIR fluorophores for in vivo fluorescence imaging; radionuclides for PET/SPECT imaging; and gadolinium contrast agents for MRI; (2) targeting modules: such as RNA aptamers or chemical ligands for binding to cancer specific cell surface receptors resulting in internalization of RNA nanoparticles into cancer cells; and (3) therapeutic modules: siRNAs and anti-miRNA to silence the expression of oncogenic genes. The multifunctional RNA constructs will then be evaluated in our well established colon cancer animal models. We will employ multimodal imaging techniques (NIRF PET/SPECT and/or MRI) for monitoring the therapeutic delivery process in real-time at various spatial and temporal resolution scales. This approach is based on the consideration that each of the three imaging modalities has advantages and an integrated approach will lead to synergistic benefits with regards to image-guided therapy.

project_terms:
Adopted;Animal Model;Animals;Architecture;Binding (Molecular Function);Biological;Biological Models;Cancer Diagnostics;Cancer Model;Catalytic RNA;Cell Surface Receptors;Cells;Chemicals;Colon Carcinoma;Contrast Media;Dendrimers;Detection;Development;Disseminated Malignant Neoplasm;Dose;Drug Delivery Systems;Dyes;Evaluation;Future;Gadolinium;Gene Silencing;Genes;Goals;Heterogeneity;Image;Imaging Techniques;In Vitro;Injection of therapeutic agent;Iowa;Lead;Ligand Binding;Ligands;Liver;Lung;Magnetic Resonance Imaging;Malignant Neoplasms;Methods;MicroRNAs;Molecular;Monitor;Motor;Multimodal Imaging;Mus;Nanotechnology;Nature;Neoplasm Metastasis;Oncogenic;Organ;Positron-Emission Tomography;Process;RNA;RNA Transport;Radioisotopes;Radiolabeled;Radionuclide Imaging;Reporter;Research;Resistance;Resolution;Side;Signal Transduction;Small Interfering RNA;Solid Neoplasm;System;Therapeutic;Therapeutic Agents;Time;Tissues;Tomography Emission-Computed Single-Photon;Toxic effect;Urea;aptamer;base;cancer cell;clinical application;design;fluorescence imaging;fluorophore;gadolinium oxide;image guided therapy;imaging modality;in vivo;innovation;mouse model;nano;nanoparticle;non-invasive imaging;prospective;public health relevance;radiotracer;response;scaffold;stem;therapeutic siRNA;therapeutic target;trafficking;tumor;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: RNA nanoparticles derived from the phi29 pRNA three-way junction (3WJ) are ultrastable and efficiently target tumor and metastatic cells in mice with littl accumulation in normal organs and tissues after systemic injection. This proposal is to construct multifunctional RNA Beacons and RNA Dendrimers as image-guided agents using the pRNA-3WJ scaffold for monitoring the in vivo delivery of cancer therapeutics in real-time and consequences of therapy.


application_id: 8773766
project_number: 4R37DE011111-21
project_title: P.gingivalis interactions with gingival epithelial cells
administering_ic: NIDCR
award_notice_date: 2013-12-31
opportunity_number: PA-07-070
application_type: 4
activity_code: R37
ic: DE
serial_number: 011111
program_official: LUNSFORD, DWAYNE
project_start_date: 2014-01-01
project_end_date: 2018-12-31
study_section: NSS
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Actins;American;Bacterial Infections;Biological;CXCL10 gene;Cell Communication;Cells;Disease;Ensure;Epithelial Cells;Equilibrium;Family;Generations;Gingiva;Goals;Health Status;Healthcare Systems;Human;IL8 gene;Immune;Instruction;Knowledge;LIMK1 gene;Lead;Life;Mediating;Microbe;Molecular Analysis;Natural Immunity;Oral cavity;Organism;Outcome;Pathway interactions;Periodontal Diseases;Phosphoric Monoester Hydrolases;Phosphotransferases;Porphyromonas gingivalis;Production;Regulation;Role;Serine;Signal Transduction;Signal Transduction Pathway;T-Lymphocyte;Therapeutic Agents;actin depolymerizing proteins;cell motility;cellular imaging;chemokine;cofilin;design;novel;pathogen;response


application_id: 8772240
project_number: 1R21DA038248-01
project_title: Spinal AMPA receptors latent central sensitization and chronic pain
administering_ic: NIDA
award_notice_date: 2014-06-17
opportunity_number: PA-13-119
application_type: 1
activity_code: R21
ic: DA
serial_number: 038248
program_official: HILLERY, PAUL
project_start_date: 2014-07-01
project_end_date: 2016-06-30
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 10670168
contact_pi: DOOLEN, SUZANNE
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): There is an overwhelming need for research leading to a greater understanding of central nervous system mechanisms that regulate the transition from acute to chronic pain. The Institute of Medicine states that 116 million Americans are burdened with chronic pain costing over $600 billion annually. While opioid medications are commonly prescribed to treat pain they are only moderately efficacious and adverse side effects and potential for abuse stress the need for greater understanding of their analgesic mechanisms. A large body of research indicates that peripheral inflammation initiates maladaptive plasticity within the spinal cord and brain termed central sensitization-that contributes to chronic pain. Less appreciated however are data which suggest that central sensitization far outlasts overt signs of pain sensitivity in a silent form termed "latent central
sensitization" (LCS). This proposal is innovative in that it suggests a novel molecular mechanism of LCS; the central hypothesis is that inflammation produces an adenylyl cyclase 1 (AC1)- and AMPA receptor (AMPAR)-dependent LCS that is masked by spinal opioid receptors. This hypothesis will be tested with three specific aims: AIM 1 tests the hypothesis that tonic mu opioid receptor (MOR) activity decreases dorsal horn AMPAR-mediated Ca2+ signaling during long-lasting LCS after injury. Aim 1 uses innovative real-time Ca2+ imaging in adult spinal dorsal horn (DH) slices to determine whether opioid receptor blockade increases AMPAR-mediated DH Ca2+ signaling. AIM 2 tests the hypothesis that AMPAR subunit GluA2 phosphorylation and internalization maintains LCS. Aim 2 will test this hypothesis by measuring GluA2 Ser880 phosphorylation and internalization in the presence or absence of NTX. AIM 3 tests the hypothesis that injury-induced long- term increases in GluA2 internalization and Ca2+ permeability are maintained by AC1 activity. In DH from mice with AC1 deletion or pharmacological inhibition Aim 3 will compare AMPAR-mediated Ca2+ responses and determine total and phosphorylated GluA2 and cell surface expression in the presence or absence of opioid receptor blockade. The proposed research is significant because if our hypotheses are correct then any event that interferes with opioid receptor activity could unleash pronociceptive AC1-AMPAR signaling and thus allow the transition to chronic pain. The results and concepts generated in this proposal may lead to a vertical leap in our understanding of pain vulnerability after tissue inflammation and has the long-term potential to reveal novel targets to
prevent the transition from acute to chronic pain.

project_terms:
AMPA Receptors;Acute;Adult;Adverse effects;American;Analgesics;Automobile Driving;Behavior;Behavioral;Brain;CTOP;Calcium;Cell surface;Complex;Data;Development;Equilibrium;Event;Freund's Adjuvant;Glutamates;Healed;Healthcare;Hyperalgesia;Image;Inflammation;Inflammatory;Injury;Institute of Medicine (U.S.);Lead;Light;Masks;Measures;Mediating;Methods;Mission;Modeling;Molecular;Mus;N-Methyl-D-Aspartate Receptors;Naltrexone;Neuraxis;Neurons;Nociception;Olives - dietary;Opioid;Opioid Receptor;Pain;Pain management;Paper;Peripheral;Permeability;Pharmaceutical Preparations;Phosphorylation;Posterior Horn Cells;Process;Receptor Activation;Receptor Signaling;Receptors Opioid mu;Reporting;Research;Science;Signal Transduction;Slice;Spinal;Spinal Cord;Stress;Synapses;System;Testing;Therapeutic Intervention;Time;Tissues;adenylyl cyclase 1;central sensitization;chronic pain;cost;density;dorsal horn;healing;innovation;neurochemistry;neurophysiology;novel;novel therapeutic intervention;pain inhibition;prevent;public health medicine (field);public health relevance;receptor function;response;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Chronic pain management is a major scientific and public health care challenge as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. We propose that injury triggers the development of a vicious cycle spinal of neuronal signaling that maintains sensitivity to pain long after tissue healing; ths is chronically masked by the body's naturally occurring pain inhibitory system that involves opioid receptors. Our studies aim to reveal the neurochemical mechanisms that maintain this vicious cycle of pain signaling. This project is relevant to NIH's mission that pertains to fundamental processes driving the transition from acute to chronic pain and promotes the development of therapeutic interventions for pain management.


application_id: 8771349
project_number: 1R21HS022583-01A1
project_title: Trial of Aggregate Data Extraction for Maintenance of Certification and Raising Q
administering_ic: AHRQ
award_notice_date: 2014-09-15
opportunity_number: PAR-08-269
application_type: 1
activity_code: R21
ic: HS
serial_number: 022583
suffix: A1
program_official: KIM, BRYAN
project_start_date: 2014-09-30
project_end_date: 2016-09-29
study_section: Health Care Technology and Decision Science[HTDS]
contact_pi_person_id: 11733013
contact_pi: PHILLIPS, ROBERT
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079659108
primary_uei: GEBSQDRBMFN5
duns_number: 079659108
uei: GEBSQDRBMFN5
fips: US
organization_id: 4602601
organization_name: AMERICAN BOARD OF FAMILY MEDICINE, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 405111338
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Most Family Physicians are now participating in Maintenance of Certification (MOC) measuring and reporting quality measures from limited patient samples before and after a quality improvement effort (Part IV requirement). It is time to take next steps towards broader and more regular assessment of quality and to simultaneously reduce reporting burden. This intention is consistent with AHRQ's aims for HIT and Quality and with those of the Office of the National Coordinator for Health Information Technology (Direct Project and Nationwide Health Information Network Exchange). The objective of the TRADEMARQ study is to make quality reporting a byproduct of ambulatory care and ongoing quality improvement. It has four aims: 1) To test the capacity for exchange of whole-panel family physician quality measures from clinical networks; 2) To study whether viewing quality measures and comparison to peers will affect the types of self-assessment modules and quality improvement efforts that are chosen by family physicians (randomized); 3) To study whether viewing quality measures and comparison to peers will influence the degree of change in outcomes after quality improvement efforts (randomized) We have developed partnerships with three clinical systems for this study: Kaiser Permanente Colorado the Oregon Community Health Information Network (now OCHIN) and the South East Texas Medical Associates (SETMA). All three use standardized physician-level quality measures and are willing to test ways to securely share these. We will develop project leadership and secure data exchange pathway to all three entities to iteratively test means of automating direct transmission of family
physician measures exploring both technical and legal solutions (Aim1). For Aim 2 physicians will be randomized within system to exposure to their measures and comparisons to peers before or after they choose their self-assessment and quality improvement projects. Within each randomization arm we will conduct a formal correlation analysis between SAM and Part IV selection and quality measures using hierarchical logistic regression adjusting for propensity of providers to select a SAM / Part IV. For Aim 3 we will assess changes in crude rates of quality measures from baseline to study completion using a difference in difference analysis which controls for physician characteristics via the propensity score calculated for Aim 2 and a longitudinal hierarchical logistic regression model fit to account for dependence of observations. This application is the first stage of three to which the ABFM has made a $2 million commitment. The partnership with AHRQ will help support our collaborators and offers critical federal data protections for the study.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The objective of the TRADEMaRQ study is to make quality reporting a byproduct of care and ongoing quality improvement. More than 84500 family physicians are already reporting limited quality measures to the American Board of Family Medicine before and after conducting a quality improvement project. This study is the first stage of a larger project to improve care through more comprehensive whole-patient panel quality measure reporting feedback quality improvement and assessment-integrated into routine provision of care. It is expected that this will make Maintenance of Certification a more robust support for quality improvement and a partner in reducing reporting burden.


application_id: 8771024
project_number: 1R03AI113648-01
project_title: The Borrelia burgdorferi transcriptional regulome
administering_ic: NIAID
award_notice_date: 2014-05-20
opportunity_number: PA-13-304
application_type: 1
activity_code: R03
ic: AI
serial_number: 113648
program_official: PERDUE, SAMUEL S
project_start_date: 2014-06-01
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1 IDM-B (80)]
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:
DESCRIPTION (provided by applicant): All organisms from bacteria to humans need to "recognize" where they are and respond accordingly. A pathogen must sense its location in the infectious cycle then produce factors necessary for that site while repressing synthesis of inappropriate factors. This is particularly important for vector-borne pathogens such as the Lyme disease agent Borrelia burgdorferi which must not only infect two very different types of animals but efficiently transmit back-and-forth between vertebrate hosts and arthropod vectors. The planned studies bring together two experts in B. burgdorferi genetics and an expert bioinformatician into an integrated systems approach that will map the regulatory networks of B. burgdorferi. The results will yield significant insight on B. burgdorferi physiology its ability t cause disease and since disruption of key regulatory pathways can inhibit a pathogen's ability to cause infection identify strategic targets for developing novel antibiotics. The substantial quantity of derived data will also be made publicly available through electronic databases providing a treasury of valuable information that can be readily mined by the global research community.

project_terms:
Animals;Antibiotics;Arthropod Vectors;Back;Bacteria;Borrelia;Borrelia burgdorferi;Communities;Complement Factor B;Complementary DNA;Complex;Data;Data Analyses;Data Quality;Databases;Disease;Electronics;Environment;Functional RNA;Funding;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Genetic;Genetic Transcription;Genome;Genus Mycobacterium;Human;Infection;Libraries;Location;Lyme Disease;Mammals;Maps;Mining;Nature;Nucleotides;Operon;Organism;Physiology;Production;Proteins;Pseudomonas;RNA;Regulatory Pathway;Regulon;Research;Resolution;Sigma Factor;Site;Structure;System;Ticks;Time;United States National Institutes of Health;cDNA Library;deep sequencing;genetic regulatory protein;insight;mutant;novel;novel therapeutics;pathogen;prevent;public health relevance;transcriptome sequencing;transmission process;vector

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Precise control of gene regulation by the Lyme disease agent Borrelia burgdorferi is critical for this bacterium to infect humans and other animals. The proposed studies will utilize deep sequencing of cDNAs (RNA-Seq) to map the regulatory networks employed by this pathogen to regulate gene expression. The results will provide significant insight on the bacterium's infectious nature and can be used to identify key checkpoints for developing novel therapeutics to prevent and cure Lyme disease.


application_id: 8770430
project_number: 1R21AG047474-01A1
project_title: Dopamine-mediated regulation of blood pressure in aging: Role of NHERF-1
administering_ic: NIA
award_notice_date: 2014-08-27
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AG
serial_number: 047474
suffix: A1
program_official: MURTHY, MAHADEV
project_start_date: 2014-09-01
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1 VH-B (02)]
contact_pi_person_id: 9017634
contact_pi: KHUNDMIRI, SYED J
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The objective of this study is to identify the mechanisms of dopamine (DA)-mediated regulation of natriuresis in aging. DA is an endogenous natriuretic hormone that regulates salt reabsorption in the kidney proximal tubules by inhibiting apical membrane sodium-hydrogen exchanger-3 (NHE3) and basolateral membrane sodium-potassium ATPase (NKA). Regulated activities of NHE3 and NKA is critical for total body salt water and mineral homeostasis and therefore contributes significantly to control of blood pressure cardiac function nerve impulses and bone metabolism. We have demonstrated that expression of a sodium-hydrogen regulatory factor (NHERF-1) is essential for DA- mediated regulation of NKA. In cells lacking NHERF expression DA fails to regulate NKA function. We demonstrated that NHERF-1 associates with NKA Dopamine 1 receptor (D1 receptors) and PKC. Upon stimulation with DA NHERF-1 association with NKA decreased while association with D1 receptor and PKC increased. Activation of protein kinase A (PKA) and C (PKC) by DA increases NHERF-1 phosphorylation at serine-77. Herein we propose that phosphorylation of NHERF-1 allows it to leave the complex allowing NKA phosphorylation and endocytosis. Further we hypothesize that in aging the loss of NHERF-1 - D1R interaction is responsible for salt-sensitive hypertension. We will address this hypothesis in two specific aims. In Aim 1 we will compare NHERF-1 expression and phosphorylation in vehicle and dopamine treated FBN rats. We will determine the association of NHERF-1 to NKA D1 and D5 receptors PKA and PKC. In Aim 2 we will treat NHERF-1 knock-out animals with high salt or dopamine and determine the importance of NHERF-1 in salt-sensitive hypertension in aging. We anticipate that these studies will provide new insights into the regulation of renal proximal tubular NHE3 and NKA by DA and provide potential therapeutic targets for treatment of disorders associated with abnormal sodium homeostasis in aging.

project_terms:
Active Biological Transport;Address;Aging;Animals;Cardiac;Cells;Cochlear structure;Complex;Cyclic AMP-Dependent Protein Kinases;Data;Development;Didelphidae;Disease;Dissociation;Dopamine;Dopamine D1 Receptor;Endocytosis;Equilibrium;Excretory function;Failure (biologic function);Female;GRK4 gene;Goals;Health;Homeostasis;Hydrogen;Hypertension;Ion Transport;Ions;Kidney;Knock-out;Knockout Mice;Knowledge;Laboratories;Left;Length;Mediating;Membrane;Mineral Waters;Molecular;Mutate;Na(+)-K(+)-Exchanging ATPase;Natriuresis;Natriuretic Factors;Nephrons;Nerve;Norway;Pathway interactions;Patients;Phosphorylation;Potassium;Protein Kinase C;Proximal Kidney Tubules;Rattus;Regulation;Research Personnel;Role;Serine;Signal Transduction;Sodium;Sodium Chloride;Testing;Transport Process;Tubular formation;age group;age related;aging population;apical membrane;base;basolateral membrane;blood pressure regulation;bone metabolism;driving force;insight;kidney epithelial cell;literature survey;novel;older patient;postnatal;prevent;receptor;response;salt sensitive hypertension;saluretic;sodium-hydrogen exchanger 3;sodium-hydrogen exchanger regulatory factor;solute;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Dopamine an endogenous natriuretic hormone inhibits the activities of both NHE3 and NKA thereby controlling blood pressure through increasing salt excretion in conditions of salt load. However this mechanism is impaired in aging. We will study the mechanisms of sodium homeostasis and blood pressure in aging.


application_id: 8770309
project_number: 1R21AG046762-01A1
project_title: Vitamin D Contribution to Muscle Metabolic Function in the Elderly
administering_ic: NIA
award_notice_date: 2014-08-13
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AG
serial_number: 046762
suffix: A1
program_official: JOSEPH, LYNDON
project_start_date: 2014-08-15
project_end_date: 2016-05-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 10544123
contact_pi: THOMAS, DAVID TRAVIS
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: ORGANIZED RESEARCH UNITS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Metabolic dysfunction is a major contributor to age-related co-morbidities; however the mechanisms underlying muscle metabolic dysfunction have not been fully elucidated in the elderly and there is a need to discover complementary interventions that could be easily and inexpensively implemented for treatment. With a novel strategy to address this knowledge gap our objective is to investigate synergy between vitamin D repletion and short-term aerobic training (AT) on lipid repartitioning and local muscle oxygen metabolism in the elderly with the use of non-invasive techniques (magnetic resonance imaging (MRI) and hybrid diffuse optical spectroscopies). We suggest based on growing theoretical rationale that a beneficial relationship exists when vitamin D repletion is accompanied by AT in the elderly. A potentiating relationship will prove to have substantial inexpensive merit for relieving metabolic dysfunction associated with aging. The aims of this study are to 1) Identify the magnitude of lipid redistribution in gastrocnemius muscle following vitamin D repletion + AT compared to vitamin D repletion or AT alone in 65-80 year olds and 2) Quantify local muscle tissue oxygen consumption rate (VO2) using hybrid diffuse optical spectroscopy to elucidate how local muscle tissue metabolism is related to muscle lipid measures. Our central hypothesis is that vitamin D repletion combined with AT will promote a greater shift from EMCL to IMCL depots than either treatment alone and that these changes will correspond to improved oxygen extraction (metabolic function) at the local muscle level. The delineation of the impact of vitamin
D repletion combined with AT on maintaining muscle health by altering muscle lipid content using novel and non-invasive techniques has the potential to refine our knowledge of the effect vitamin D and exercise have on muscle biology in aging. The positive impact of this project is consistent with our long-term objectives and are twofold 1) provide the framework to advance our use of non-invasive diffuse optical spectroscopy to efficiently characterize muscle metabolic function and nutrition/exercise treatment response and 2) generate novel data describing the interrelationships between vitamin D exercise muscle lipid and metabolic function in aging muscle.

project_terms:
2 year old;Address;Aerobic;Aerobic Exercise;Affect;Age;Aging;Biological Preservation;Biology;Chronic Disease;Clinical Trials;Combined Modality Therapy;Comorbidity;Coupled;Data;Development;Diffuse;Economic Burden;Elderly;Enrollment;Exercise;Exercise Tolerance;Fatigue;Fatty acid glycerol esters;Functional disorder;Gastrocnemius muscle structure;Goals;Health;Hybrids;Imaging Techniques;Individual;Insulin Resistance;Intervention;Knowledge;Life Style;Link;Lipids;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Measures;Metabolic;Metabolism;Mitochondria;Monitor;Muscle;Muscle function;Nutritional;Optical Instrument;Optics;Oxygen;Oxygen Consumption;Pharmacotherapy;Physical Function;Population;Protocols documentation;Quality of life;Recovery;Reporting;Retrieval;Role;Spectrum Analysis;Techniques;Technology;Tissues;Training;Vitamin D;Work;age related;aged;base;body physical activity;combat;design;improved;instrumentation;insulin sensitivity;lipid metabolism;mitochondrial dysfunction;muscle aging;muscle metabolism;non-invasive imaging;novel;novel strategies;nutrition;nutritional guideline;oxidation;post intervention;public health relevance;response;sedentary;tissue oxygenation;tool;treatment response

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Despite drug therapy many aged individuals with chronic disease associated with metabolic dysfunction remain symptomatic leading to poor quality of life and significant economic burden. This proposed study is aimed at 1) investigating synergy between vitamin D repletion and moderate aerobic training to potentiate improvements in muscle metabolic function and 2) the development of a portable assessment tool capable of identifying the most effective combined nutrition-exercise intervention in aged individuals to combat metabolic dysfunction. The knowledge to be gained by advancing the utility of our assessment tool in elderly who suffer from metabolic decline is invaluable and will pave the way for inexpensive non-invasive future research.


application_id: 8769380
project_number: 1U19AI113182-01
project_title: Project 3: PREVENT: A first-in-human clinical trial of Griffithsin an HIV entry
administering_ic: NIAID
award_notice_date: 2014-06-19
opportunity_number: RFA-AI-13-023
application_type: 1
activity_code: U19
ic: AI
serial_number: 113182
project_start_date: 2014-07-01
project_end_date: 2019-06-30
study_section: Special Emphasis Panel[ZAI1 BP-A (M2)]
subproject_number: 6667
contact_pi_person_id: 7904401
contact_pi: MCGOWAN, IAN MICHAEL
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
AIDS prevention;Address;Affinity;Animals;Antigens;Antiviral Agents;Anus;Awareness;Binding (Molecular Function);Biopsy;Carbopol;Cell surface;Cells;Clinical Trials;Clinical Trials Design;Community Health;Data;Data Set;Detection;Dimensions;Dose;Drug Exposure;Drug Formulations;Drug Kinetics;Environment;Epithelial;Epithelial Cells;Exposure to;Flow Cytometry;Gel;Gene Expression;Goals;HIV;HIV Entry Inhibitors;HIV Infections;HIV Receptors;HIV-1;HIV-2;Health;Hepatitis C virus;Human;Human Development;Immune;Immune response;Immunohistochemistry;In Vitro;Incidence;Inflammatory;Laboratories;Laboratory Animals;Lectin;Link;Lymphocyte;Measures;Metagenomics;Mucous Membrane;Mus;Natural Immunity;Oryctolagus cuniculus;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Phase;Phase I Clinical Trials;Placebo Control;Placebos;Plants;Polysaccharides;Prevention;Proteins;Proteomics;Randomized;Recruitment Activity;Rectum;Risk;Safety;Sampling;Simplexvirus;Staging;Structure;Surface;Systems Biology;T-Lymphocyte;Techniques;Tissues;Toxic effect;Vagina;Viral;adaptive immunity;base;crosslink;cytokine;design;healthy volunteer;human study;immunotoxicity;inhibitor/antagonist;men;men who have sex with men;microbial community;microbicide;microbiome;novel;preclinical safety;prevent;programs;prospective;rRNA Genes;rectal;rectal microbicide;response;transcriptomics;transmission process;volunteer


application_id: 8769379
project_number: 1U19AI113182-01
project_title: Project 2: PREVENT Preclinical safety and efficacy studies
administering_ic: NIAID
award_notice_date: 2014-06-19
opportunity_number: RFA-AI-13-023
application_type: 1
activity_code: U19
ic: AI
serial_number: 113182
project_start_date: 2014-07-01
project_end_date: 2019-06-30
study_section: Special Emphasis Panel[ZAI1 BP-A (M2)]
subproject_number: 6666
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adult;Affect;Affinity;Anal Sex;Animals;Anti-Retroviral Agents;Antiviral Agents;Anus;Attention;Awareness;Binding (Molecular Function);Biological Assay;Biopsy;CCR5 gene;CD209 gene;Carbopol;Cell surface;Cells;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Colorectal;Communities;Community Health;Control Animal;Data;Data Set;Detection;Development;Dose;Drug Formulations;Drug Kinetics;Effectiveness;Environment;Enzyme-Linked Immunosorbent Assay;Epithelial;Epithelial Cells;Exposure to;Female;Flow Cytometry;Gel;Gene Expression;Goals;HIV;HIV-1;Health;Hepatitis C virus;Heterosexuals;Human;Human Herpesvirus 2;Human Volunteers;Immune;Immune response;Immunity;Immunoassay;Immunohistochemistry;Incidence;Infection;Laboratories;Lectin;Link;Liquid substance;Local Microbicides;Lymphocyte;Macaca;Macaca mulatta;Mass Spectrum Analysis;Measures;Metagenomics;Methods;Metric;Modeling;Mucous Membrane;Mus;Outcome;Pharmaceutical Preparations;Pharmacodynamics;Phenotype;Placebo Control;Placebos;Polysaccharides;Population;Prevention;Proteins;Proteomics;Rectum;Reporting;Research Design;Safety;Sexual Transmission;Staging;Structure;Surface;Systems Biology;Techniques;Testing;Tissues;Trauma;Vagina;Viral;Virus Diseases;Virus Receptors;Virus Shedding;Woman;base;cohort;crosslink;design;experience;immunotoxicity;in vivo;inflammatory marker;langerin;male;men who have sex with men;microbial community;microbicide;microbiome;novel;placebo controlled study;preclinical efficacy;preclinical safety;prevent;product development;protective efficacy;rRNA Genes;rectal;rectal microbicide;research clinical testing;response;safety testing;simian human immunodeficiency virus;transcriptomics;transmission process


application_id: 8769376
project_number: 1U19AI113182-01
project_title: Core C: PREVENT Program Pharmacokinetics and Pharmacodynamics Services Core
administering_ic: NIAID
award_notice_date: 2014-06-19
opportunity_number: RFA-AI-13-023
application_type: 1
activity_code: U19
ic: AI
serial_number: 113182
project_start_date: 2014-07-01
project_end_date: 2019-06-30
study_section: Special Emphasis Panel[ZAI1 BP-A (M2)]
subproject_number: 6663
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adverse effects;Affinity;Anti-HIV Agents;Antibodies;Binding (Molecular Function);Biochemical;Biological;Biological Assay;Biological Markers;Blood specimen;Body Fluids;Cell Line;Cell fusion;Cells;Clinical Research;Complement;Complex;Cyclic GMP;Detection;Development;Drug Formulations;Drug Kinetics;Ensure;Environment;Enzyme-Linked Immunosorbent Assay;Epithelial Cell Junction;Evaluation;Fluorescence;Gel;Gene Expression Profiling;Giant Cells;Glycoproteins;HIV;HIV Envelope Protein gp120;HIV-1;Hela Cells;High Pressure Liquid Chromatography;Histopathology;Human;Human Herpesvirus 2;IgE;Immune;Immune response;Immunoassay;Immunoblotting;Immunoglobulin A;Immunoglobulin G;Immunoglobulin M;Immunoglobulins;Immunohistochemistry;Lead;Liquid substance;Location;Macaca;Macaca mulatta;Measures;Methods;Molecular Sieve Chromatography;Monitor;Mucous Membrane;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Prevention;Procedures;Proteins;Proteomics;Quality Control;Reagent;Rectal Administration;Reference Standards;Reporter Genes;Research;Safety;Sampling;Series;Services;Structure;Surface Plasmon Resonance;Systems Biology;Techniques;Technology Transfer;Testing;Tissues;Toxicology;Validation;Viral;analytical method;base;immunogenicity;in vivo;microbicide;pre-clinical;pre-clinical research;preclinical study;programs;rRNA Genes;rectal;rectal microbicide


application_id: 8769374
project_number: 1U19AI113182-01
project_title: Core A: PREVENT Program Administrative Core
administering_ic: NIAID
award_notice_date: 2014-06-19
opportunity_number: RFA-AI-13-023
application_type: 1
activity_code: U19
ic: AI
serial_number: 113182
study_section: Special Emphasis Panel[ZAI1 BP-A (M2)]
subproject_number: 6661
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH 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: 2014-07-01
budget_end_date: 2015-06-30
project_abstract:
The overall objective of the PREVENT Program is to advance into clinical trials a candidate microbicide gelcontaining griffithsin (GRFT) that is designed to prevent rectal transmission of HIV-1. The primaryresponsibility of the Administrative Core (Core A) is to monitor direct and coordinate activities of the threeresearch projects and three scientific cores to ensure that this objective is achieved efficiently as quickly aspossible and in compliance with regulatory and sponsor requirements. The overarching goal of Core A is toprovide scientific support to the PREVENT program's projects and cores to enable progression into thePREVENT clinical trial. Specific Aim 1 is to ensure effective PREVENT Program leadership throughcoordinated efforts of a Steering Committee (SC). Aim 2 is to provide administrative support for the effectivefunctioning of the entire GRFT PREVENT program. Aim 3 is to provide centralized fiscal management ofprojects and cores and Aim 4 is to provide an internal structure for both internal and external review ofscientific progress.

project_terms:
Archives;Award;Biometry;Calendar;Clinic;Clinical Trials;Collaborations;Communication;Consensus;Consult;Decision Making;Ensure;Experimental Designs;Gel;Goals;Grant;HIV-1;Information Dissemination;Leadership;Methods;Monitor;Online Systems;Paper;Prevention;Problem Solving;Progress Reports;Proteins;Protocols documentation;Research Project Grants;Secure;Sexual Transmission;Site;Structure;TimeLine;United States National Institutes of Health;Universities;Vaccines;Viral;Work;base;condoms;design;meetings;microbicide;novel;posters;prevent;programs;rectal;rectal microbicide;transmission process

public_health_relevance:
In the absence of a preventative vaccine microbicides offer an alternative to condoms as a feasible method forprevention of HIV-1 sexual transmission. This Core manages the key administrative and fiscal tasks to bring tothe clinic a novel candidate microbicide gel containing the potent anti-HIV01 protein griffithsin.


application_id: 8767337
project_number: 1R21NS085660-01A1
project_title: Use of IL-1alpha to Promote Angiogenesis and Functional Recovery After Experiment
administering_ic: NINDS
award_notice_date: 2014-06-12
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: NS
serial_number: 085660
suffix: A1
program_official: KOENIG, JAMES I
project_start_date: 2014-07-01
project_end_date: 2016-06-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7568819
contact_pi: BIX, GREGORY JAYE
other_pis: PINTEAUX, EMMANUEL
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:
DESCRIPTION (provided by applicant): Treatments for stroke-induced cerebral ischemia (CI) have failed in part due to lack of efficacy against post- stroke neuroinflammation. However while acute inflammation may contribute to worse patient outcomes w e h y p o t h e s i z e t h a t chronic/delayed inflammation could promote brain repair and may b e an attractive therapeutic target. In particular we have demonstrated a significant role for the inflammatory cytokine interleukin-1 (IL-1) in CI. Although the deleterious role of IL-1 (the main isoform of IL-1 released following CI) in CI is established IL-1 is also critically important and in contrast toIL-1 may play a beneficial role. We have recently shown that IL-1 causes c u l t u r e d cells of the neurovascular unit to generate laminin globular domain 3 (LG3) the neuroprotective and pro-angiogenic protein fragment of the extracellular matrix component perlecan. Importantly LG3 is persistently (weeks) generated in the brain after stroke but whether this is caused even in part by IL-1 or is of any pathophysiologic or therapeutic benefit is completely unknown. Our preliminary data now suggest that IL-1 activates brain endothelium is pro-angiogenic in vitro remains chronically elevated in stroked brains where it could persistently impact recovery and when absent (IL-1 knockout mice (KO)) results in or contributes to diminished post-stroke angiogenesis. Therefore we hypothesize that IL-1 is a key enhancer of angiogenesis (a brain repair mechanism) after stroke-induced CI via generation of LG3. To explore this hypothesis we propose the following specific aims: 1) Determine the role of IL-1 in modulating angiogenesis in brain endothelium under normal conditions and after CI 2) Determine the role of perlecan LG3 in IL-1 regulation of angiogenesis under normal conditions and after CI. We will use a number of in vitro angiogenesis assays and a transient middle cerebral artery occlusion model in wild-type and IL-1 KO mice to determine the angiogenic effects of IL-1 in vitro and in vivo. Functional/behavioral analysis will also be performed to correlate the extent of angiogenesis and infarct volume with functional recovery. The importance of LG3 to IL-1 angiogenesis effects in vitro and in vivo (after stroke) will be determined using a perlecan transgenic mouse that expresses 10% of normal total perlecan levels (pln -/-). Finally we will employ various genetic and biochemical methods to determine how IL-1 increases LG3 generation in brain endothelial cells in vitro with a focus on key cellular proteases and determine whether disruption of this impacts IL-1 angiomodulatory activity. Successful completion of this proposal will demonstrate a novel beneficial effect of inflammatory cytokines specifically IL-1 in brain recovery after stroke.

project_terms:
Acute;Angiogenic Proteins;Behavioral;Biochemical;Biological Assay;Brain;Bromodeoxyuridine;C-terminal;Cathepsin L;Cathepsins;Cause of Death;Cell Line;Cells;Cerebral Ischemia;Chronic;Clinical Trials;Data;Endothelial Cells;Endothelium;Enhancers;Extracellular Matrix;Generations;Genetic;Goals;Immunohistochemistry;In Vitro;Infarction;Inflammation;Inflammatory;Inflammatory Response;Injury;Interleukin-1;Interleukin-1 alpha;Ischemic Penumbra;Knockout Mice;Label;Laminin;Methods;Middle Cerebral Artery Occlusion;Modeling;Mus;Outcome;Oxidative Stress;Patients;Peptide Hydrolases;Peripheral;Play;Process;Production;Protein Fragment;Protein Isoforms;Recovery;Recovery of Function;Regulation;Role;Therapeutic;Transgenic Mice;Western Blotting;angiogenesis;behavior test;brain repair;brain tissue;cytokine;disability;excitotoxicity;immunocytochemistry;improved;in vivo;innovation;interest;neurogenesis;neuroinflammation;neurovascular unit;novel;perlecan;post stroke;prevent;public health relevance;repaired;research study;stroke;stroke therapy;therapeutic target;tissue repair

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cerebral ischemia (CI) caused by stroke is one of the leading causes of death and disability worldwide and is critically regulated by inflammation. Although acute inflammation after stroke is detrimental to the brain and contributes to a poor outcome components of chronic inflammation may promote recovery. Our goal is to understand how one such chronic inflammatory component interleukin-1 alpha promotes recovery with the aim to develop new stroke therapies.


application_id: 8766976
project_number: 1R01CA188354-01
project_title: Non-peptide proteasome inhibitors as a novel anticancer agent
administering_ic: NCI
award_notice_date: 2014-07-07
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: CA
serial_number: 188354
program_official: VERMA, SHARAD KUMAR
project_start_date: 2014-07-07
project_end_date: 2019-05-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 8152159
contact_pi: KIM, KYUNG BO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this project is to develop next-generation proteasome inhibitors that will serve as effective therapies 1) for multiple myeloma (MM) patients refractory to the existing proteasome-targeting drugs bortezomib and carfilzomib as well as 2) for patients with solid cancers. In the last decade the FDA has approved the proteasome-targeting drugs bortezomib (Velcade(R)) and carfilzomib (Kyprolis(R)) for the treatment of MM patients. These agents have greatly improved the prognosis of MM and firmly validated the proteasome as an important anticancer target. However many patients eventually develop resistance after prolonged proteasome inhibitor therapy and few effective treatment options exist for such patients. In addition the potential of proteasome-targeting drugs remain untapped for the treatment of solid cancers despite their promising anticancer activities in preclinical models of solid cancers. Thus it is critically important to develop novel proteasome inhibitors which can overcome the limitations of existing proteasome inhibitors and deliver the therapeutic benefits of proteasome inhibitor therapy to cancer patients of all types including solid cancers. We hypothesize that a new class of proteasome inhibitors with non-peptide scaffolds will provide new therapeutic options for MM patients refractory to bortezomib or carfilzomib and solid cancer patients. This is based on the drawbacks arising from the structural features shared among bortezomib carfilzomib and nearly all proteasome inhibitors in drug development pipelines. Specifically the structural features of peptide backbones and reactive pharmacophores contribute to a high susceptibility to chemical/metabolic inactivation and off-target interactions causing unwanted toxicities and an inability to achieve sufficient drug penetration within solid cancer sites. Using step-wise screening approaches combining virtual screen and in vitro enzyme kinetics we identified several promising hits with diverse non-peptide scaffolds and proteasome inhibitory potencies. G4-1 a 135-substitutive pyrazole derivative is our current lead candidate displaying its anticancer activity in multiple cancer cel lines including cell lines resistant to bortezomib or carfilzomib. In addition to having excellent
metabolic stability G4-1 displayed promising anticancer efficacy and safety profiles in vivo. With
the goal of further improving the potency and other pharmacokinetic properties of G4-1 to be suitable for oral dosing we propose the following aims: 1) to extend our lead optimization efforts
in developing more potent proteasome inhibitors with improved drug-like properties 2) to investigate the cytotoxic mechanism of action of optimized non-peptide proteasome inhibitors and 3) to evaluate the in vivo anticancer efficacy safety and pharmacokinetic profiles of selected lead non-peptide proteasome inhibitors. Successful completion of the proposed work will yield novel non-peptide proteasome inhibitors that can advance to next stages of drug development efforts and ultimately lead to effective therapies for patients with MM and solid cancers.

project_terms:
Active Sites;Antineoplastic Agents;Bioavailable;Bortezomib;Cancer Patient;Cancer cell line;Cell Line;Chemicals;Clinic;Clinical;Clinical Trials;Data;Dose;Drug Kinetics;Drug Stability;Drug Targeting;Drug resistance;Effectiveness;Enzyme Kinetics;Evaluation;FDA approved;Goals;Hematologic Neoplasms;Human;In Vitro;Lead;Left;Libraries;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic;Mind;Molecular;Multiple Myeloma;Mus;Oral;Patients;Penetration;Peptides;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Pre-Clinical Model;Predisposition;Property;Proteasome Inhibitor;Pyrazoles;Refractory;Relapse;Research;Resistance;Resistance development;Safety;Solid;Specificity;Staging;Structure-Activity Relationship;Therapeutic;Toxic effect;Translating;Velcade;Vertebral column;Work;Xenograft procedure;anticancer activity;base;cancer cell;cancer site;cell killing;chymotrypsin;cytotoxic;design;drug candidate;drug development;effective therapy;improved;in vitro testing;in vivo;in vivo Model;inhibitor/antagonist;intraperitoneal;molecular dynamics;multicatalytic endopeptidase complex;next generation;novel;novel therapeutics;outcome forecast;pharmacophore;pre-clinical;public health relevance;scaffold;screening;small molecule;success;virtual


application_id: 8765910
project_number: 1R01ES021771-01A1
project_title: Apoptosis resistance and Cr(VI) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2014-07-29
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: ES
serial_number: 021771
suffix: A1
program_official: REINLIB, LESLIE J
project_start_date: 2014-08-01
project_end_date: 2019-04-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
other_pis: SHI, XIANGLIN
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Animal Model;Antioxidants;Apoptosis;Apoptotic;BCL2 gene;Binding (Molecular Function);Carcinogens;Cell Nucleus;Cell Proliferation;Cell Survival;Cells;Chromates;Cleaved cell;Comparative Study;DNA Damage;Down-Regulation;Enzymes;Epithelial;Equilibrium;Event;Exhibits;Generations;Heme;Human;Induction of Apoptosis;Industry;Lung;Malignant - descriptor;Mediating;Modification;Mutate;NQO1 gene;Neoplasm Metastasis;Normal Cell;Nuclear;Oxidases;Oxidoreductase;Oxygenases;Pathway interactions;Play;Poisons;Poly(ADP-ribose) Polymerases;Process;Production;Proliferating;Promoter Regions (Genetics);Proteins;Quinine;Reaction;Reactive Oxygen Species;Regulation;Resistance;Response Elements;Role;Staging;Superoxide Dismutase;System;Testing;Up-Regulation (Physiology);carcinogenesis;caspase-9;catalase;cell transformation;chromium hexavalent ion;exposed human population;genetic regulatory protein;migration;overexpression;public health relevance;small hairpin RNA;tumor;tumorigenesis

public_health_relevance:
PROJECT NARRATIVE Cr(VI)-containing compounds are human carcinogens. The mechanism of their carcinogenesis remains tobe investigated. This application will study the roles of p62 Nrf2 reactive oxygen species and apoptosisresistance in Cr(VI)-induced carcinogenesis.


application_id: 8765760
project_number: 1R21AI113253-01
project_title: Regulation of hyaluronic acid capsule biosynthesis in Streptococcus pyogenes
administering_ic: NIAID
award_notice_date: 2014-06-30
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AI
serial_number: 113253
program_official: GU, XIN-XING
project_start_date: 2014-07-01
project_end_date: 2016-06-30
study_section: Special Emphasis Panel[ZRG1 IDM-B (80)]
contact_pi_person_id: 8869391
contact_pi: KOROTKOVA, NATALIA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
Streptococcus pyogenes (Group A Streptococcus GAS) is an important human pathogen that causes numerous diseases ranging from minor skin and throat infections such as impetigo and pharyngitis to life-threatening invasive infections such as streptococcal toxic syndrome and necrotizing fasciitis. Worldwide GAS infections account for more than 600 million cases of pharyngitis and more than 650000 cases of invasive disease annually. Since the late 1980s there has been a worldwide increase in invasive GAS disease. Although the pathogen is susceptible to antibiotic therapy severe invasive GAS infections are often difficult to treat. Hyaluronic acid (HA) capsule is considered one of the major determinants of GAS virulence. Highly encapsulated GAS strains are associated with both invasive infections and outbreaks of acute rheumatic fever. GAS mutants lacking capsule are sensitive to neutrophil killing and have reduced virulence in murine model of GAS infection. In addition to its role in bacterial resistance
to host defense attack HA capsule mediates adherence and promotes GAS colonization of the pharynx. Capsule expression requires effective and sensitive control mechanisms to avoid excessive capsule overproduction. In the current model CovR binds to the promoter region of the has capsule gene operon comprised of hasABC genes and represses its transcription. However the details of this mechanism are mostly unclear. The primary objective of the proposed research is to understand the molecular mechanisms of HA capsule regulation. In our preliminary studies we identified a novel regulatory noncoding region that controls capsule operon transcription. We confirmed that the region is physiologically significant and is important for full virulence in a mouse model of GAS invasive disease. Moreover we found that the region is under strong selective pressure resulting in accumulation of spontaneous mutations in GAS clinical strains. We propose to define this novel capsule regulation mechanism using advanced genetic and biochemical techniques. The outcomes of this research are expected to have a positive impact on the development of diagnostic analysis during outbreaks of GAS infection and highly targeted therapeutics to control the invasive GAS disease.

project_terms:
Accounting;Acute;Adherence (attribute);Anabolism;Antibiotic Therapy;Bacteria;Bacterial Infections;Binding (Molecular Function);Biochemical;Biological;Clinical;Data;Development;Diagnostic;Disease;Disease Outbreaks;Encapsulated;Future;Genes;Genetic;Genetic Polymorphism;Genetic Transcription;Genome;Genomics;Goals;Host Defense;Human;Hyaluronic Acid;Immune response;Impetigo;Infection;Investigation;Killings;Knowledge;Lead;Life;Link;Mediating;Messenger RNA;Metabolism;Methods;Minor;Modeling;Modification;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Mus;Mutation;Necrotizing fasciitis;Nucleic Acid Regulatory Sequences;Operon;Organism;Outcomes Research;Pathogenesis;Pharyngeal structure;Pharyngitis;Phenotype;Production;Prokaryotic Cells;Promoter Regions (Genetics);Promotor (Genetics);Regulation;Regulator Genes;Research;Research Personnel;Resistance;Rheumatic Fever;Role;Series;Serotyping;Signal Transduction;Skin;Small RNA;Specificity;Streptococcal Infections;Streptococcus pyogenes;Syndrome;System;Techniques;Toxic Shock Syndrome;Variant;Virulence;Virulence Factors;Virulent;bacterial resistance;base;capsule (pharmacologic);follow-up;innovation;interest;mouse model;mutant;neutrophil;novel;novel therapeutics;pathogen;pressure;public health relevance;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed research investigates the mechanism of regulation of hyaluronic acid capsule biosynthesis in the important human pathogen Streptococcus pyogenes. Hyaluronic acid capsule is one of the major determinants of S. pyogenes virulence. The expected findings will guide a development of diagnostic analysis during outbreaks of infections and novel therapeutics to control S. pyogenes invasive disease.


application_id: 8764444
project_number: 1K07CA181351-01A1
project_title: The Dynamics of Smoking Cessation After Cancer Diagnosis: A Naturalisitic Study
administering_ic: NCI
award_notice_date: 2014-08-26
opportunity_number: PAR-12-067
application_type: 1
activity_code: K07
ic: CA
serial_number: 181351
suffix: A1
program_official: PERKINS, SUSAN N
project_start_date: 2014-09-01
project_end_date: 2019-08-31
study_section: Career Development Study Section (J)[NCI-J]
contact_pi_person_id: 9524802
contact_pi: BURRIS, JESSICA L
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_terms:
Abstinence;Affective;Alcohol consumption;Anxiety;Attention;Attitude;Behavior;Behavioral;Belief;Biochemical;Cancer Control;Cancer Patient;Cancer Survivor;Cereals;Cigarette;Clinical;Clinical Investigator;Clinical Research;Cognitive;Complement;Complex;Cotinine;Data;Data Analyses;Data Collection;Distress;Educational workshop;Electronics;Ensure;Environment;Ethics;Event;Eye;Future;Goals;Head and Neck Cancer;Health;Health Status;High-Risk Cancer;Home environment;Hour;Individual;Intention;Intervention;Journals;Knowledge;Lead;Life;Malignant Neoplasms;Measures;Medical;Mentors;Modeling;Motivation;Nature;Newly Diagnosed;Nicotine Dependence;Outcome;Outcome Study;Participant;Perception;Play;Prevention;Process;Recurrence;Relapse;Research;Research Design;Research Training;Resources;Risk;Risk Behaviors;Risk Factors;Role;Saliva;Sampling;Second Primary Cancers;Self Concept;Self Efficacy;Smoke;Smoker;Smoking;Smoking Behavior;Smoking Cessation Intervention;Social Environment;Social support;South Carolina;Survival Rate;Symptoms;Techniques;Technology;Testing;Time;Tobacco;Tobacco Use Cessation;Training;Universities;Voice;Withdrawal;Withholding Treatment;Work;cancer complication;cancer diagnosis;cancer prevention;cancer recurrence;cancer therapy;career;career development;cigarette smoking;craving;depressive symptoms;design;dissemination research;distress tolerance;emotional distress;factor A;head and neck cancer patient;innovation;longitudinal design;novel;programs;psychologic;public health medicine (field);response;skills;smoking cessation;smoking restriction;social;success;symposium;therapy development;tobacco control;treatment response


application_id: 8762450
project_number: 5R01ES020870-04
project_title: Cell survival and arsenic carcinogenesis
administering_ic: NIEHS
award_notice_date: 2014-10-28
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: ES
serial_number: 020870
program_official: REINLIB, LESLIE J
project_start_date: 2012-01-15
project_end_date: 2015-10-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
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): Although the molecular mechanism of arsenic-induced carcinogenesis remains to be investigated reactive oxygen species (ROS) generated by arsenic are considered to be important. Arsenic-generated ROS could cause DNA damage lipid peroxidation and protein modification leading to various carcinogenic responses. Our preliminary studies have shown that the capacity of ROS generation induced by arsenic is substantially reduced in arsenic-transformed human lung bronchial epithelial (BEAS-2B) cells relative to the non-transformed cells. Such a reduction in ROS generation endows cells with premalignant features including rapid growth. Arsenic- transformed cells exhibit a decreased apoptosis (apoptosis resistance) upon arsenic exposure. This proposal hypothesizes that due to a low potency of ROS generation arsenic-transformed cells develop apoptosis resistance and increased cell survival contributing to the overall mechanism of arsenic-induced carcinogenesis. Three aims are proposed to test this hypothesis. Aim 1 will investigate the mechanism of decreased ROS generation in the arsenic-transferred cells. We will investigate whether impairment of the ROS generating pathway is responsible for a low level of arsenic-induced ROS generation in arsenic transformed BEAS-2B cells. We will also investigate whether the increased level of antioxidant enzymes in transformed cells contributes to the decreased level of ROS generation. The completion of this aim will establish the mechanism of decreased ROS generation in arsenic-transformed cells. Aim 2 will investigate the role of reduced ROS generation in apoptosis resistance of arsenic-transformed cells. We investigate (a) whether reduced ROS generation of arsenic- transformed cells is responsible for apoptosis resistance in arsenic-transformed cells; (b) whether arsenic- transformed cells have higher antioxidant activities of SOD and catalase than their passage-matched control cells; (c) whether knock-down of antioxidant enzymes or overexpressing NADPH oxidase in the transformed cells increases ROS generation and enhances apoptosis in response to arsenic stimulation; (d) whether knocking down of Bcl-2 increases apoptosis of arsenic-transformed cells; and (e) whether arsenic- transformed cell will show fast growth and enhanced invasion and migration due to the decreased ROS generation and apoptosis resistance. Overall this aim will demonstrate the role of ROS in apoptosis resistance of arsenic-transformed cells. Aim 3 will investigate the arsenic-transformed cells-induced tumorigenesis and the role of apoptosis. We will investigate the role of apoptosis resistance in tumorigenesis of arsenic-transformed cells. We will also investigate the roles of ROS and apoptosis regulatory proteins Bcl-2 in arsenic-transformed cells-induced tumorigenesis using both skin tumorigenesis model and orthotopic lung cancer model. It is expected that the increase of apoptosis of arsenic-transformed cells by Bcl-2 knockdown will decrease tumor growth. Similarly alterations in the ROS generating capacity of the cells i.e. by ectopic overexpression and knockdown of the ROS-scavenging and producing enzymes will have an effect on tumorigenesis of arsenic-transformed cells.

project_terms:
Antioxidants;Apoptosis;Apoptotic;Arsenic;Arsenites;BCL2 gene;Cancer Model;Cell Death;Cell Survival;Cells;Characteristics;Chronic;DNA Damage;Dose;Enzymes;Epithelial;Epithelial Cells;Exhibits;Exposure to;GADD45;Generations;Growth;Health;Human;Impairment;Kidney;Lipid Peroxidation;Liver;Lung;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;Microfilaments;Modeling;Molecular;NADPH Oxidase;Pathway interactions;Post-Translational Protein Processing;Premalignant;Prevention strategy;Property;Reactive Oxygen Species;Relative (related person);Resistance;Role;Skin;Testing;Toxic effect;Transcription Factor AP-1;antioxidant enzyme;arsenic-induced carcinogenesis;cancer cell;carcinogenesis;catalase;cell growth;cell motility;cell transformation;genetic regulatory protein;knock-down;migration;novel;overexpression;rapid growth;response;tumor growth;tumorigenesis

public_health_relevance:
Health effects of chronic exposure to arsenic are one of the major health concerns. The present study will investigate the mechanism of arsenic-induced carcinogenesis with a focus on decreased generation of reactive oxygen species and apoptosis resistance in arsenic transformed cells. The results will help understand the mechanism of arsenic carcinogenesis and to develop preventive strategy.


application_id: 8761749
project_number: 3U01DA030916-03S2
project_title: NDA-Enabling Phase I Lofexidine Program
administering_ic: NIDA
award_notice_date: 2014-07-18
opportunity_number: PA-13-302
application_type: 3
activity_code: U01
ic: DA
serial_number: 030916
suffix: S2
program_official: ANDERSON, ANN
project_start_date: 2011-03-01
project_end_date: 2016-02-28
study_section: Special Emphasis Panel[ZDA1 JXR-D (07)]
contact_pi_person_id: 10466426
contact_pi: LONGSTRETH, JAMES ALVAN
other_pis: GORODETZKY, CHARLES W.
congressional_district: 03
department: Unavailable
primary_duns: 087875626
primary_uei: NKGSYBV5UGN1
duns_number: 087875626
uei: NKGSYBV5UGN1
fips: US
organization_id: 10003722
organization_name: US WORLDMEDS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40241
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The proposed research is aimed at characterizing the pharmacokinetic pharmacodynamics and clinical pharmacological profiles of lofexidine hydrochloride an alpha-2 adrenergic agonist under development for the treatment of acute withdrawal from short acting opioids. The application revision entails an increased scope for two of the originally planned drug-drug interaction studies and adding intensive ECG monitoring and centralized analysis for the entire program. The research program consists of seven studies each with a particular objective that will add to the overall understanding of the pharmacology of the investigational drug. The studies include evaluation of (1) absolute bioavailability and mass balance of lofexidine (2) effect of food on lofexidine's bioavailability (3 and 4) drug-drug pharmacodynamic interaction with a focus on heart interval interaction effects between lofexidine and methadone or buprenorphine (5) drug-drug pharmacokinetic interaction of lofexidine and naltrexone (methadone buprenorphine and naltrexone are drugs for related indications that may be used concurrently in a clinical setting) (6) pharmacokinetics of lofexidine in renally-impaired patients and (7) pharmacokinetics of lofexidine in hepatically-impaired patients. The studies will be conducted in normal healthy volunteers or special populations (as in the case of the hepatic and renal impairment studies and methadone/buprenorphine interaction studies) and employ appropriate methodology to evaluate levels of lofexidine and related compounds in urine and plasma. Holter monitoring will be used in each study to ensure quality ECG recording and centralized analysis through a specialized core lab. Quantification of lofexidine and/or its major metabolites over time in addition to observed tolerance and evaluation of other clinical parameters in each of the planned studies will add to the overall understanding of the pharmacokinetics and pharmacodynamics of lofexidine in the body. This revision application focuses on the change in studies 3 and 4 noted above and the addition of intensive ECG monitoring across the program. This information is needed to allow appropriate labeling of the product for its entrance to the US market. Furthermore the planned research has been defined by the FDA as critical to complete the clinical pharmacology section requirements for a New Drug Application for lofexidine hydrochloride approval of which will allow entrance of the first and only non-narcotic non-addictive drug indicated for the treatment of opiate withdrawal to the US market.

project_terms:
Acute;Adrenergic Agonists;Age;Analgesics;Area;Biological Availability;Body mass index;Buprenorphine;Clinical;Clinical Pharmacology;Dose;Drug Interactions;Drug Kinetics;Electrocardiogram;End stage renal failure;Ensure;Equilibrium;Evaluation;FDA approved;Fasting;Fatty acid glycerol esters;Feces;Food;Heart;Hepatic;Heroin;Holter Electrocardiography;Hydrochloride Salt;Impairment;Intravenous;Investigational Drugs;Kidney;Marketing;Medical;Methadone;Methodology;Monitor;Naltrexone;National Institute of Drug Abuse;Opiate Addiction;Opiates;Opioid;Oral;Oxycodone;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Phase;Plasma;Population;Process;Product Labeling;Radiolabeled;Recovery;Relative (related person);Renal function;Research;Rural;Safety;Tablets;Time;United States National Institutes of Health;United States Substance Abuse and Mental Health Services Administration;Urine;Withdrawal;Work;healthy volunteer;intravenous administration;liver function;lofexidine;named group;opioid abuse;opioid withdrawal;prescription opiate;programs;public health relevance;radiotracer;sex;suburb;therapy development;volunteer

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Opioid abuse and dependence is a serious and growing problem in the US with an estimated 5.2 million nonmedical-related users of prescription opiate pain killers such as Lortab(R) and OxyContin(R) (SAMHSA 2008) 1 million heroin addicts in the US (National Institutes of Health 2006) and recent articles suggesting that abuse is spreading into rural and suburban areas (Archibold 2009). There is an unmet medical need in the opioid-dependent population with only two FDA-approved drugs (methadone and buprenorphine) currently available to treat opioid withdrawal which are both opiate products that effectively operate as replacement or substitution therapies have abuse potential and are themselves controlled substances. FDA approval of lofexidine hydrochloride will enable the entrance of the first non-narcotic non- addictive product to the market for the treatment of opioi withdrawal the first hurdle in recovery from opioid dependence. The planned research is required to understand how lofexidine works in the body so that appropriate dosing meal requirements the safety of combination with other treatment drugs and safety considerations for patients with poor liver and kidney functions can be evaluated.


application_id: 8761360
project_number: 1R01GM107586-01A1
project_title: Light-responsive ruthenium compounds for applications in disease
administering_ic: NIGMS
award_notice_date: 2014-07-16
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: GM
serial_number: 107586
suffix: A1
program_official: FABIAN, MILES
project_start_date: 2014-08-01
project_end_date: 2019-07-31
study_section: Synthetic and Biological Chemistry A Study Section[SBCA]
contact_pi_person_id: 8085279
contact_pi: GLAZER, EDITH C
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This proposal seeks to develop a new class of light-responsive inorganic materials as chemotherapeutic agents. Cisplatin and its analogues remain the standard therapy for a variety of cancers despite their nonspecific mechanism of action with nucleic acids resulting in general cytotoxicity and debilitating side-effects. A promising approach that will provide several key advantages is to combine the reactivity of metal- based drugs with the selectivity of photodynamic therapy (PDT) to increase the targeting of malignant tissues and reducing side-effects. We have recently shown that structural distortion can be utilized to promote photochemical reactions to create reactive ruthenium species that are strongly electrophilic and highly photo-toxic in cell based assays. We hypothesize that distortion can be used to control light-activated cytotoxicity for the creation of selective and potent chemotherapeutics. We propose a new class of ruthenium-based compounds that have a readily modifiable modular design to facilitate rapidly incorporation of key molecular components to efficiently develop materials exhibiting selectivity and controlled reactivity. Coordination chemistry will be used to generate a structurally diverse family of three-dimensional chiral ruthenium compounds in a self-assembled manner. The structural variations in the materials will be correlated to cytotoxic efficacy using high-throughput cell survival assays and the most promising compounds will be assessed for Pharmacokinetic (PK) properties Maximum Tolerated Dose (MTD) and efficacy in mouse xenograft models of lung cancer and melanoma. Mechanism of action studies will be used to define the currently unknown process of cell killing. In order to accomplish this aim a novel chemical labeling strategy is proposed to facilitate imaging of the subcellular and potentially sub-organellar localization of active compounds using Electron Microscopy. If successfully validated this approach could be extended to additional imaging applications in tissues. Alternative approaches utilize biotin-labeled ruthenium materials for target pull-down with cellular targets identified through a process of gel electrophoresis chromatography and mass spectrometry. In vitro and in cell transcription and translation assays will support these findings. Cisplatin the benchmark inorganic chemotherapeutic will be used for comparison in all mechanism of action studies. The goal is to determine if the proposed ruthenium materials utilize the same biological target(s) as cisplatin or may be directed to different functional targets via structural modification. Upon completion of these studies we will
have expanded our knowledge of the fundamental photochemistry of ruthenium complexes developed potent and selective cytotoxic chemical entities identified their mechanism of action and developed a new tool for the imaging of small molecules in biological systems. 1

project_terms:
Adverse effects;Animals;Benchmarking;Biological;Biological Assay;Biotin;Cancer cell line;Cell Death;Cell Survival;Cells;Cessation of life;Charge;Chemicals;Chemistry;Chromatography;Cisplatin;Combined Modality Therapy;Complex;DNA;DNA Damage;Development;Disease;Dose-Limiting;Drug Kinetics;Electron Microscopy;Engineering;Exhibits;Family;Genetic Transcription;Goals;Health;Image;Imaging Device;In Vitro;Killings;Knowledge;Label;Lead;Ligands;Light;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mass Spectrum Analysis;Maximum Tolerated Dose;Metals;Modality;Modeling;Modification;Molecular;Motivation;Mus;Neutropenia;Nucleic Acids;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Photochemistry;Photochemotherapy;Platinum;Process;Prodrugs;Property;Radiation;Reaction;Resistance;Resistance profile;Resolution;Ruthenium;Ruthenium Compounds;Sampling;Singlet Oxygen;Site;System;Therapeutic;Tissues;Toxic effect;United States;Variant;Xenograft Model;analog;base;biological systems;cancer cell;cancer therapy;cancer type;cell injury;cell killing;cell type;cellular targeting;chemotherapeutic agent;chemotherapy;clinical application;crosslink;cytotoxic;cytotoxicity;design;gel electrophoresis;in vivo;innovation;lung melanoma;novel;oxidative damage;preclinical study;screening;small molecule;translation assay;tumor


application_id: 8761249
project_number: 2R01CA138688-06A1
project_title: Convergence of MicroRNAs and p53 Signaling in Multiple Myeloma: Environmental Co
administering_ic: NCI
award_notice_date: 2014-09-04
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: CA
serial_number: 138688
suffix: A1
program_official: JOHNSON, RONALD L
project_start_date: 2009-07-01
project_end_date: 2015-01-31
study_section: Special Emphasis Panel[ZRG1 DKUS-C (90)]
contact_pi_person_id: 8146758
contact_pi: LI, YONG
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
project_abstract:
DESCRIPTION (provided by applicant): Multiple myeloma (MM) is one of the most common hematological neoplasms constituting about 1% of all human cancers and 2% of all cancer deaths. MM is preceded by monoclonal gammopathy of undetermined significance (MGUS) one of the most common pre-cancerous conditions afflicting 3% of the United States population over 50 years old. Although MM is regarded as an environmental disease it is not yet clear what promotes the progression from MGUS to the deadly MM. One of the unique features of MM is the extremely low mutation rate of the tumor suppressor p53 gene. Genomic instability (chromosome translocation aneuploidy and gene mutation) is widely observed in MM cases suggesting that the function of p53 as the guardian of the human genome is compromised. We previously analyzed the molecular mechanisms of p53 inactivation in MM cells by a new class of noncoding small RNAs microRNAs (miRNAs). Data from our laboratory and others have shown that multiple miRNAs suppress expression of the human p53 gene and that a majority of these miRNAs are overexpressed in MM. We hypothesize that the ubiquitous environmental pollutants benzo[a]pyrene (BaP) and tetrachlorodibenzodioxin (TCDD) disrupt functional interactions of miRNA:p53 to mediate p53 inactivation over the course of MM. In this renewal application we propose 3 specific aims to advance our investigations into the molecular etiology of MM and identify potential treatment and preventive strategies. In Aim 1 we will dissect the underlying mechanisms of upregulation of miRNAs in MM cells exposed to BaP and TCDD. In Aim 2 we will determine using murine syngeneic xenograft and genetic models whether BaP directly promotes MM progression via one miRNA gene cluster that targets p53. In Aim 3 we will determine whether epigallocatechin gallate (EGCG the main component in the botanical drug Polyphenon(R) E) prevents or inhibits MM progression induced by BaP or TCDD. Completion of the goals in this proposal will reveal the role of environmental hydrocarbons in p53:miRNA interaction and in MM etiology and provide a repurposed drug for MM prevention and therapeutic intervention.

project_terms:
Address;Aneuploidy;Aromatic Polycyclic Hydrocarbons;Aryl Hydrocarbon Receptor;Benzo(a)pyrene;Botanicals;Burn injury;Cancerous;Carcinogens;Cells;Cessation of life;Chromosomal translocation;Data;Development;Dioxins;Disease;Dose;Down-Regulation;Environmental Pollutants;Epidemiologic Studies;Epidemiology;Epigallocatechin Gallate;Etiology;Exposure to;Food;Funding;Gene Cluster;Gene Mutation;Genetic Models;Genomic Instability;Goals;Green tea (dietary);Health;Hematologic Neoplasms;Human;Human Genome;Hydrocarbons;Individual;Investigation;Laboratories;Ligands;Link;Malignant Neoplasms;Measures;Mediating;MicroRNAs;Molecular;Monoclonal gammopathy of uncertain significance;Multiple Myeloma;Mus;Mutation;Oncogenic;Pathogenesis;Pathway interactions;Pharmaceutical Preparations;Plasma Cells;Population;Premalignant;Prevention strategy;Preventive;Preventive Intervention;Process;Recovery;Regulation;Research;Risk;Role;Signal Transduction;Small RNA;Smoke;Smoking;Somatic Mutation;Source;Specimen;TP53 gene;Testing;Tetrachlorodibenzodioxin;Therapeutic Intervention;Toxic Environmental Substances;Tumor Suppressor Genes;Tumor Suppressor Proteins;United States;Up-Regulation (Physiology);Wood material;Work;World Trade Center disaster;Xenograft Model;Xenograft procedure;agent orange;base;cancer prevention;exhaust;inhibitor/antagonist;overexpression;prevent;public health medicine (field);research study;response;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed research will provide a better understanding of the role of environmental toxicants in the interaction of miRNAs and the p53 pathway over the course of MM development. By using EGCG (a natural compound in green tea) to modulate the expression of miRNAs for p53 reactivation our work will identify an accessible option to treat MM with no p53 mutations. In addition these studies may result in new strategies of cancer prevention for over a million individuals with MGUS a pre-malignant condition that precedes virtually all cases of MM.


application_id: 8759723
project_number: 1K18DC014050-01
project_title: Odorant Receptor Expression and Sensitivity to Odorants
administering_ic: NIDCD
award_notice_date: 2014-06-27
opportunity_number: PAR-13-186
application_type: 1
activity_code: K18
ic: DC
serial_number: 014050
program_official: RIVERA-RENTAS, ALBERTO L
project_start_date: 2014-07-01
project_end_date: 2015-12-31
study_section: Special Emphasis Panel[ZDC1 SRB-Y (56)]
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:
DESCRIPTION (provided by applicant): The application proposes to allow an investigator experienced in the molecular biology of the olfactory epithelium to cross the gap from his expertise in microarray-based genomics to more computationally challenging next generation sequencing approaches. The plan includes: (1) training in R programming to allow the investigator take advantage of flexible analysis methods for ChIP-seq and RNA-seq techniques (2) mentored pilot experiments in both of these approaches and (3) mentored analyses of the data. The pilot studies take advantage of a unique resource that allows purification of olfactory neurons expressing subsets of odorant receptors to work toward testing two fundamental hypotheses about odorant receptors. (1) Active chromatin modifications (which can only be detected by enrichment for neurons expressing an odorant receptor) are critical for the tightly regulated expression of odorant receptors. Active chromatin modifications will be measured by ChIP-seq. The exquisitely specific control of odorant receptor expression is perhaps the greatest remaining mystery about the function of olfactory sensory neurons. (2) Odorants activate sets of odorant receptors that may overlap but must have at least one distinct member if the odorants can be discriminated. Enrichment for olfactory sensory neurons marked by expression of GFP from an activity-dependent gene locus will allow RNA-seq methods to identify sets of odorant receptors activated by specific odorants. Understanding the fundamental question of how hundreds of odorant receptors allow the detection and discrimination of thousands of odorant chemicals should help explain some causes of hyposmia and anosmia; and should allow the future development of odorant agonists and antagonists that could be used to improve the quality of human life.

project_terms:
Afferent Neurons;Agonist;Alleles;Anosmia;Axon;Chemical Structure;Chemicals;Chip seq;Color Visions;Data;Data Analyses;Detection;Development;Dimensions;Discrimination (Psychology);Ear structure;Event;Future;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genomics;Human;Life;Measures;Mentors;Methods;Modification;Molecular Biology;Molecular Biology Techniques;Mus;Nature;Neurons;Odorant Receptors;Odors;Olfactory Epithelium;Outcome;Pattern;Pilot Projects;Receptor Activation;Receptor Gene;Regulation;Research;Research Personnel;Research Project Grants;Resources;Role;Signal Transduction;Solutions;Stimulus;System;Techniques;Technology;Testing;Training;Variation (Genetics);Work;base;chromatin modification;detector;experience;flexibility;homeodomain;hyposmia;improved;in vivo;member;neural patterning;next generation sequencing;olfactory bulb;programs;public health relevance;receptor;receptor expression;receptor sensitivity;research study;response;tool;transcription factor;transcriptome sequencing

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Unlike color vision and pitch detection by the ear how the quality dimension of odorant stimuli (differences in chemical structure) is divided among the detectors (odorant receptors) remains a mystery. Differences in the pattern of receptors activated must exist between odorants that can be discriminated but these patterns are unknown. Given the strict expression of just one odorant receptor in each olfactory sensory neuron these patterns depend critically on mechanisms controlling expression of the odorant receptor genes mechanisms that remain mysterious and when defective may also contribute to hyposmias and anosmias.


application_id: 8759227
project_number: 1R01EY024173-01A1
project_title: Parallel Tectothalamic Pathways
administering_ic: NEI
award_notice_date: 2014-09-02
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: EY
serial_number: 024173
suffix: A1
program_official: ARAJ, HOUMAM H
project_start_date: 2014-09-02
project_end_date: 2019-08-31
study_section: Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section[SPC]
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: GUIDO, WILLIAM
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_terms:
Address;Affect;Animals;Back;Brain;Butyric Acids;Cell Nucleus;Cells;Code;Detection;Disease;Dorsal;Dyslexia;Electron Microscopy;Electrons;Health;Homologous Gene;In Vitro;Investigation;Lateral;Lateral Geniculate Body;Lateral posterior nucleus of thalamus;Literature;Microscopic;Motion;Motion Perception;Movement;Mus;Neurons;Output;Pathway interactions;Perception;Population;Process;Property;Pulvinar structure;Reaction;Relative (related person);Research;Rodent;Schizophrenia;Signal Transduction;Site;Stimulus;Stream;Structure;Synapses;Techniques;Tectum Mesencephali;Thalamic structure;Vision;Visual;Visual Motion;Visual system structure;Whole-Cell Recordings;area striata;base;cell type;detector;extrastriate;extrastriate visual cortex;insight;magnocellular;motion sensitivity;novel;optogenetics;parvocellular;receptive field;research study;response;segregation;superior colliculus Corpora quadrigemina;visual neuroscience;visual stimulus


application_id: 8757790
project_number: 1R01EY024068-01A1
project_title: Inflammasome Activation in Geographic Atrophy
administering_ic: NEI
award_notice_date: 2014-09-17
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: EY
serial_number: 024068
suffix: A1
program_official: MCKIE, GEORGE ANN
project_start_date: 2014-09-01
project_end_date: 2018-08-31
study_section: Diseases and Pathophysiology of the Visual System Study Section[DPVS]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Geographic atrophy (GA) is an untreatable advanced form of age-related macular degeneration (AMD) that is characterized by degeneration of the retinal pigmented epithelium (RPE). Neither the mechanisms that promote this RPE degeneration nor the basis for the centrifugal expansion of GA that can ultimately lead to blindness have been resolved. This enigmatic nature of GA pathogenesis has precluded the development of any FDA-approved therapy for the one million Americans diagnosed with GA and the millions more at risk of developing GA. In new and exciting studies we discovered an unconventional immune activation of the NLRP3 inflammasome complex in the RPE of human eyes with GA (Tarallo et al. Cell 2012) that occurs in response to a specific accumulation of toxic non-coding Alu RNAs during deficiency in the RNase DICER1 and induces RPE degeneration (Kaneko et al. Nature 2011). This surprising finding of pathologic inflammasome activation in a non-immune cell is a critical step in understanding GA pathogenesis and elucidating the essential effector pathways that determine retinal vitality. Our findings which introduce a novel definition of auto-immunity: The RPE activation of the NLRP3 inflammasome in response to self-derived Alu RNAs represents the first description of inflammasome activation to endogenous all the while causing pathology in a classically immune privileged ocular milieu. Crucially blockade at multiple molecular steps along NLRP3 inflammasome activation blocked RPE cell death thus providing an important mechanism-based strategy to alleviating the worldwide burden of GA. However we still lack an integrated understanding of whether other AMD-related stressors also cause inflammasome activation in GA and if so precisely how these mechanisms converge upon common effector pathways that induce RPE degeneration. A rigorous definition of these mechanisms is crucial to enhancing our understanding of the molecular drivers of GA and to developing rational treatments. We will provide novel functional insights into how dysregulated NLRP3 inflammasome activation contributes to GA pathogenesis and develop a novel therapeutic strategy via the following Aims: (1) Generate a spatiotemporal map of known AMD-related stressors and markers of NLRP3 inflammasome activation in relation to the locus of pathology in GA and early AMD eyes; (2) Decipher the molecular mechanisms underlying inflammasome activation by known GA-associated stresses; (3) Determine whether blockade of inflammasome machinery and its effector pathways in acute and chronic animal models of AMD inhibit RPE degeneration. These studies will illuminate novel aspects of the molecular and biochemical bases of GA and help validate a molecular targeting strategy that could be translated into clinical trials. As such this proposal is aligned with the -year goals of the NEI's Retinal Diseases Program strategic plan.

project_terms:
Acute;Affect;Age;Age related macular degeneration;American;Amyloid;Animal Disease Models;Animal Model;Biochemical;Blindness;Blood Vessels;Cell Death;Cell model;Cells;Characteristics;Cholesterol;Choroidal Neovascularization;Chronic;Clinical Trials;Complex;DICER1 gene;Data;Deposition;Developed Countries;Development;Diagnosis;Disease;Drusen;Economics;Elements;Etiology;Exhibits;Eye;FDA approved;Fatty acid glycerol esters;Functional RNA;Genes;Genetic;Goals;Health Expenditures;Human;Hyperactive behavior;Immune;Immunity;Lead;Link;MAPK3 gene;Maps;Molecular;Molecular Target;Mus;Nature;Nerve Degeneration;Pathogenesis;Pathologic;Pathology;Pathway interactions;Patients;Peptides;Population;Prevalence;Productivity;RNA;Regulation;Retina;Retinal;Retinal Diseases;Retrotransposon;Ribonucleases;Risk;Severities;Signal Transduction;Strategic Planning;Stress;Structure of retinal pigment epithelium;Testing;Transcript;Translating;Translational Research;United States National Institutes of Health;Vision;Vision research;apolipoprotein E-4;base;biological adaptation to stress;effective therapy;feeding;geographic atrophy;immune activation;improved;insight;novel;novel therapeutics;programs;public health relevance;response;spatiotemporal;stressor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: There is no FDA-approved treatment for the one million Americans with geographic atrophy (GA) or for the millions more who are at risk of developing GA. We recently discovered an enzymatic deficiency that leads to accumulation of toxic RNA molecules and immune activation in the eyes of patients with GA. By understanding how these newly discovered pathways cause GA and testing therapies that will be suitable for advancing to clinical trials this proposal is aligned with the National Vision Research Agenda's Needs Gaps and Opportunities for the NEI's Retinal Diseases Program strategic plan and embraces the NIH Director's recent challenge to advance translational science using creative approaches.


application_id: 8757744
project_number: 2R01DE014605-12
project_title: Inter-kingdom signaling by A. actinomycetemcomitans
administering_ic: NIDCR
award_notice_date: 2014-06-10
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: DE
serial_number: 014605
program_official: LUNSFORD, DWAYNE
project_start_date: 2003-02-01
project_end_date: 2019-07-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 1859425
contact_pi: DEMUTH, DONALD R
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  widespread  and  costly  disease  that  is  primarily  manifest  in  the  oral  cavity  but  is  also  associated  with  systemic  dieases  such  as  atherosclerosis  and  rheumatoid  arthritis.    Although  several  organisms  have  been 
identified  as  periodontal  pathogens  A. actinomycetemcomitans has  been  strongly  associated with aggressive forms of periodontitis.  Our prior work showed that quorum sensing is essential for A.  actinomycetemcomitans  virulence  and  we  identified  the  QseBC  two  component  system  as  a  critical  component  of  the  quorum  sensing  pathway.    Our  new  results  suggest  that  QseBC  may  interact  with  catecholamine hormones produced by the host and thus QseBC may mediate both cell density dependent  signaling and inter-kingdom signaling.  This application focuses on the mechanisms of interaction of the two  component  system  with  catecholamine  hormones  and  is  potential  role  in  regulating  iron  uptake  by  A. actinomycetemcomitans.  Aim 1 will determine if catecholamine hormones and iron represent signals that activate QseBC and identify functional motifs of the QseC sensor that are required for binding.  The genes  that  are  regulated  upon  activation  of  QseBC  will  also  be  identifed  using  genomic  microarrays.  Aim 2 will study an operon encoding a putative enterobactin receptor and transporter and determine if this receptor interacts with catecholamine-iron complexes.    The  contribution  of  the  enterobactin  receptor  to  virulence  will  also be examined  using  a  mouse  model  of  periodontitis.    We have also shown that QseBC may be coupled to the cell stress response through the activity of two iron responsive toxin-antitoxin (TA) systems. This regulatory  network  will  be  studied  in  Aim  3  to  determine  if  the  expression  of  stress  proteases  is  induced under iron limiting conditions and whether these proteases activate the TA toxins by degrading the  labile  antitoxin.    The  effect  of  TA  toxin activation  on  the  expression  of  QseBC  and  virulence  of  A. actinomycetemcomitans will also be determined.  The overall goal of this study is to better understand the functional outcomes of activation of the essential QseBC two component system and how signaling through QseBC contributes to virulence.

project_terms:
ATP-Binding Cassette Transporters;Actinobacillus actinomycetemcomitans;Address;Adult;Antitoxins;Atherosclerosis;Bacterial Proteins;Binding (Molecular Function);Binding Proteins;Bordetella;Catecholamines;Cell Density;Cells;Cellular Stress;Cellular Stress Response;Complex;Coupled;Data;Disease;Enterobactin;Environment;Expenditure;Family;Funding;Genes;Genome;Genomics;Gingival Pocket;Goals;Growth;Heart Diseases;Hormones;Infection;Inflammatory;Iron;Lactoferrin;Ligands;Mediating;Microbial Biofilms;Mouth Diseases;Operon;Oral cavity;Organism;Orphan;Pathway interactions;Peptide Hydrolases;Periodontitis;Phagocytes;Phenotype;Population;Prevention;Production;Proteins;Regulation;Regulon;Rheumatoid Arthritis;Role;Siderophores;Signal Transduction;Stimulus;Stress;System;Testing;Toxin;Transferrin;United States;Virulence;Work;biological adaptation to stress;deprivation;functional outcomes;macrophage;mouse model;mutant;neutrophil;pathogen;periplasm;prevent;public health relevance;quorum sensing;receptor;response;sensor;solute;therapeutic target;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Periodontitis  is  a  common  oral  disease  that  is  present  in  up  to  40%  of  the  adult  population  in  the  United  States. Annual expenditures for treatment
and prevention of periodontitis exceed $15 billion.  Although periodontitis is primarily manifest i the oral cavity it is also  associated  with  systemic illnesses  such as heart disease and rheumatoid  arthritis. Our recent studies suggest that the periodontal pathogen A. actinomycetemcomitans  interacts  with  host  hormones  and  iron  and  that  this  interaction  contributes  to  its  virulence.  This study will characterize the bacterial proteins that are invoved in this interaction in order to understand their role in disease.  These proteins represent new potential targets for therapies that may control or prevent periodontitis and the systemic illnesses associated with this disease.


application_id: 8757738
project_number: 1R01DK098176-01A1
project_title: Thrombospondin 1 in obesity associated inflammation and insulin resistance
administering_ic: NIDDK
award_notice_date: 2014-08-19
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: DK
serial_number: 098176
suffix: A1
program_official: CHAN, KEVIN E
project_start_date: 2014-08-20
project_end_date: 2018-05-31
study_section: Integrative Physiology of Obesity and Diabetes Study Section[IPOD]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: 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:
Address;Adipocytes;Adipose tissue;Binding (Molecular Function);CD36 gene;Cardiovascular Diseases;Cells;Chemotactic Factors;Chronic;Data;Development;Diet;Disease;Fatty acid glycerol esters;Fibrosis;Genotype;Human;Hypertension;In Vitro;Infiltration;Inflammation;Inflammatory;Injury;Insulin Resistance;Kidney;Kidney Diseases;Knockout Mice;Lead;Macrophage Activation;Mediating;Mediator of activation protein;Metabolic;Modeling;Molecular;Mus;N-terminal;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Obesity;Peptides;Phenotype;Play;Proteins;Reporting;Resistance development;Rodent;Role;Signal Transduction;Structure;TLR4 gene;Testing;Thrombospondin 1;Tissues;Visceral;Wild Type Mouse;Work;base;chemokine;clinically relevant;clinically significant;design;glucose tolerance;human subject;improved;in vivo;insulin sensitivity;macrophage;migration;novel;novel therapeutics;obesity treatment;prevent;public health relevance;receptor;therapeutic target


application_id: 8757134
project_number: 1R01DA036550-01A1
project_title: Human Laboratory Screening of Pregabalin and Tiagabine for Cannabis Dependence
administering_ic: NIDA
award_notice_date: 2014-08-28
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: DA
serial_number: 036550
suffix: A1
program_official: HAMPSON, AIDAN
project_start_date: 2014-09-01
project_end_date: 2019-06-30
study_section: Special Emphasis Panel[ZRG1 RPIA-N (09)]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Cannabis use disorders are a significant public health concern and the absence of effective medications is a critical barrier to overcome. This application is founded on promising results from our laboratory suggesting that drugs that act at a2d-1 subunit containing voltage-dependent calcium channels (VDCCs) and/or elevate g- aminobutyric acid (i.e. GABA) will be effective medications for cannabis-use disorders. Our laboratory results are supported by a recent pilot clinical trial showing that gabapentin which is
a VDCC ligand and elevates GABA reduced cannabis use in dependent treatment-seeking adults. The goal of the present proposal is to build upon these promising laboratory and clinical findings by determining the ability of outpatient maintenance on pregabalin a "next generation" VDCC ligand and tiagabine a GABA reuptake inhibitor to attenuate the reinforcing effects of cannabis. Pregabalin will be tested because although their mechanism of action is the same the pharmacokinetic profile of pregabalin is improved compared to gabapentin and clinical results suggest that this translates into greater pharmacotherapeutic effectiveness. Tiagabine will be tested because its effects overlap with gabapentin and pregabalin GABA elevation is a possible mechanism for gabapentin's effects on cannabis use and our recent data demonstrated that tiagabine produced a profile of effects that was comparable to gabapentin when tested in combination with D9-THC. Outpatient maintenance dosing will be tested because it more closely resembles the clinical treatment situation. Cannabis self-administration using a concurrent progressive-ratio drug-money choice procedure will be the primary outcome because drug seeking and drug taking behaviors and the choice to use drugs to the exclusion of other behaviors are defining characteristics of drug dependence and drug self-administration procedures are predictive of therapeutic efficacy. Cannabis use in the natural environment will also be monitored during drug maintenance as a secondary outcome to optimize resource management and quicken the pace of intervention development. Our preliminary data with the proposed procedures support the feasibility of the project the assembled research team is highly qualified and the environment will significantly contribute to the success of the research. The proposed project is innovative because it employs a novel hybrid procedure to study the impact of medication maintenance on direct cannabis effects in the laboratory as well as cannabis use in the natural environment the effects of pregabalin and tiagabine on cannabis self-administration have not been tested previously and a novel real-time medication maintenance compliance technology will be implemented. Positive findings will exert an immediate and sustained impact by rapidly advancing currently available medications for the treatment of cannabis-use disorders promoting novel pharmacological targets for further medications development and providing valuable basic science information about the mechanisms underlying cannabis reinforcement.

project_terms:
Abstinence;Acute;Admission activity;Adult;Adverse effects;Aminobutyric Acids;Attenuated;Award;Basic Science;Behavior;Behavior Therapy;Calcium Channel;Cannabis;Characteristics;Choice Behavior;Clinical;Clinical Treatment;Clinical Trials;Cost Savings;Data;Dependence;Development;Disease;Dose;Double-Blind Method;Drug Addiction;Drug Kinetics;Drug usage;Effectiveness;Environment;Exclusion;Goals;Human;Hybrids;Illicit Drugs;Independent Scientist Award;Intervention;Laboratories;Ligands;Maintenance;Marijuana Dependence;Measures;Methods;Modeling;Monitor;Motivation;Outpatients;Patients;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacotherapy;Placebo Control;Principal Investigator;Procedures;Process;Psychological reinforcement;Qualifying;Randomized;Relapse;Relative (related person);Research;Resources;Role;Schedule;Self Administration;Statistical Models;Study Subject;Techniques;Technology;Testing;Therapeutic;Therapeutic Effect;Time;Translating;Treatment Efficacy;United States;career development;cost effectiveness;drug maintenance;experience;gabapentin;gamma-Aminobutyric Acid;improved;inhibitor/antagonist;innovation;next generation;novel;pregabalin;primary outcome;public health medicine (field);public health relevance;reinforcer;response;reuptake;screening;secondary outcome;success;therapy development;tiagabine

public_health_relevance:
PROJECT NARRATIVECannabis is the most commonly used illicit drug in the United States and its use is associated with rates ofdevelopment of abuse and dependence treatment admission and relapse that are comparable to other illicitdrugs that are often perceived as more harmful. Currently there are no effective pharmacological treatments forcannabis-use disorders. This project will evaluate pregabalin and tiagabine for cannabis-use disorders usingstate-of-the-art human laboratory methods.


application_id: 8756286
project_number: 271201100017C-2-0-1
project_title: OTHER FUNCTIONS: Development and Manufacture of Pharmaceutical Products for Addic
administering_ic: NIDA
project_start_date: 2011-09-18
project_end_date: 2015-09-17
contact_pi_person_id: 12066318
contact_pi: MURTY, RAM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 943117366
primary_uei: DNJBTJ3XBQM6
duns_number: 943117366
uei: DNJBTJ3XBQM6
fips: US
organization_id: 3514301
organization_name: MURTY PHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405091016
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The purpose of this contract is to carry out the development and manufacture of pharmaceutical preparations to be used in the medications development program of the National Institute on Drug Abuse (NIDA) for addiction treatment

project_terms:
Clinical Trials;Contractor;Contracts;Data Reporting;Development;Documentation;Dosage Forms;Drug Formulations;Evaluation;Generations;Maintenance;National Institute of Drug Abuse;Pharmaceutical Preparations;Pharmacologic Substance;Placebos;Preparation;Program Development;Resources;Site;Validation;addiction;analytical method;method development;pre-clinical


application_id: 8754832
project_number: 1DP1GM114862-01
project_title: Form and function of our Janus faced genome
administering_ic: NIGMS
award_notice_date: 2014-09-24
opportunity_number: RFA-RM-13-006
application_type: 1
activity_code: DP1
ic: GM
serial_number: 114862
program_official: GOROSPE, RAFAEL
project_start_date: 2014-09-30
project_end_date: 2019-07-31
study_section: Special Emphasis Panel[ZRG1 BCMB-N (50)]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project title: Form and function of our Janus faced genome The conversion of RNA into DNA via reverse transcription has transformed the human genome: insertion of RNA-derived DNA copies has roughly doubled the mass of our hereditary material. However integration of reverse transcribed RNAs is an inefficient process even for the most successful genomic parasites (e.g. retroviruses retrotransposons and pseudogenes). The reverse transcribed copies that fail to integrate may be considered microcosms of the Roman god Janus: with one face they gaze towards the past as an imperfect copy of a previous life (i.e. the RNA they are derived from) and with another face they look towards the future capable of directing the fate of their molecular environment. Remarkably the identity and function of these genomic misfits that lie outside the confines of the traditional landscape of DNA is largely unexplored but expected to be vast and powerful. We find that endogenous cDNA formation (i.e. reverse transcribed DNA derived from host RNA) is robust and has important biological and disease-modifying function. Blocking reverse transcription prevents endogenous cDNA formation and interestingly also blocks an endogenous cDNA-mediated mouse model of blindness. Here we will extend these observations to systematically analyze the host-derived reverse transcriptome to produce the first draft atlas of the identity and function of endogenous cDNA in health and disease. We will also experimentally demonstrate the relevance of endogenous cDNA to molecular and metabolic pathways and provide an alternate explanation of toxicity attributed nucleoside reverse transcriptase inhibitors (e.g. peripheral neuropathy and developmental defects). We expect our work to demonstrate that the collision of host-derived RNA and the bidirectional flow of genetic information produces a powerful regulatory class of hereto underappreciated molecules that control health and disease and can be harnessed to understand and manipulate basic tenets of cellular biology.

project_terms:
Atlases;Biological;Blindness;Cellular biology;Complementary DNA;DNA;Defect;Development;Disease;Ensure;Environment;Face;Future;Gene Expression Profile;Genetic;Genome;Genomics;Head;Health;Human Genome;Inherited;Life;Mediating;Metabolic Pathway;Molecular;Nucleosides;Organism;Parasites;Peripheral Nervous System Diseases;Process;Pseudogenes;RNA;Retrotransposon;Retroviridae;Reverse Transcriptase Inhibitors;Reverse Transcription;Side;Toxic effect;Work;fitness;gaze;mouse model;prevent

public_health_relevance:
Project Narrative Form and function of our Janus faced genome The Roman god Janus is said to have two faces on either side of his head - one which faces forward staring into the future and one which faces backwards gazing towards the past. In much the same way genetic information within an organism contains not only the blueprints needed to ensure its current and future fitness but also a distinct form: an imperfect copy of a previous life.


application_id: 8754322
project_number: 1R21ES024158-01
project_title: Lead Exposure in a Novel Mouse Model of Neurologic Disease
administering_ic: NIEHS
award_notice_date: 2014-07-31
opportunity_number: RFA-ES-13-007
application_type: 1
activity_code: R21
ic: ES
serial_number: 024158
program_official: KIRSHNER, ANNETTE G
project_start_date: 2014-08-01
project_end_date: 2016-07-31
study_section: Special Emphasis Panel[ZES1 LWJ-K (R)]
contact_pi_person_id: 8535896
contact_pi: MURPHY, MICHAEL PAUL
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): Environmental exposure to lead (Pb) has been linked to risk of late-onset Alzheimer's disease (AD) and dementia. Although Pb has long been known as a neurotoxic agent in children a recent and growing body of both toxicological and epidemiological research indicates that cumulative environmental Pb exposure is toxic to adults as well and may be a significant contributor to age-related neurologic dysfunction. The biological mechanism underlying this link is not known. It has been proposed based on a limited number of animal studies that the linkage is through epigenetic changes in the methylation state of DNA although evidence for this mechanism in human disease has been lacking. This proposal considers another possibility that the linkage is through a combination of Pb-driven neuropathologic change and that cerebrovascular pathology is the major contributor to this form of neurologic dysfunction. The amount of cerebrovascular pathology is a significant co-morbidity in all forms of age-related dementia. Most individuals with AD have some degree of comorbid cerebrovascular pathology although individuals with a history of obesity and T2DM have substantial amounts of this pathology. To investigate this problem we created a line of knock-in mice that co-develops amyloid pathology and cerebrovascular abnormalities with increasing age. The most remarkable feature of this novel mouse model (db/AD) is that it develops a striking phenotype of cerebrovascular pathology including aneurysms and strokes and also displays a profound cognitive impairment. We believe that we have created an innovative model of AD with significant cerebrovascular disease an understudied variant with limited treatment options. The unique db/AD mouse does not overexpress disease related proteins or use artificial promoter systems making it an ideal system for the study of how aberrant gene regulation in disease can influence brain pathology. This presents an unparalleled opportunity to study and potentially dissociate the role of Pb exposure at different times in an animal's lifespa and gauge the ultimate impact on neuropathology. This proposal thus seeks to answer three key questions relating to Pb exposure and neurologic disease that occurs later in life. First is early life Pb exposure more damaging than exposure as an adult? Second can Pb cause late-life cognitive dysfunction by increasing cerebrovascular pathology such as strokes through increased hypertension a well-known outcome of Pb exposure? Finally how much does Pb exposure affect the development of AD-related pathology by affecting the expression of AD related genes? We believe that our mouse model is uniquely suited to answering these questions. A major innovative feature of this proposal is the use of a novel mouse model with unique features exhibiting significant age associated AD-related amyloid deposition cerebrovascular pathology and cognitive dysfunction. This project not only has clear implications for the prevention and treatment of age-related cerebrovascular disease but also has the potential to advance our understanding of the major underlying causes of cerebrovascular disease as comorbidity in the AD brain.

project_terms:
Adult;Affect;Age;Alzheimer's Disease;Alzheimer's disease model;American;Amyloid deposition;Aneurysm;Animal Disease Models;Animal Model;Animals;Biological;Blood Pressure Monitors;Blood Vessels;Brain;Brain Pathology;Cerebrovascular Disorders;Child;Comorbidity;Complex;Cryopreservation;DNA;Dementia;Development;Disease;Elderly;Embryo;Employee Strikes;Ensure;Environmental Exposure;Epidemiology;Epigenetic Process;Exhibits;Experimental Designs;Exposure to;Gene Expression;Gene Expression Regulation;Genes;Goals;Grant;Hypertension;Impaired cognition;Individual;Institution;Kentucky;Knock-in Mouse;Late Onset Alzheimer Disease;Life;Link;Longevity;Magnetic Resonance Imaging;Mediating;Methylation;Modeling;Mus;National Institute of Environmental Health Sciences;Neurodegenerative Disorders;Neurologic;Neurologic Dysfunctions;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Pathology;Phenotype;Play;Prevention;Promotor (Genetics);Proteins;Recording of previous events;Recovery;Relative (related person);Research;Resources;Risk;Risk Factors;Role;Specimen;Spectrum Analysis;System;Testing;Therapeutic;Time;Toxic effect;Universities;Variant;Vascular Dementia;age related;amyloid pathology;base;behavior test;cerebrovascular;chronic Pb exposure;cognitive function;environmental Pb exposure;human disease;innovation;lead exposure;mouse model;neuropathology;neurotoxic;novel;overexpression;public health relevance;response;sharing data;stroke;success

public_health_relevance:
PUBLIC HEALTH RELEVANCE: A strong connection exists between risk for vascular dementia Alzheimer's disease type 2 diabetes (T2D) and obesity but the mechanisms are unknown. The connection may involve strokes and other forms of cerebrovascular pathology. This project will investigate the role of environmental lead exposure as an underlying risk factor in this complex disease state.


application_id: 8753852
project_number: 1R01DA036553-01A1
project_title: Selective Monoamine Release as a Treatment for Cocaine Use Disorders
administering_ic: NIDA
award_notice_date: 2014-08-28
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: DA
serial_number: 036553
suffix: A1
program_official: HAMPSON, AIDAN
project_start_date: 2014-09-01
project_end_date: 2017-05-31
study_section: Special Emphasis Panel[ZRG1 RPIA-N (09)]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Cocaine (COC) addiction is an unrelenting public health concern. An effective medication has not been identified for COC dependence despite being a high priority for the National Institute on Drug Abuse for nearly 30 years and extensive efforts by the scientific and treatment communities. The results of preclinical studies have shown that monoamine releasers attenuate the reinforcing effects of COC. The results of human laboratory studies also suggest that monoamine releasers attenuate the reinforcing effects of COC although the effects are small in magnitude and dependent on the methods used to assess drug reinforcement. The results of clinical trials that tested monoamine releasers for COC abuse are mixed. Monoamine releasers vary along a continuum from DA/NE selective to 5-HT selective. Theoreticians have postulated that the 5-HT/DA releasing ratio is a critical determinant of the efficacy and specificity of a monoamine releaser to attenuate the reinforcing effects of COC. Compounds with intermediate 5-HT/DA release ratios (i.e. 30-40) were the most effective and specific in terms of reducing cocaine taking. For example methamphetamine (5-HT/DA ratio = 31) completely and specifically eliminated responding for COC. Consistent with these findings methamphetamine dramatically reduced COC use in a clinical trial although it is NOT a viable option for managing COC abuse because of its high abuse and diversion potential. Compounds with a desirable 5- HT/DA releasing ratio and minimal abuse potential need to be tested for COC dependence. Phendimetrazine (PHEN) is indicated for treating obesity. After oral administration PHEN is converted to phenmetrazine which is largely responsible for its behavioral and neuropharmacological effects. Consistent with the notion that compounds with intermediate 5-HT/DA release ratios selectively attenuate the reinforcing effects of COC phenmetrazine (5-HT/DA ratio = 37) also completely and specifically eliminated COC-maintained responding. Moreover PHEN reduces COC-maintained responding but does not maintain self-administration or produce high magnitude positive subjective effects suggesting that its abuse potential is low. Although PHEN has not yet been tested as a potential pharmacotherapy for COC dependence in human laboratory experiments or clinical trials to our knowledge the results of extant preclinical experiments suggest it may be a viable option. We will conduct two rigorous within-subject experiments to fill this gap. These studies will 1) establish the safety and tolerability of PHEN-COC combinations and 2) demonstrate that PHEN reduces COC self- administration. The results of this project will provide critical information regarding the initial efficacy of PHEN for COC dependence which will enhance the probability of success when advanced to a clinical trial.

project_terms:
Abstinence;Amphetamines;Attenuated;Behavior Therapy;Behavioral;Binding (Molecular Function);Cardiovascular system;Clinical Research;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Cocaine Users;Communities;Data;Development;Dextroamphetamine;Disease;Dopamine;Dose;Enrollment;Goals;Human;Laboratories;Laboratory Procedures;Laboratory Study;Maintenance;Methamphetamine;Methods;Modeling;Monkeys;National Institute of Drug Abuse;Norepinephrine;Obesity;Oral Administration;Outcome Measure;Parents;Participant;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase II Clinical Trials;Phenmetrazine;Placebos;Presynaptic Terminals;Probability;Procedures;Psychostimulant dependence;Research;Safety;Schedule;Self Administration;Serotonin;Specificity;Testing;clinical efficacy;clinical practice;cocaine use;drug reinforcement;indexing;innovation;meetings;monoamine;novel;pre-clinical;preclinical study;prevent;primary outcome;programs;public health medicine (field);public health relevance;reinforcer;research study;reuptake;success

public_health_relevance:
PROJECT NARRATIVEPreclinical data indicate that maintenance on selective monoamine releasers reduces cocaine taking. The goalof this project is to demonstrate that maintenance on a selective monoamine releaser with limited abusepotential phendimetrazine reduces cocaine taking in a sophisticated predictive human laboratory self-administration model.


application_id: 8753290
project_number: 1R21CA187345-01
project_title: Plasma DSC for early detection of disease and therapeutic efficacy in melanoma
administering_ic: NCI
award_notice_date: 2014-08-01
opportunity_number: PAR-13-146
application_type: 1
activity_code: R21
ic: CA
serial_number: 187345
program_official: THURIN, MAGDALENA
project_start_date: 2014-08-01
project_end_date: 2016-07-31
study_section: Special Emphasis Panel[ZCA1 SRLB-Y (M2)]
contact_pi_person_id: 11129807
contact_pi: GARBETT, NICHOLA C.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Stage IV melanoma kills approximately 40000 individuals per year globally. Early detection of new metastases is essential since up to three metastastic tumors can be resected for cure and patients with limited disease burden have improved clinical outcomes to immunotherapeutic agents such as ipilimumab (anti- CTLA4). As a result full-body FDG-PET and CT imaging assessments are routinely conducted every three months for surveillance and every two months for response assessment. However the utility of these scans is limited by both cost and the contribution of cumulative radiation exposure to secondary malignancies. The development of new non-invasive approaches for melanoma detection and frequent monitoring thus is expected to result in a marked reduction in melanoma-related deaths. The overarching goal of our research is the development of differential scanning calorimetry (DSC) analysis of blood plasma as a new non- invasive diagnostic to enable more frequent monitoring and facilitate early detection of recurrences and early assessment of therapeutic response. Importantly the University of Louisville's Melanoma Multi- Disciplinary Clinic and Tissue Repository has a large and growing collection of detailed de-identified clinical information and multiple longitudinal plasma specimens from stage I-IV melanoma patients (>3000 plasma samples and currently 219 resected melanoma metastases) which we propose to access in order to test this novel diagnostic approach. The application of DSC analysis to characterize the blood plasma proteome in our lab has provided an entirely new and complementary bioanalytical approach for the detection and monitoring of disease. DSC monitors heat changes associated with the thermal denaturation of biomolecules yielding a unique profile characteristic of the components their amounts and interactions. Preliminary data indicate that direct analysis of small volumes of plasma using DSC yields profiles (or thermograms) that are sensitive to differences in the thermodynamic properties of abundant plasma proteins related to health status. DSC thermograms show sensitivity to disease pathology and therapeutic response and therefore could have considerable utility as a new diagnostic approach. The goals of this proposal are to examine the performance of DSC thermograms alongside standard PET/CT imaging for the diagnosis the early detection of recurrence and the assessment of therapeutic efficacy in melanoma. If we are successful the proposed research has the potential to contribute to earlier clinical assessment that can directly impact the care of melanoma patients. We propose three aims. Aim 1 addresses the utility of DSC thermograms for the detection and stage differentiation of melanoma compared with PET/CT. Aim 2 will determine the diagnostic performance of DSC analysis of longitudinal plasma samples to detect disease recurrence following surgical resection in stage III patients. In Aim 3 we will determine the utility of DSC for the assessment of early response to treatment in BRAF+ stage IV melanoma patients.

project_terms:
Address;Aftercare;BRAF gene;Blood;Blood Plasma Volume;CTLA4 gene;Cancer Center;Caring;Cessation of life;Characteristics;Classification;Clinic;Clinical;Clinical assessments;Collection;Control Groups;Data;Databases;Deposition;Detection;Development;Diagnosis;Diagnostic;Differential Scanning Calorimetry;Discrimination (Psychology);Disease;Early Diagnosis;Enrollment;Excision;Exposure to;Goals;Health Status;Heating;Image;Immunotherapeutic agent;Immunotherapy;Incidence;Individual;Killings;Link;Monitor;Neoplasm Metastasis;Operative Surgical Procedures;Outcome;PET/CT scan;Pathology;Patient Care;Patients;Performance;Plasma;Plasma Proteins;Positron-Emission Tomography;Property;Proteome;Proteomics;Protocols documentation;Radiation;Recurrence;Research;Resectable;Resected;Risk;Sampling;Scanning;Second Primary Cancers;Specimen;Staging;Systemic Therapy;Testing;Therapeutic;Therapeutic Agents;Thermodynamics;Time;Tissues;Treatment Efficacy;Tumor Burden;Universities;X-Ray Computed Tomography;burden of illness;clinical care;cost;disease diagnosis;effective therapy;high risk;imaging modality;improved;longitudinal analysis;melanoma;novel;novel diagnostics;novel strategies;public health relevance;repository;response;standard of care;tool;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Although effective treatment of melanoma is critically dependent on early and accurate detection PET/CT imaging is only used every 2-3 months as a result of radiation burden and expense. The goal of this proposal is to build upon our significant promising preliminary data to demonstrate the feasibility and utility of DSC analysis o blood plasma as a new non-invasive diagnostic tool. Our approach could enable more frequent monitoring and facilitate early detection of recurrences and early assessment of therapeutic response in melanoma that can directly impact the clinical care of patients.


application_id: 8751481
project_number: 1R34MH104208-01
project_title: Improving Transition Outcomes in ASD using COMPASS
administering_ic: NIMH
award_notice_date: 2014-08-21
opportunity_number: RFA-MH-14-101
application_type: 1
activity_code: R34
ic: MH
serial_number: 104208
program_official: JULIANO-BULT, DENISE M
project_start_date: 2014-08-22
project_end_date: 2017-07-31
study_section: Special Emphasis Panel[ZMH1 ERB-K (05)]
contact_pi_person_id: 1960113
contact_pi: RUBLE, LISA A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application responds to the identified need for developing and testing a model for transition to adult supports and services for individuals with autism spectrum disorders (ASD) that prevents lapses in services and enhances functional life outcomes. The proposal also addresses concerns raised by the Interagency Autism Coordinating Committee of a "critical lack of tested interventions for adolescents and young adults." Although federal education law mandates that public schools provide transition services as part of the Individualized Education Program (IEP) the promise and potential for a well-coordinated and planned transition is not being met. The proposed study builds on two randomized controlled trials of a parent-teacher consultation intervention called the Collaborative Model for Promoting Competence and Success (COMPASS) for young children with ASD data on efficacy for both traditional face-to-face and videoconferencing technology delivery methods and a book-length treatment manual. COMPASS is an implementation strategy that assists in transferring evidence based approaches into classrooms and assists public school special educators and parents in ecological assessment research-informed goal development and person-centered decision-making for individualizing evidence-based interventions for children with ASD. The COMPASS intervention consists of an initial parent-teacher session (3 hours) occurring near the start of the school year followed by four 1-hour teacher coaching. The first aim is to conduct focus groups with stakeholders including policy makers parents teachers service providers and persons with ASD to get feedback on (i) strengths and weaknesses of state policies and services and resources that exist or are needed to support effective implementation of best practices for transition age youth with ASD; (ii) other
concerns impacting adult services such as housing social security health insurance transportation; and (iii) specific aspects of COMPASS that would need to be adapted/revised to meet the needs of transition age youth. Based on these results we will identify measures that would need to be adapted/developed and obtain feedback from a subsample of focus group members on the measures. Our second aim is to conduct a two wave pilot randomized controlled trial of the adapted COMPASS for transition planning using the new procedures and measures (n = 32 participant triads-consultant teacher student with ASD) using a mixed methods approach. We will obtain qualitative feedback on the intervention (acceptability feasibility outcomes) and use data to revise/adapt second wave implementation as well as to help inform further applications in adult settings. Lastly we will conduct qualitative case studie based on individuals with ASD who have low and high performing outcomes to understand factors that might explain differential response to the intervention and use to revise/adapt second wave implementation.

project_terms:
Accounting;Address;Adolescent and Young Adult;Adult;Age;Autistic Disorder;Books;Case-Control Studies;Characteristics;Child;Competence;Consultations;Control Groups;Data;Decision Making;Development;Educational aspects;Employment;Environmental Risk Factor;Evidence based intervention;Feedback;Focus Groups;Funding;Future;Goals;Health Insurance;Hour;Housing;Individual;Intervention;Laws;Length;Life;Manuals;Measures;Methods;Modeling;National Institute of Mental Health (U.S.);Occupations;Outcome;Parents;Participant;Persons;Placebo Control;Policies;Policy Maker;Procedures;Process;Provider;Randomized Controlled Trials;Reporting;Research;Resources;Sampling;School Teachers;Schools;Services;Social Security;Students;Technology;Testing;Transportation;Triad Acrylic Resin;United States National Institutes of Health;Videoconferences;Videoconferencing;Youth;autism spectrum disorder;base;evidence base;implementation research;improved;meetings;member;person centered;prevent;programs;public health relevance;research study;response;skills;success;teacher


application_id: 8751431
project_number: 271201300015C-0-0-1
project_title: IGF::OT::IGF Contract Award to Care Team Solutions LLC: Using mHealth to Aid Opi
administering_ic: NIDA
project_start_date: 2013-08-01
project_end_date: 2014-01-31
contact_pi_person_id: 7691024
contact_pi: BRUE, VESTA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 830125485
duns_number: 830125485
fips: US
organization_id: 10023819
organization_name: CARE TEAM SOLUTIONS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071936
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
Opiate-agonist pharmacotherapy utilizing buprenorphine/naloxone is known to decrease illicit opiate use. However poor medication management and misuse during self-managed opioid substitution therapy (OST) constrains efficacy while aggrandizing relapse hospitalizations and mortality. One of the most inescapable challenges confronted by professionals treating opioid dependence (OD) is assuring medications are taken as prescribed. Affording patients and physicians an interactive toolset to effectively monitor and promote adherence during OST represents a major unmet need that this project will address. Utilizing a forward-thinking approach in mobile health (mHealth) solutions the Contractor will develop a smartphone application (APP) named SubAID to engage and support patients and caregivers during OST to promote adherent behavior and provide timely assessment of adherence.

project_terms:
Address;Adherence (attribute);Agonist;Award;Behavior;Buprenorphine;Caregivers;Caring;Contractor;Contracts;Evaluation;Focus Groups;Health;Hospitalization;Measures;Medication Management;Monitor;Mortality Vital Statistics;Naloxone;Names;Opiate Addiction;Opiates;Opioid Rotation;Participant;Patients;Pharmaceutical Preparations;Pharmacotherapy;Physicians;Relapse;Solutions;Thinking function;cohort;medication compliance;usability


application_id: 8751197
project_number: 1P30GM110787-01
project_title: Genetic Technologies Core
administering_ic: NIGMS
award_notice_date: 2014-06-27
opportunity_number: PAR-13-238
application_type: 1
activity_code: P30
ic: GM
serial_number: 110787
study_section: Special Emphasis Panel[ZGM1 TWD-C (3C)]
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: 2014-07-01
budget_end_date: 2015-04-30
project_terms:
Adenoviruses;American;Animal Model;Biological Assay;Cell model;Cells;Centers of Research Excellence;Clinical;Complex;Consultations;DNA;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 (motion);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;meetings;member;operation;outreach program;programs;recombinant virus;tool


application_id: 8749662
project_number: 261201300013I-0-26100002-1
project_title: Patterns of Care/Quality of Care - Diagnosis Year 2012
administering_ic: NCI
project_start_date: 2013-08-15
project_end_date: 2014-08-14
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
SEER Patterns of Care Studies describe characterize and compare practice patterns and treatments provided for cancer in different geographic areas of the United States. SEER Patterns of Care Studies are conducted to satisfy a Congressional directive (under Public Law 100-607 Sec. 413 (a)(2)(C) adopted November 4 1988) to the National Cancer Institute to assess the incorporation of state-of-the-art cancer treatments into clinical practice and the extent to which cancer patients receive such treatments and include the results of such assessment in the biennial reports. To select the cancers to satisfy this directive the Division of Cancer Control and Population Sciences has been working closely with the Division of Cancer Treatment. This years Patterns of Care (POC) Study will investigate state-of-the-art therapies for hepatocellular CML and female late stage breast cancer.

project_terms:
Adjuvant Therapy;Adopted;Age;Beds;Biological Markers;Cancer Patient;Characteristics;Communities;Comorbidity;Data;Diagnosis;Diagnostic tests;Division of Cancer Control and Population Sciences;Educational process of instructing;Ethnicity aspects;Female;Geographic Locations;Hospitals;Laws;Link;Malignant Neoplasms;Medicare;National Cancer Institute;Operative Surgical Procedures;Patients;Pattern;Patterns of Care;Physicians;Quality of Care;Race;Radiation therapy;Reporting;Staging;Time;United States;Work;cancer therapy;chemotherapy;clinical practice;hormone therapy;malignant breast neoplasm;sex


application_id: 8747218
project_number: 1R01DE024509-01
project_title: Filifactor alocis interactions with neutrophils
administering_ic: NIDCR
award_notice_date: 2014-06-11
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: DE
serial_number: 024509
program_official: LUNSFORD, DWAYNE
project_start_date: 2014-07-01
project_end_date: 2019-03-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 8652094
contact_pi: URIARTE, SILVIA M
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractPeriodontitis is a microbial-induced chronic inflammatory disease that affects the gingival tissues supportingthe tooth. With the development of high-throughput sequencing technologies and their application to the oralmicrobiota several newly appreciated organisms have become recognized as associated with periodontallesions. Among these is the Gram-positive anaerobic rod Filifactor alocis which is present in high numbers inperiodontal disease sites compared to healthy sites. However association does not establish causality andthe challenge now is to determine the potential pathogenicity of F. alocis. Chronic inflammatory infectiousdiseases such as periodontitis can occur because the pathogens are able to evade or disable the innateimmune system. Neutrophils are a major component of the innate host response and the outcome of theinteraction between periodontal pathogens and neutrophils is a key determinant of oral health status. Anunderstanding of both microbial and host factors is therefore essential to increase our knowledge of theperiodontal disease process. The current proposal will test the hypothesis that Filifactor alocis modulatesneutrophil functional responses as an immune evasion strategy to avoid killing and promote inflammation. Wewill test our hypothesis by the following specific aims: Aim 1: To characterize neutrophil respiratory burstresponse to F. alocis challenge. The goal of this aim will be to test the hypothesis that F. alocis stimulationcauses dysfunction of select neutrophil responses and thus compromises bacterial killing. Aim 2: Tocharacterize the neutrophil oxygen-independent antimicrobial response to F. alocis challenge. The goal of thisaim will be to test the hypothesis that F. alocis will modulate neutrophil degranulation and thus subvertneutrophil antimicrobial mechanisms. Aim 3: To determine the effect of F. alocis on neutrophil recruitment andactivation in an animal model. The goal of this aim will be to test the hypothesis that F. alocis infection willstimulate neutrophil recruitment activation and matrix metalloproteinases release to promote inflammation invivo. The current project is a collaborative effort from a new/early stage investigator with expertise inneutrophil biology and inflammation (Dr. Uriarte) and an expert in the field of oral pathogens and host cellresponses (Dr. Lamont). The proposed collaborative efforts offer an innovative and strong framework to studythe interaction between F. alocis and neutrophils. Furthermore the data generated from this application are anecessary component of the information that will be required to allow the development of novel therapeuticstrategies for controlling periodontal disease.

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

public_health_relevance:
Project NarrativePeriodontal disease is an inflammatory condition induced by oral pathogenic bacteria that affects over half ofthe adult population in the United States. Oral health status is maintained by the presence of white blood cellswhich are involved in killing the oral bacteria that cause periodontal disease. In the current study we proposeto define the interaction between white blood cells and a newly appreciated bacterium which has beenproposed as a diagnostic indicator of periodontal disease; with the intention of filling a significant gap in theunderstanding of which factors contribute to periodontal disease.


application_id: 8744925
project_number: 7P01CA163223-02
project_title: Administration Bioinformatics and Biostatistics Core
administering_ic: NCI
award_notice_date: 2014-08-18
opportunity_number: PAR-12-005
application_type: 7
activity_code: P01
ic: CA
serial_number: 163223
project_start_date: 2014-08-19
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: 2014-03-01
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;Imagery;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;System;Translational Research;Universities;Validation;base;cost;data management;improved;interoperability;meetings;novel strategies;operation;outcome forecast;programs;reconstruction


application_id: 8744924
project_number: 7P01CA163223-02
project_title: Determining Molecular Mechanisms of NSCLC and Response to beta-glucan
administering_ic: NCI
award_notice_date: 2014-08-18
opportunity_number: PAR-12-005
application_type: 7
activity_code: P01
ic: CA
serial_number: 163223
project_start_date: 2014-08-19
study_section: ZCA1-RPRB-0
subproject_number: 7603
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: 2014-03-01
project_terms:
Adenocarcinoma;Age;Anabolism;Animals;Benign;Biochemical;Biochemistry;Cancer Patient;Cell Culture Techniques;Cell model;Cells;Cessation of life;Characteristics;Citric Acid Cycle;Clinical;Coupled;Data;Defect;Diagnostic Neoplasm Staging;Early Diagnosis;Excision;Future;Gene Expression Profile;Genes;Glucose;Glutamine;Goals;Gold;Growth;Human;Immune;Immune response;In Situ;Infusion procedures;Instruction;Knowledge;Label;Learning;Link;Lipids;Literature;Lung Neoplasms;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Modeling;Molecular;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;North America;Oncogenes;Oncogenic;Operative Surgical Procedures;Outcome;Pathological Staging;Pathway interactions;Patients;Pilot Projects;Plasma;Pyruvate Carboxylase;Recruitment Activity;Regulation;Resected;Sample Size;Sampling;Slice;Squamous cell carcinoma;Staging;Structure of parenchyma of lung;System;Testing;Therapeutic;Time;Tissues;Tracer;Treatment Efficacy;Tumor Subtype;Tumor Tissue;Tumor stage;base;beta-Glucans;cancer cell;cohort;design;human subject;improved;mRNA Expression;macrophage;malignant breast neoplasm;metabolomics;mouse model;novel diagnostics;novel strategies;outcome forecast;protein expression;response;stable isotope;tumor;tumor metabolism;tumor microenvironment;tumor progression


application_id: 8744923
project_number: 7P01CA163223-02
project_title: Determining Tumor Metabolism and Biochemical Mechanism of beta-glucan Action in
administering_ic: NCI
award_notice_date: 2014-08-18
opportunity_number: PAR-12-005
application_type: 7
activity_code: P01
ic: CA
serial_number: 163223
project_start_date: 2014-08-19
study_section: ZCA1-RPRB-0
subproject_number: 7602
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
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: 2014-03-01
project_terms:
Affect;Antigen Presentation;Arginine;Biochemical;Biochemical Pathway;Biochemistry;Cancer Biology;Cell Communication;Cell Line;Cells;Cessation of life;Clinical;Complex;Data;Development;Early Diagnosis;Event;Genes;Glucans;Glucose;Glutamine;Glutathione;Goals;Human;Human Characteristics;Immune;Immune response;Immune system;Immunomodulators;Immunophenotyping;Implant;In Situ;In Vitro;In Vivo NMR Spectroscopy;Instruction;Investigation;Knowledge;Label;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Measurement;Mediating;Mediator of activation protein;Metabolic;Metabolism;Modeling;Mus;Natural immunosuppression;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;North America;Nutrient;Outcome;Particulate;Pathway interactions;Patients;Pattern;Phenotype;Play;Polysaccharides;Primary Neoplasm;Process;Protein Analysis;Role;SCID Mice;Slice;Source;System;T-Lymphocyte;Tissues;Tracer;Tumor Angiogenesis;Yeasts;angiogenesis;beta-Glucans;cancer cell;chemotherapy;immunoregulation;improved;in vivo;lung Carcinoma;macrophage;metabolomics;neoplastic cell;novel strategies;outcome forecast;response;stable isotope;subcutaneous;transcriptomics;tumor;tumor growth;tumor metabolism;tumor microenvironment;tumor xenograft;uptake


application_id: 8743254
project_number: 5U01HL121807-02
project_title: The Impact of Oxidative Stress on HIV-induced Lung Disease
administering_ic: NHLBI
award_notice_date: 2014-07-28
opportunity_number: RFA-HL-13-026
application_type: 5
activity_code: U01
ic: HL
serial_number: 121807
program_official: CALER, ELISABET V
project_start_date: 2013-09-26
project_end_date: 2018-07-31
study_section: ZHL1-CSR-S(S1)
contact_pi_person_id: 8816315
contact_pi: RAMIREZ, JULIO ALBERTO
other_pis: ROMAN, JESSE
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;Binding (Molecular Function);Blood;Brain;Bronchoalveolar Lavage Fluid;Cause of Death;Cells;Chronic Disease;Chronic Obstructive Airway Disease;Chronic lung disease;Clinical Research;Clinical Trials;Cysteine;Data;Data Analyses;Databases;Dementia;Deposition;Deterioration;Diet;Disease;Disulfides;Epidemiologic Studies;Epithelial;Fibroblasts;Fibronectins;Genetic;Glycoproteins;Goals;Growth Factor;HIV;HIV Envelope Protein gp120;HIV-1;Immunologist;In Vitro;Incidence;Individual;Infection;Inflammatory;Interleukin-1;Interleukins;Intervention;Lung;Lung Inflammation;Lung diseases;Malignant neoplasm of lung;Mediating;Mesenchymal;Morbidity - disease rate;Mortality Vital Statistics;Myofibroblast;Nicotinic Receptors;Oxidation-Reduction;Oxidative Stress;Patients;Peptide Hydrolases;Physicians;Process;Production;Proteins;Pulmonary Fibrosis;Pulmonary Hypertension;Research Personnel;Scientist;Severities;Signal Transduction;Smoking;Structure of parenchyma of lung;Sulfhydryl Compounds;Testing;Tissues;Transforming Growth Factors;Universities;Virus Diseases;antiretroviral therapy;base;cytokine;design;env Gene Products;follow-up;injury and repair;oxidant stress;oxidation;prevent;programs;public health relevance;pulmonary function;research and development;transdifferentiation


application_id: 8743207
project_number: 5R01ES023470-02
project_title: Endocrine disruptor mediated activation of PXR causes dyslipidemia
administering_ic: NIEHS
award_notice_date: 2014-06-27
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: ES
serial_number: 023470
program_official: HEINDEL, JERROLD
project_start_date: 2013-09-26
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)S]
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: 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;Adverse effects;Affect;Agonist;Animal Model;Animals;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;CD36 Antigens;Cardiovascular Diseases;Cause of Death;Cells;Chemical Exposure;Chemicals;Chlorinated Hydrocarbons;Cholesterol;Chronic;Citrates;Cosmetics;Development;Diabetes Mellitus;Diet;Disease;Dose;Dyslipidemias;Endocrine Disruptors;Environment;Environmental Risk Factor;Etiology;Exposure to;FDA approved;Food Packaging;Future;Gene Expression;Genetic;Genetic Transcription;Goals;Health;Homeostasis;Human;Hyperlipidemia;In Vitro;Individual;Intestines;Knowledge;Lead;Link;Lipids;Liver;Mediating;Medical Device;Modeling;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Mus;Nuclear Receptors;Obesity;Organophosphates;Pesticides;Pharmaceutical Preparations;Pharmacologic Substance;Pilot Projects;Plasma;Plasticizers;Play;Polychlorinated Biphenyls;Receptor Activation;Regulation;Research;Risk Assessment;Role;Testing;Variation (Genetics);Wild Type Mouse;Xenobiotic Metabolism;Xenobiotics;absorption;analog;bisphenol A;cardiovascular disorder risk;cholesterol transporters;environmental chemical;gene environment interaction;human disease;in vivo;interest;mouse model;novel;packaging material;phthalates;pregnane X receptor;public health relevance;receptor function;research study;sensor;tool;uptake


application_id: 8741903
project_number: 5R21AG043721-02
project_title: Effect of Satellite Cell Ablation on the Aging Diaphragm
administering_ic: NIA
award_notice_date: 2014-06-18
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: AG
serial_number: 043721
program_official: WILLIAMS, JOHN
project_start_date: 2013-09-30
project_end_date: 2017-06-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
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): Motor dysfunction and skeletal muscle wasting are major causes of poor quality of life increased health care costs and institutionalization in the elderly. However age-related dysfunction of the respiratory muscles has an even greater impact on quality of life: impairment of the aging diaphragm disrupts a number of important behaviors such as breathing airway protective reflexes (coughing and sneezing) and voice. Since the diaphragm and accessory respiratory muscles must be active throughout life to sustain ventilation it is not surprising that their response to aging diverges from that seen in other skeletal muscles. In contrast to limb muscles atrophy does not explain the weakness and increased fatigability of the aging diaphragm; however since the diaphragm is constantly active it may have a need for constant remodeling. Indirect evidence for this notion stems from the fact that there is an apparent depletion of satellite cells in diaphragm muscle of mdx mice rendering it more susceptible to damage. Whether a similar situation exists for aging diaphragm muscle and whether satellite cell depletion and/or dysfunction play a role in decreased diaphragm function with age are completely unexplored issues. We are in the unique position to test the role of satellite cells in diaphragm muscle with aging using the Pax7-DTA mouse which allows for temporal and specific control of satellite cell ablation; we showed previously that >90% of satellite cells are ablated in response to tamoxifen treatment using this genetic model. It is currently unknown what the role of satellite cells is in the maintenance of diaphragm function with aging by itself or when the muscle is functionally challenged. Therefore our hypothesis is that satellite cells are necessary to sustain the structure and function of the aging diaphragm allowing it to withstand functional challenges. We will test the hypothesis using two specific aims. In Aim 1 we will determine whether satellite cell ablation in Pax7-DTA mice alters structure and function of the diaphragm with aging. Satellite cells will be ablated at 4 months of age and mice will be tested at 6 18 and 24 months of age. The efficiency of satellite cell ablation will be measured and analyses will be performed to assess morphological as well as functional changes in the diaphragm and in ventilation in vivo. In Aim 2 we will establish whether satellite cell ablation impairs the ability of the aging diaphragm to adapt to functional challenges. Satellite cells will be ablated at 4 months of age and mice will be subjected to normobaric hypoxia for 4 weeks or running activity for 8 weeks. Analyses will be performed as in Aim 1 and compared to measures obtained from mice in Aim 1. We expect that satellite cell ablation causes detrimental functional and structural changes in the aged diaphragm and that the ability of the diaphragm to adapt to changes in functional demand is impaired particularly in the aged. With the studies proposed in this application we will provide insight into the role of satellite cells in diaphragm muscle with advancing age which is an unexplored area; this knowledge will enable us to develop effective intervention strategies for the loss of diaphragm function with age.

project_terms:
A Mouse;Ablation;Age;Age-Months;Aging;Area;Behavior;Breathing;Coughing;Data;Diaphragm (Anatomy);Diphtheria Toxin;Elderly;Environmental air flow;Exercise;Extracellular Matrix Protein Gene;Fibrosis;Functional disorder;Genetic Models;Health;Health Care Costs;Hypoxia;Impairment;In Vitro;Inbred mdx Mice;Institutionalization;Intervention;Knowledge;Lead;Life;Limb structure;Maintenance;Measures;Mediating;Modeling;Motor;Mus;Muscle;Muscle Fibers;Muscle function;Muscle satellite cell;Muscular Atrophy;Pathology;Play;Positioning Attribute;Process;Protein Biosynthesis;Quality of life;Reflex action;Respiratory Muscles;Respiratory physiology;Role;Running;Skeletal muscle structure;Sneezing;Structure;Tamoxifen;Testing;Time;Voice;Work of Breathing;Workload;age related;aged;combat;effective intervention;frailty;in vivo;insight;muscle aging;muscular structure;protein degradation;public health relevance;respiratory;response;satellite cell;skeletal muscle wasting;stem;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Diaphragm muscle function is decreased with age but the role of muscle stem cells (satellite cells) in this process is unclear. We propose to study whethersatellite cells are required to maintain muscle structure and function of diaphragm with age and in response to a functional challenge. The knowledge from these studies will enable us to design therapies to combat decreased ventilatory reserve with age.


application_id: 8740638
project_number: 5P30CA177558-02
project_title: PROJECT 8. Biospecimen
administering_ic: NCI
award_notice_date: 2014-07-23
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8632
contact_pi_person_id: 8828637
contact_pi: CIBULL, MICHAEL
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: 2014-07-01
budget_end_date: 2015-06-30
project_terms:
Appalachian Region;Basic Science;Blood;Cancer Center;Cancer Center Support Grant;Cancer Research Project;Clinical;Clinical Data;Clinical Research;Collaborations;Colorectal Cancer;Commit;Formalin;Freezing;Funding;Goals;Hospitals;Human;Immunohistochemistry;Incidence;Individual;Kentucky;Laboratories;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Medicine;Molecular;Outcome;Paraffin Embedding;Pathology;Positioning Attribute;Process;Production;Quality Control;Research Personnel;Research Project Grants;Resource Sharing;Resources;Sampling;Services;Specimen;Structure of nail of toe;Surgical Pathology;Techniques;Tissue Microarray;Tissue Procurements;Tissue Sample;Tissues;Translational Research;Underserved Population;Universities;Urine;animal tissue;anticancer research;data management;digital imaging;follow-up;human tissue;meetings;neoplasm registry;neoplastic;novel;population based;repository;research clinical testing;research study


application_id: 8740637
project_number: 5P30CA177558-02
project_title: PROJECT 7. Free Radical
administering_ic: NCI
award_notice_date: 2014-07-23
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8631
contact_pi_person_id: 8329002
contact_pi: BUTTERFIELD, D. ALLAN
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: 2014-07-01
budget_end_date: 2015-06-30
project_terms:
Address;Adverse effects;Advisory Committees;Area;Bioenergetics;Biological;Biological Assay;Biology;Buffers;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Etiology;Cellular biology;Chemotherapy-Oncologic Procedure;Clinical Research;Clinical Trials;Detection;Development;Electron Spin Resonance Spectroscopy;Etiology;Evaluation;Free Radicals;Freezing;Genus Hippocampus;Grant;Injury;Investigation;Ions;Kentucky;Lipids;Malignant Neoplasms;Manuscripts;Measurement;Measures;Mediating;Membrane;Metabolism;Metals;Methodology;Methods;Mitochondria;Modeling;Modification;Molecular;Morphologic artifacts;Neoplasm Metastasis;Normal tissue morphology;Nucleic Acids;Oxidation-Reduction;Oxidative Stress;Preparation;Proteins;Proteomics;Reagent;Research;Research Personnel;Resource Sharing;Resources;Role;Sampling;Services;Signal Transduction;Strategic Planning;System;Techniques;Technology;Therapeutic;Training;Universities;biological systems;cancer cell;cancer prevention;cancer therapy;carcinogenesis;cell injury;chemotherapy;drug discovery;injury and repair;insight;instrumentation;interest;member;mitochondrial dysfunction;nitrosative stress;organizational structure;oxidative damage;pre-clinical;programs;sample fixation;tumor progression


application_id: 8740623
project_number: 1P30CA177558-01
project_title: PROJECT 12. Protocal Review
administering_ic: NCI
award_notice_date: 2013-09-24
opportunity_number: PAR-11-005
application_type: 1
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2018-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8636
contact_pi_person_id: 9360703
contact_pi: HAYSLIP, JOHN
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:
The Markey Cancer Center (MCC) Protocol Review and Monitoring System (PRMS) provides thorough review of clinical trials for scientific validity feasibility and prioritization within the clinical trials portfolio and monitoring of scientific progress. The PRMS must approve all interventional cancer research prior to study initiation and has the authority to recommend closure of trials for lack of scientific progress or patient accrual. The PRMS provides a framework which aims to balance appropriate resource utilization while maximizing the opportunities for current and future patients with cancer in this region to participate in clinical trials including the underserved area of Appalachian Kentucky. The development of novel MCC investigator initiated clinical trials and participation in high-priority national trials provide a robust portfolio of therapeutic research studies available to MCC patients.

project_terms:
Area;Basic Science;Behavioral Sciences;Cancer Center;Cancer Center Support Grant;Charge;Clinical;Clinical Data;Clinical Research;Clinical Sciences;Clinical Trials;Colorectal Cancer;Development;Documentation;England;Ensure;Equilibrium;Future;Incidence;Instruction;Kentucky;Lead;Malignant Neoplasms;Malignant neoplasm of lung;Medical center;Monitor;Patient Care;Patients;Population Heterogeneity;Population Sciences;Poverty;Process;Protocols documentation;Research Personnel;Resource Sharing;Resources;Risk Behaviors;Services;Smoking;System;Therapeutic Human Experimentation;Translations;United States;Universities;anticancer research;authority;data management;health disparity;novel;operation;research study;screening;translational clinical trial


application_id: 8740621
project_number: 1P30CA177558-01
project_title: PROJECT 11. Clinical Research and Data
administering_ic: NCI
award_notice_date: 2013-09-24
opportunity_number: PAR-11-005
application_type: 1
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2018-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8635
contact_pi_person_id: 9360703
contact_pi: HAYSLIP, JOHN
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:
The Markey Cancer Center (MCC ) Clinical Research and Data Management Shared Resource Facility (CRDM SRF ) coordinates and facilitates clinical cancer trials at the MCC . The major goals of this shared resource are to provide support of the clinical trial process including implementing and regulating trials provide a centralized clinical trial database and integrate with the following: investigational pharmacy support financial accounting data safety monitoring and quality assurance. This shared resource also assists physician investigators in the design and subsequent conduct of clinical trials through its support of the Investigator Initiated Trial Protocol Development Unit . It epidermis all regulatory reporting and quality assurance needed to comply with Good Clinical Practice in the performance of clinical trials. The CRDM SR F has Standard Operating Procedures for all its activities including training of all new faculty and staff. From Ma y 2011 through April l 2012  2542 new patients with cancer were seen at the MCC . Of these 1451 were from Appalachia n Kentucky . During this time period the CRDM SR F administrate d therapeutic cancer clinical trials that engaged 253 (10% ) participants in therapeutic intent clinical trials. Importantly 141 Appalachian patients were engaged in therapeutic intent clinical research a 10 % accrual rate from this disadvantaged and unique population.

project_terms:
Accounting;Appalachian Region;Area;Cancer Center;Cancer Center Support Grant;Clinical;Clinical Data;Clinical Nursing Research;Clinical Research;Clinical Research Associate;Clinical Trials;Clinical Trials Database;Conduct Clinical Trials;Data;Databases;Development;Disadvantaged;Ensure;Epidermis;Faculty;Financial Support;Goals;Good Clinical Practice;Industry;Kentucky;Location;Maintenance;Malignant Neoplasms;Mission;Monitor;Nurses;Participant;Patients;Performance;Pharmacy facility;Phase;Physicians;Population;Procedures;Process;Protocols documentation;Quality Control;Reporting;Research;Research Activity;Research Infrastructure;Research Personnel;Research Priority;Resource Sharing;Resources;Risk;Safety;Services;Therapeutic;Time;Training;Training and Education;Translational Research;Universities;Update;anticancer research;base;data management;design;digital;experience;protocol development;quality assurance;tool

public_health_relevance:
The CRD M SRF provides central management and oversight for coordinating  facilitating  and reporting on MCC cancer clinical trials . The CRDM SRF provides a central location for digital and hard copy cancer protocols a central database of protocol-specific data  an updated list of active protocols for investigators an d protocol status reports . The CRDM SRF supports quality control functions including education and training services for data managers and nurse and data auditing in support of the audit committee.


application_id: 8740587
project_number: 261201300031I-0-26100001-1
project_title: Development and Production of Parenteral Dosage Forms for Clinical Studies
administering_ic: NCI
project_start_date: 2013-09-20
project_end_date: 2013-10-30
contact_pi_person_id: 12066682
contact_pi: UNKNOWN, UNKNOWN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 794520721
primary_uei: SVL2JANHGDR5
duns_number: 794520721
uei: SVL2JANHGDR5
fips: US
organization_id: 10076826
organization_name: PIRAMAL PHARMA SOLUTIONS INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405111267
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The primary objective of this project is to develop and produce pharmaceutically acceptable parenteral dosage forms of cancer drugs for human use. Certain agents selected by the NCI DCTD will be assigned for development and production as parenteral products. Batch sizes shall range from small batches (less than 100 units) to intermediate size batches to be used in Phase I and II trials; however escalation to large batch sizes (10 to 30000 or more units) for advanced Phase II/III trials is also possible. The Contractor shall furnish services qualified personnel materials and a complete ongoing and fully operational facility including all necessary equipment for all aspects of the manufacture and testing of sterile freeze-dried liquid- filled and other injectable dosage forms. This facility and equipment shall conform to and be maintained for the production of human drugs in accordance with FDA prescribed Current Good Manufacturing Practices. They shall be capable of handling developing and manufacturing cytotoxic drugs.

project_terms:
Antineoplastic Agents;Clinical Research;Contractor;Contracts;Cytotoxic agent;Development;Dosage Forms;Equipment;Freeze Drying;Human;Human Resources;Injectable;Liquid substance;Pharmaceutical Preparations;Phase I/II Trial;Phase II/III Trial;Production;Qualifying;Services;Sterility;Testing;meetings


application_id: 8740481
project_number: 5R21ES024030-02
project_title: Novel Treatments of Acrolein-induced Cardiotoxicity
administering_ic: NIEHS
award_notice_date: 2014-08-18
opportunity_number: PAR-13-005
application_type: 5
activity_code: R21
ic: ES
serial_number: 024030
program_official: NADADUR, SRIKANTH
project_start_date: 2013-09-24
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1-MDCN-B(55)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): The overall goal of this project is to develop new and improved countermeasures and therapeutics for preventing human mortality and morbidity associated with chemical threats. Such threats might be imposed by a terrorist attack accidental leakage of chemicals used in industrial production or those released during natural disasters and fires. The most common and abundant reactive chemicals relevant to all these situations are reactive carbonyl compounds (RCCs). A prototypical member of this class is acrolein. Acrolein and related RCCs are the most abundant and toxic constituents generated in lethal amounts (600 ppm) during forest and structural fires. Profound respiratory and cardiovascular effects of exogenous and endogenous RCCs have also been described; however neither the toxicological effects of RCCs nor their mechanisms of toxicity have been systematically delineated. Similarly the specific vulnerability of young old and women to RCC exposure has not been assessed. Most importantly no effective countermeasures or therapeutic interventions are currently available. Possible therapeutic interventions include treatment with inhibitors of RCC receptors known as transient receptor potential (TRP) channels. These antagonists including TRPV1 and TRPA1 inhibitors hold promise to diminish the pain and inflammation in the cardiovascular and pulmonary systems associated with high dose exposure to RCC. Evaluation of mitigation therapies following high level RCC exposure will provide the first step in judging their relative efficacy for use in the case of a chemical emergency threat in humans.

project_terms:
1 year old;2-butenal;Accounting;Acrolein;Acute;Adult;Adverse effects;Age;Animals;Arthritis;Asthma;Autonomic nervous system;Biocide;Blood Pressure;Breathing;C57BL/6 Mouse;Calcium;Cardiac;Cardiopulmonary;Cardiotoxicity;Cardiovascular system;Chemical Warfare;Chemicals;Chronic;Clinical;Dermal;Development;Diesel Exhaust;Dose;Dyslipidemias;Echocardiography;Edema;Emergency Situation;Evaluation;Event;Exposure to;Extravasation;Eye;FDA approved;Female;Fire - disasters;Formaldehyde;Foundations;Gases;Goals;Heart;Herbicides;Human;Hydra Polyps;Industry;Inflammation;Injection of therapeutic agent;Injury;Intervention;Irrigation;Irritants;Lead;Lung;Measures;Mediating;Monitor;Mucins;Natural Disasters;Neurons;Nose;Oils;Pain;Pesticides;Pharmaceutical Preparations;Phase;Plasma;Production;Relative (related person);Research;Route;Safety;Shipping;Ships;Signal Transduction;Skin;Structure of parenchyma of lung;System;TRPA1 Channel;TRPV1 gene;Testing;Therapeutic;Therapeutic Intervention;Toxic effect;Translational Research;Troponin I;Water;activin A;atherogenesis;capsazepine;carbonyl compound;combat;effective intervention;effectiveness measure;efficacy testing;forest;human morbidity;human mortality;improved;inhibitor/antagonist;insight;irritation;male;member;novel;older women;preclinical study;preconditioning;prevent;public health relevance;receptor;respiratory;response;sex

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Profound respiratory and cardiovascular effects of exogenous and endogenous reactive carbonyl compounds (RCCs) such as acrolein have been described; yet neither the toxicological effects of RCCs nor their mechanisms of toxicity have been systematically delineated. Moreover the specific vulnerability of the young old and females to inhaled RCCs including acrolein has not been assessed. Possible therapeutic interventions include treatment with known transient receptor potential (TRP) channel inhibitors including TRPA1 and TRPV1 antagonists and evaluation of mitigation therapy following high level RCC exposure will provide the first step in judging their efficacy in the case of a chemical emergency threat in humans.


application_id: 8739560
project_number: 5R21NS085830-02
project_title: Sexually dimorphic miR-497 regulates alpha-synuclein and alpha-synucleinopathy
administering_ic: NINDS
award_notice_date: 2014-08-26
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: NS
serial_number: 085830
program_official: SIEBER, BETH-ANNE
project_start_date: 2013-09-25
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1-BDCN-Y(02)M]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: 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): Dementia with Lewy bodies (DLB) is a devastating neurodegenerative disease. Cortical Lewy body pathology (LBP) which is the pathological substrate of DLB is observed in 10%-30% of brains in most autopsy series of dementia patients. At the molecular level LBP consists of aberrant deposits of alpha-synuclein (alpha-SN) protein and there is evidence that increased alpha-SN gene dosage is seen in some cases of DLB. The biochemical pathways that contribute to LBP are poorly understood and our overall goal is to help fill this knowledge gap. Men have strongly (~three-fold) increased risk for developing autopsy-confirmed cortical LBP compared to women; this is an observation replicated in many autopsy series. Our overarching hypothesis is that a particular microRNA (miRNA; miR-497) contributes to sexually-dimorphic DLB pathogenesis. In preliminary studies we made the following observations: miR-497 is expressed sexually dimorphically in human brain and in rat primary cultured neurons; miR-497 is enriched in human brains with LBP and in LBP- vulnerable brain areas; and miR-497 expression in cultured cells alters alpha-SN and DJ-1/PARK7 expression. Our lab has expertise in both LBP and miRNAs which enable us to test the hypothesis that miR- 497 regulates alpha-SN expression and may influence LBP in a sexually dimorphic manner. Specific Aim 1: Test the hypothesis that miR-497 is sexually dimorphically expressed in human brain and dysregulated in human brains with LBP. Proposed studies will represent the state of the art in miRNA profiling using miRNA microarrays to test for associations between miRNA expression and both LBP and gender status. Preliminary data indicate a systematic tendency for sexually dimorphic miR-497 to be dysregulated in brains with LBP and in human brain areas vulnerable to LBP. Specific Aim 2: Test the hypothesis that sexually dimorphic miR-497 regulates alpha-SN expression. Preliminary data indicate that miR-497 regulates alpha-SN. Primary rat neurons will be transduced with lentiviral vectors expressing miR-497 versus other control miRNAs to test the hypothesis that miR-497 regulates alpha-SN. Further experiments in these cells will query whether the regulation of alpha-SN by miR- 497 is direct or via an intermediate regulation of PARK7/DJ-1 gene. Following viral transduction with miR-497 and control miRNAs we will determine the full list of miR-497 targets in cultured primary neurons. These mechanistic experiments will aid our ultimate goal of therapies to combat this currently untreatable disease. Public health significance: Understanding how sexually dimorphic miR-497 alters alpha-SN expression to induce sex-dimorphic pathology would be a major novel paradigm in neurochemistry with clinical/translational significance for both diagnostic and therapeutic strategies. The primary cel culture system will offer an experimental paradigm for testing novel methods of attenuating the dimorphic expression of miR-497 that drives alpha-SN expression.

project_terms:
Age;Age-Years;Alzheimer's Disease;Area;Attenuated;Autopsy;Biochemical;Biochemical Pathway;Biological Markers;Brain;Cells;Cessation of life;Clinical;Cultured Cells;Data;Data Analyses;Data Set;Databases;Dementia;Deposition;Diagnostic;Disease;Elderly;Female;Gender;Gene Dosage;Gene Expression;Genes;Goals;Human;Knowledge;Lentivirus Vector;Lewy Bodies;Lewy Body Dementia;Methods;MicroRNAs;Molecular;Neurodegenerative Disorders;Neurons;PARK7 gene;Pathogenesis;Pathology;Patients;Proteins;Rattus;Regulation;Regulator Genes;Reporting;Research Personnel;Risk;Role;Sampling;Series;Small RNA;System;Testing;Therapeutic;Viral;Woman;age group;alpha synuclein;alpha synuclein gene;base;combat;data registry;disease diagnosis;high risk;male;men;neocortical;nervous system disorder;neurochemistry;novel;novel diagnostics;novel therapeutics;public health medicine (field);public health relevance;pup;research study;sex;synucleinopathy;trend

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Dementia with Lewy bodies (DLB) is a devastating and relatively prevalent neurological disease with no known cure. We found that men have far higher risk of developing this disease and our preliminary data support a testable hypothesis that the difference between the sexes is due to a novel biochemical agent called microRNAs. We will test the hypothesis and try to move the field forward by exploiting the role of microRNAs in DLB for new diagnostic and therapeutic strategies.


application_id: 8738158
project_number: 261201300034C-0-0-1
project_title: IGF::OT::IGF DETECTION ISOLATION AND ANALYSIS OF SINGLE CTCS
administering_ic: NCI
project_start_date: 2013-09-13
project_end_date: 2014-06-12
contact_pi_person_id: 12067592
contact_pi: LINDER, MARK
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 012986391
primary_uei: ZFN5J433DCT1
duns_number: 012986391
uei: ZFN5J433DCT1
fips: US
organization_id: 10019586
organization_name: PGXL TECHNOLOGIES, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40206
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The objective of this project is to deliver a fully integrated CLIA-certified technology that provides diagnostic characterization of individually identified CTCs harvested from human specimens. We will use a novel patented chip-based dielectrophoretic-controlled isolation process (DEPArray) to identify and isolate single CTCs while maintaining their functional biological integrity. Using this technology we have developed a strategy for classifying CTCs into defined subsets with identifiable characteristics useful for clinical research and diagnosis. The specific tasks for this Phase I contract are to:  1) Establish a robust method for comprehensive detection and isolation of single circulating tumor cells 2) Define and isolate specific subsets of CTCs based on extracellular antigen expression 3) Demonstrate the ability to perform molecular analysis on single cells isolated from subgroups of CTCs 4) Demonstrate reproducibility of an integrated CTC Detection Recovery and Analysis system  This SBIR contract will enable development of a fully-integrated and robust cell-identification and separation system to support CTC cancer research and diagnostics. This novel technology promises to revolutionize the identification of new subsets of CTCs and also assign clinically useful characteristics such as metastatic potential to each subset of cells.

project_terms:
Antigens;Biological;Cancer Diagnostics;Cells;Characteristics;Clinical Research;Contracts;Detection;Development;Diagnostic;Harvest;Human;Legal patent;Methods;Molecular Analysis;Neoplasm Circulating Cells;Phase;Process;Recovery;Reproducibility;Small Business Innovation Research Grant;Specimen;Subgroup;System;Systems Analysis;Technology;anticancer research;base;clinical Diagnosis;extracellular;new technology;novel


application_id: 8737965
project_number: 5R01HL120746-02
project_title: Tobacco Products and Atherosclerotic Disease
administering_ic: NHLBI
award_notice_date: 2014-08-11
opportunity_number: PAR-12-267
application_type: 5
activity_code: R01
ic: HL
serial_number: 120746
program_official: PUNTURIERI, ANTONELLO
project_start_date: 2013-09-19
project_end_date: 2018-08-31
study_section: Special Emphasis Panel[ZRG1-HDM-Q(54)R]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
2-butenal;Acrolein;Affect;Aldehydes;Animal Model;Animals;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Biological Markers;Blood Platelets;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Chemicals;Cholesterol Homeostasis;Chronic Disease;Cigarette;Development;Disease;Doctor of Philosophy;Evaluation;Excision;Exposure to;Family Smoking Prevention and Tobacco Control Act;Future;Gender;Goals;Harm Reduction;Health;Heart Diseases;Heart failure;Human;Individual;Injury;Ischemia;Knockout Mice;Lead;Lesion;Link;Marketing;Measures;Mediating;Mortality Vital Statistics;Mus;Nature;Nicotine;Policies;Principal Investigator;Rattus;Regulation;Reperfusion Therapy;Risk;Risk Factors;Smoke;Smokeless Tobacco;Smoking;Surrogate Markers;Thrombosis;Time;Tobacco;Tobacco smoke;Tobacco use;Toxic effect;atherogenesis;authority;cardiovascular disorder risk;cardiovascular injury;cigarette smoke;cigarette smoking;design;indexing;novel;programs;public health medicine (field);research study;stroke;tobacco exposure;urinary


application_id: 8737894
project_number: 5R01DK100892-02
project_title: The role of hepatic insulin resistance on SR-BI dependant HDL cholesterol uptake
administering_ic: NIDDK
award_notice_date: 2014-08-28
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DK
serial_number: 100892
program_official: LAUGHLIN, MAREN R
project_start_date: 2013-09-20
project_end_date: 2017-08-31
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
arra_indicator: N
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;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;public health relevance;reverse cholesterol transport;trafficking;translational approach;treatment strategy;uptake


application_id: 8737800
project_number: 5R44CA136017-05
project_title: SapC-DOPS Nanovesicles for Treating Glioblastoma Multiforme
administering_ic: NCI
award_notice_date: 2014-08-25
opportunity_number: RFA-CA-12-023
application_type: 5
activity_code: R44
ic: CA
serial_number: 136017
program_official: HAIM, TODD E
project_start_date: 2008-09-25
project_end_date: 2016-08-31
study_section: ZCA1-SRLB-V(M1)
contact_pi_person_id: 8717940
contact_pi: XU, KEVIN
other_pis: QI, XIAOYANG
congressional_district: 04
department: Unavailable
primary_duns: 782233501
primary_uei: HJPDQTK95NS8
duns_number: 782233501
uei: HJPDQTK95NS8
fips: US
organization_id: 10010035
organization_name: BEXION PHARMACEUTICALS, INC.
organization_city: COVINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 410112312
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Our goal is to develop a new molecular entity with a novel mechanism of action for targeting and eliminating glioblastoma multiforme (GBM high grade glioma) a deadly and invasive brain tumor with no effective treatment. Of the 12000 patients expected to be diagnosed with GBM this year most will succumb within a year. There is an urgent demand for an efficacious anti-glioma drug. We are developing a new class of therapeutic proteolipid nanovesicle that can target and destroy glioma tumors. Composed of the small lysosomal sphingolipid activator protein saposin C (SapC 80 aa) and the phospholipid dioleoylphosphatidylserine (DOPS); the stable 200 nm SapC-DOPS nanovesicles (clinical formulation is called BXQ-350) have unusually high affinity for phosphatidylserine-enriched membrane surfaces that occur widely in many types of tumor cells and tumor neovasculature. Consistent with sphingolipid activator function BXQ-350 appear to selectively induce tumor cells to undergo ceramide-mediated cell death apparently sparing non-tumor cells. In Phase I of this proposal we demonstrated the feasibility of using SapC-DOPS to target and kill intracranial gliomas. Intravenous administration of SapC-DOPS in mice with orthotopically implanted gliomas resulted in dose-dependent improvement in survival. In Phase II a GMP compliant formulation of SapC-DOPS (i.e. BXQ-350) was developed and potency was confirmed in additional orthotopic preclinical GBM models. IND-enabling studies are in progress. Pharmacokinetics and toxicity studies thus far indicate favorable distribution and safety profiles in rodent and non-rodent studies. In this three-year Phase IIB proposal the key objectives are to file the IND for BXQ-350 complete a Phase 1 clinical trial and prepare for Phase 2. Recognizing that gliomas are highly heterogeneous another objective is to identify and link biochemical factors (e.g. cell surface PS levels; genetic markers) to the degree of BXQ-350 tumoricidal activity. Understanding of these factors will improve dosing strategies and reduce the risk of variable therapeutic response. Specific Aims are: (1) Scale- up GMP production of BXQ-350; (2) File the IND and complete the Phase 1 clinical trial; and (3) Correlate susceptibility to killing by BXQ-350 with molecular and cellular characteristics of glioma cell lins (from a tumor bank). BXQ-350 offers an innovative and potentially powerful approach for slowing tumor growth and eliminating deep-seated brain tumors. Ultimately we will progress this technology for treating other tumors and for developing tumor-targeted imaging diagnostics.

project_terms:
Activator Appliances;Affinity;Animal Model;Animals;Antineoplastic Agents;Behavioral;Biochemical;Biological Assay;Biological Markers;Brain Neoplasms;Catabolism;Cell Death;Cell surface;Cells;Ceramides;Characteristics;Chemistry;Clinical;Clinical Trials;Data;Diagnosis;Diagnostic Imaging;Dose;Drug Formulations;Drug Kinetics;Genetic;Genetic Markers;Glioblastoma;Glioma;Glucosylceramides;Goals;Grant;Growth;Heterogeneity;Human;Implant;Investigational Drugs;Investigational New Drug Application;Killings;Link;Mediating;Membrane;Methods;Modeling;Molecular;Morbidity - disease rate;Mus;Normal Cell;Nude Mice;Outcome;Patients;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Phase II Clinical Trials;Phosphatidylserines;Phospholipids;Plasmids;Predisposition;Primates;Procedures;Production;Property;Proteins;Proteolipids;Protocols documentation;Qualifying;Radiosurgery;Research;Risk;Rodent;Safety;Small Business Innovation Research Grant;Solid Neoplasm;Sphingolipid Activator Proteins;Sphingolipids;Surface;Techniques;Technology;Testing;Therapeutic;Toxic effect;Tumor Bank;Tumor-Derived;Xenograft Model;analytical method;annexin A5;beta-Glucosidase Stimulating Protein;cancer cell;cell bank;chemotherapy;drug candidate;effective therapy;efficacy trial;expression vector;glioma cell line;improved;in vivo;innovation;intravenous administration;lysosomal proteins;meetings;nanovesicle;neoplastic cell;neovasculature;nonhuman primate;novel;oncology;phase 1 study;pre-clinical;preclinical study;public health relevance;response;scale up;success;treatment strategy;tumor;tumor growth

public_health_relevance:
PUBLIC HEALTH RELEVANCE: We are developing a new treatment for glioblastoma multiforme a deadly form of brain tumor that kills over 90% of afflicted patients. Current treatment methods consisting of surgery radiation and chemotherapy have not been effective in significantly reducing morbidity. Our strategy involves using new proteolipid nanovesicles that can penetrate the tumors and selectively destroy malignant cells without harming normal cells. Success in clinical trials will enable us to offer an effective new strategy to treat patients withaggressive brain tumors.


application_id: 8737216
project_number: 5R01DA033394-02
project_title: Targeting GABA and Opioid Systems for a Pharmacotherapy for Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2014-08-22
opportunity_number: PA-10-268
application_type: 5
activity_code: R01
ic: DA
serial_number: 033394
program_official: HAMPSON, AIDAN
project_start_date: 2013-09-30
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Methamphetamine (MA) abuse and dependence are significant public-health concerns. Treatment admissions for MA use increased at an alarming rate from 1998 to 2007 in the US. Behavioral treatments reduce MA use. However many patients enrolled in behavioral treatment programs are unable to achieve a significant period of abstinence suggesting other strategies like pharmacotherapy are urgently needed. G-Aminobutyric-acid (GABA) and opioid systems modulate dopamine. GABAA receptor modulators (e.g. oxazepam [OXP]) and opioid antagonists (e.g. naltrexone [NTX]) attenuate the abuse-related effects of amphetamines. The attenuation of the abuse-related effects of amphetamine by GABAA receptor modulators or opioid antagonists while statistically significant is modest in magnitude. Novel strategies are needed to enhance the efficacy of these drugs. Targeting GABA and opioid systems simultaneously is an innovative strategy in that combining NTX and OXP may produce greater attenuation of the abuse-related effects of MA. A rigorous within-subject experiment will be conducted in non-treatment-seeking MA-abusing participants. NTX (0 and 50 mg/day) and OXP (0 and 40 mg/day) alone and in combination will be tested with MA (0 10 20 and 30 mg). The four NTX-OXP maintenance conditions will be tested in random order. Similarly within each NTX-OXP condition the MA doses will be tested in random order. The reinforcing effects of intranasal MA doses will be determined after four days of maintenance on each of the NTX-OXP conditions using a sensitive progressive-ratio procedure. The ability to attenuate the reinforcing effects of drugs isa reliable predictor of an effective pharmacotherapy. We hypothesize that combining NTX and OXP will produce an additive or supra-additive reduction in the reinforcing effects of MA relative to the constituent drugs alone. This research will provide critical information regarding the initil efficacy a novel drug combination NTX and OXP for MA dependence. Innovations of the proposed research include: 1) testing a combination of marketed drugs that demonstrated some efficacy when tested as mono-therapies; 2) testing a GABAA receptor modulator that has minimal abuse potential and dependence liability which will likely be more acceptable to clinicians; 3) the use of a sensitive drug self-administration procedure; 4) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of NTX-OXP combinations for MA dependence; and 5) demonstrating the initial efficacy of commercially available drugs as opposed to waiting for novel molecules to be available for testing in humans thereby impacting clinical research and practice more quickly. In these ways the proposed project will shift the current clinical research paradigm in pharmacotherapy development and have a significant impact on the treatment of MA dependence.

project_terms:
Abstinence;Admission activity;Adverse effects;Alprazolam;Aminobutyric Acids;Amphetamines;Animals;Attenuated;Behavior Therapy;Behavioral;Cardiovascular system;Chronic;Clinical Research;Clinical Trials;Cocaine Dependences;Cognitive Therapy;Communicable Diseases;Crime;Data;Data Analyses;Dependence;Development;Dopamine;Dose;Drug Combinations;Drug-sensitive;Enrollment;Human;Impaired cognition;Laboratories;Maintenance;Mediating;Medical;Methamphetamine;Methamphetamine dependence;Mono-S;Naltrexone;Narcotic Antagonists;National Institute of Drug Abuse;Opioid;Outcome Measure;Oxazepam;Participant;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase II Clinical Trials;Physiological;Play;Premature Mortality;Probability;Procedures;Productivity;Questionnaires;Relative (related person);Reporting;Research;Role;Safety;Self Administration;System;Testing;United States;addiction;attenuation;clinical practice;contingency management;cost;dopamine system;double-blind placebo controlled trial;drug efficacy;drug market;drug reinforcement;indexing;innovation;methamphetamine abuse;novel;novel strategies;public health medicine (field);public health relevance;receptor;research study;secondary outcome;stimulant abuse;success;tool;treatment program

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The research proposed in this application will provide critical information regarding the initial efficacy safety and tolerability of a novel drug combination naltrexone and oxazepam as a pharmacotherapy for methamphetamine dependence. The proposed research is innovative because it will demonstrate the initial efficacy of commercially available drugs as opposed to waiting for novel molecules to be available for testing in humans thereby impacting clinical research and practice more quickly. The proposed study is important because it will provide the impetus for the conduct of double blind placebo-controlled trials to further demonstrate the efficacy of naltrexone-oxazepam combinations for managing cocaine dependence. If these trials demonstrate efficacy they will provide clinicians with a pharmacological tool for managing methamphetamine dependence.


application_id: 8735905
project_number: 5R43CA179911-02
project_title: Virtual Fly-Over Colonoscopy System for Clinical Test-SBIR Phase 1
administering_ic: NCI
award_notice_date: 2014-08-29
opportunity_number: PA-12-088
application_type: 5
activity_code: R43
ic: CA
serial_number: 179911
program_official: NARAYANAN, DEEPA
project_start_date: 2013-09-17
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1-SBIB-T(10)B]
contact_pi_person_id: 12040739
contact_pi: ELSHAZLY, SALWA A
other_pis: Not Applicable
congressional_district: 02
department: Unavailable
primary_duns: 828955026
primary_uei: JU9YMZGJMNS5
duns_number: 828955026
uei: JU9YMZGJMNS5
fips: US
organization_id: 10027536
organization_name: KENTUCKY IMAGING TECHNOLOGIES, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402456516
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Colorectal cancer is the third most common form of cancer and the second leading cause of cancer-related death in the US. Yet if polyps are detected and removed early colorectal cancer is largely preventable. Although optical colonoscopy (OC) the current gold standard detects more than 90% of colorectal neoplasms; it is invasive and can be uncomfortable inconvenient and perceived as undesirable by patients. Furthermore even experienced endoscopists may have difficulty reaching the cecum resulting in incomplete visualizations of the colon. As a consequence virtual colonoscopy (VC) has emerged as an alternative to OC. During VC a virtual camera is used to view the internal walls of a virtual colon reconstructed from CT scans of the abdominal cavity. However current VC systems have had limited clinical appeal as they are limited to specific types of polyps may generate a large number of false positives or have poor detection rates for significant polyps in the size range of 5-9 mm. The new technology we propose to commercialize through this SBIR work is a game changing patented visualization technique for VC called the "virtual fly-over" technique. The technique is sensitive effective and efficient for detecting colon polyps. The overall objective of this proposal is to complete the development and validation of a novel visualization technique for virtual colonoscopy which was patented by the University of Louisville. The hypothesis is that the new visualization technique will enable better viewing of the complex colonic topology and hence a better capability to detect polyps especially those that may be hidden behind haustral folds. The current prototype has been utilized to evaluate twenty clinical datasets with excellent results. However artifact removal and user friendly features must be incorporated prior to Phase II in which the technology will be utilized in a larg scale clinical validation trial leading to a commercial product. Also we propose to (1) generate more convincing preliminary data in a pilot study of 160 datasets and (2) introduce several phantom polyps in the size range of 5-9 mm into the clinical datasets in order to provide statistical significance of the technology's effectiveness. The phantom polyps will be placed in traditionally difficult-to-analyze positions which pose significant detection problems for both OCand current VC methods. According to the literature current OC methods result in a 61-91% (average 80%) viewing of the Colon. The University of Louisville's work in the "fly-through VC method" which mimics classic OC results in 93.4 percent viewing and the new "fly-over" method results in 97.5% percent viewing. Even more important is the improved point of view ("eye-in-the-sky") the lack of optical distortion and enhanced CAD functionality that will increase polyp recognition dramatically especially when detecting small colon polyps polyps hidden behind haustral folds and polyps in folded colonic segments at anatomical inflection points. We anticipate the overall improvement in the ability to visualize difficult polyps to be upwards of 30% compared to today's methods and we are excited about commercializing this technology with the University of Louisville.

project_terms:
Abdominal Cavity;Area;Cancer Etiology;Cecum;Cessation of life;Clinical;Clinical Trials;Colon;Colon Carcinoma;Colonic Polyps;Colonoscopy;Colorectal Cancer;Colorectal Neoplasms;Complex;Computational Geometry;Computed Tomographic Colonography;Computer Graphics;Computer Vision Systems;Data;Data Set;Databases;Detection;Development;Early Diagnosis;Effectiveness;Engineering;Excision;Eye;Flying body movement;Foundations;Funding;General Population;Goals;Gold;Helicopter;Human;Imagery;Implant;Kentucky;Lead;Legal patent;Literature;Location;Medial;Medical center;Methods;Morbidity - disease rate;Morphologic artifacts;Optical Methods;Optics;Patients;Phase;Pilot Projects;Polyps;Population;Positioning Attribute;Procedures;Reading;Rivers;Science;Second Primary Cancers;Sedation procedure;Small Business Innovation Research Grant;Surface;System;Techniques;Technology;Testing;Universities;Validation;Work;X-Ray Computed Tomography;base;clinically significant;design;experience;fly;improved;new technology;novel;prototype;public health relevance;research clinical testing;screening;three-dimensional modeling;user-friendly;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Colorectal cancer is the third most common form of cancer and the second leading cause of cancer-related death in the US with only approximately 50% of the eligible population take advantage of current screening methods. The importance of this proposed technology is the early detection of colon cancer in an acceptable manner that the general population will agree to and without the associated morbidity of sedation that is required for the vast majority of endoscopic colonoscopy. We believe our technology has the potential to serve as a foundation for a huge step forward in automating and facilitating large scale screening of human colons providing a more effective and much more acceptable method to the general population than the currently invasive optical colonoscopy which 50 % of the population still refuses to undergo.


application_id: 8735428
project_number: 1P30GM110788-01
project_title: CTDL Laboratory Core
administering_ic: NIGMS
award_notice_date: 2014-08-15
opportunity_number: PAR-13-238
application_type: 1
activity_code: P30
ic: GM
serial_number: 110788
study_section: Special Emphasis Panel[ZGM1 TWD-C (C3)]
subproject_number: 8149
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
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: 2014-08-15
budget_end_date: 2015-07-31
project_terms:
Bacteria;Basic Science;Biological Assay;Biology;Cell Culture Techniques;Clinical Sciences;Communities;DNA;Dentistry;Genetic;Genomics;Immune response;In Vitro;Knowledge;Laboratories;Liquid substance;Measures;MicroRNAs;Molecular Analysis;Mouth Diseases;Oral;Oral health;Organism;Outcome;Phase;Population;Preparation;RNA;Research Personnel;Saliva;Sampling;Serum;Services;Specimen;Systemic disease;Tissues;Translational Research;Virus;base;bone;college;design;epigenetic variation;genome wide association study;improved;mucosal site;operation;oral bacteria;oral biology;vaginal fluid


application_id: 8735424
project_number: 1P30GM110788-01
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2014-08-15
opportunity_number: PAR-13-238
application_type: 1
activity_code: P30
ic: GM
serial_number: 110788
study_section: Special Emphasis Panel[ZGM1 TWD-C (C3)]
subproject_number: 8147
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
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: 2014-08-15
budget_end_date: 2015-07-31
project_terms:
Administrator;Adoption;Award;Bioinformatics;Centers of Research Excellence;Clinical Sciences;Communities;Dental;Dental Faculty;Dental Students;Education and Outreach;Grant;Health;Health Services Research;Housing;Kentucky;Knowledge;Link;Metric;Oral;Oral health;Phase;Play;Population;Research;Research Personnel;Resources;Role;Systemic disease;Technology Transfer;Training and Education;Translational Research;Work;base;design;improved;organizational structure;outreach program;public health medicine (field)


application_id: 8734276
project_number: 5F31NS083292-02
project_title: Methylglyoxal and TRPA1 contribution to neuropathic pain in type 2 diabetes
administering_ic: NINDS
award_notice_date: 2014-04-16
opportunity_number: PA-11-111
application_type: 5
activity_code: F31
ic: NS
serial_number: 083292
program_official: OSHINSKY, MICHAEL L
project_start_date: 2013-04-01
project_end_date: 2016-09-30
study_section: Special Emphasis Panel[ZRG1-F02B-M(20)L]
contact_pi_person_id: 10806881
contact_pi: GRIGGS, RYAN B
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): Diabetes affects almost 9% of the United States population and 20-50% of diabetic patients experience painful diabetic neuropathy. Painful diabetic neuropathy (PDN) results in increased somatosensory responsiveness increased patient-reported pain and has a greater prevalence in type 2 versus type 1 diabetic patients. Ninety percent of diabetic patients are type 2 pointing to the need to understand the mechanisms that underlie PDN. Plasma methylglyoxal a catabolic cellular metabolite of glucose is markedly increased in hyperglycemic diabetic patients mice and rats. Very recent studies also suggest that methylglyoxal causes pain via TRPA1-dependent neuronal sensitization but this mechanism has only been investigated in the streptozotocin (STZ) model of type 1 diabetes. Other chronic studies in the STZ model indicate increased neuronal responsiveness to peripheral stimulation (sensitization) and pain. Lack of comparable longitudinal studies in a rat model of type 2 diabetes is an important gap in knowledge. The proposed studies will use the Zucker Diabetic Fatty (ZDFfa/fa) rat model of type 2 diabetes to test the central hypothesis that hyperglycemia-induced increases in methylglyoxal cause painful diabetic neuropathy in type 2 diabetes. By understanding how changes in peripheral nerves lead to alteration of sensory processing in the spinal cord we can learn how to effectively treat painful diabetic neuropathy. The goal of this project is to discover new therapeutic targets for PDN treatment.  Specific Aim 1 will test the hypothesis that methylglyoxal produces spontaneous pain-like behavior in type 2 diabetes. Reactive methylglyoxal directly activates nociceptive sensory neurons to cause pain. We will attempt to inhibit methylglyoxal-induced pathology by several different methods including the FDA-approved diabetes therapy pioglitazone and assess whether pain is diminished. Specific Aim 2 will test the hypothesis that methylglyoxal contributes to painful diabetic neuropathy via increasing TRPA1-dependent sensory neuron activity. TRPA1 is a protein expressed in sensory neurons that results in painful sensation upon activation. It is thought that methylglyoxal causes sustained activation of TRPA1 which is at least partially responsible for pain in type 2 diabetes. We will use behavioral assays mechanistic pharmacology and calcium imaging as a marker for sensory neuron activation to test the overall hypothesis that type 2 diabetic pain is mediated by glucose-related neurological deficits. Our long-term objective is to substantially reduce the burden of neuropathic pain in type 2 diabetes.

project_terms:
Affect;Afferent Neurons;Age;Agonist;Animals;Attenuated;Behavior;Behavioral Assay;Burn injury;Calcium;Chemosensitization;Chronic;Clinical;Data;Diabetes Mellitus;Diabetic Neuralgia;Esthesia;FDA approved;Genetic;Glucose;Goals;Heating;Human;Hyperalgesia;Hyperglycemia;Hypersensitivity;Image;Insulin-Dependent Diabetes Mellitus;Knowledge;Lactoylglutathione Lyase;Lead;Learning;Longitudinal Studies;Measures;Mediating;Methods;Modeling;Mus;Neurologic;Neurons;Nociception;Non-Insulin-Dependent Diabetes Mellitus;PPAR gamma;Pain;Paresthesia;Pathology;Patients;Peptides;Peripheral;Peripheral Nerves;Peripheral nerve injury;Peroxisome Proliferator-Activated Receptors;Pharmacology;Pioglitazone;Plasma;Population;Prevalence;Prevention;Procedures;Proteins;Pyruvaldehyde;Rattus;Reporting;Rodent;Rodent Model;Sensory Process;Spinal Cord;Spinal Ganglia;Spinal cord posterior horn;Streptozocin;Testing;United States;behavioral pharmacology;cohort;diabetes mellitus therapy;diabetic;diabetic patient;diabetic rat;experience;heat stimulus;in vivo;new therapeutic target;non-diabetic;overexpression;painful neuropathy;preference;pressure;public health relevance;research study;response;somatosensory;spontaneous pain;type I diabetic;vector

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Neuropathic pain is commonly associated with diabetes yet glucose management alone does not eliminate diabetic pain. Our goal is to elucidate mechanisms of peripheral neuropathic pain in type 2 diabetes. Our findings will contribute to the discovery of new therapeutic targets such as PPAR agonists and TRPA1 antagonists for the treatment and prevention of diabetic pain.


application_id: 8733724
project_number: 5P20GM103527-07
project_title: Quantifying the effect of obesity and comorbid hypertension on cardiac function
administering_ic: NIGMS
award_notice_date: 2014-08-12
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
study_section: ZGM1-TWD-Y
subproject_number: 5039
contact_pi_person_id: 9404495
contact_pi: FORNWALT, BRANDON K
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: 2014-08-01
budget_end_date: 2015-07-31
project_abstract:
Obesity is a major public health problem affecting over one third of adults in the United States and one in five children. Obesity is related to an increased risk of cardiovascular mortality which may in part be mediated through a direct effect on the heart leading to dysfunction. However the time course over which obesity leads to cardiac dysfuncfion the underlying mechanisms of myocardial dysfunction in obesity and potential treatments have not been fully elucidated. Our preliminary data ufilizing cardiac magnefic resonance imaging (MRI) show abnormalifies in the magnitude of contracfion synchrony of contraction and myocardial mass in the hearts of mice fed a high-fat Western diet. The objective of this project is to define the time course over which this dysfunction occurs in mice evaluate the role of hypertension in the development of this dysfunction and to translate this work into humans by determining whether children in our pediatric obesity clinic have evidence of cardiac dysfunction. This project has 3 specific aims as follows: 1) Determine the time course over which myocardial dysfunction develops in mice fed a high-fat Western diet. We will quantify advanced measures of cardiac function assessing mass contraction and relaxation and synchrony overtime in a longitudinal study using magnetic resonance imaging. 2) Determine the effect of anti-hypertensive therapy on the development of hypertrophy and cardiac dysfunction in mice fed a high-fat Western diet. Mice on a high-fat Western diet develop obesity-related hypertension that is reversible with anti-hypertensive therapy. However the effect of anti-hypertensive therapy on cardiac function in obese mice has not been studied and may elucidate underiying mechanisms. We will compare cardiac function measured in the'mice on a high-fat Western diet in specific aim 1 to a group of mice on a high-fat Western diet and hydralazine. 3) Quantify cardiac function in children with obesity using advanced MRI. State-of-the-art technology at the University of Kentucky enables us to directly translate our findings in mice into our pediatric obesity clinic with over 800 patients. The effect of obesity on myocardial function in children is largely unknown.

project_terms:
Adult;Affect;Animals;Antihypertensive Agents;Blood Pressure;Cardiac;Cardiac Function Study;Cardiovascular Diseases;Child;Childhood;Clinic;Computer software;Data;Development;Diet;Fat-Restricted Diet;Fatty acid glycerol esters;Functional disorder;Heart;Heart Hypertrophy;Human;Hydralazine;Hypertension;Image;Kentucky;Longitudinal Studies;Magnetic Resonance Imaging;Measures;Mediating;Mortality Vital Statistics;Mus;Myocardial;Myocardial Contraction;Myocardial dysfunction;Obese Mice;Obesity;Obesity Related Hypertension;Patients;Pharmaceutical Preparations;Protocols documentation;Relaxation;Research;Role;Technology;Time;Translating;Translations;United States;Universities;Weight;Work;cardiovascular risk factor;feeding;heart function;mouse model;normotensive;public health medicine (field)


application_id: 8733722
project_number: 5P20GM103527-07
project_title: Pathology Core D
administering_ic: NIGMS
award_notice_date: 2014-08-12
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
study_section: ZGM1-TWD-Y
subproject_number: 5037
contact_pi_person_id: 1879534
contact_pi: KATZ, WENDY S
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: 2014-08-01
budget_end_date: 2015-07-31
project_abstract:
The Pathology Core (D) will be located in the Charles T. Wethington Building at the University of Kentucky. This core will provide equipment services and training for processing and sectioning tissues embedded in paraffin. Dr. Katz will oversee this core which includes sectioning and basic stains as well as immunostains for common epitopes linked to obesity and adipose inflammation. Equipment includes a tissue processor two paraffln microtomes microscope and stage for stitching paraffin sections together through imaging software.

project_terms:
Adipose tissue;Cardiovascular Diseases;Common Epitope;Computer software;Equipment;Frozen Sections;Image;Image Analysis;Inflammation;Kentucky;Link;Mentors;Microscope;Microtome - medical device;Obesity;Paraffin;Paraffin Embedding;Paraffin Tissue;Pathology;Pilot Projects;Process;Research;Research Personnel;Sampling;Services;Staging;Staining method;Stains;Technical Expertise;Tissue Embedding;Tissue Sample;Tissue Stains;Tissues;Training;Universities;interest;tissue processing


application_id: 8732752
project_number: 1R56HL116517-01A1
project_title: Enhancing Internet behavioral weight loss programs with portion controlled foods
administering_ic: NHLBI
award_notice_date: 2013-09-13
opportunity_number: PA-11-260
application_type: 1
activity_code: R56
ic: HL
serial_number: 116517
suffix: A1
program_official: BOYINGTON, JOSEPHINE
project_start_date: 2013-09-20
project_end_date: 2015-02-28
study_section: Special Emphasis Panel[ZRG1-HDM-R(02)M]
contact_pi_person_id: 9848799
contact_pi: WEBBER, KELLY HARMON
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: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Enhancing Internet behavioral weight loss programs with portion controlled foods (Webber PI) Obesity is arguably the most pressing public health concern in the U.S. Currently two-thirds of U.S. adults are overweight or obese. Excess weight is associated with increased risk of chronic diseases including coronary heart disease Type 2 diabetes and some cancers. Modest weight loss even as little as 5-10% of baseline body weight can reduce chronic disease risk. Both Internet and face-to-face behavioral weight loss programs produce clinically significant weight loss results. Research has shown that adding structure to a low-calorie diet increases adherence and weight loss. Therefore one possible enhancement to weight loss involves bringing together behavioral programs with portion controlled foods (PCD). The Overall Goal of this project is to develop deliver and evaluate four different weight loss interventions. To achieve this goal the following specific aims are proposed: 1. To evaluate the effectiveness and cost effectiveness of four different weight loss intervention approaches: (1) face-to-face program alone (2) face-to-face program supplemented with six months of  PCD (3) Internet program alone and (4) Internet program supplemented with six months of PCD for  producing weight loss and improvements in metabolic syndrome biomarkers at 3 6 and 12 months. 2. To evaluate each of the four different intervention approaches for differences in the behavioral mediators of self-monitoring social support self-efficacy and motivation at 3 6 and 12 months. Participants will be randomized to one of four groups for the six month intervention which will be followed with a six month follow-up period. Primary and secondary outcomes including weight abdominal and waist circumferences dietary intake physical activity resting blood pressure blood lipids fasting glucose and insuli HbAlc hs-crp and psychosocial variables will be taken in the clinic at baseline 3 6 and 12 months. The study will be powered using a non-inferiority trial design to demonstrate that the Internet plus PCD intervention is clinically at least as effective as the face-to-face alone intervention over six months of treatment.

project_terms:
Abdomen;Accountability;Adherence (attribute);Adult;Behavioral;Biological Markers;Blood Pressure;Body Weight;Body Weight decreased;Body mass index;Chronic Disease;Clinic;Clinical Trials Design;Coronary heart disease;Coupled;Diet;Dietary intake;Effectiveness;Federal Government;Food;Goals;Incidence;Insulin;Insurance;Insurance Carriers;Internet;Intervention;Malignant Neoplasms;Mediator of activation protein;Medicare;Metabolic syndrome;Methods;Monitor;Motivation;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Overweight;Participant;Patients;Persons;Physical activity;Pilot Projects;Privacy;Professional counselor;Psychosocial Factor;Randomized;Research;Research Personnel;Rest;Risk;Self Determination;Self Efficacy;Social support;Structure;Technology;Travel;United States;Visit;Weight;base;blood lipid;clinically significant;cost;cost effective;cost effectiveness;disorder risk;evidence base;fasting glucose;follow-up;improved;obesity treatment;peer;portion control;primary outcome;programs;public health medicine (field);public health relevance;secondary outcome;theories;tool;waist circumference;weight loss intervention

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Excess weight is associated with increased risk of chronic diseases while modest weight loss even as little as 5-10% of baseline body weight can reduce chronic disease risk. However it is unclear what types of interventions are the most effective or cost-effective to achieve weight loss. Internet behavioral weight loss programs are one available cost-effective tool and coupled with a portion controlled diet hold immense promise. There is a need to determine if adding a portion controlled diet to an Internet-based program can produce similar weight loss results as the more expensive in-person treatments. These findings will have implications for weight loss treatment coverage by large insurers and the federal government and will also contribute to the basic understanding of weight loss treatments.


application_id: 8732645
project_number: 5U24DK097215-02
project_title: ANALYTICAL CORE
administering_ic: NIDDK
award_notice_date: 2014-08-25
opportunity_number: RFA-RM-11-016
application_type: 5
activity_code: U24
ic: DK
serial_number: 097215
study_section: Special Emphasis Panel[ZRG1-BST-F]
subproject_number: 6290
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;LANE, ANDREW N.;MOSELEY, HUNTER NATHANIEL
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: 2014-09-01
budget_end_date: 2015-08-31
project_terms:
Age;Biochemical;Biochemical Pathway;Biological;Biomass;Cell Culture Techniques;Cells;Chromatography;Client;Collaborations;Communities;Complement;Consult;Consultations;Coupled;Culture Media;Data;Data Analyses;Data Collection;Databases;Detection;Development;Diagnosis;Experimental Designs;Fourier transform ion cyclotron resonance;Gas-Liquid Chromatography;Goals;Human Resources;Image;Informatics;Infusion procedures;Instruction;Isotopes;Journals;Label;Letters;Mass Spectrum Analysis;Measures;Metabolic;Metabolic Pathway;Methods;Mole the mammal;NMR Spectroscopy;Pathway interactions;Procedures;Process;Protocols documentation;Research;Resolution;Resources;Running;Sampling;Services;Study Section;System;Techniques;Technology;Therapeutic;Therapeutic Intervention;Tissues;Tracer;United States National Institutes of Health;Update;Work;analytical method;base;computerized data processing;coping;data acquisition;data reduction;human disease;improved;in vivo;instrument;instrumentation;meetings;metabolomics;operation;outcome forecast;outreach;pre-clinical;reconstruction;research study;response;stable isotope;wiki


application_id: 8732643
project_number: 5U24DK097215-02
project_title: ADMINISTRATIVE
administering_ic: NIDDK
award_notice_date: 2014-08-25
opportunity_number: RFA-RM-11-016
application_type: 5
activity_code: U24
ic: DK
serial_number: 097215
study_section: Special Emphasis Panel[ZRG1-BST-F]
subproject_number: 6288
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;LANE, ANDREW N.;MOSELEY, HUNTER NATHANIEL
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: 2014-09-01
budget_end_date: 2015-08-31
project_terms:
Annual Reports;Award;Biochemical;Biological Markers;Budgets;Cancer Center Support Grant;Charge;Client;Clinical;Complex;Consultations;Contracts;Core Facility;Cost Effectiveness Analysis;Data;Data Analyses;Databases;Development;Diagnostic;Distance Learning;Doctor of Philosophy;Educational workshop;Ensure;Fees;Funding;Goals;Grant;Health;Health Services Research;Human Resources;Income;Informatics;Instruction;Legal patent;Letters;Occupational activity of managing finances;Personnel Management;Pharmaceutical Preparations;Phase;Policies;Reporting;Resources;Role;Sampling;Schedule;Scientist;Services;Source;Stream;Structure;System;Technology;Training;Translating;Travel;United States National Institutes of Health;base;commercialization;cost;human disease;meetings;metabolomics;novel;operation;outreach;programs;research study;stable isotope;symposium;therapeutic target;web interface;web site


application_id: 8731866
project_number: 5R01DK091338-02
project_title: Low-dose irradiation as a novel intervention for diabetic nephropathy
administering_ic: NIDDK
award_notice_date: 2014-08-25
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DK
serial_number: 091338
program_official: FLESSNER, MICHAEL FRANCIS
project_start_date: 2013-09-15
project_end_date: 2016-08-31
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 6879103
contact_pi: CAI, LU
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    The goal of this study is to develop low-dose radiation (LDR) as a new tool to prevent and treat diabetic nephropathy. Currently no effective preventive or therapeutic approaches are available to treat diabetic nephropathy which is the most common cause of renal failure. We have been investigating the biological effects of LDR including its hormesis and adaptive response in vitroand in vivo. A major advantage of LDR is that it activates many genes in antioxidant and anti-inflammatory pathways rather than just single protective gene potentially making LDR a very potent and novel therapeutic approach. This was borne out by our preliminary studies that show that LDR at 25 mGy decreases diabetic nephropathy by significantly reducing diabetes-induced renal oxidative damage and inflammation. Our latest preliminary data show up-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression and protein kinase B (also called Akt) phosphorylation in the kidney of diabetic mice also exposed to LDR at 25 mGy. NRF2 is a transcription factor involved in expression of a broad range of protective genes. Therefore our central hypothesis is that exposure of diabetic animals to LDR can prevent and treat diabetic nephropathy by activation of many protective genes through stimulation of the Nrf2 pathway.  This hypothesis will be tested through three specific Aims: (1) LDR at the optimal condition not only prevents but also delay diabetic nephropathy; (2) the optimal LDR is safe for diabetic subjects; (3) the renal protection by the optimal LDR is predominantly mediated by up- regulating Nrf2-mediated multiple antioxidant components.  The great advantage of LDR is that it offers a highly controllable non-invasive method for eliciting endogenous synergistic tissue protection and repair mechanisms. This innovative approach will be particularly valuable for the diabetic patient who already has significantly decreased renal function that increases the toxicityof invasive drugs. Therefore this project will open a new avenue for the prevention and treatment of diabetic complications.

project_terms:
Adverse effects;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Apoptotic;Biological;Cell Death;Cell Nucleus;Cell Proliferation;Complications of Diabetes Mellitus;Cytogenetics;Cytosol;Data;Diabetes Mellitus;Diabetic Nephropathy;Diabetic mouse;Disease;Dose;Drug Combinations;Drug Targeting;Drug usage;Frequencies (time pattern);Genes;Germ Cells;Glycogen Synthase Kinase 3;Goals;Harvest;In Vitro;Inflammation;Intervention;Kidney;Kidney Diseases;Kidney Failure;Low Dose Radiation;Mediating;Methods;Modality;Modeling;Mus;Organ;Pathway interactions;Pharmaceutical Preparations;Phosphorylation;Prevention;Preventive;Protein Tyrosine Kinase;Proto-Oncogene Proteins c-akt;Proto-Oncogenes;Radiation;Radiation therapy;Reactive Oxygen Species;Renal function;Renin-Angiotensin System;Risk;Rodent;Role;Safety;Streptozocin;Testing;Therapeutic;Therapeutic Effect;Tissues;Toxic effect;Up-Regulation (Physiology);Work;cytotoxic;diabetic;diabetic patient;in vivo;innovation;irradiation;mouse model;novel;novel strategies;novel therapeutic intervention;nuclear factor-erythroid 2;oxidative damage;prevent;public health relevance;repaired;response;safety testing;tool;transcription factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    The objective of this study is to apply low-dose radiation (LDR) as a new and non-invasive tool to prevent and treat diabetic nephropathy through stimulation of renal multiple protective mechanisms against oxidative damage and inflammation. We will firstly define the optimal condition of LDR to prevent and treat diabetic nephropathy with type 1 and type 2 diabetic mouse models and then determine the safety for diabetic subjects to expose to LDR and underlying mechanisms for the renal protection from diabetes by LDR. This project represents a unique approach to apply LDR to activate multiple protective pathways unlike most currently- used drugs only working on a single pathway.


application_id: 8731642
project_number: 5R00CA158009-04
project_title: The role of the first mammalian N-term. methyltransferase NRMT in tumorigenesis
administering_ic: NCI
award_notice_date: 2014-07-30
opportunity_number: PA-10-063
application_type: 5
activity_code: R00
ic: CA
serial_number: 158009
program_official: OKANO, PAUL
project_start_date: 2011-09-05
project_end_date: 2016-08-31
study_section: NSS
contact_pi_person_id: 8476980
contact_pi: SCHANER-TOOLEY, CHRISTINE E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The list of genes involved in tumorigenesis is quite extensive however many of their biological functions remain unknown. One such gene Mettl11a (now renamed NRMT) has been shown to be under-expressed in breast cancers but has only recently been identified as the first mammalian N-terminal methyltransferase. Reduction of NRMT also results in a multi-spindle phenotype and the associated aneuploidy is often considered to contribute to cancer progression. As NRMT is a newly discovered protein the goals of this proposal are to understand the role of N-terminal methylation on protein and cellular function in order to study how its misregulation leads to tumorigenesis. The first two aims determining whether N-terminal methylation is constitutive and determining whether N-terminal methylation universally alters the DNA binding of its substrates are designed to better understand the basic biology of N-terminal methylation. These aims will involve mass spectrometry fluorescent-activating cell sorting FRET analysis and construction of a knockout mouse. The objective of the third aim is to determine the role of NRMT in development and tumorigenesis. A mouse mammary transplant model will be established for assaying if the multi-spindle NRMT knockdown phenotype leads to developmental defects and/or tumorigenesis. The key element of the career development aspect of this proposal will be learning the mouse system needed for successful completion of the third aim. The experiments of aims one and two have been designed for the downtime between surgeries and gland or tumor harvesting. Environment The University of Virginia is well equipped for completion of all three aims of this proposal. The on-campus mass spectrometry facility of advisory committee member Dr. Don Hunt has a Fourier transform mass spectrometer necessary for distinguishing N-terminal methylation from acetylation. The UVA Flow Cytometry Core will provide the training necessary for all fluorescent-activating cell sorting experiments. The UVA Gene Targeting and Transgenic Facility will create the NRMT knockout mouse. The Research Histology Core will paraffin embed and make slides of all normal mouse tissue and tumors. My advisory committee member Dr. Amy Bouton will aid in interpretation of the histology. The expertise and reagents of advisory committee member Dr. Todd Stukenberg will aid in characterization of the NRMT multi-spindle phenotype. The UVA W.M. Keck Center for Cellular Imaging supplies state-of-the art imaging facilities for immunofluorescent imaging of mouse tissue samples and training in FRET analysis. The Macara lab currently has three expert mouse biologists available for training in mouse handling and surgical techniques. In addition UVA offers numerous courses aimed at career development/training including the UVA transgenic methods and applications workshop the Flow Cytometry Training Workshop the Workshop on FRET Microscopy and a monthly career development seminar series offered by the Office of Postdoctoral Professional Development.

project_terms:
A Mouse;Acetylation;Advisory Committees;Affect;Aneuploidy;Antibodies;Apoptotic;Binding (Molecular Function);Biological;Biological Assay;Biological Process;Biology;Breast Epithelial Cells;Cell Cycle;Cell Line;Cell Proliferation;Cell Separation;Cell physiology;Chromatin;Committee Members;Consensus Sequence;Cytoplasm;DNA;DNA Binding;DNA repair protein;DNA-Binding Proteins;Data;Defect;Development;Educational workshop;Elements;Embryo;Environment;Exhibits;Fatty acid glycerol esters;Fibroblasts;Flow Cytometry;Fluorescence Resonance Energy Transfer;Fourier Transform;Future;Gene Combinations;Gene Targeting;Genes;Genetic;Gland;Glioblastoma;Goals;Growth;Harvest;Histology;Image;Immunoprecipitation;In Vitro;Knockout Mice;Learning;Mammary gland;Mass Spectrum Analysis;Measures;Mentors;Methods;Methylation;Methyltransferase;Microarray Analysis;Microscopy;Mitotic;Modeling;Modification;Monitor;Mono-S;Mus;Mutation;N-terminal;Neoplasm Metastasis;Nuclear;Oncogene Proteins;Operative Surgical Procedures;Paraffin Embedding;Patients;Pattern;Pharmaceutical Preparations;Phase;Phenotype;Post-Translational Protein Processing;Process;Proteins;Reagent;Research;Retinoblastoma Protein;Role;Running;Series;Site;Slide;System;Techniques;Testing;Therapeutic Agents;Tissue Sample;Training;Transgenic Organisms;Transplantation;Tumor Suppressor Genes;Tumor Suppressor Proteins;Tumor Tissue;Universities;Virginia;career development;cellular imaging;chromatin immunoprecipitation;design;in vitro Assay;in vivo;interest;leukemia;malignant breast neoplasm;mass spectrometer;mouse model;mutant;myosin light chain 2;protein function;research study;skills;stoichiometry;tool;tumor;tumor progression;tumorigenesis

public_health_relevance:
The biological roles of many genes involved in tumorigenesis remain unknown. We need to study their functions in order to achieve a complete understanding of cancer progression and obtain an inclusive list of potential druggable targets. One such protein NRMT the newly identified mammalian N-terminal methyltransferase is under-expressed in breast cancers and its knockdown results in mitotic defects often considered to contribute to cancer progression. The goal of this proposal is to understand how NRMT is regulated and how its misregulation contributes to tumorigenesis.


application_id: 8731428
project_number: 1R15HD076643-01A1
project_title: miRNA expression after spinal cord compression injury in Xenopus laevis
administering_ic: NICHD
award_notice_date: 2014-08-14
opportunity_number: PAR-12-057
application_type: 1
activity_code: R15
ic: HD
serial_number: 076643
suffix: A1
program_official: HENKEN, DEBORAH B
project_start_date: 2014-08-15
project_end_date: 2018-07-31
study_section: Special Emphasis Panel[ZRG1 CB-L (80)]
contact_pi_person_id: 11524442
contact_pi: GIBBS, KURT
other_pis: Not Applicable
congressional_district: 05
department: BIOLOGY
primary_duns: 041957010
primary_uei: MRGUP99ZAZ59
duns_number: 041957010
uei: MRGUP99ZAZ59
fips: US
organization_id: 569601
organization_name: MOREHEAD STATE UNIVERSITY
organization_city: MOREHEAD
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 403511684
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): In the United States alone a new spinal cord injury occurs every 40 minutes and to date there are no effective treatments to restore lost sensory and motor function resulting from injury. This is largely due to the lack of regenerative capacity of the mammalian central nervous system (CNS). Unlike mammals Xenopus frogs are able to regenerate their spinal cord after injury as tadpoles but lose this ability as adult frogs. The ability to regenerate the CNS declines as development progresses a phenomenon that can be observed throughout the vertebrate subphylum. By using Xenopus as an experimental model for spinal cord injury we have the opportunity to elucidate the molecular factors that promote and inhibit functional recovery after spinal cord injury by comparing the regeneration response of the tadpole to that of the adult frog. The body of literature encompassing the efforts of several decades of research suggests it is unlikely that an effective treatment for SCI will be found by the targeted deletion or addition of a single gene. As microRNAs (miRNAs) can simultaneously modulate the expression of hundreds of genes we feel that they make excellent candidates to enhance functional recovery after SCI. In previous work we found miR-133b to promote CNS regeneration. Our preliminary data shows miR-133b to be developmentally regulated in Xenopus as it is robustly expressed in the tadpole CNS and is substantially reduced in the adult. In the research proposed herein we will establish Xenopus laevis as a new model for spinal cord compression injury research and use Next-Generation sequencing to assay the changes in miRNA expression that occur during successful CNS regeneration in the tadpole compared to failed regeneration in the adult frog. We will select candidate miRNAs that promote regeneration in tadpoles and express them in adult frogs in an effort to promote functional recovery in the adult. We will also inhibit the expression of these same miRNAs in developing embryos to confirm their contribution to spinal cord regeneration and determine their role in nervous system development. We expect the results of this research to generate new therapeutic targets to promote functional recovery from SCI in humans.  The National Institutes of Health (NIH) is interested in providing undergraduate research opportunities (URO) to develop the nation's best and brightest aspiring scientists. Universities whose primary focus is education are not regular recipients of NIH funding and therefore have fewer research opportunities for undergraduates interested in careers in science. The results of a survey of URO participants indicated that undergraduates were more interested in research careers and advanced degrees when provided UROs [1]. Thus funding developmental biology research in educationally focused universities will expand the pool of future developmental scientists by training students who would otherwise not be provided such opportunities. The research proposed herein will help accomplish this goal by engaging undergraduates and providing UROs in developmental biology while simultaneously strengthening the research environment in our university.

project_terms:
Adult;Affect;Amphibia;Biological Assay;Contusions;Data;Development;Developmental Biology;Devices;Educational aspects;Embryo;Environment;Experimental Models;Funding;Future;Genes;Genetic;Goals;Human;In Situ Hybridization;Injury;Literature;Mammals;MicroRNAs;Modeling;Molecular;Molecular Profiling;Motor;Natural regeneration;Nerve Regeneration;Neuraxis;Outcome;Participant;Process;Rana (genus);Recovery;Recovery of Function;Regulation;Research;Role;Science;Scientist;Sensory;Spinal Cord;Spinal Cord transection injury;Spinal cord injury;Students;Surveys;Swimming;Tadpoles;Therapeutic;Training;United States;United States National Institutes of Health;Universities;Validation;Vertebrates;Work;Xenopus;Xenopus laevis;career;cell type;effective therapy;interest;nervous system development;new therapeutic target;next generation sequencing;public health relevance;regenerative;response;small molecule;spinal cord compression;spinal cord regeneration;therapeutic target;tool;undergraduate research;xenopus development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Xenopus frogs can regenerate their spinal cord as tadpoles but lose the ability to do so after developing into adult frogs. microRNAs are small molecules that regulate the expression of many other genes during development in all vertebrates. This project will determine how developmental changes in microRNA expression affect the ability of Xenopus frogs to regenerate their spinal cords. In doing so we hope to increase our understanding of the genetic regulation associated with recovery from spinal cord injury and generate new therapeutic targets to promote recovery in humans.


application_id: 8731267
project_number: 5R01HD075783-02
project_title: Evaluating the long-term effects of Green Dot on teen dating violence prevention
administering_ic: NICHD
award_notice_date: 2014-04-24
opportunity_number: PA-09-169
application_type: 5
activity_code: R01
ic: HD
serial_number: 075783
program_official: NEWCOMER, SUSAN
project_start_date: 2013-09-06
project_end_date: 2018-05-31
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 1894149
contact_pi: COKER, ANN L
other_pis: FOLLINGSTAD, DIANE RUTH
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: 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:
Accounting;Address;Adolescent;Adult;Binding (Molecular Function);Cohort Studies;Collection;Data;Data Analyses;Diffuse;Educational Status;Educational aspects;Elements;Equation;Evaluation;Exposure to;Family Violence;Frequencies (time pattern);Funding;High School Student;Incidence;Individual;Intervention;Intervention Trial;Kentucky;Length;Life;Life Experience;Long-Term Effects;Measurement;Measures;Military Personnel;Outcome;Participant;Poa plant;Population;Pregnancy;Prevention program;Preventive Intervention;Primary Prevention;Randomized;Recruitment Activity;Relative (related person);Risk Estimate;Schools;Students;Substance abuse problem;Teen Dating Violence;Testing;Time;Training;Universities;Victimization;Violence;base;cohort;college;dating violence;dating violence prevention;design;emerging adult;experience;follow-up;high risk;high school;innovation;member;novel;partner violence;peer;peer violence;population based;programs;prospective;public health relevance;randomized trial;sexual violence;social norm;stressor;therapy design;twelfth grade;violence prevention;young adult


application_id: 8731241
project_number: 5K08EY021757-04
project_title: Endothelial Cell Dysregulation in Neovascular AMD
administering_ic: NEI
award_notice_date: 2014-08-20
opportunity_number: PA-10-059
application_type: 5
activity_code: K08
ic: EY
serial_number: 021757
program_official: AGARWAL, NEERAJ
project_start_date: 2011-09-01
project_end_date: 2016-08-31
study_section: ZEY1-VSN(11)
contact_pi_person_id: 8784086
contact_pi: KLEINMAN, MARK E
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The candidate is applying for a Mentored Clinical Scientist Research Career Development Award (K08) to  support a 5 year research career training program that will significantly bolster his transition to faculty  independence as a fellowship trained clinician-scientist specializing in vitreoretinal and macular diseases. The  rigorous training program has been designed with extensive input and unyielding support from the candidate's  mentor co-mentor chairman and advisory committee. All training will take place in the excellent scientific and  academic environment of the University of Kentucky Department of Ophthalmology and Visual Sciences which  includes an ocular angiogenesis research consortium consisting of four independent investigators. The  applicant will spend the first 3 years of the program as a Research Assistant Professor and Clinical Fellow. The  specific design of the fellowship is precisely detailed in the Career Development section and accompanied by a  very strong institutional commitment that allows the candidate at least 80% effort performing research and 20%  performing clinical duties. After completion of the fellowship the candidate will transition to a full-time faculty  position as Assistant Professor at University of Kentucky with the same institutional commitment of 80%  research and 20% clinical effort. The long-term goal of the award is to offer the candidate the critical career  development support to establish a pathway to faculty independence that will extensively train him as a  biomedical researcher confident and masterful specialist in the diagnosis and treatment of vitreoretinal and  macular diseases and leading academician. The candidate aims to have an independent laboratory up and  running within the initial 12-18 months of the award period in order to gain early independence with his  research project and develop critical principal investigator skills with guidance from his established mentors  and advisory committee. The research plan has been devised by the candidate and his mentors and aims to  extend his scientific expertise beyond basic vascular biology with a rich experience to develop new techniques  and to utilize such methods in experimental designs to obtain critical data that expand his current fund of  knowledge in order to yield fundamental insights on endothelial cell dysregulation immuno-modulation in  vascular growth and therapeutic targets in neovascular age-related macular degeneration (AMD).  AMD is a devastating blinding disease that affects as many as 10 million Americans a number that rivals the  prevalence of all cancers combined and is unfortunately expected to double by 2020. The overwhelming cause  of severe vision loss in AMD is choroidal neovascularization (CNV) the growth of abnormal blood vessels  beneath the retina. Despite the use of recently approved molecular therapeutics targeting vascular endothelial  growth factor (VEGF)-A the majority of patients do not regain functional vision and a significant fraction  progress to legal blindness. This treatment failure is attributed to the frequent clinical situation in which patients  present to eye physicians after vision is already lost and irreversible structural and functional tissue damage  has already occurred. Moreover while patients with AMD often undergo at least one or more dilated eye  examinations per year the physician is often not able to detect CNV before it grows beneath the retina and  wreaks havoc. Fortunately there is an exciting development that may provide the first available technique for  detecting incipient CNV in patients with AMD thereby allowing for earlier detection and treatment to prevent  loss of vision and quality of life. This discovery was recently reported in the journal Nature and described as  the first molecular marker that is specific for human CNV (Takeda et al. Nature 2009). It is an immune receptor  called chemokine receptor 3 (CCR3) that is involved in allergic response and recruitment of white blood cells  but may also be found on inflamed and growing blood vessels.  The identification of CCR3 as a molecular signature has opened a gateway to a new understanding in vascular  disease in AMD. CCR3 expression is found on the surface of the specialized endothelial cells that line the  abnormal blood vessels. In this proposal rigorous basic science investigations of the cellular circuitry that  mediates this pathogenic switch will be explored in conjunction with the biological relationships between  endothelial cell dysregulation aging immune activation and oxidative stress. The initial aim of the study is to  decipher how these established AMD risk factors regulate the progression of disease through chemokine and  other immune signaling pathways in order to develop appropriately targeted diagnostics and therapeutics that  will enable clinicians to offer improved care of patients suffering from AMD. A second aim focuses specifically  on CCR3 biology with scientific exploration of its pathogenetic induction expression patterns and signaling  effects during endothelial cell dysregulation in neovascular AMD. In a final aim optimized fluorescent CCR3-  targeting probes will be engineered and applied to pre-clinical animal models of CNV and human cellular  toxicology studies in order to obtain necessary data to proceed with future clinical studies. These specific  experimental aims will provide fundamental insights into the modulatory function of the immune system  chemokine signaling and the role of CCR3 as a molecular switch during the endothelial cell dysregulation that  heralds vision loss in neovascular AMD.

project_terms:
Ablation;Accounting;Advisory Committees;Affect;Age related macular degeneration;Aging;American;Animal Model;Architecture;Area;Automobile Driving;Award;Basic Science;Biological;Biological Markers;Biology;Biomedical Research;Blindness;Blood;Blood Vessels;Bone Marrow Transplantation;Cell Line;Cells;Chairperson;Choroidal Neovascularization;Chromatin Remodeling Factor;Clinical;Clinical Research;Complement Activation;Coupled;Data;Detection;Development;Diagnosis;Diagnostic;Disease;Disease Progression;Drusen;Dyes;Early Diagnosis;Early Intervention;Early treatment;Endothelial Cells;Engineering;Environment;Experimental Designs;Exudative age-related macular degeneration;Eye;Faculty;Fellowship;Fluorescein Angiography;Funding;Future;Gene Expression Profile;Genetic;Goals;Grant;Growth;Human;Hypersensitivity;Image;Imaging Techniques;Immune;Immune system;Immunoglobulin Fragments;Immunologic Receptors;In Vitro;Inflammation;Interleukins;Invaded;Investigation;Journals;K-Series Research Career Programs;Kentucky;Knowledge;Laboratories;Lead;Legal;Legal Blindness;Lesion;Leukocytes;Ligands;Malignant Neoplasms;Maps;Mediating;Medicine;Mentors;Methods;Molecular;Molecular Profiling;Molecular Target;Mus;Nature;Nonexudative age-related macular degeneration;Ophthalmic examination and evaluation;Ophthalmology;Outcome;Oxidative Stress;Pathogenesis;Pathologic Processes;Pathway interactions;Patient Care;Patients;Pattern;Physicians;Positioning Attribute;Prevalence;Principal Investigator;Process;Progressive Disease;Quality of life;Regulation;Relative (related person);Reporting;Research;Research Personnel;Research Project Grants;Research Training;Retina;Retinal Diseases;Risk Factors;Role;Running;Safety;Scientist;Sensitivity and Specificity;Signal Pathway;Signal Transduction;Signaling Molecule;Specialist;Specimen;Staging;Structure of retinal pigment epithelium;Sum;Surface;Symptoms;Techniques;Testing;Therapeutic;Therapeutic Uses;Time;Tissues;Toxicology;Training;Training Programs;Transgenic Mice;Treatment Efficacy;Treatment Failure;United States;Universities;Uveal Melanoma;Vascular Diseases;Vascular Endothelial Growth Factor A;Vision;Visual;Work;allergic response;base;career;career development;cell type;chemokine;chemokine receptor;cost;cytokine;cytotoxicity;design;disorder of macula of retina;experience;imaging probe;immune activation;improved;in vivo;insight;molecular marker;mouse model;nanocrystal;neutralizing antibody;next generation;normal aging;ocular angiogenesis;pre-clinical;prevent;professor;programs;research study;response;skills;small molecule;therapeutic development;therapeutic target;vision science

public_health_relevance:
The abnormal growth of blood vessels beneath the retina results in devastating vision loss in  age-related macular degeneration (AMD) yet the specific molecular and cellular mechanisms  by which this process occurs are an area of active scientific investigation. The proposal aims to  provide fundamental insights into the dysregulation of the specialized endothelial cells that line  the abnormal blood vessels during AMD progression. Importantly this award will grant the  candidate a critical opportunity to gain essential research training while greatly enhancing  career development and a confident transition to faculty independence.


application_id: 8728092
project_number: 5R01AG038651-04
project_title: Role of impaired cognitive states & risk factors in conversion to mixed dementias
administering_ic: NIA
award_notice_date: 2014-07-10
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AG
serial_number: 038651
program_official: ANDERSON, DALLAS
project_start_date: 2011-09-01
project_end_date: 2016-05-31
study_section: Neurological, Aging and Musculoskeletal Epidemiology Study Section[NAME]
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-15
project_abstract:
DESCRIPTION (provided by applicant): Population demographics suggest that with the expected dramatic increase in age-associated dementias a public health crisis is looming. Current emphasis is on disease prevention with a focus on elderly individuals who express some cognitive impairment. We propose to identify authoritatively the risk and protective factors for cognitive decline in older persons. We have shown how to define these impaired states retrospectively how to account for reverse transitions how to distinguish prevalence from incidence and how to account for competing risks by using a unique statistical (Markov) model. But sufficient longitudinal and neuropathological data is currently not available to distinguish among different types of dementia. No single Alzheimer's Disease Center (ADC) or cooperative study has an adequate sample size to reliably track transitions to dementia and differentiate Alzheimer's disease (AD) from other prevalent brain diseases that include vascular dementia (VaD) and Lewy body disease (LBD). This project will pool data from six well established longitudinal cohorts to identify risk factors for (1) preservation of intact cognition in those meeting neuropathological criteria for varying types of dementia and MCI and (2) specific forms of dementia (clinical and neuropathological). This will improve our understanding of intervening impaired states and factors that promote resistance to clinical symptoms despite the presence of neuropathology. These considerations lead to the specific aims below. Specific Aim 1: To merge databases from six large projects that follow cohorts of cognitively intact subjects to dementia for the purpose of rigorous statistical biologically-informed analyses that accentuate longitudinal follow-up: BRAiNS (University of Kentucky) Nun Study (University of Minnesota) Memory and Aging Project (Washington U) Kuakini Honolulu-Asia Aging Study Religious Orders Study (ROS Rush Medical University) and the OHSC ADC (Oregon Health & Science University). The database would be made publicly accessible. Specific Aim 2: To identify appropriate intervening states between intact cognition and dementia based on periodic assessments of cognition and functional skills from data collected at these centers. Specific Aim 3: To study transitions and associated risk factors (e.g. genetic medical time in an impaired state) using novel statistical methods. Specific Aim 4: To standardize the neuropathological findings across databases (including quantitative neuropathological assessments) to enable the analysis of novel pathogenetic determinants of outcomes. This aim allows us to evaluate how actual brain pathology (e.g. microinfarcts Lewy bodies hippocampal sclerosis and mixed pathologies) relates to antemortem states in the subset of participants coming to autopsy. This aim could support proposed revisions of current neuropathological and clinical research diagnostic criteria in dementia and preclinical dementia conditions.

project_terms:
Accounting;Age;Aging;Alzheimer's Disease;Americas;Asia;Autopsy;Biological Markers;Biological Preservation;Brain Diseases;Brain Pathology;Caring;Clinical;Clinical Data;Clinical Research;Clinical assessments;Cognition;Cognitive;Cohort Studies;Communities;Complement;Complex;Consensus;Data;Databases;Dementia;Diagnostic;Disease;Elderly;Epidemiology;Evaluation;Funding;Gray unit of radiation dose;Health Care Costs;Health Sciences;Hippocampus (Brain);Impaired cognition;Incidence;Individual;Investigation;Kentucky;Lead;Lewy Bodies;Lewy Body Disease;Magnetic Resonance Imaging;Measures;Medical;Medical Genetics;Memory;Meta-Analysis;Minnesota;Modeling;National Institute on Aging;Oregon;Outcome;Participant;Pathology;Patients;Population;Prevalence;Prevention strategy;Registries;Religion and Spirituality;Research;Research Personnel;Resistance;Resources;Risk;Risk Factors;Role;Sample Size;Sampling;Sclerosis;Series;Statistical Methods;Statistical Models;Symptoms;Time;United States National Institutes of Health;Universities;Validation;Vascular Dementia;Washington;aging brain;base;cohort;cooperative study;cost;demographics;design;disorder prevention;experience;follow-up;improved;innovation;insight;markov model;meetings;mild cognitive impairment;mixed dementia;neuropathology;novel;pre-clinical;prevent;prevention clinical trial;public health medicine (field);skills;treatment strategy

public_health_relevance:
With the graying of America the cost of caring for demented elderly will rise substantially in the next few decades. Current emphasis is on preventing this disease. This project will identify risk factors for various forms of dementia as well as impaired states that precede this disease.

other_pis:
KAYE, JEFFREY A;LIM, KELVIN O.;LIPTON, RICHARD B.;MASAKI, KAMAL ;SCHMITT, FREDERICK ;TYAS, SUZANNE LEIGH;XIONG, CHENGJIE ;YU, LEI


application_id: 8727511
project_number: 5F31DE022679-03
project_title: MicroRNAs and Parotid Acinar Cell Differentiation
administering_ic: NIDCR
award_notice_date: 2014-08-13
opportunity_number: PA-11-111
application_type: 5
activity_code: F31
ic: DE
serial_number: 022679
program_official: FRIEDEN, LESLIE A
project_start_date: 2012-09-01
project_end_date: 2016-08-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 11005944
contact_pi: METZLER, MELISSA A
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long term goal of this fellowship project is to be able to provide clinical intervention to patients suffering from salivary gland loss of function. Parotid gland dysfunction affects millions of people across the nation and stems from several causes. Sjogren's syndrome (which affects 2 - 4 million Americans) for instance results in hypofuction of the gland. Also radiation damage severely affects the parotid gland and is common among patients receiving treatment for head and neck carcinomas. Loss of function in patients results in chronic xerostomia. This leads to a reduction in quality of life for these patients as well as a reduction in overall oral health as the incidence of dental caries and periodontal disease increases. The ability to regenerate or restore function to damaged parotid glands would greatly increase patient health and quality of life. This requires further knowledge of how the gland develops and differentiates into its different cell types. Defining the molecular mechanisms of parotid differentiation is a significant goal. Specifically the parotid acinar cellsare responsible for producing and secreting the salivary proteins amylase parotid secretory protein (PSP) and others in response to parasympathetic nerve stimulation. Parotid salivary proteins contribute to defense against bacteria and yeast and initiation of digestion. These cells are highly specialized; however the terminal differentiation of this cell type is poorly understoo. Within the last decade the importance of microRNAs on the process of development and differentiation has been identified in many cell types. This suggests that microRNAs are a common mechanism used by the cell to control differentiation. However the role of microRNAs in acinar terminal differentiation has yet to be explored. It remains to be investigated if microRNA levels correlate with acinar differentiation in vivo and which microRNAs are important. This project addresses the hypothesis that microRNA expression drives gene networks that are important for parotid acinar differentiation through two separate aims. Aim one is to determine if microRNAs are differentially expressed during parotid acinar differentiation in vivo and as compared to undifferentiated acinar cells. And to identify potential microRNA target genes and networks. MicroRNA (and well as mRNA) levels will be measured throughout the course of parotid acinar differentiation in the rat with the goal of using bioinformatics techniques to identify potentially biologically relevant miRNA:mRNA interactions and gene regulatory networks. Aim 2 will experimentally test the function of the predicted interactions by determining if microRNAs drive expression of differentiation associated gene networks in parotid acinar cells. This project contributes to the long term goal of understanding salivary gland biology to the point that clinical interventions can be developed to regenerate or restore glands to those patients suffering from parotid hypofunction.

project_terms:
Acinar Cell;Address;Affect;American;Amylases;Bacteria;Bioinformatics;Biological Assay;Biology;Cell Differentiation process;Cell Line;Cells;Chronic;Clinical;Dental caries;Development;Digestion;Fellowship;Functional disorder;Gene Expression;Gene Targeting;Genes;Gland;Goals;Head and Neck Squamous Cell Carcinoma;Health;Incidence;Intervention;Knowledge;Lead;Luciferases;Measures;Messenger RNA;MicroRNAs;Molecular;Natural regeneration;Nerve;Oral health;Parotid Gland;Pathway interactions;Patients;Periodontal Diseases;Process;Publications;Quality of life;Radiation;Rattus;Regulator Genes;Relative (related person);Research;Role;Salivary;Salivary Glands;Salivary Proteins;Sjogren's Syndrome;Small RNA;Staging;Symptoms;System;Techniques;Testing;Transfection;Translational Repression;Undifferentiated;Untranslated Regions;Work;Xerostomia;Yeasts;base;cell type;functional restoration;gene interaction;in vivo;interest;knock-down;laser capture microdissection;loss of function;mRNA Transcript Degradation;member;parotid secretory protein;protein expression;response;stem;transcription factor

public_health_relevance:
The long term goal of this fellowship project is to be able to provide clinical intervention to patients suffering from salivary gland loss of function. The abiliy to regenerate or restore function to damaged parotid glands would greatly increase patient health and quality of life. This requires further knowledge of how the gland develops and differentiates into its different cell types. Defining the molecular mechanisms of parotid differentiation is the goal of this proposal.


application_id: 8727476
project_number: 5U54CA153604-05
project_title: Administrative Core
administering_ic: NCI
award_notice_date: 2014-08-28
opportunity_number: RFA-CA-09-032
application_type: 5
activity_code: U54
ic: CA
serial_number: 153604
project_end_date: 2018-02-28
study_section: ZCA1-PCRB-G
subproject_number: 7552
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
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: 2014-09-01
project_abstract:
The proposed Administrative Core builds upon the successful experience of the current ACCN leadership structure. The proposed structure will be led by a Headquarters unit located at the University of Kentucky (UK) and directed by Dr. Dignan proposed ACCN Director. The Administrative Core will also include Dr. Nancy Schoenberg UK Dr. Electra Paskett The Ohio State University (OSU) Dr. Samuel Lesko Northeast Regional Cancer Institute Dr. Eugene Lengerich Penn State University (PSU) Ms. Pamela Brown West Virginia University (WVU) and Dr. Karen Roberto Virginia Polytechnic Institute and State University (VT). This team has been working together for the past five years and over that time has amassed extensive experience with strategic planning and project management. Overall strategic planning for the ACCN will continue to take place through three means of communication; email correspondence monthly conference calls and semi-annual project meetings. Semi-annual face-to-face meetings are an essential opportunity for planning and will include community advisors investigators trainees the NCI CRCHD Program Director and project staff. These 2-day meetings are critical to management of the ACCN as they provide opportunities for lengthy discussions between the Community Advisory Committee and investigators a venue for sharing research progress a forum for proposing new research an opportunity for informal networking with the local community and an opportunity for CRCHD project monitoring. As we have done in the current ACCN project the locations for the meetings will rotate through each ACCN region. The first meeting ofthe ACCN will be held in the fall of 2010 in Blacksburg VA.

project_terms:
Address;Advisory Committees;Appalachian Region;Budgets;Communication;Communities;Community Outreach;Education and Outreach;Electronic Mail;Ensure;Faculty;Fostering;Goals;Grant;Information Dissemination;Information Services;Institutes;Kentucky;Leadership;Location;Malignant Neoplasms;Monitor;Ohio;Program Research Project Grants;Regional Cancer;Research;Research Personnel;Research Training;Services;Strategic Planning;Structure;Students;Time;Universities;Virginia;West Virginia;Work;cancer health disparity;community based participatory research;computerized data processing;experience;falls;health disparity;meetings;programs;symposium


application_id: 8727475
project_number: 5U54CA153604-05
project_title: Community Outreach Program
administering_ic: NCI
award_notice_date: 2014-08-28
opportunity_number: RFA-CA-09-032
application_type: 5
activity_code: U54
ic: CA
serial_number: 153604
project_end_date: 2018-02-28
study_section: ZCA1-PCRB-G
subproject_number: 7551
contact_pi_person_id: 8383256
contact_pi: BROWN, PAMELA K
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: 2014-09-01
project_abstract:
The focus of the ACCN Community Outreach Program is to use Community-Based Participatory Research (CBPR) principles and methodology to increase knowledge of access to and use of beneficial biomedical and behavioral procedures that will ultimately decrease the cancer burden in Appalachian counties in Kentucky Ohio Pennsylvania Virginia and West Virginia.

project_terms:
Appalachian Region;Area;Behavioral;Cancer Burden;Clinical Trials;Communities;Community Health;Community Outreach;County;Data Collection;Detection;Funding;Health Educators;Health Personnel;Kentucky;Knowledge;Malignant Neoplasms;Methodology;Ohio;Pennsylvania;Policy Maker;Population;Procedures;Program Evaluation;Resources;System;Virginia;West Virginia;base;cancer prevention;community based participatory research;design;evidence base;health disparity;health literacy;innovation;intervention program;literacy;member;outreach;outreach program;programs


application_id: 8727474
project_number: 5U54CA153604-05
project_title: Training Program
administering_ic: NCI
award_notice_date: 2014-08-28
opportunity_number: RFA-CA-09-032
application_type: 5
activity_code: U54
ic: CA
serial_number: 153604
project_end_date: 2018-02-28
study_section: ZCA1-PCRB-G
subproject_number: 7550
contact_pi_person_id: 6192172
contact_pi: LENGERICH, EUGENE 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: 2014-09-01
project_abstract:
There is a growing awareness in the academic and public health communities that biologic social and environmental factors all affect cancer risks and outcomes. In Appalachia residents tend to value individualism and self-reliance traditionalism family and place and religious fundamentalism.^^" Appalachian families often have a multigenerational character that influences all aspects of life. For example the health of family members across generations often is closely linked with lifestyle factors such as eating and physical activity habits. In the states comprising the ACCN there is a high prevalence of inadequate fruit and vegetable consumption among adult men (range 52-89%) and women (range 36-80%).Similariy residents reports of no physical activity within a month's time ranges from 24-37% for adult males and 29-41% for adult females.(211) Thus it is not surprising that almost one-third of residents in each of the ACCN states are obese. Obesity and inactivity has been associated with increased risk of cancers of the breast (postmenopausal) endometrium colon kidney gallbladder ovaries pancreas and esophagus.(212) Explanations for these linkages vary and are inconclusive but include limited education and lack of risk awareness higher illness burden associated with obesity low self-perception and body image social discrimination and poor patient-physician relationships and communication all of which may influence participation in screening and other cancer prevention activities. To further understanding of cancer risk factors such obesity and inactivity as well as the implementation of evidence-based prevention and intervention programs to promote cancer awareness screening and behavioral change requires a well-trained cadre of researchers and community professionals working together to develop test and disseminate new and culturally appropriate strategies that lead to improved outcomes and reduced cancer risk in Appalachia. The Appalachian Cancer Scholars Program (ACSP) will build upon the solid foundation of individual ACCN senior investigators and their collaborative efforts as a team dedicated to using CBPR to reduce the cancer burden in Appalachia. The previous ACCN had four pilots funded by the National Cancer Institute [Project Directors: Drs. Curry (Penn State University) Vanderpool (University of Kentucky) Kluhsman (Penn State University) and Demian (West Virginia University)]. The ACCN has provided a framework for promotion in rank of two investigators: Dr. Kluhsman Penn State University from Senior Research Associate to Assistant Professor and Dr. Katz Ohio State University from Assistant Professor to Associate Professor. Dr. Kluhsman's 2008 dissertation was an investigation of factors associated with adoption of evidence-based strategies by ACCN cancer coalitions to increase cancer screening. While Kluhsman was based at Penn State University and her PhD was awarded from the University of Colorado her dissertation committee was chaired by Dr. Dignan at University of Kentucky. Dr. Raup-Krieger the principal investigator of the proposed pilot project received her PhD from Penn State University with a dissertation supported by the ACCN. After her dissertation. Dr. Raup-Krieger accepted a position as Assistant Professor at Ohio State University and continued her research with ACCN. Dr. Oralia Dominic received her PhD in Biobehavioral Health from Penn State University in 2008 and then became a post-doctorate scholar with ACCN scholar funded by a Minority Supplement from the National Cancer Institute to ACCN. Based upon pilot data collected through ACCN Dr. Dominic submitted a KOI application to the National Cancer Institute in October 2009. These individual training successes demonstrate the solid foundation in training that ACCN has already created and the successful background of the individual investigators in training and mentoring post-doctoral scholars and junior faculty to use CBPR for cancer prevention and control research in Appalachia.

project_terms:
Adoption;Adult;Advisory Committees;Affect;Appalachian Region;Applications Grants;Award;Awareness;Behavioral;Body Image;Cancer Burden;Cancer Control Research;Cancer Research Network;Colon;Colorado;Communication;Communities;Community Outreach;Community Participation;Computer software;Consumption;Data;Development;Doctor of Philosophy;Eating;Educational aspects;Endometrium;Environment;Environmental Risk Factor;Esophagus;Evaluation;Faculty;Family;Family member;Feedback;Female;Foundations;Funding;Gallbladder;Generations;Habits;Health;High Prevalence;Individual;Institution;Investigation;Kentucky;Kidney;Lead;Life;Link;Malignant Neoplasms;Mentors;Methods;Minority;NCI Scholars Program;National Cancer Institute;Obesity;Ohio;Outcome;Ovary;Pancreas;Physical activity;Physician-Patient Relations;Pilot Projects;Policy Maker;Positioning Attribute;Postdoctoral Fellow;Postmenopause;Prevention program;Primary Cancer Prevention;Principal Investigator;Process;Recording of previous events;Recruitment Activity;Religion and Spirituality;Reporting;Research;Research Personnel;Research Training;Risk;Risk Factors;Screening for cancer;Self Perception;Site;Social Discrimination;Solid;Structure;Technology;Testing;Time;Training;Training Programs;Training and Education;United States National Institutes of Health;Universities;West Virginia;Woman;Work;anticancer research;base;biobehavior;burden of illness;cancer health disparity;cancer prevention;cancer risk;evidence base;experience;fruits and vegetables;improved;innovation;intervention program;investigator training;lifestyle factors;male;malignant breast neoplasm;medically underserved population;meetings;member;men;outreach program;professor;public health medicine (field);screening;self reliance;social;success;surveillance strategy;trend


application_id: 8727473
project_number: 5U54CA153604-05
project_title: Pilot Project
administering_ic: NCI
award_notice_date: 2014-08-28
opportunity_number: RFA-CA-09-032
application_type: 5
activity_code: U54
ic: CA
serial_number: 153604
project_end_date: 2018-02-28
study_section: ZCA1-PCRB-G
subproject_number: 7549
contact_pi_person_id: 9323351
contact_pi: RAUP-KRIEGER, JANICE L
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: 2014-09-01
project_abstract:
Pilot Project: Development of a family-based clinical trials intervention for rural Appalachian cancer patients Project Leader: Janice Raup-Krieger PhD Key Personnel and Calendar month effort: Janice Raup-Krieger PhD 3.00 calendar months (1.8 academic 1.2 summer) Electra Paskett PhD (Mentor) (1.20 calendar months on Research Program and 0.6 on Administrative Core) Nancy Schoenberg PhD (Mentor) (1.20 calendar months on Administrative Core)   Project Summary: Guided by multiple goals theory the purpose of the proposed study is to develop and pilot test a culturally grounded family-based intervention to assist cancer patients living in Appalachia and their families in making a decision about participation in a clinical treatment trial. The development of the intervention will be informed by two sources: (1) in-depth interviews conducted with cancer patients who had previously been offered a clinical treatment trial and their family members and (2) input from members of the Appalachia Community Cancer Network (ACCN) community cancer coalitions. Upon completion of data collection and analysis the intervention will be pilot tested with ten different newly diagnosed cancer patients and their families. In the pilot test a patient navigator will facilitate a family discussion about participation in a Phase III clinical trial using the intervention video and other educational materials. The results of the pilot test will be used as the basis of an R21 grant to test the efficacy of the intervention. The training component of the award will focus on broadening Dr. Krieger's expertise in health communication to include community-based participatory research (CBPR). Dr. Krieger will complete an intensive summer course on CBPR as well as attend monthly workshops facilitated by the ACCN. In addition Dr. Krieger will meet on a weekly or bi-weekly basis with her mentors Dr. Electra Paskett (Ohio State University-Epidemiology) and Dr. Nancy Schoenberg (University of Kentucky-Medical Anthropology) both of whom have extensive experience with CBPR methods in Appalachia.

project_terms:
Address;Affect;Anthropology;Appalachian Region;Award;Calendar;Cancer Patient;Clinical Treatment;Clinical Trials;Communication;Communities;Community Networks;County;Data Analyses;Data Collection;Decision Making;Development;Doctor of Philosophy;Educational Materials;Educational workshop;Enrollment;Epidemiology;Family;Family member;Future;General Population;Goals;Grant;Health;Health Communication;Human Resources;Intervention;Interview;Kentucky;Life;Malignant Neoplasms;Medical;Mentors;Mississippi;Mortality Vital Statistics;New York;Newly Diagnosed;Ohio;Patients;Phase III Clinical Trials;Pilot Projects;Relative (related person);Research;Research Methodology;Rural;Source;Stretching;Testing;Training;Treatment Efficacy;Universities;base;burden of illness;community based participatory research;efficacy testing;experience;improved;medically underserved;medically underserved population;meetings;member;programs;skills;social group;theories;therapy development;treatment trial


application_id: 8727472
project_number: 5U54CA153604-05
project_title: Research Project
administering_ic: NCI
award_notice_date: 2014-08-28
opportunity_number: RFA-CA-09-032
application_type: 5
activity_code: U54
ic: CA
serial_number: 153604
project_end_date: 2018-02-28
study_section: ZCA1-PCRB-G
subproject_number: 7548
contact_pi_person_id: 1878622
contact_pi: PASKETT, ELECTRA 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: 2014-09-01
project_abstract:
Project SummaryiA transdisciplinary heaith disparities research team in ACCN will partner with churches in the 5-state ACCN region to refine and test a previously piloted faith-based intervention program "Walk by Faith" to address obesity by focusing on environmental and individual level changes. Community-based participatory research strategies will be used in all phases of this inten/ention that will target two behavioral causes of obesity a sedentary lifestyle and an unhealthy diet. The proposed project will be implemented in 5 Appalachian regions which are mainly rural have medically underserved populations characterized by low incomes deficits in education poor health increased rates of obesity and increased cancer incidence and mortality rates. Additionally adults living in these areas have higher rates of no leisure activity and higher rates of eating less than 5 servings of fruits and vegetables daily compared to adults living in the U.S. In addition to individual causes of obesity an obesogenic environment promotes obesity on a population level by encouraging physical inactivity and limiting healthy food choices. The goal of the application is to test a faithbased intervention from 10 intervention churches compared to a comparison program (cancer screening tests) in 10 additional churches. The specific aims ofthis proposal are to: 1) Refine a previously piloted faith-based intervention focused on environmental and individual level changes to increase physical activity and to improve consumption of healthy food choices among members of male and female church members; 2) implement and test the intervention program using a group-randomized design to decrease BMI among members of 10 randomly selected churches vs. a comparison condition in 10 churches; 3) Utilize process and outcome evaluation strategies to assess the effectiveness of the different components of the intervention including an ehealth computer program that will track the number of steps per day and provide tailored message and letters to intervention participants; and 4) utilize the results to plan the dissemination of the inten/ention to churches located in other Appalachian states. The results of this proposed project will have immediate impact among the members of participating churches and the successful strategies could be used to improve the health of residents of other Appalachian states in the future.

project_terms:
Address;Adult;Appalachian Region;Area;Behavior;Behavioral;Blood Pressure;Body mass index;Cancer Control;Centers for Disease Control and Prevention (U.S.);Cessation of life;Church;Colon Carcinoma;Communities;Community Networks;Computer Programs and Programming;Consumption;Country;County;Data;Diet;Direct Costs;Eating;Educational Status;Educational aspects;Effectiveness;Environment;Evaluation;Facilities and Administrative Costs;Female;Food;Frequencies (time pattern);Future;Goals;Health;Health Food;Height;High Prevalence;Incidence;Individual;Intervention;Leisure Activities;Letters;Life;Life Style;Link;Low income;Malignant Neoplasms;Measures;Mortality Vital Statistics;Obesity;Outcome;Participant;Phase;Physical activity;Planets;Population;Process;Questionnaires;Randomized;Reporting;Research;Research Project Grants;Rural;Screening for cancer;Technology;Testing;United States;Walking;Weight;Woman;base;community based participatory research;cost;design;disorder prevention;eHealth;environmental change;faith-based intervention;follow-up;fruits and vegetables;health disparity;improved;intervention effect;intervention program;low socioeconomic status;male;medically underserved population;member;men;posters;prevent;programs;public health medicine (field);rural area;screening;sedentary;social health determinants


application_id: 8727238
project_number: 3U01DA030916-03S1
project_title: NDA-Enabling Phase I Lofexidine Program
administering_ic: NIDA
award_notice_date: 2013-08-29
opportunity_number: RFA-DA-10-018
application_type: 3
activity_code: U01
ic: DA
serial_number: 030916
suffix: S1
program_official: ANDERSON, ANN
project_start_date: 2011-03-01
project_end_date: 2016-02-28
study_section: ZDA1-JXR-D(10)R
contact_pi_person_id: 10466426
contact_pi: LONGSTRETH, JAMES ALVAN
other_pis: GORODETZKY, CHARLES W.
congressional_district: 03
department: Unavailable
primary_duns: 087875626
primary_uei: NKGSYBV5UGN1
duns_number: 087875626
uei: NKGSYBV5UGN1
fips: US
organization_id: 10003722
organization_name: US WORLDMEDS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40241
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): (Part 1: Description) the proposed research "NDA-Enabling Phase I Lofexidine Program" is aimed at characterizing the pharmacokinetic and clinical pharmacological profiles of lofexidine hydrochloride an alpha-2 adrenergic agonist under development for the treatment of acute withdrawal from short acting opioids. The research program consists of seven studies each with a particular objective that will add to the overall understanding of the pharmacology of the investigational drug. The studies include evaluation of (1) effect of food on lofexidine's bioavailability (2) pharmacokinetics in hepatically-impaired patients (3) pharmacokinetics in renally-impaired patients drug-drug pharmacokinetic interactions between lofexidine and (4) methadone (5) naltrexone and (6) buprenorphine (drugs for related indications that may be used concurrently in a clinical setting) and (7) a study of absolute bioavailability and mass balance of lofexidine. The studies will be conducted in normal healthy volunteers or special populations (as in the case of the hepatic and renal impairment studies) and will employ use of liquid chromatography tandem mass spectrometry (LC/MS/MS) methodology to detect lofexidine hydrochloride parent molecule in the urine and plasma. Additionally for one of the planned studies tracer amounts (approximately 100 nCi) of radio-labeled 14C-lofexidine will be used in an oral dose and analyzed by Accelerated Mass Spectrometry in order to follow the plasma and excretion pharmacokinetics of parent drug and to identify and quantify the excreted metabolites of lofexidine. The 14C-lofexidine dose and the appropriate AMS methods for specific identification and quantification of lofexidine metabolites is proposed to be developed as part of the research plan which will allow identification and quantification of both lofexidine and its major metabolites in the plasma and urine. Quantification of lofexidine and/or its major metabolites over time in addition to observed tolerance and evaluation of other clinical parameters in each of the planned studies will add to the overall understanding of the pharmacokinetics and pharmacodynamics of lofexidine in the body. This information is needed to allow appropriate labeling of the product for its entrance to the US market. Furthermore the planned research has been defined by the FDA as critical to complete the clinical pharmacology section requirements for a New Drug Application for lofexidine hydrochloride approval of which will allow entrance of the first non-narcotic non-addictive drug indicated for the treatment of opiate withdrawal to the US market.

project_terms:
Acute;Adrenergic Agonists;Age;Analgesics;Applications Grants;Area;Biological Availability;Body mass index;Buprenorphine;Clinical;Clinical Pharmacology;Development;Dose;Drug Kinetics;Drug Metabolic Detoxication;End stage renal failure;Equilibrium;Evaluation;Excretory function;FDA approved;Fasting;Fatty acid glycerol esters;Food;Hepatic;Heroin;Hydrochloride Salt;Impairment;Intravenous;Investigational Drugs;Kidney;Label;Liquid Chromatography;Literature;Marketing;Mass Spectrum Analysis;Medical;Methadone;Methodology;Methods;Naltrexone;Opiate Addiction;Opiates;Opioid;Oral;Oxycodone;Parents;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Phase;Plasma;Population;Product Labeling;Property;Radio;Radiolabeled;Recovery;Relative (related person);Renal function;Reporting;Research;Rural;Safety;Staging;Tablets;Time;Tracer;United Kingdom;United States Food and Drug Administration;United States National Institutes of Health;United States Substance Abuse and Mental Health Services Administration;Urine;Withdrawal;Work;base;healthy volunteer;intravenous administration;liquid chromatography mass spectrometry;liver function;lofexidine;meetings;named group;opioid abuse;opioid withdrawal;phase 3 study;prescription opiate;programs;radiotracer;sex;suburb;tandem mass spectrometry;therapy development;volunteer

public_health_relevance:
(Project Summary Part 2: Relevance) Opioid abuse and dependence is a serious and growing problem in the US with an estimated 5.2 million nonmedical-related users of prescription opiate pain killers such as Lortab(R) and OxyContin(R) (SAMHSA 2008) 1 million heroin addicts in the US (National Institutes of Health 2006) and recent articles suggesting that abuse is spreading into rural and suburban areas (Archibold 2009). There is an unmet medical need in the opioid-dependent population with only two FDA-approved drugs (methadone and buprenorphine) currently available to treat opioid withdrawal. Both are opiate products that effectively operate as replacement or substitution therapies have abuse potential and are themselves controlled substances. FDA approval of lofexidine hydrochloride will enable the entrance of the first non-narcotic non-addictive product to the market for the treatment of opioid withdrawal the first hurdle in recovery from opioid dependence. The planned research is required to understand how lofexidine works in the body so that appropriate dosing meal requirements the safety of combination with other treatment drugs and safety considerations for patients with poor liver and kidney functions can be evaluated.


application_id: 8726307
project_number: 5R25CA148005-05
project_title: The Development of an Interdisciplinary Oncology Palliative Care Curriculum
administering_ic: NCI
award_notice_date: 2014-08-29
opportunity_number: PAR-08-120
application_type: 5
activity_code: R25
ic: CA
serial_number: 148005
program_official: KORCZAK, JEANNETTE F
project_start_date: 2010-09-01
project_end_date: 2016-08-31
study_section: Education Study Section (G)[NCI-G]
contact_pi_person_id: 8126973
contact_pi: PFEIFER, MARK P
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): In 2010 cancer is expected to surpass heart disease as the highest health-related cause of mortality in the world. Almost every family has or will face a loved one needing cancer care including curative treatment symptom control and end-of-life care. The increasing needs of our patient population and the emerging science of palliative care call for new efforts in innovative education. National organizations have called for new efforts in interdisciplinary understanding and education in approaching palliative care. Each discipline however has continued to teach palliative care principles largely in silos using existing curricular structure and constructs; there are no reports of mandatory interdisciplinary education in palliative care involving all four disciplines - medicine nursing social work and chaplaincy.     The aim of this project is to design implement and evaluate an innovative integrated and interdisciplinary oncology palliative care curriculum for medical nursing social work and chaplaincy students.     Specific aims are:   1) Design an innovative interdisciplinary oncology palliative care curriculum;   2) Implement the interdisciplinary oncology palliative care curriculum;   3) Develop and utilize an evaluation system that measures the effectiveness of the curriculum learner outcomes and the long term impact on practitioners and patients.     Project efforts will focus the design implementation and testing of an interdisciplinary oncology palliative care curriculum. Innovative as well as proven education modalities will be utilized to determine:   1) If the educational objectives are aligned with the desired outcomes;   2) Which modalities are most effective for each discipline?   3) How the modalities are best integrated; and   4) What factors contribute to the sustainability and portability of the curriculum.     The new curriculum will include eight learning activities that will become a required part of the curriculum for all 3rd year medical students 3rd and 4th year nursing students masters level social work students and clinical pastoral education residents. In addition to traditional educational modalities such as clinical rotations didactic sessions and self-study modules non-traditional methods including standardized patients and families reflective writing a palliative care vignette case-solving and capstone projects will be used. The added value of interdisciplinary education will be evaluated in this field.

project_terms:
Address;Adult;Awareness;Cancer Control;Cancer Patient;Caring;Clinical;Communities;Development;Discipline;Discipline of Nursing;Educational Curriculum;Educational aspects;Educational process of instructing;Environment;Evaluation;Face;Family;Health;Health Professional;Health Sciences;Healthcare;Heart Diseases;Institute of Medicine (U.S.);Interdisciplinary Education;Knowledge;Learning;Malignant Neoplasms;Mandatory Reporting;Medical;Medical Students;Medicine;Methods;Modality;Mortality Vital Statistics;NIH Program Announcements;Nurses;Nursing Students;Outcome;Palliative Care;Patient Care;Patients;Physicians;Rotation;Science;Services;Social Workers;Social work (field);Structure;Students;Symptoms;System;Technology;Testing;Training;Translating;United States National Institutes of Health;Work;Writing;cancer care;career;clinical practice;design;effectiveness measure;end of life;evidence base;evidence based guidelines;experience;flexibility;innovation;loved ones;novel;oncology;patient population;portability;programs;public health relevance

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Almost every family has or will face a loved one needing cancer care including curative treatment symptom control and end-of-life care. In receiving this care patients and their families will need the services of physicians nurses chaplains and social workers. The Institute of Medicine lists working in interdisciplinary teams as one of five core competencies all health care clinicians should possess and calls for health professionals to be educated in an interdisciplinary manner to prepare them for the real world team environments they will participate in once entering the field. This project will create implement and test a novel mandatory interdisciplinary oncology palliative care curriculum for medical nursing social work and chaplaincy students.       PROJECT NARRATIVE - RELEVANCEAlmost every family has or will face a loved one needing cancer care including curativetreatment symptom control and end-of-life care. In receiving this care patients and theirfamilies will need the services of physicians nurses chaplains and social workers. The Instituteof Medicine lists working in interdisciplinary teams as one of five core competencies all healthcare clinicians should possess and calls for health professionals to be educated in aninterdisciplinary manner to prepare them for the real world team environments they willparticipate in once entering the field. This project will create implement and test a novelmandatory interdisciplinary oncology palliative care curriculum for medical nursing social workand chaplaincy students. __SpecificAimsTextDelimiter__ A. SPECIFIC AIMSOverall Aim: To design implement and evaluate an innovative integrated and interdisciplinaryoncology palliative care curriculum for medical nursing social work and chaplaincy students.Specific Aims:Aim 1: Design an innovative interdisciplinary oncology palliative care curriculumAim 2: Implement the interdisciplinary oncology palliative care curriculumAim 3: Develop and utilize an evaluation system that measures the effectiveness of thecurriculum learner outcomes and the long term impact on practitioners Project efforts will focus the design implementation and testing of an interdisciplinaryoncology palliative care curriculum. Innovation as well as proven education modalities will beutilized to determine: 1) if the educational objectives are aligned with the desired outcomes; 2)which modalities are most effective for each discipline; 3) how the modalities are bestintegrated; and 4) what factors contribute to the sustainability and portability of the curriculum.The curriculum will: 1. be centrally-driven mandatory integrated flexible multi-modal and portable; 2. be driven by best clinical practices evidence-based guidelines and tested palliative care and oncology curricula; 3. demonstrate palliative care's core principles by integrating the technical scientific and humanistic qualities into holistic care of the cancer patient; 4. include learning experiences that promote collaborative learning and teamwork and broaden interdisciplinary awareness; 5. combine innovative as well as proven learning modalities and technologies; 6. integrate interdisciplinary team approaches in both learning and practice of palliative care; 7. draw upon the principles of adult learning. The proposal's aims specifically address the National Institute of Health's ProgramAnnouncement Number PAR-08-120 which calls for: "Innovative educational programsintended to motivate health science students to pursue careers around cancer control...(the)training of cancer care practitioners in evidence-based cancer control approaches... and (the)development of innovative education approaches to translate recent knowledge gained intocommunity applications."


application_id: 8725797
project_number: 3R01NS079637-02S1
project_title: Vascular breakdown in Alzheimers Disease with cerebrovascular disease
administering_ic: NINDS
award_notice_date: 2013-08-29
opportunity_number: PA-10-067
application_type: 3
activity_code: R01
ic: NS
serial_number: 079637
suffix: S1
program_official: CORRIVEAU, RODERICK A
project_start_date: 2012-07-01
project_end_date: 2017-04-30
study_section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT]
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
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:
DESCRIPTION (provided by applicant): Microhemorrhages and vasogenic edema are pathological phenomena that occur in both cerebrovascular disease (CBVD) and Alzheimer's disease (AD). In CBVD these can occur throughout the brain yet are most frequently subcortical. In AD they usually occur at sites of vascular amyloid deposition. Given that CBVD and AD are not always mutually exclusive but often co-exist it is important that we understand the mechanisms of microhemorrhages and vasogenic edema. We hypothesize that inflammatory-mediated activation of matrix metalloproteinases leads to degeneration of tight junction proteins and basement membrane proteins resulting in vascular leakage producing microhemorrhages and/or vasogenic edema.  Our goal for this proposal is to model CBVD in mouse models of amyloid deposition to produce vasogenic edema and microhemorrhage and determine the role of the MMP system in their onset and the impact CBVD has on response to amyloid-targeted therapies. We will assess inflammatory changes and activation of the MMP systems as mechanisms for these abnormalities. Importantly we propose to acquire MR FLAIR and Susceptibility Weighted (SWI) images to assess vasogenic edema and microhemorrhage as well as any other brain changes occurring through the course of the studies. Immediately prior to tissue harvest we will acquire arteral spin label (ASL) scans to measure brain perfusion and thus enable a comparison of the density of microhemorrhages and brain health. Additionally we will acquire contrast enhanced T1-weighted scans following administration of Magnevist and Galbumin contrast agents to assess vascular leakage. We propose to use AAV and pharmacological agents to inhibit MMPs directly or inhibit the inflammatory signals thought to be increasing MMP activity. We will also examine whether the efficacy and side-effect profile of two A- targeted therapies in trials are influenced by the presence of CBVD in amyloid-depositing mice.  The overall goal of our proposal is to determine the time-course of CBVD pathology when we generate CBVD in APP/PS1 transgenic mice determine the roles of inflammation and MMPs in the generation of microhemorrhage and vasogenic edema and finally to establish the effect CBVD has on the response to A-targeted therapies. We believe that CBVD is common co- morbidity with AD that influences the pathogenesis of AD and response to therapy.

project_terms:
APP-PS1;Adverse effects;Affect;Aging;Alzheimer's Disease;Amyloid;Amyloid deposition;Animals;Basement membrane;Blood Vessels;Blood flow;Brain;Brain Pathology;Cerebrovascular Circulation;Cerebrovascular Disorders;Clinical Trials;Cognition;Comorbidity;Contrast Media;Deposition;Diet;Edema;Extravasation;Gadopentetate Dimeglumine;Generations;Genetic;Goals;Health;Hippocampus (Brain);Hyperhomocysteinemia;Image;Immunotherapy;Inflammation;Inflammatory;Inhibition of Matrix Metalloproteinases Pathway;Injection of therapeutic agent;Interleukin-1;Left;MMP2 gene;MMP9 gene;Magnetic Resonance Imaging;Matrix Metalloproteinase Inhibitor;Matrix Metalloproteinases;Measures;Mediating;Membrane Proteins;Modeling;Modification;Mus;Pathogenesis;Pathology;Patients;Perfusion;Predisposition;Production;Proteins;Research Proposals;Role;Scanning;Signal Transduction;Site;Spin Labels;System;TIMP1 gene;TIMP2 gene;Thalamic structure;Tight Junctions;Time;Tissue Harvesting;Transgenic Mice;Weight;amyloid pathology;anakinra;arteriole;density;inhibitor/antagonist;mouse model;neuroinflammation;receptor;response;secretase;therapeutic target

public_health_relevance:
Cerebrovascular disease commonly occurs with aging as does Alzheimer's disease. In fact it is estimated that 40% of Alzheimer's patients also have cerebrovascular disease. Our research proposal will examine the impact cerebrovascular disease has on the progression of amyloid pathology a brain pathology in Alzheimer's disease. Our overall goal is to enhance our understanding of the relationship between cerebrovascular disease and Alzheimer's disease and how one can affect the other.


application_id: 8725696
project_number: 5R01GM104123-02
project_title: Functional analysis of programmed genome rearrangement
administering_ic: NIGMS
award_notice_date: 2014-08-13
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: GM
serial_number: 104123
program_official: CARTER, ANTHONY D
project_start_date: 2013-09-01
project_end_date: 2018-08-31
study_section: Genetic Variation and Evolution Study Section[GVE]
contact_pi_person_id: 9381521
contact_pi: SMITH, JERAMIAH JAMES
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Binding (Molecular Function);Biological;Biological Assay;Biological Process;Biology;Candidate Disease Gene;Cell Death;Cell Lineage;Cell Proliferation;Cells;Chromosomes;Code;Computer Analysis;Control Animal;DNA;DNA Sequence Rearrangement;Data;Data Set;Development;Developmental Biology;Disease;Embryo;Embryonic Development;Epigenetic Process;Event;Fertility;Fertilization in Vitro;Gene Deletion;Genes;Genetic;Genetic Polymorphism;Genetic Recombination;Genome;Genome Stability;Genomics;Homologous Gene;Human;Human Genome;Individual;Knowledge;Lampreys;Light;Maintenance;Maps;Mass Spectrum Analysis;Measures;Mediating;Meiosis;Methods;Modeling;Molecular;National Institute of General Medical Sciences;Outcome;Pattern;Petromyzon marinus;Play;Population;Promotor (Genetics);Property;Protein Binding;Proteins;Regulation;Research;Resistance;Resolution;Resources;Role;Site;Somatic Cell;Specificity;Staging;Stem cells;Study models;Testing;Transcript;Vertebrates;Work;analog;base;comparative;design;developmental genetics;gene function;genome sequencing;insight;novel;pleiotropism;pluripotency;programs;public health relevance;recombinational repair;research study;scaffold;stem;stem cell biology;tumorigenesis;vertebrate genome

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    Programmed rearrangement of the lamprey genome provides a highly reproducible model for studying the causes and consequences of genome rearrangement especially as it relates to the biology of germline stem cells. Proposed research will use the lamprey as a model for studying 1) the genetic consequences of programmed gene deletions 2) the molecular basis of rearrangement and 3) the capacity of specific human genes to mediate rearrangement. This work will shed new light on the molecular basis of genome stability/instability and fundamental molecular properties of germline stem cells focusing on genes with human homologs.             __SpecificAimsTextDelimiter__ SPECIFIC AIMSThis proposal stems from our recent discovery that the sea lamprey (Petromyzon marinus) undergoesdevelopmentally programmed genome rearrangements (PGRs). These rearrangements result in the loss of~20% of the germline genome during the establishment of somatic cell lineages in the early embryo. Excisedregions include hundreds of genes and other single-copy DNAs many of which have vertebrate homologs thatcontribute to germline pluripotency (or oncogenesis if misexpressed). The discovery of PGR in lamprey (avertebrate) therefore fills an important gap in our understanding of dysregulated rearrangement of vertebrategenomes that are often associated with disease vs. the capacity for tight regulation of genome rearrangementthat is known for a few diverse metazoan and protist lineages. The specific aims of this proposal will seek tofurther characterize lamprey PGR at the genetic level in order to deduce its molecular mechanisms and usethis information to aid in the development of functional studies that will dissect the biological causes andconsequences of genome rearrangement. Functional studies will focus on resolving the developmental(maintenance of pluripotency / regulation of somatic pleiotropy) and recombinational functions of PGR both ofwhich are highly relevant toward understanding the biology of the human genome. Functional studies ofrecombination will aim to discover and characterize human genes that mediate recombination.Specific Aim 1) Define chromosome-scale patterns of gene loss: The current lamprey genome assemblyprovides kilobase to megabase resolution of somatic genome sequences sufficient to identify genespromotors and local gene syntenies (preliminary studies). Our preliminary studies indicate that deletion eventsinvolve segments of DNA that may exceed the upper end of this range. In order to understand the true scale ofindividual deletion events and refine our functional models of deletion we will generate long-range linkageinformation for lamprey via recombinational mapping. Mapping information will be rapidly generated using asite-anchored (RAD-tag) sequencing approach that leverages the high fecundity of lampreys the abundance ofsegregating polymorphisms in natural populations of sea lampreys and ease of performing controlled crossesvia in vitro fertilization. This information will be used to 1) scaffold the germline assembly to form chromosome-scale ultrascaffolds 2) identify broad-scale regions that differ between germline and somatic genomes and 3)define transitions (breakpoints) between deleted and retained sequence. This information will facilitate studiescarried out under Specific Aims 2 and 3 and will provide invaluable information for comparative genetic andgenomic studies that use lamprey for its unique evolutionary perspective.Specific Aim 2) Characterize the biological effects of gene loss: We will use the genomic data alreadycollected through our preliminary studies and supplemented by Specific Aim 1 to dissect the biological effectsof gene loss (a major outcome of PGR). Genes that are lost from somatic cell lineages during PGR will beanalyzed using morpholino (MO)-mediated knockdown in lamprey embryos and will therefore focus particularlyon genes that are expressed during lamprey embryonic development. We will also perform rescue experimentswith synthetic analogs of lamprey transcripts and their human homologs to confirm the specificity ofknockdowns and test for functional equivalence of lamprey and human homologs. These experiments will beused to elucidate both the function of somatically deleted genes in the developing germline and the effects oftheir somatic misexpression. Preliminary studies have led to the hypothesis that many of these genes areimportant for regulating cell proliferation and the maintenance of pluripotency. We will generate phenotypicinformation for MO-treated rescue and control animals using markers for cell death proliferation and cell fatein order to test this hypothesis and elucidate the function of PGR-eliminated genes and their human homologs.Specific Aim 3) Characterize the molecular underpinnings of gene loss: Our validated backgroundstudies indicate that site-specific recombination plays a role in PGR. Under this aim we will isolate the proteinsthat mediate PGR and functionally characterize human gene homologs in the context of PGR. Probesdesigned from experimentally validated sites of recombination will be used to isolate the proteins that bindthese sequences during the embryonic stages in which PGR occurs (Specific Aim 3.1). Isolated proteins will becharacterized by mass spectrometry in order to further develop a panel of candidate genes that arehypothesized to contribute to PGR. These candidate genes will be then be targeted for morpholino-mediatedknockdown (Specific Aim 3.2). As morpholinos will be designed to inhibit PGR machinery the effects of theseknockdowns will be measured using molecular assays for several PGR events. For lamprey genes that areidentified as contributing to recombination we will attempt to rescue experiments with morpholino-resistantlamprey transcripts and their human homologs which will provide a direct assay for the capacity of identifiedhuman genes to participate in somatic recombination. Critically this approach does not rely on pre-existingknowledge regarding the function of human genes and therefore holds great potential for the discovery of novelgene functions. Such assays will provide unique insight into the biological function of human genes andprovide functional information that might not be achievable outside of the context of PGR.


application_id: 8725337
project_number: 261201300013I-0-26100001-1
project_title: Core Infrastructure Support
administering_ic: NCI
project_start_date: 2013-08-01
project_end_date: 2014-05-31
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The Surveillance Epidemiology and End Results (SEER) Program was established by the National Cancer Institute (NCI) to collect and report periodically on population-based cancer incidence and survival data. It is a core component of the NCI's surveillance activities which provide information used for planning cancer control and research programs and for evaluating the impact of such programs on cancer rates. The SEER Program was initiated in 1972 in response to requirements of the National Cancer Program for assessing the magnitude of the cancer burden in the United States and for identifying factors related to cancer risk and/or patient survival. Objectives of the SEER Program include: 1. Assemble and report on a periodic basis estimates of cancer incidence. 2. Monitor annual cancer incidence trends to identify unusual changes in specific forms of cancer occurring in population subgroups defined by geographic demographic and social characteristics. 3. Provide continuing information on changes over time in extent of disease at diagnosis trends in therapy and changes in cancer patient survival. 4. Identify the occurrence of possible iatrogenic cancers i.e. cancers that are caused by cancer therapy. 5. Serve as a research resource to the National Cancer Institute and conduct studies dealing with current cancer control issues as well as issues related to the operation of the SEER Program which may lead to improved and/or more cost-effective operating procedures.

project_terms:
Cancer Burden;Cancer Control;Cancer Control Research Program;Cancer Etiology;Cancer Patient;Data;Diagnosis;Disease;Incidence;Lead;Malignant Neoplasms;Monitor;National Cancer Institute;National Cancer Program;Patients;Population;Procedures;Reporting;Research Infrastructure;Resources;SEER Program;Social Characteristics;Subgroup;Time;Treatment-Related Cancer;United States;base;cancer risk;cancer therapy;cost effective;improved;operation;population based;programs;response;trend


application_id: 8725228
project_number: 5R01HL118474-02
project_title: Hyperamylinemia in Diabetic Heart Disease: Mechanisms Responses and Prevention
administering_ic: NHLBI
award_notice_date: 2014-07-01
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 118474
program_official: BUXTON, DENIS B
project_start_date: 2013-08-23
project_end_date: 2017-07-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
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): Increased secretion of amylin by pancreatic beta-cells (hyperamylinemia) is common in obese and insulin resistant patients coincides with hyperinsulinemia and promotes formation of toxic amylin oligomers. Oligomeric amylin induces beta-cell apoptosis contributing to the development of type-2 diabetes. Recent studies demonstrate that amylin oligomers also affect the vascular system kidneys and heart. Our data show large deposits of oligomerized amylin in failing hearts from obese and T2D patients but not in hearts from controls. Oligomeric amylin was found in myocyte injury areas suggesting a role in the mechanism of injury. Indeed our pilot study on a "humanized" rat model of hyperamylinemia (the HIP rat) indicates that amylin oligomers attach to cardiac myocytes and induce oxidative stress and Ca2+ dysregulation leading to diastolic dysfunction and hypertrophy. The pilot study also suggests that endogenous molecules with anti-aggregation properties such as plasmin and epoxyeicosanoids limit cardiac accumulation of amylin and its myopathic response. Based on these preliminary results our research proposal will test the hypotheses that 1) cardiac accumulation of oligomerized amylin accelerates diabetic heart injury by inducing sarcolemmal damage and oxidative stress and 2) limiting amylin deposition in the heart may reduce/ delay the onset of diabetic heart failure. These hypotheses will mechanistically be assessed by using transgenic rat models overexpressing either the amyloido- genic human amylin (HIP rats) or the non-amyloidogenic rat amylin isoform (UCD rats). Specifically planned studies will determine how accumulation of oligomerized amylin in the HIP rat heart a) disrupts sarcolemmal processes b) induces oxidative stress and myocyte Ca2+ dysregulation and c) activates Ca2+-mediated CaMKII-HDAC and calcineurin-NFAT hypertrophy signaling pathways. Based on the results of our pilot study cardiac dysfunction in HIP rats is expected to develop even in pre-diabetes as often observed in humans. In contrast our pilot study predicts that UCD rats matched for age and glucose but lacking cardiac amylin deposition may show signs of cardiac dysfunction after the onset of diabetes. Our research will also determine if disrupting deposition of oligomeric amylin in the heart and recovering sarcolemmal integrity improve cardiac function in the HIP rat model. This innovative concept will be explored in longitudinal studies using membrane sealants and scavengers of circulating amylin oligomers. Hence our research project proposes that amylin buildup is a key contributor to the multifactorial pathogenesis of diabetic heart injury and that mitigating amylin oligomer accumulation could delay the onset of diabetic heart failure. If our hypothesis of cardiotoxic amylin oligomer is proven then circulating amylin oligomers are a feasible therapeutic target to reduce diabetic heart injury.

project_terms:
Adjuvant;Affect;Age;Apoptosis;Area;Beta Cell;Binding (Molecular Function);Blood;Calcineurin;Cardiac;Cardiac Myocytes;Cardiotoxicity;Cell membrane;Cells;Data;Deposition;Development;Diabetes Mellitus;Diagnosis;Epidemic;Excretory function;Figs - dietary;Functional disorder;Glucose;Heart;Heart Diseases;Heart Hypertrophy;Heart Injuries;Heart failure;Histone Deacetylase;Hormones;Human;Hyperinsulinism;Hypertrophy;Injury;Insulin;Insulin Resistance;Ion Channel;Ions;Kidney;Left;Lipid Peroxidation;Longitudinal Studies;Mediating;Membrane;Membrane Potentials;Metabolic syndrome;Mitochondria;Modeling;Muscle Cells;Myocardial;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oligonucleotides;Onset of illness;Oxidative Stress;Pancreas;Pathogenesis;Pathway interactions;Patients;Pilot Projects;Plasmin;Poloxamer;Poloxamers;Prediabetes syndrome;Prevention;Process;Production;Property;Protein Isoforms;Rattus;Research;Research Project Grants;Research Proposals;Risk;Role;Sarcolemma;Signal Pathway;Solubility;Structure;Structure of beta Cell of islet;System;Testing;Therapeutic;Tissues;Transgenic Organisms;Vascular System;Ventricular;base;calmodulin-dependent protein kinase II;catalyst;diabetic;high risk;improved;in vivo;inhibitor/antagonist;innovation;islet amyloid polypeptide;overexpression;public health relevance;response;therapeutic target;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Obesity and type-2 diabetes have reached epidemic proportions in the US1 and are associated with a high risk of heart failure. The pathogenesis of heart dysfunction in obesity and T2D is multifactorial and not fully elucidated which makes diagnosis and treatment of diabetic heart disease challenging. Our study aims at understanding how hyperamylinemia a common condition in obese and insulin resistant patients promotes toxic accumulation of oligomerized amylin in the heart and how the buildup of amylin affects cardiac function. Planned studies also attempt to find therapeutic tools that can mitigate cardiac accumulation of oligomerized amylin and its deleterious effects. The focus is on modulating the endogenous system of scavenging the amylin oligomers circulating in the blood as a possible mean to reduce cardiotoxicity of hyperamylinemia. If our hypothesis of cardiotoxic amylin oligomer is proven then hyperamylinemia and the oligomerized amylin circulating in the blood will be feasible therapeutic targets to limit the risk of diabetic heart injury.


application_id: 8723796
project_number: 5R01DA033862-03
project_title: Epidemiologic Study of the Effectiveness of an ADF in Reducing Opioid Abuse
administering_ic: NIDA
award_notice_date: 2014-08-12
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DA
serial_number: 033862
program_official: DUFFY, SARAH Q
project_start_date: 2012-09-01
project_end_date: 2016-04-30
study_section: Behavioral and Social Consequences of HIV/AIDS Study Section[BSCH]
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overarching goal of this time-sensitive application is to measure the effectiveness of the new abuse deterrent formulation (ADF) for OxyContin(R) in decreasing abuse of OxyContin(R). Prescription opioid abuse is a major public health concern and has plagued the rural United States in particular. The Office of National Drug Control Policy (ONDCP) and the FDA have strongly encouraged the pharmaceutical industry to develop formulations that protect against abuse; however apart from clinical trials among pain patients demonstrating efficacy of the drug for treating pain there have been no epidemiologic studies to date that have examined whether ADFs are actually effective in reducing abuse of any drug. A longitudinal epidemiologic study of prescription opioid abuse is currently in the latter phase of follow-up in rural Kentucky (R01-DA024598) in which 94.8% of participants abused OxyContin(R) in their lifetime and 81% abused the drug in the 6-months prior to the formulation change. Given this high prevalence of OxyContin(R) abuse before the formulation change this study sample is ideal for detecting changes in signals of abuse with the new ADF for OxyContin(R). The specific aims include: 1) evaluation of the effectiveness of the ADF for OxyContin(R) in reducing abuse via oral intranasal and injection routes; 2) determining whether opioid users transitioned to abuse of other prescription opioids once the non-ADF version was no longer available on the street; and 3) examination of changes in prevalence and incidence of HIV and hepatitis C (HCV) as a result of changes in route of administration after the old formulation was no longer available. This time-sensitive study is highly significant given the paucity of epidemiologic data related to the effectiveness of ADFs in reducing abuse of prescription opioids. Further this study is uniquely positioned to measure the effectiveness of the ADF for OxyContin(R) expeditiously and without the potential bias that would result if abuse were assessed retrospectively. Given the importance that the ONDCP and the FDA have placed on further development of ADFs for prescription opioids the results from this study have vast implications for public policy in addition to public health. This highly relevant study will evaluae the effectiveness of a model ADF across multiple public health domains including changes in this product's abuse and misuse via the oral intranasal and injection routes of administration. The results from this study in turn will have vast implications for not only public health but aso policies surrounding development of ADFs in order to prevent abuse of prescription opioids.

project_terms:
Accounting;Clinical Trials;Data;Data Correlations;Development;Dose;Drug Controls;Drug Formulations;Drug Industry;Drug abuse;Drug user;Effectiveness;Epidemiologic Methods;Epidemiologic Studies;Evaluation;Goals;HIV;Hepatitis C;Hepatitis C Transmission;Hepatitis C virus;High Prevalence;Hydrocodone;Incidence;Injection of therapeutic agent;Kentucky;Manufacturer Name;Marketing;Measures;Methadone;Modeling;Names;Opioid;Oral;Outcome;Outcome Measure;Overdose;Oxycodone;Pain;Participant;Patients;Pattern;Percocet;Pharmaceutical Preparations;Phase;Plague;Policies;Positioning Attribute;Prevalence;Public Policy;Recommendation;Research;Risk Behaviors;Route;Rural;Sample Size;Sampling;Sampling Studies;Serologic tests;Severities;Shares syringes;Signal Transduction;Time;United States;Visit;addiction;cohort;combat;design;disease transmission;drug efficacy;effectiveness measure;epidemiologic data;follow-up;indexing;injection drug use;opioid abuse;pill (pharmacologic);prescription opioid;prescription opioid abuse;prevent;primary outcome;public health medicine (field)

public_health_relevance:
Prescription opioid abuse is a significant public health problem in the United States. Abuse deterrent formulations (ADFs) are one strategy that are being used to combat the growing issue. However there is a paucity of longitudinal epidemiologic data on the effectiveness of ADFs in reducing opioid abuse. Therefore this study seeks to examine the effectiveness of the ADF for OxyContin(R) in reducing OxyContin(R) abuse via the oral intranasal and injection routes of administration and to determine whether drug users transition to abusing non-ADF opioids as well as whether rates of HIV and HCV differ as a result of changes in abuse patterns once the old formulation is off the street.


application_id: 8723151
project_number: 5T32DK007778-15
project_title: Training Program in Oxidative Stress and Nutrition
project_terms: Oxidative Stress;Training Programs;nutrition
administering_ic: NIDDK
award_notice_date: 2014-08-13
opportunity_number: PA-08-226
application_type: 5
activity_code: T32
ic: DK
serial_number: 007778
program_official: DENSMORE, CHRISTINE L
project_start_date: 2000-08-15
project_end_date: 2015-07-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
other_pis: ST CLAIR, DARET K
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: 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:
DESCRIPTION (provided by applicant): This is a competing renewal of a training program in Nutrition and Oxidative Stress. The primary goal of the training program is to prepare PhD students for successful careers in nutritional sciences. The focus is on nutrition as a modulator of oxidative stress in metabolic diseases cancer and neuroscience/aging. The training program is located in the Graduate Center for Nutritional Sciences (GCNS) a multi-disciplinary center crossing departmental and college boundaries. The goals of the training program are to provide state-of-the-art education in nutritional sciences with an emphasis on oxidative stress and to provide training in ethical conduct of high quality laboratory research focused on nutritional modulation of oxidative stress. Twenty seven training faculty all members of the GCNS will provide training around 3 theme areas (metabolic disease cancer neuroscience/aging) representing strength of current research and research areas significant to the fields of nutrition and chronic disease. Support for 4 trainees is requested based on growth of the programs and training expertise. Students wil [sic] be recruited from an integrated biomedical sciences program or directly into the GCNS increasing the number and quality of the applicant pool of students. Strengths of the training program include a newly revised curriculum integrating basic and clinical aspects of nutritional sciences training faculty with extensive training experience and productive and funded research programs of direct relevance to the training program research cores for training and facilitation of research within the theme areas the use of a multidisciplinary center to increase and diversify opportunities for training. A unique aspect of the training program is an annual symposia [sic] on nutrition and oxidative stress organized by the trainees with excellent opportunites [sic] for trainees to interact with nationally prominent researchers in the fields of nutritional sciences and oxidative stress. A multiple-PI model has been incorporated into the renewal to assure rigorous attention to the major focus areas of nutritional sciences and oxidative stress.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Most chronic diseases especially those on the rise in prevalence in the US are influenced by nutrition. Imbalances in oxidative mechanisms within cells underly [sic] many of these chronic diseases and nutritional approaches can be used to influence oxidative stress of cells. We propose to train future scientists to identify ways that nutrition can modify oxidative stress in metabolic diseases (diabetes obesity) cancer and neuroscience/aging.


application_id: 8722208
project_number: 1R21AI108260-01A1
project_title: Hendra virus trafficking and assembly
administering_ic: NIAID
award_notice_date: 2014-02-10
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: AI
serial_number: 108260
suffix: A1
program_official: CASSETTI, CRISTINA
project_start_date: 2014-02-10
project_end_date: 2016-01-31
study_section: Special Emphasis Panel[ZRG1 IDM-S (02)]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
other_pis: SCHMITT, ANTHONY P
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:
DESCRIPTION (provided by applicant): Hendra virus (HeV) and Nipah virus members of the Henipavirus genus of the paramyxovirus family are zoonotic viruses with high mortality rates in humans. Henipavirus particle assembly is coordinated by the viral matrix (M) proteins which link together the viral glycoproteins and the viral ribonucleoproteins. The Dutch lab recently defined a novel mechanism for proteolytic cleavage of the Henipavirus fusion (F) proteins. In contrast to other paramyxovirus F proteins Henipavirus F proteins reach the cell surface in the inactive uncleaved form are endocytosed from the plasma membrane (PM) and encounter cathepsin proteases within early endosomes (EEs). Following cathepsin cleavage F is routed through Rab11-containing recycling endosomes (REs) before returning to the PM for incorporation into budding virus particles. The Schmitt lab recently identified interactions between Henipavirus matrix (M) proteins and the beta subunit of AP-3 adapter complexes which are involved in endosomal trafficking. M protein localized in Rab11 compartments and this localization was disrupted upon expression of M- binding AP3B1-derived inhibitory polypeptides. To explore the significance of M and F protein convergence in Rab11-positive REs the Dutch and Schmitt labs have now combined their efforts and discovered that an F mutant defective in endocytic trafficking fails to participate in VLP assembly and that introduction of a dominant negative Rab11 protein dramatically inhibits Hendra VLP production. We therefore hypothesize that Rab-11 containing endosomal compartments serve as a critical assembly site for key viral proteins prior to viral budding. In Aim 1 we will examine the role of HeV virus F protein trafficking in vius assembly through use of a comprehensive set of trafficking-altered F protein mutants and will analyze F- M interactions in Rab11 REs using a sensitive proximity ligation assay. Our second aim will build on the exciting preliminary data defining an interaction between HeV M protein and the beta subunit of the AP-3 adapter complex examining the role of this interaction in M trafficking delineating the trafficking pathway and examining the role of this interaction in apial targeting of the HeV M protein. Finally in Aim 3 we will address the role of HeV G protein interactions with M or F on G assembly testing the hypothesis that G protein assembly into VLPs is mediated by redundant interactions with M and F proteins. These experiments will provide critical new information on HeV assembly and test the novel hypothesis that Rab11 REs may serve as viral assembly sites. If this hypothesis is correct Rab11 RE components involved in membrane bending may serve as novel host factors for non-ESCRT mediated budding.

project_terms:
Address;Antiviral Agents;Apical;Binding (Molecular Function);Biological Assay;Cathepsins;Cell membrane;Cell surface;Cells;Complex;Cytoplasmic Tail;Data;Defect;Development;Dominant-Negative Mutation;Early Endosome;Endocytosis;Endosomes;Family;GTP-Binding Proteins;Glycoproteins;Hendra Virus;Henipavirus;Henipavirus Infections;Human;Integration Host Factors;Lead;Ligation;Link;Measures;Mediating;Membrane;Mortality Vital Statistics;Nipah Virus;Paramyxovirus;Pathway interactions;Peptide Hydrolases;Process;Production;Proteins;Reagent;Recycling;Ribonucleoproteins;Role;Series;Site;Surface;Testing;Ubiquitination;Vaccines;Viral;Viral Proteins;Virion;Virus;Virus Assembly;member;multiple myeloma M Protein;mutant;novel;particle;pathogen;polarized cell;polypeptide;protein transport;public health relevance;rab11 protein;research study;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The highly pathogenic Hendra and Nipah viruses are recently emerged human pathogens for which no vaccines or antivirals for human use are available. The proposed experiments will provide new understanding of the process of Hendra virus assembly and budding and could lead to development of new antiviral reagents.


application_id: 8721943
project_number: 5R01DK091584-04
project_title: Novel biomarker validation and dosing algorithms for anemia management in ESRD
administering_ic: NIDDK
award_notice_date: 2014-07-29
opportunity_number: PA-09-204
application_type: 5
activity_code: R01
ic: DK
serial_number: 091584
program_official: GOSSETT, DANIEL ROBERT
project_start_date: 2011-09-20
project_end_date: 2016-08-31
study_section: ZDK1-GRB-G(O5)S
contact_pi_person_id: 8638276
contact_pi: MERCHANT, MICHAEL L
other_pis: BRIER, MICHAEL E
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):  Erythropoietin (EPO) and erythropoiesis-stimulating agents (ESAs) are used to treat the anemia of chronic renal disease in greater than 90% of all in-center hemodialysis patients at a cost of approximately 2 billion dollars per year. Despite protocols for anemia management in the end stage renal disease (ESRD) population a large proportion of patients do not respond predictably to typical doses of EPO. Several recent randomized controlled trials looking to increase hemoglobin (Hb) in patients with the anemia of renal disease have uncovered many questions about the treatment of anemia with ESAs not previously addressed in new drug applications or in subsequent research. A call has been made for the establishment of the optimal Hb target dosing algorithm and monitoring approach for patients with anemia from chronic renal disease. We suggest that our poor understanding of the mechanisms leading to EPO resistance prevents the ability to objectively predict and design dosing algorithms for anemia management. We propose that this problem is best addressed with a semi-empirical method which uses surrogate markers of EPO responsiveness and computer-directed algorithms to achieve a specific Hb target range and to exaggerated oscillations in Hb levels. The broad-based long term goals of our research are to address a critical barrier to the progress with personalization of anemia management by developing more objective patient specific approaches to EPO dosing in ESRD populations.  Data developed in our labs suggests that the abundances of specific serum proteins and protein fragments correlate with EPO responsiveness in ESRD patients receiving dialysis therapy. These data suggest these proteins and protein fragments classify EPO response with more sensitivity and specificity than C-reactive protein and hepcidin. We hypothesize that specific serum proteins and peptides are candidate surrogate biomarkers for EPO responsiveness and can be used to improve existing algorithms for predictive EPO response indexing. We propose 2 aims. Aim 1 - We propose to validate selected candidate surrogate biomarkers in a larger population of ESRD patients enrolled from three geographically distinct centers. Within this aim we will address the null hypothesis that EPO resistance is characterized by altered expression of Th1- and Th2-cytokines and address the hypothesis that serum peptides and proteins can predict EPO responsiveness. In Aim 2 - We propose to investigate the contribution of our surrogate biomarkers to dosage prediction in long-term administration of EPO and compare models base on these new biomarkers to established models. Using a novel Model Predictive Control (MPC) tool that we have previously published and demonstrated to be superior to standard EPO dosing techniques we will access and incorporate the validated surrogate biomarkers to develop a refined clinical tool for dosing of ESAs.

project_terms:
Address;Algorithms;Anemia;Biological Markers;C-reactive protein;Chronic Kidney Failure;Clinical;Computer Assisted;Computers;Data;Decision Support Systems;Development;Dialysis procedure;Dose;End stage renal failure;Enrollment;Enzyme-Linked Immunosorbent Assay;Erythropoiesis;Erythropoietin;Goals;Grant;Hemodialysis;Hemoglobin;Hemoglobin concentration result;Inflammatory;Investigation;Iron;Kidney Diseases;Kidney Failure;Knowledge;Laboratories;Methods;Modeling;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Nutritional status;Outcome;Overdose;Patients;Peptides;Pharmaceutical Preparations;Plasma;Population;Process;Protein Fragment;Proteins;Proteome;Protocols documentation;Publishing;Randomized Controlled Clinical Trials;Randomized Controlled Trials;Research;Resistance;Risk;Sensitivity and Specificity;Serum;Serum Proteins;Surrogate Markers;Techniques;Testing;Treatment outcome;Validation;base;cardiovascular risk factor;cost;cytokine;design;dosage;hepcidin;improved;indexing;novel;predictive modeling;prevent;response;tool;trend

public_health_relevance:
The empirical treatment of anemia with erythropoiesis stimulating agents does not achieve optimal results in a significant number of end-stage renal disease patients receiving hemodialysis. Our laboratories have independently identified candidate surrogate serum biomarkers of erythropoiesis in end-stage renal disease hemodialysis patients that are associated with treatment outcome and have led the development and testing of computation methods for dosing of erythropoiesis stimulating agents. We propose to merge these two novel advances and determine their combined utility to improve erythropoiesis stimulating agent dosing in end-stage renal disease.


application_id: 8720982
project_number: 1R01CA186661-01
project_title: Small molecule targeting of MIF as a novel melanoma therapeutic
administering_ic: NCI
award_notice_date: 2014-04-03
opportunity_number: PA-11-260
application_type: 1
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 are
proposed: 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: Evaluate
the 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 (Molecular Function);Biological Availability;Cancer Center;Cancer Patient;Cells;Chemotherapy-Oncologic Procedure;Chimeric Proteins;Chronic;Clinical;Clinical Trials;Denileukin Diftitox;Diagnosis;Disease Progression;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;In-Migration;Individual;Inhibitory Concentration 50;Invaded;Lead;Lesion;Lifetime Risk;Ligands;Lung;Malignant Neoplasms;Mediator of activation protein;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;Staging;Suppressor-Effector T-Lymphocytes;Survival Rate;Testing;Therapeutic;Toxic effect;Tumor-Derived;United States;analog;angiogenesis;base;cancer cell;cell motility;clinical efficacy;combinatorial;cytokine;design;improved;in vivo;inhibitor/antagonist;insight;macrophage;melanoma;monocyte;mouse model;multicatalytic endopeptidase complex;neovascularization;novel;novel therapeutics;partial response;phenylpyruvate tautomerase;prevent;public health relevance;receptor;scaffold;small molecule;subcutaneous;therapeutic target;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 50
Americans 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: 8720572
project_number: 5DP5OD012132-03
project_title: Exploring the role of dyssynchrony in pediatric heart disease with MRI
administering_ic: OD
award_notice_date: 2014-08-27
opportunity_number: RFA-RM-11-007
application_type: 5
activity_code: DP5
ic: OD
serial_number: 012132
program_official: MILLER, BECKY
project_start_date: 2012-09-25
project_end_date: 2014-12-31
study_section: Special Emphasis Panel[ZRG1-BBBP-E(53)R]
contact_pi_person_id: 9404495
contact_pi: FORNWALT, BRANDON K
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_abstract:
DESCRIPTION (provided by applicant): Pediatric heart failure cost the United States an estimated $2 billion in 2006 and is increasing in prevalence and cost despite hospital mortality unfortunately remaining constant at 7%. The big-picture goal of our current research program is to attempt to address this problem by adapting a relatively new highly successful therapy for adult heart failure called cardiac resynchronization therapy (CRT) into a treatment option for children with heart failure. The most critical knowledge gap is identifying which children are mostlikely to benefit from CRT. The current application addresses this challenge in a population of patients with a common serious congenital heart defect known as tetralogy of Fallot (TOF). Patients born with tetralogy of Fallot (TOF) the most common cyanotic congenital heart defect currently undergo surgical repair as children but later develop heart failure as adults. This research will investigate whether the surgical repair predisposes these patients to uncoordinated contraction in the heart as a result of disruption of electrical conduction pathways which occurs during surgery. If this uncoordination (or "dyssynchrony") proves to be a significant factor it can be treated with CRT thus yielding a new treatment for patients with heart failure due to TOF. We are able to explore the role of dyssynchrony in these patients because we recently developed unique methodology and software to derive indices of dyssynchrony in the heart from standard magnetic resonance images (MRI). We hypothesize that patients with surgically repaired TOF suffer from dyssynchronous contraction in the heart and that dyssynchrony contributes to the development of heart failure and eventual mortality in these patients. We propose to test our hypotheses with the following specific aims: 1) evaluate whether patients with repaired TOF suffer from dyssynchrony when compared to normal subjects 2) evaluate whether dyssynchrony leads to worsening ventricular function over time in patients with repaired TOF and 3) determine whether dyssynchrony is related to mortality in patients with repaired TOF. Completion of this application should therefore improve the health and care of patients with repaired TOF through identifying potentially lifesaving treatment options for them. Additionally our approach can be used in future work to explore the role of dyssynchrony in patients with other diseases associated with electrical conduction abnormalities such as dilated cardiomyopathy thus furthering our long-term goal to translate cardiac resynchronization therapy into a treatment option to improve the health of children with heart failure.

project_terms:
Address;Adult;Age;Blood;Cardiac;Cessation of life;Child;Child health care;Childhood;Computer software;Congenital Heart Defects;Development;Dilated Cardiomyopathy;Disease;Failure (biologic function);Figs - dietary;Future;Goals;Healthcare;Heart;Heart Atrium;Heart Diseases;Heart failure;Hospital Mortality;Infant;Intervention;Investigation;Knowledge;Lead;Left;Left ventricular structure;Magnetic Resonance Imaging;Methodology;Modeling;Mortality Vital Statistics;Operative Surgical Procedures;Outcome;Output;Pacemakers;Pathway interactions;Patient Care;Patients;Prevalence;Research;Right ventricular structure;Role;Testing;Tetralogy of Fallot;Time;Translating;United States;Ventricular;Ventricular Ejection Fractions;Ventricular Function;Work;congenital heart disorder;cost;design;improved;indexing;patient population;programs;repaired;tool

public_health_relevance:
Pediatric heart failure cost the United States an estimated $2 billion in 2006 and is increasing in prevalence and cost with no corresponding improvement in hospital mortality. The big-picture goal of our research program is to attempt to address this problem by adapting a relatively new highly successful therapy for adult heart failure called cardiac resynchronization therapy into a treatment option to improve the health of children with heart failure.


application_id: 8720322
project_number: 1R01AG046920-01A1
project_title: Novel Actions of Metformin to Augment Resistance Training Adaptations in Older Ad
administering_ic: NIA
award_notice_date: 2014-09-16
opportunity_number: PA-12-271
application_type: 1
activity_code: R01
ic: AG
serial_number: 046920
suffix: A1
program_official: DUTTA, CHHANDA
project_start_date: 2014-09-30
project_end_date: 2019-05-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: BAMMAN, MARCAS M;KERN, PHILIP A
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
project_abstract:
DESCRIPTION (provided by applicant): The loss of skeletal muscle mass and strength with advancing age reduces quality of life and is a major factor limiting an elderly person's chance of living independently. Progressive resistance exercise training (PRT) is the most effective intervention identified to increase muscular strength and combat muscle atrophy of aging; however overall the muscle response to PRT is blunted and highly variable in the elderly. Our research team has determined that the abundance of anti-inflammatory alternatively activated M2 macrophages in muscle predicts response to PRT in the elderly; those with the highest number of M2 macrophages and lowest inflammatory gene expression prior to the start of training gained the most mass. Further reexamination of muscle biopsies obtained in a study on insulin resistance showed that metformin treatment increased M2 macrophage abundance and decreased inflammatory cytokine gene expression. These provocative findings have led us to our central hypothesis that adjuvant metformin may improve the responses to PRT in the elderly by altering the muscle tissue inflammatory environment thereby enhancing mechanisms that drive PRT-induced myofiber hypertrophy. In Aim 1 we will determine if metformin treatment augments skeletal muscle size and strength gains in conjunction with PRT in older functionally limited adults. Participants will be recruited and randomized to receive either placebo or metformin for 2 weeks followed by a 14 week PRT program with continued drug/placebo treatment. Gains in muscle size and strength will be quantified. In Aim 2 we will identify cellula and molecular responses in muscle to metformin which are associated with improved response to PRT. Muscle macrophages inflammatory gene expression and anabolic and inflammatory signaling pathways will be examined in muscle biopsies. Finally mechanisms underlying metformin effects on muscle response to training using a human muscle cell culture system modeling exercise and the muscle microenvironment will be explored in Aim 3. Prospective identification of individuals likely to be refractory to routine exercise programs and determining
the effectiveness of metformin in improving muscle growth response to PRT may contribute to the development of an affordable personalized approach to maintain or restore skeletal muscle mass and strength thereby promoting longer healthspan.

project_terms:
Adjuvant;Adult;Aging;Anti-Inflammatory Agents;Anti-inflammatory;Area;Biopsy;Blinded;Cell Culture System;Clinical Research;Coculture Techniques;Conditioned Culture Media;Cytokine Gene;Development;Disabled Persons;Effectiveness;Elderly;Environment;Exercise;Gene Expression;Goals;Growth;Health;Human;Hypertrophy;In Vitro;Individual;Inflammatory;Insulin;Insulin Resistance;Intervention;Life;Mediating;Metabolic;Metformin;Modeling;Molecular;Muscle;Muscle Cells;Muscle Fibers;Muscular Atrophy;Myoblasts;Nuclear;Organ;Participant;Persons;Pharmaceutical Preparations;Phenotype;Physiological;Placebo Control;Placebos;Positioning Attribute;Quality of life;Randomized;Recruitment Activity;Refractory;Regulation;Relative (related person);Research;Resistance;Risk;Signal Pathway;Skeletal muscle structure;Stretching;System;Testing;Time;Training;Training Programs;age related;cell type;combat;cost;effective intervention;frailty;glucose uptake;improved;improved functioning;in vivo;insulin sensitivity;macrophage;monocyte;muscle form;muscle hypertrophy;muscle strength;novel;prevent;programs;prospective;public health relevance;response;sarcopenia;satellite cell;strength training;vastus lateralis


application_id: 8720019
project_number: 5R25GM102776-03
project_title: Kentucky Bridge to a Biomedical Doctorate for Appalachian Students
administering_ic: NIGMS
award_notice_date: 2014-06-24
opportunity_number: PAR-11-279
application_type: 5
activity_code: R25
ic: GM
serial_number: 102776
program_official: HAMLET, MICHELLE R
project_start_date: 2012-09-01
project_end_date: 2017-06-30
study_section: Minority Programs Review Subcommittee A[MPRC-A]
contact_pi_person_id: 1879406
contact_pi: SPEAR, BRETT
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:
DESCRIPTION (provided by applicant): This Bridges to Doctorate Program is an initiative by faculty at Eastern Kentucky University (EKU) and the University of Kentucky (UK) to prepare underrepresented students for careers in biomedical research. The primary target student population for this Bridges grant will be those from Appalachian counties considered to be "distressed" or "at-risk" due to their significant unemployment and poverty rates. The rationale tofocus on distressed Appalachian counties is that they comprise a large part of the EKU service region although this Bridges program will also endeavor to recruit students from other underrepresented groups. EKU and UK are ideal partners for this particular Bridges program; both are geographically situated close to the region targeted in this grant a strong relationship already exists between these two institutions and their proximity will allow Bridge students to travel easily from EKU to UK for symposia and classes. A comprehensive plan is proposed to provide strong masters level training to Bridge students while at EKU to prepare them to transition to the UK Integrated Biomedical Sciences (IBS) program where they will pursue doctoral studies in biomedical research. The aims of this proposal are to: (1) recruit talented Appalachian students to a comprehensive interdisciplinary master's program to EKU with mentoring from EKU and UK faculty (2) provide Appalachian Bridge students with the skill sets needed for continued training at the PhD level including an intensive research experience that requires a written research proposal and thesis workshops courses and seminars (3) provide opportunities to showcase the achievements of Appalachian Bridge students at local regional and national meetings and (4) develop a series of metrics to rigorously evaluate the success of the EKU-UK Bridges to Doctorate program and make adjustments/improvements when warranted. With an excellent group of faculty from EKU and UK who have agreed to serve as mentors for this program we anticipate the ability to recruit 5 students/year to this 2-year master's program.

project_terms:
Achievement;Address;Admission activity;Appalachian Region;Attention;Award;Bachelor's Degree;Biomedical Research;Books;Country;County;Data;Data Reporting;Degree Completion;Disadvantaged;Distress;Doctor of Philosophy;Doctor's Degree;Educational Background;Educational Curriculum;Educational Status;Educational aspects;Educational workshop;Ensure;Ethics;Evaluation;Faculty;Financial Support;Goals;Grant;Institution;Joints;Kentucky;Lead;Life;Master's Degree;Measures;Mentors;Methods;Metric;Online Systems;Oral;Peer Review;Population;Poverty;Preparation;Publications;Recruitment Activity;Research;Research Proposals;Resources;Rest;Risk;Schools;Science;Scientist;Series;Services;Students;Training;Travel;Underrepresented Minority;Unemployment;Universities;Work;Writing;abstracting;base;career;college;experience;improved;meetings;news;programs;skills;sobriety;success;symposium;undergraduate education

public_health_relevance:
The goal of this Bridges to Doctorate program is to prepare underrepresented baccalaureate students with master level training at Eastern Kentucky University in preparation for transition to the Integrated Biomedical Sciences PhD program at the University of Kentucky. This Bridges program will primarily target students from Appalachia a disadvantaged region that is already a large part of the Eastern Kentucky University service region. The aims of this grant will provide comprehensive research-intensive training and includes an evaluation plan to insure that the program is achieving its stated objectives.


application_id: 8719903
project_number: 5K25AG043546-02
project_title: Statistical Genetics Methods for Mixed Pathologies
administering_ic: NIA
award_notice_date: 2014-05-12
opportunity_number: PA-11-196
application_type: 5
activity_code: K25
ic: AG
serial_number: 043546
program_official: MILLER, MARILYN
project_start_date: 2013-08-15
project_end_date: 2016-05-31
study_section: Basic Neuroscience of Aging Study Section[NIA-N]
contact_pi_person_id: 9594976
contact_pi: FARDO, DAVID WILLIAM
other_pis: Not Applicable
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
project_abstract:
DESCRIPTION (provided by applicant): This mentored career development grant application proposes a training program to integrate Dr. Fardo's previous research in biostatistics and statistical genetics into investigations of aging disorders including highly prevalent neurodegenerative diseases. His long-term career goal is to develop an independent research program focusing on the advancement of statistical methodologies to understand the genetics underlying complex diseases with an emphasis on diseases of brain aging. This will be achieved through acquiring knowledge in the area of brain diseases of aging through formal coursework and mentored experiences; training in the management analysis and interpretation of associated research data; comprehensive examination of the large-scale genetic data used in aging studies and the areas where novel cutting-edge biostatistical methodologies could improve analyses; application refinement and development of statistical genetic approaches to the analysis of this large-scale genetic data; and the continuation of training in the responsible conduct of research. Dr. Fardo's research training will involve an enthusiastic team of cross- disciplinary researchers with a strong research track record. An overall goal of this K25 application is to capitalize on the clinical and neuropathologic data available from large multicenter-derived databases to identify single nucleotide polymorphisms (SNPs) associated with specific neuropathologic endophenotypes. Most research investigating the genetic predisposition of age-related complex diseases has been conceptualized with a model directly comparing those with or without a disease for example with or without Alzheimer's disease (AD). However this disease/non-disease approach is inefficient and not appropriate for investigating the genetic risk factors for so-called mixed pathologies which are the norm in advanced age. The proposed research program will interrogate genetic associations with neuropathologic features of a large cohort of autopsied brains. This will be done by utilizing data collected from large NIH-funded resources. Neuropathology data and genome-wide genetic data will be merged from these resources and genetic associations for mixed-pathology dementias and neuropathologic features will be comprehensively tested. This work will result in new methods to analyze mixed-pathology dementias and neuropathologic features as well as the exploration of associated genetic risk factors and gene-environment interactions.

project_terms:
Achievement;Age;Aging;Alzheimer's Disease;Alzheimer's disease model;Applications Grants;Area;Autopsy;Biological;Biometry;Brain;Brain Diseases;Brain Pathology;Classification;Clinical;Complex;Data;Data Set;Data Storage and Retrieval;Databases;Dementia;Detection;Development;Diagnosis;Disease;Disease Progression;Drug Targeting;Elderly;Funding;Genes;Genetic;Genetic Predisposition to Disease;Genetic Risk;Goals;Health;Hippocampus (Brain);Impaired cognition;Impairment;Intervention;Investigation;Knowledge;Lewy Body Dementia;Link;Memory;Mentors;Methodology;Methods;Modeling;National Institute on Aging;Neurodegenerative Disorders;Outcome;Pathology;Phenotype;Postdoctoral Fellow;Predisposition;Prevention;Process;Quality Control;Religion and Spirituality;Research;Research Personnel;Research Training;Resources;Risk Factors;Sclerosis;Series;Single Nucleotide Polymorphism;Site;Susceptibility Gene;Testing;Training;Training Programs;United States National Institutes of Health;Variation (Genetics);Vascular Dementia;Work;age related;aging brain;base;career;career development;case control;clinical Diagnosis;cohort;disease diagnosis;endophenotype;experience;gene environment interaction;genetic association;genetic risk factor;genome wide association study;genome-wide;improved;insight;interest;mixed dementia;neuroimaging;neuropathology;novel;programs;responsible research conduct;risk variant;skills

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Understanding better the biological mechanisms that underlie complex diseases of brain aging can aid in the ability to diagnose disease early track disease progression and identify drug targets for treatment. The genetic knowledge to be garnered from this proposal is critical to discover and refine risk factors and the associated biological mechanisms of diseases of brain aging.


application_id: 8719650
project_number: 1R01NS084857-01A1
project_title: Carbonyl Scavenging for Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2014-01-28
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: NS
serial_number: 084857
suffix: A1
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2014-02-01
project_end_date: 2018-01-31
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
project_abstract:
DESCRIPTION (provided by applicant): Our laboratory has documented that generation of the potent reactive nitrogen species (RNS) peroxynitrite (PN) is responsible for oxidative damage by lipid peroxidation (LP) and neurotoxic protein modification by binding of LP-derived carbonyl-containing aldehydes such as 4-hydroxynoneal (4-HNE) and acrolein to mitochondrial and other cellular elements during the first 72 hrs after traumatic brain injury (TBI). This oxidative damage causes brain mitochondrial respiratory compromise and decreased calcium (Ca++) buffering which worsens post-TBI neuronal intracellular Ca++ overload calpain-mediated neuronal cytoskeletal degradation neurodegeneration and neurological impairment. Recently a novel antioxidant approach for post-central nervous system (CNS) injury for decreasing and possibly reversing oxidative damage has been identified that involves scavenging the LP-derived carbonyl compounds ("carbonyl scavenging") preventing their neurotoxic effects. Preliminary support from other laboratories and our own has shown that certain clinically used drugs that contain hydrazine function groups can covalently bind to 4-HNE or acrolein and prevent their neurotoxicity. The proposed 3 Aim project will employ phenelzine a long used hydrazine-containing anti-depressant that contains has been found to be an effective carbonyl scavenger as a tool to investigate the antioxidant neuroprotective effects of carbonyl scavenging in isolated rat brain mitochondria and the rat controlled cortical impact TBI model. Specifcally the project will define the neuroprotective pharmacology (e.g. mechanism of action dose-response and therapeutic window) of phenelzine's "carbonyl scavenging" in terms of neuronal mitochondrial and cytoskeletal protection along with the ability to improve chronic motor and cognitive recovery and to decrease post-traumatic neurodegeneration. Since phenelzine has a long history of clinical use and a well understood human safety profile the translation of the drug's use into clinical TBI trials would be facilitated.

project_terms:
4 hydroxynonenal;Acrolein;Acute;Aldehydes;Antihypertensive Agents;Antioxidants;Binding (Molecular Function);Brain;Brain Injuries;Buffers;Calcium;Calpain;Cell Culture Techniques;Cell membrane;Chemicals;Chronic;Clinical;Data;Dose;Drug usage;Elements;Exposure to;Functional disorder;Generations;Health;Human;Hydralazine;Hydrazine;Impairment;Injury;Ischemia;Laboratories;Lesion;Lipid Peroxidation;Lipids;Mediating;Membrane Lipids;Mitochondria;Mitochondrial Proteins;Modeling;Modification;Mortality Vital Statistics;Motor;Mus;Nerve Degeneration;Neurologic;Neurons;Patients;Peroxonitrite;Pharmacology;Phase;Phase III Clinical Trials;Phenelzine;Polyunsaturated Fatty Acids;Post-Translational Protein Processing;Rattus;Reaction;Reactive Nitrogen Species;Reactive Oxygen Species;Recording of previous events;Regimen;Reperfusion Therapy;Reporting;Research Personnel;Safety;Spinal cord injury;Staging;Stress;Testing;Therapeutic;Time;Tissues;Toxic effect;Translations;Traumatic Brain Injury;Traumatic Subarachnoid Hemorrhage;Treatment Efficacy;attenuation;axonal degeneration;base;carbonyl compound;carbonyl group;central nervous system injury;clinically relevant;cognitive function;cognitive recovery;controlled cortical impact;cytotoxic;improved;in vivo;injured;lipid peroxidation inhibitor;morris water maze;motor function improvement;nerve injury;neurotoxic;neurotoxicity;novel;oxidative damage;perhydroxyl radical;prevent;protective effect;respiratory;response;stroke;tool


application_id: 8719016
project_number: 5R21AI103717-02
project_title: Targeting functional assembly of the bacterial multidrug efflux transporter
administering_ic: NIAID
award_notice_date: 2014-07-01
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: AI
serial_number: 103717
program_official: XU, ZUOYU
project_start_date: 2013-08-09
project_end_date: 2017-07-31
study_section: Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section[DDR]
contact_pi_person_id: 10386925
contact_pi: WEI, YINAN
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The World Health Organization has identified antimicrobial resistance as one of the top three threats to human health. In contrast with the fastevolution and spreading of drug-resistant pathogens the number of effective antimicrobials that are available to healthcare workers is dwindling. The long-term goal of the research is to find solutions to treat bacterial infections caused by drug resistant pathogens. The biogenesis process of the primary multidrug efflux pump in bacterial pathogen will be used as a novel target. In Gram-negative bacteria such as Escherichia coli the triplex AcrA-AcrB-TolC pump is a major player in both intrinsic and acquired multidrug resistance. Mutant strains of E. coli deficient in the pump exhibit drastically decreased tolerance to many drugs. Therefore inhibitors that interrupt drug efflux should be very useful in reversing drug- resistance in pathogens. The central hypothesis is that the protein assembly process can be blocked to prevent or disrupt the production of functional MDR pumps. Specifically the objective of the proposed study is to identify inhibitors to block the oligomerization of AcrB which exists and functions as a homotrimer. The following Specific Aims will be pursued: 1) To develop an assay to identify compounds that promote AcrB trimer dissociation. 2) To develop an assay to identify compounds that prevent AcrB subunit association. 3) To screen a small collection of compounds to validate and optimize assays. In year one the work focus will be the development of assays (Aims 1 and 2). In year two approximately 5000 compounds will be screened to validate the assay and identify hit compounds. For identified active compounds we will confirm their activity using bacteria culture and measure binding parameters of their interaction with the target protein. Outcomes of the proposed study include the establishment of useful assays and methodologies to interfere with membrane protein oligomerization. Similar methodologies will be directly applicable to AcrB homologues in other Gram- negative pathogens. In addition the collection of hit compounds that will be obtained will serve as seed structures to generate follow up compound for future screening effort. Upon completion of the project we will seek additional funding and collaborate with the University of Cincinnati Drug Discovery Center to adapt our assay for high throughput screening using 384-well plates. It would also include a collaborative medicinal chemistry synthetic effort based on the results of this R21 and results from the expanded screening. These extended efforts would also involve development of a biology component to test compound efficacy including mammalian cellular toxicity. Another option is broader screening through a proposal to the NIH Molecular Libraries Program or partnering with an interested pharmaceutical company. We expect the proposed research will lead to new compound classes and validate novel target mechanisms for the development of effective antimicrobial treatments for drug-resistant E. coli and other Gram-negative bacterial pathogens.

project_terms:
Affinity;Amino Acids;Antibiotics;Antimicrobial Resistance;Bacteria;Bacterial Infections;Binding (Molecular Function);Biogenesis;Biological Assay;Biology;Cell membrane;Chimeric Proteins;Clinical Trials;Collaborations;Collection;Development;Dissociation;Drug Binding Site;Drug Efflux;Drug resistance;Escherichia coli;Escherichia coli drug resistance;Evolution;Exhibits;Fluorescence;Funding;Future;Goals;Gram-Negative Bacteria;Growth;Health;Health Personnel;Homologous Gene;Human;In Vitro;Incidence;Infection;Lead;Libraries;Link;Measures;Membrane Fusion;Membrane Proteins;Methodology;Methods;Microbe;Molecular Bank;Monitor;Multi-Drug Resistance;Outcome;Oxidation-Reduction;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacologic Substance;Process;Production;Proteins;Pump;Reporter;Research;Seeds;Site;Solutions;Staging;Structure;Testing;Toxic effect;United States National Institutes of Health;Universities;Work;World Health Organization;antimicrobial;assay development;base;design;disulfide bond;drug discovery;efflux pump;expectation;flexibility;follow-up;high throughput screening;inhibitor/antagonist;interest;monomer;mutant;novel;novel strategies;pathogen;pathogenic Escherichia coli;prevent;programs;protein protein interaction;public health medicine (field);public health relevance;screening;small molecule;success

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The rapid increase in the incidence of drug resistance in pathogenic strains of Gram-negative bacterium is an especially worrisome and critical global public health challenge. The goal of the proposed studies is to identify inhibitors to block the biogenesis of the major multidrug resistant pump AcrAB-TolC. Two assays will be developed to identify compounds that interfere with the trimerization of AcrB which will disable the efflux pump and drastically increase the potency of antimicrobial treatment.


application_id: 8718271
project_number: 1F31AG047762-01
project_title: Astrocytic Calcineurin and Connexin43 Gap Junctions in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2014-08-15
opportunity_number: PA-11-111
application_type: 1
activity_code: F31
ic: AG
serial_number: 047762
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2015-02-01
project_end_date: 2018-01-31
study_section: Special Emphasis Panel[ZRG1 F05-R (20)]
contact_pi_person_id: 11629027
contact_pi: PLEISS, MELANIE
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): As the sixth leading cause of death that affects over 5.2 million people Alzheimer's disease (AD) is becoming a health crisis. To much disappointment previous clinical trials have shown little success in finding a treatment for this devastating disease. Thus it is critical that new and alternative molecular targets be explored. The proposed project will test the overarching hypothesis that calcineurin (CN) and connexin43 (Cx43) interactions disrupt gap junction (GJ) coupling in astrocytes during the progression of AD leading to detrimental changes in neurologic function. This project will use a multi-disciplinary approach to investigate the hypothesis using an array of AD model systems including human hippocampal specimens APP/PS1 transgenic mice and rat primary astrocyte cultures. In addition to the excellent model systems this project will use a variety of cutting-edge techniques including fluorescence resonance energy transfer (FRET) adeno-associated virus (AAV) - mediated gene delivery and slice electrophysiology. The overarching hypothesis will be examined through three independent specific aims which are as follows: to test the hypothesis that CN interacts with Cx43 during the progression of AD using techniques such as FRET and co-immunoprecipitations (Co-IPs); to test the hypothesis that beta amyloid (A-beta) disrupts gap junction (GJ) coupling in a CN-dependent manner using techniques such as dye coupling and Western blot; to test the hypothesis that CN/Cx43 interactions disrupt GJ coupling and neurologic function in a mouse model of AD using cognitive measures such as the active avoidance paradigm and techniques such as dye coupling Western blot and slice electrophysiology. This project not only provides superior training in neuroscience research but also will provide extremely valuable information into a potential new therapeutic target for AD.

project_terms:
APP-PS1;Acute;Affect;Age;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Animal Model;Astrocytes;Autopsy;Biological Assay;Biological Models;Brain;Calcineurin;Calcineurin inhibitor;Cause of Death;Clinical Trials;Co-Immunoprecipitations;Cognitive;Communication;Connexin 43;Connexins;Coupled;Coupling;Critical Thinking;Custom;Cyclosporine;Data;Dependovirus;Development;Disease;Disease Progression;Dyes;Electrophysiology (science);Experimental Designs;Exposure to;Fluorescein-5-isothiocyanate;Fluorescence Resonance Energy Transfer;Gap Junctions;Gene Delivery;Gene Transfer;Glial Fibrillary Acidic Protein;Goals;Harvest;Health;Hippocampus (Brain);Human;Inflammatory;Injury;Interleukin-1;Label;Measurement;Measures;Mediating;Modeling;Molecular Target;Mus;Nervous System Physiology;Neurosciences Research;Outcome;Peptides;Production;Promotor (Genetics);Protein Dephosphorylation;Protein phosphatase;Rattus;Relative (related person);Research;Role;Sampling;Scientist;Signal Transduction;Slice;Specimen;Staging;Synapses;Techniques;Testing;Time;Time Study;Tissue Sample;Tissues;Training;Transgenic Mice;United States;Western Blotting;Work;base;behavior test;brain tissue;cytokine;design;insight;mild cognitive impairment;mimetics;mouse model;neuroinflammation;new therapeutic target;novel;peptide A;public health relevance;relating to nervous system;research study;success;transgene expression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: As the sixth leading cause of death that affects over 5.2 million people in the United States Alzheimer's disease (AD) is becoming an impending health crisis. To much disappointment previous clinical trials have shown little success in finding a treatment for this devastating disease. Thus it is critical that new and alternative molecular targets be explored which is the goal of the proposed research.


